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1.  Anti-diabetic effect of purple corn extract on C57BL/KsJ db/db mice 
BACKGROUND/OBJECTIVES
Recently, anthocyanins have been reported to have various biological activities. Furthermore, anthocyanin-rich purple corn extract (PCE) ameliorated insulin resistance and reduced diabetes-associated mesanginal fibrosis and inflammation, suggesting that it may have benefits for the prevention of diabetes and diabetes complications. In this study, we determined the anthocyanins and non-anthocyanin component of PCE by HPLC-ESI-MS and investigated its anti-diabetic activity and mechanisms using C57BL/KsJ db/db mice.
MATERIALS/METHODS
The db/db mice were divided into four groups: diabetic control group (DC), 10 or 50 mg/kg PCE (PCE 10 or PCE 50), or 10 mg/kg pinitol (pinitol 10) and treated with drugs once per day for 8 weeks. During the experiment, body weight and blood glucose levels were measured every week. At the end of treatment, we measured several diabetic parameters.
RESULTS
Compared to the DC group, Fasting blood glucose levels were 68% lower in PCE 50 group and 51% lower in the pinitol 10 group. Furthermore, the PCE 50 group showed 2- fold increased C-peptide and adiponectin levels and 20% decreased HbA1c levels, than in the DC group. In pancreatic islets morphology, the PCE- or pinitol-treated mice showed significant prevention of pancreatic β-cell damage and higher insulin content. Microarray analyses results indicating that gene and protein expressions associated with glycolysis and fatty acid metabolism in liver and fat tissues. In addition, purple corn extract increased the phosphorylation of AMP-activated protein kinase (AMPK) and decreased phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6pase) genes in liver, and also increased glucose transporter 4 (GLUT4) expressions in skeletal muscle.
CONCLUSIONS
Our results suggested that PCE exerted anti-diabetic effects through protection of pancreatic β-cells, increase of insulin secretion and AMPK activation in the liver of C57BL/KsJ db/db mice.
doi:10.4162/nrp.2015.9.1.22
PMCID: PMC4317475
Purple corn; diabetes; insulin; microarray assay; AMPK
2.  Prediction of cardiovascular disease risk using waist circumference among Aboriginals in a remote Australian community 
BMC Public Health  2015;15:57.
Background
Elevated waist circumference (WC) is an important risk factor for cardiovascular disease (CVD). Aboriginals in Australia are at higher risk of CVD compared to non-Aboriginals. We examined the association between waist circumference and CVD, and developed a model for projecting absolute risk of cardiovascular disease using WC and age in one high risk Australian Aboriginal community.
Methods
We followed up 920 (470 men, 450 women) participants (more than 80% of the eligible population) aged 18 to 76 years, without CVD at baseline, for up to 20 years. Hazard ratios were estimated using Cox proportional hazards models adjusting for potential confounding factors. Absolute risk was estimated using the Weibull regression model.
Results
Of 920 study participants, 156 males and 177 females developed CVD in the follow-up period. Incidence rates for males and females in the 4th WC quartile (Q4) were 38.3 (95% CI 29.6, 49.7) and 47.2 (95% CI 37.1, 60.3) respectively. Crude hazard ratios of CVD for Q4 WC group using Q1 (quartile 1) as the referent quartile were 2.9 (95% CI 1.8- 4.6) for males and 3.5 (95% CI 2.2- 5.5) for females. Association remained after controlling for age, smoking status and alcohol drinking status (HR = 1.8 for males and HR = 3.1 for females). At 45 years of age with baseline waist circumference of 100 cm, a male had an absolute CVD risk of 32.5%, while a female had a 30.6% risk of the disease.
Conclusions
Risk of CVD among participants increased with increasing WC, and the relationship was accentuated with increasing age. The prediction model provides a tool for understanding the combined effects of WC with age on CVD events in the Australian Aboriginal community. It is simple and easily understood and will assist in identifying individuals at risk of CVD in relation to waist circumference values.
doi:10.1186/s12889-015-1406-1
PMCID: PMC4318125  PMID: 25636174
Waist circumference (WC); Cardiovascular disease (CVD); Hazard ratio; Absolute risk
3.  Identification and comparative analysis of differentially expressed miRNAs in leaves of two wheat (Triticum aestivum L.) genotypes during dehydration stress 
BMC Plant Biology  2015;15:21.
Background
MicroRNAs (miRNAs) play critical roles in the processes of plant growth and development, but little is known of their functions during dehydration stress in wheat. Moreover, the mechanisms by which miRNAs confer different levels of dehydration stress tolerance in different wheat genotypes are unclear.
Results
We examined miRNA expressions in two different wheat genotypes, Hanxuan10, which is drought-tolerant, and Zhengyin1, which is drought-susceptible. Using a deep-sequencing method, we identified 367 differentially expressed miRNAs (including 46 conserved miRNAs and 321 novel miRNAs) and compared their expression levels in the two genotypes. Among them, 233 miRNAs were upregulated and 10 were downregulated in both wheat genotypes after dehydration stress. Interestingly, 13 miRNAs exhibited opposite patterns of expression in the two wheat genotypes, downregulation in the drought-tolerant cultivar and upregulation in the drought-susceptible cultivar. We also identified 111 miRNAs that were expressed predominantly in only one or the other genotype after dehydration stress. We verified the expression patterns of a number of representative miRNAs using qPCR analysis and northern blot, which produced results consistent with those of the deep-sequencing method. Moreover, monitoring the expression levels of 10 target genes by qPCR analysis revealed negative correlations with the levels of their corresponding miRNAs.
Conclusions
These results indicate that differentially expressed patterns of miRNAs between these two genotypes may play important roles in dehydration stress tolerance in wheat and may be a key factor in determining the levels of stress tolerance in different wheat genotypes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0413-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-015-0413-9
PMCID: PMC4312605  PMID: 25623724
Dehydration stress; Triticum aestivum L; Differentially expressed miRNAs; Comparative analysis
4.  Biocompatibility and osteogenic properties of porous tantalum 
Porous tantalum has been reported to be a promising material for use in bone tissue engineering. In the present study, the biocompatibility and osteogenic properties of porous tantalum were studied in vitro and in vivo. The morphology of porous tantalum was observed using scanning electron microscopy (SEM). Osteoblasts were cultured with porous tantalum, and cell morphology, adhesion and proliferation were investigated using optical microscopy and SEM. In addition, porous tantalum rods were implanted in rabbits, and osteogenesis was observed using laser scanning confocal microscopy and hard tissue slice examination. The osteoblasts were observed to proliferate over time and adhere to the tantalum surface and pore walls, exhibiting a variety of shapes and intercellular connections. The porous tantalum rod connected tightly with the host bone. At weeks 2 and 4 following implantation, new bone and small blood vessels were observed at the tantalum-host bone interface and pores. At week 10 after the porous tantalum implantation, new bone tissue was observed at the tantalum-host bone interface and pores. By week 12, the tantalum-host bone interface and pores were covered with new bone tissue and the bone trabeculae had matured and connected directly with the materials. Therefore, the results of the present study indicate that porous tantalum is non-toxic, biocompatible and a promising material for use in bone tissue engineering applications.
doi:10.3892/etm.2015.2208
PMCID: PMC4316955  PMID: 25667628
porous tantalum; osteogenesis; biocompatibility; cell toxicity; bone tissue engineering
5.  p38 MAPK-inhibited dendritic cells induce superior antitumor immune responses and overcome regulatory T cell-mediated immunosuppression 
Nature communications  2014;5:4229.
Dendritic cell (DC)-based cancer immunotherapy is a promising method but so far has demonstrated limited clinical benefits. Regulatory T cells (Treg) represent a major obstacle to cancer immunotherapy approaches. Here we show that inhibiting p38 MAPK during DC differentiation enables DCs to activate tumor-specific effector T cells (Teff), inhibiting the conversion of Treg and compromising Treg inhibitory effects on Teff. Inhibition of p38 MAPK in DCs lowers expression of PPARγ, activating p50 and upregulation of OX40L expression in DCs. OX40L/OX40 interactions between DCs and Teff and/or Treg are critical for priming effective and therapeutic antitumor responses. Similarly, p38 MAPK inhibition also augments the T cell-stimulatory capacity of human monocyte-derived DCs in the presence of Treg. These findings contribute to ongoing efforts to improve DC-based immunotherapy in human cancers.
doi:10.1038/ncomms5229
PMCID: PMC4249595  PMID: 24957461
6.  Effect modification by gender and smoking status on the association between obesity and atopic sensitization in Chinese adults: a hospital-based case–control study 
BMC Public Health  2014;14(1):1105.
Background
There is an ongoing debate on the potential association between obesity and atopy. However, no previous studies have investigated whether this relationship depends on sex and smoking status in Chinese adults.
Methods
In this hospital-based, case–control study, we recruited 1150 atopic cases aged 18 years or older and 1245 healthy control participants during April 2009 and December 2012 in Harbin, China. We conducted structured questionnaire interviews, anthropometry measurements and serum allergen-specific immunoglobulin E (IgE) testing. Univariate and multivariate logistic regression models were used to explore the relationship between obesity and atopy risk stratified by sex and smoking status.
Results
There was an association between obesity and an increased risk of atopic sensitization after adjusting for age, educational, family history, smoking and alcohol consumption (OR: 2.61, 3.25; 95% CI: 1.57-4.33,1.91-5.56 in males and females, respectively). The association between BMI and allergic sensitization depended on smoking status. In both genders, the association of obesity with atopic sensitization risk was stronger in non-smokers than in current smokers. In males, ORs of atopic sensitization for obesity were 3.15 (95% CI, 1.46-6.68) for non-smokers and 2.22 (95% CI, 1.10-4.48) for current smokers. The corresponding ORs in females were 3.51 (95% CI, 1.98-6.24) and 2.22 (95% CI, 0.46-10.68) for non-smokers and current smokers, respectively. After excluding those subjects who with pre-existing allergic conditions, the same relationship still remained.
Conclusions
Obesity is positively and significantly associated with the risk of atopy in both men and women as well in both smokers and non-smokers in China. In addition, the relationship between obesity and atopic sensitization is stronger in non-smokers than in current smokers.
doi:10.1186/1471-2458-14-1105
PMCID: PMC4228147  PMID: 25344653
Obesity; Body mass index; Atopy; Adult
7.  Trend of Urban-Rural Disparities in Hospital Admissions and Medical Expenditure in China from 2003 to 2011 
PLoS ONE  2014;9(9):e108571.
Objectives
To assess the trend of urban-rural disparities in hospital admissions and medical expenditure between 2003 and 2011 in the context of Chinese health-care system reform.
Methods
The data were from three different national surveys: the Third National Health Services Survey in 2003, the Fourth National Health Services Survey in 2008 and the national health-care reform phased assessment survey in 2011. There were 151421, 143380 and 48356 respondents aged 15 years or older in 2003, 2008 and 2011, respectively.
Results
The health insurance coverage expanded considerably from 27.7% in 2003 to 96.4% in 2011 among respondents aged 15 years or older. Hospitalization rate increased rapidly from 4.1% in 2003 to 9.6% in 2011. Urban respondents had higher hospital admissions than rural respondents, and the RR (95% CI) of hospitalization was 1.23 (1.17–1.30), 1.06 (1.02–1.10) and 1.16 (1.10–1.23) in 2003, 2008 and 2011, respectively. The urban-rural disparity in hospital admissions significantly narrowed over time. Urban respondents had a higher admission rate if insured and a lower admission if not insured than their rural counterparts. Of the six medical expenditure measures, the disparities in reimbursement rate and the proportion of hospitalization direct cost to the total consumer spending significantly narrowed.
Conclusions
The health insurance coverage has been continually expanding and health service utilization has been substantially improved. Urban-rural disparities have been narrowed but still exist. Therefore, policy-makers should focus on increasing investment and reimbursement levels, developing a uniform standard health insurance system for urban and rural residents and improving the medical assistance system.
doi:10.1371/journal.pone.0108571
PMCID: PMC4177550  PMID: 25251367
8.  XIAP Downregulation Promotes Caspase-dependent Inhibition of Proteasome Activity in AML Cells 
Leukemia research  2013;37(8):974-979.
To further understand the role of XIAP in acute myeloid leukemia (AML), we suppressed XIAP expression by antisense oligonucleotides and determined the effect on gene expression profiles and biological pathways. XIAP inhibition upregulated expression of proteasome genes in a manner similar to the proteasome inhibitor bortezomib or MG132; decreased 20S proteasome activity, an effect which was diminished in the presence of a pan-caspase inhibitor; and increased IκBα, Mcl-1, and HSP70in AML cells. In addition to multiple functions already described, XIAP contributes to increased proteasome activity in AML cells, and the antitumor effect of XIAP inhibition may be mediated in part through caspase-dependent proteasome inhibition.
doi:10.1016/j.leukres.2013.04.018
PMCID: PMC3700666  PMID: 23669290
XIAP; proteasome; gene expression; AML; caspase; IκBα
9.  ATRA-Induced Cellular Differentiation and CD38 Expression Inhibits Acquisition of BCR-ABL Mutations for CML Acquired Resistance 
PLoS Genetics  2014;10(6):e1004414.
Acquired resistance through genetic mutations is a major obstacle in targeted cancer therapy, but the underlying mechanisms are poorly understood. Here we studied mechanisms of acquired resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) by examining genome-wide gene expression changes in KCL-22 CML cells versus their resistant KCL-22M cells that acquire T315I BCR-ABL mutation following TKI exposure. Although T315I BCR-ABL is sufficient to confer resistance to TKIs in CML cells, surprisingly we found that multiple drug resistance pathways were activated in KCL-22M cells along with reduced expression of a set of myeloid differentiation genes. Forced myeloid differentiation by all-trans-retinoic acid (ATRA) effectively blocked acquisition of BCR-ABL mutations and resistance to the TKIs imatinib, nilotinib or dasatinib in our previously described in vitro models of acquired TKI resistance. ATRA induced robust expression of CD38, a cell surface marker and cellular NADase. High levels of CD38 reduced intracellular nicotinamide adenine dinucleotide (NAD+) levels and blocked acquired resistance by inhibiting the activity of the NAD+-dependent SIRT1 deacetylase that we have previously shown to promote resistance in CML cells by facilitating error-prone DNA damage repair. Consequently, ATRA treatment decreased DNA damage repair and suppressed acquisition of BCR-ABL mutations. This study sheds novel insight into mechanisms underlying acquired resistance in CML, and suggests potential benefit of combining ATRA with TKIs in treating CML, particularly in advanced phases.
Author Summary
Acquired resistance through genetic mutations is a major mechanism for cancer drug resistance and accounts for the short life of targeted therapy in several types of human cancer. Mechanistically, however, very little is understood about how resistant mutations are actually acquired during cancer therapy. In this manuscript, we used chronic myelogenous leukemia (CML) as a disease model and showed that mutation acquisition process is accompanied by global genome transcriptional reprogramming and reduction of cellular differentiation status. Forced cell differentiation by all-trans retinoic acid (ATRA) potently blocks acquisition of genetic mutations and CML acquired resistance. ATRA effect is mediated, in part, through stimulating CD38 gene expression, which reduces cellular cofactor nicotinamide adenine dinucleotide (NAD+) content and thus the activity of NAD+-dependent protein deacetylase SIRT1 that promotes error-prone DNA damage repair and mutagenesis. Our findings provide novel insight of mutation acquisition process during targeted therapy for CML. This study has translational implication in clinical treatment of CML, and perhaps other malignancies, by combining a differentiation agent to overcome mutation-mediated drug resistance if possible.
doi:10.1371/journal.pgen.1004414
PMCID: PMC4072521  PMID: 24967705
10.  The Hedgehog processing pathway is required for NSCLC growth and survival 
Oncogene  2012;32(18):10.1038/onc.2012.243.
Considerable interest has been generated from the results of recent clinical trials using SMOOTHENED (SMO) antagonists to inhibit the growth of HEDGEHOG (HH) signaling dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH-processing proteins, SKINNY HEDGEHOG (SKN) or DISPATCHED-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently over-expressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand dependent cancers.
doi:10.1038/onc.2012.243
PMCID: PMC3821972  PMID: 22733134
DISPATCHED; Lung Cancer; Hedgehog; HEDGEHOG ACYLTRANSFERASE; SKINNY HEDGEHOG
11.  Yangjing Capsule Extract Promotes Proliferation of GC-1 Spg Cells 
Objective. To investigate the effect of Yangjing Capsule (YC) extract on proliferation of GC-1 spermatogonia (spg) cells and the mechanism. Methods. GC-1 spg cells were treated with 0.01, 0.1, and 1 mg/mL YC extract. MTT assay was performed to detect the cell viability. Flow cytometry was used to measure the cell cycle and apoptosis of GC-1 spg cells. Real-time PCR and western blot were applied to determine the mRNA and protein expression of Oct-4 and Plzf. Gfrα1 knockdown and LY294002 (PI3K inhibitor) were applied to explore the underlying mechanism. Results. After 48 h treatment of YC, the viability of GC-1 spg cells increased significantly and the ratio of apoptotic cells reduced significantly. The increased mRNA and protein expression of Oct-4 and Plzf suggested YC promoted self-renewal of GC-1 spg cells. Both Gfrα1 siRNAs and LY294002 treatments held back YC extract's stimulation effects on mRNA and protein expression of Oct-4 and Plzf and consequently inhibited the proliferation of GC-1 spg cells induced by YC extract. Conclusion. YC extract could stimulate the proliferation of GC-1 spg cells. Partly via Gfrα1, YC extract is able to trigger the activation of PI3K pathway and finally lead to self-renewal of GC-1 spg cells.
doi:10.1155/2014/640857
PMCID: PMC4003789  PMID: 24817900
12.  Sirtuins in Hematological Aging and Malignancy 
Critical reviews in oncogenesis  2013;18(6):531-547.
Aging of the hematological system causes anemia, reduced immunity, and increased incidence of hematological malignancies. Hematopoietic stem cells (HSCs) play a crucial role in this process as their functions decline during aging. Sirtuins are a family of protein lysine modifying enzymes that have diverse roles in regulating metabolism, genome stability, cell proliferation, and survival, and have been implicated in mammalian aging and longevity. Here we provide an updated overview of sirtuins in aging research; particularly, how increased activity of SIRT1, SIRT3, or SIRT6 improves several aging parameters, and may possibly increase lifespan in mice. We review the literature on how sirtuins may play a role in HSC aging and hematological malignancies, and how key signaling pathways of HSCs may be affected by sirtuins. Among them, SIRT1 plays a critical role in chronic myelogenous leukemia, an age-dependent malignancy, and inhibition of SIRT1 sensitizes leukemic stem cells to tyrosine kinase inhibitor treatment and blocks acquisition of resistant oncogene mutations. In-depth understanding of sirtuins in HSC aging and malignancy may help design novel strategies to deter hematological aging and improve treatment of hematological malignancies.
PMCID: PMC3951433  PMID: 24579733
Sir2; sirtuin; aging; hematopoietic stem cells; leukemia; lymphoma
13.  Anthropometric predictors of gestational hypertensive disorders in a remote aboriginal community: a nested case–control study 
BMC Research Notes  2014;7:122.
Background
Australian Aboriginal women tend to have body shape and pregnancy risk profiles different from other Australian women. This study aims to examine the associations of anthropometric indices with gestational hypertensive disorders (GHD), and to determine the index that can best predict the risk of this condition occurring during pregnancy.
Methods
This is a nested case–control study. Baseline body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were measured as part of a broader health screening program between 1992 and 1995 in a remote Aboriginal community. All subsequent pregnancies among the original participants were identified during 20 year follow-up period through hospital records (up to May 2012). Twenty eight women were diagnosed as having GHD, each of whom were individually matched by age at baseline with five women who were hospitalised for other pregnancy-related conditions and were free from GHD (n = 140). The associations of the baseline anthropometric measurements with GHD were assessed using conditional logistic regression.
Results
The best predictor of GHD was WC (OR = 1.8; (95% CI, 1.1-2.9) for one standard deviation increase in WC), followed by BMI with the corresponding OR = 1.7 (95% CI, 1.1- 2.6). Other measurements, HC, WHR, and WHtR, were also positively associated with GHD, but those associations were not statistically significant.
Conclusions
WC and BMI prior to pregnancy are anthropometric predictors of GHD in Aboriginal women, and WC is the best predictor. These findings imply the importance of early weight control in preventing GHD in Aboriginal women.
doi:10.1186/1756-0500-7-122
PMCID: PMC3946005  PMID: 24593885
Gestational hypertensive disorders; BMI; Waist circumference; Aboriginal women
14.  Uncovering the Rare Variants of DLC1 Isoform 1 and Their Functional Effects in a Chinese Sporadic Congenital Heart Disease Cohort 
PLoS ONE  2014;9(2):e90215.
Congenital heart disease (CHD) is the most common birth defect affecting the structure and function of fetal hearts. Despite decades of extensive studies, the genetic mechanism of sporadic CHD remains obscure. Deleted in liver cancer 1 (DLC1) gene, encoding a GTPase-activating protein, is highly expressed in heart and essential for heart development according to the knowledge of Dlc1-deficient mice. To determine whether DLC1 is a susceptibility gene for sporadic CHD, we sequenced the coding region of DLC1 isoform 1 in 151 sporadic CHD patients and identified 13 non-synonymous rare variants (including 6 private variants) in the case cohort. Importantly, these rare variants (8/13) were enriched in the N-terminal region of the DLC1 isoform 1 protein. Seven of eight amino acids at the N-terminal variant positions were conserved among the primates. Among the 9 rare variants that were predicted as “damaging”, five were located at the N-terminal region. Ensuing in vitro functional assays showed that three private variants (Met360Lys, Glu418Lys and Asp554Val) impaired the ability of DLC1 to inhibit cell migration or altered the subcellular location of the protein compared to wild-type DLC1 isoform 1. These data suggest that DLC1 might act as a CHD-associated gene in addition to its role as a tumor suppressor in cancer.
doi:10.1371/journal.pone.0090215
PMCID: PMC3938602  PMID: 24587289
15.  Safety and Activity of PD1 Blockade by Pidilizumab in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma: a Single Group, Open-label, Phase 2 Trial 
The lancet oncology  2013;15(1):69-77.
Background
Endogenous or iatrogenic antitumor immune responses can improve the course of follicular lymphoma (FL), but may be diminished by immune checkpoints in the tumor microenvironment. These may include effects of programmed death (PD)-1, a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. In a Phase II trial, we determined the activity of pidilizumab, a humanized anti-PD-1 monoclonal antibody, with rituximab in patients with relapsed FL.
Methods
FL patients with rituximab-sensitive disease relapsing after 1–4 prior therapies were eligible. Pidilizumab was administered at 3 mg/kg every 4 weeks for 4 infusions, plus 8 optional infusions every 4 weeks for patients with stable disease or better. Starting 2 weeks after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 weekly for 4 weeks. The primary endpoint was to assess the overall response rate. Analysis was by intention to treat. Peripheral blood and tumor biopsies were studied to assess immunological effects of pidilizumab. This trial has been completed and was registered at www.clinicaltrials.gov as NCT00904722.
Findings
The combination was well-tolerated, with no autoimmune or therapy-related grade 3/4 toxicities. The most common grade 1 adverse events were anemia (14 patients) and fatigue (13 patients), and the most common grade 2 adverse event was respiratory infection (5 patients). Overall 19/29 (66%) and complete 15/29 (52%) response rates in 29 evaluable patients were high, with tumor regression in 25/29 (86%) of patients. Median progression-free survival was 18.8 months (95% CI: 14.7 months to not reached). The median response duration for the 19 responders was 20.2 months (95% CI: 13.9 months to not reached). Correlative studies of blood and tumor provided insights into predicting response and understanding mechanisms involved.
Interpretation
Pidilizumab with rituximab is well-tolerated and its activity compared favorably to historical retreatment with rituximab monotherapy in patients with relapsed FL. Our results establish that immune checkpoint blockade is worthy of further study in FL.
Funding
National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech Ltd, and UT MD Anderson Cancer Center.
doi:10.1016/S1470-2045(13)70551-5
PMCID: PMC3922714  PMID: 24332512
16.  A new technique combining virtual simulation and methylene blue staining for the localization of small peripheral pulmonary lesions 
BMC Cancer  2014;14:79.
Background
Quickly and accurately localizing small peripheral pulmonary lesions can avoid prolonged operative time and unplanned open thoracotomy. In this study, we aimed to introduce and evaluate a new technique combining virtual simulation and methylene blue staining for the localization of small peripheral pulmonary lesions.
Methods
Seventy four (74) patients with 80 peripheral pulmonary lesions <20 mm in size on computer tomography (CT) were virtually punctured using a radiotherapy planning simulator on the day before operation. Under general anaesthesia, methylene blue dye was injected to the virtually identified point according to the surface point, angle and depth previously determined by the simulator. The wedge resection of the marked lesion was performed under video-assisted thoracoscopic surgery (VATS) and the specimens were sent for immediate pathologic examination. According to pathology results, appropriate surgical procedures were decided and undertaken.
Results
The average lesion size was 10.4±3.5 mm (range: 4-17 mm) and the average distance to the pleural surface was 9.4±4.9 mm. Our preoperative localization procedure was successful in 75 of 80 (94%) lesions. Histological examination showed 28 benign lesions and 52 lung cancers. The shortest distance between the edges of the stain and lesion was 5.1±3.1 mm. Localization time was 17.4±2.3 min. All patients with malignant lesions subsequently underwent lobectomy and systematic lymph node dissection. No complications were observed in all participants.
Conclusions
The novel technique combining the preoperative virtual simulation and methylene blue staining techniques has a high success rate for localizing small peripheral pulmonary lesions, particularly for those tiny lesions which are difficult to visualise and palpate during VATS.
doi:10.1186/1471-2407-14-79
PMCID: PMC3926337  PMID: 24512571
Lung cancer; Pulmonary lesions; Thoracoscopy; Localization; Simulation; Methylene blue
17.  A Two-Stage Association Study Suggests BRAP as a Susceptibility Gene for Schizophrenia 
PLoS ONE  2014;9(1):e86037.
Schizophrenia (SZ) is a neurodevelopmental disorder in which altered immune function typically plays an important role in mediating the effect of environmental insults and regulation of inflammation. The breast cancer suppressor protein associated protein (BRAP) is suggested to exert vital effects in neurodevelopment by modulating the mitogen-activated protein kinase cascade and inflammation signaling. To explore the possible role of BRAP in SZ, we conducted a two-stage study to examine the association of BRAP polymorphisms with SZ in the Han Chinese population. In stage one, we screened SNPs in BRAP from our GWAS data, which detected three associated SNPs, with rs3782886 being the most significant one (P  =  2.31E-6, OR  =  0.67). In stage two, we validated these three SNPs in an independently collected population including 1957 patients and 1509 controls, supporting the association of rs3782886 with SZ (P  =  1.43E-6, OR  =  0.73). Furthermore, cis-eQTL analysis indicates that rs3782886 genotypes are associated with mRNA levels of aldehyde dehydrogenase 2 family (ALDH2) (P  =  0.0039) and myosin regulatory light chain 2 (MYL2) (P < 1.0E-4). Our data suggest that the BRAP gene may confer vulnerability for SZ in Han Chinese population, adding further evidence for the involvement of developmental and/or neuroinflammatory cascades in the illness.
doi:10.1371/journal.pone.0086037
PMCID: PMC3893271  PMID: 24454952
18.  Age-dependent decline of association between obesity and coronary heart disease: a cohort study in a remote Australian Aboriginal community 
BMJ Open  2013;3(11):e004042.
Objective
To determine whether the association between obesity and coronary heart disease (CHD) in Aboriginal adults depends on age.
Design, setting and participants
A cohort study with up to 20 years of follow-up of 849 participants aged 18–76 years in a remote Aboriginal community in the Northern Territory of Australia.
Main outcome measures
Newly diagnosed CHD cases were identified through hospital records according to ICD codes during the follow-up period. Cox proportional hazard model was used to assess whether the association between obesity and CHD depends on age.
Results
During the follow-up period, 171 participants were diagnosed with CHD. On an average, the incidence rate of CHD increased with the increasing baseline BMI, 11.3%, 16.3% and 20.2% for normal weight, overweight and obese groups, respectively. HR of CHD for obesity were 2.6 (95% CI 1.1to 6.3), 1.2 (0.7 to 2.0) and 0.5 (0.1 to 2.1) for those <40, 40–59 and 60+ years, respectively. HRs corresponding to 1 SD increase in BMI were 1.4 (1.0 to 2.0), 1.2 (1.0 to 1.5) and 0.8 (0.5 to 1.2) for those <40, 40–59 and 60+ years, respectively. The interaction terms between age and BMI as category variables or as a continuous variable were statistically significant.
Conclusions
The association between obesity and CHD is stronger for younger adults than for older adults in Aboriginal Australians in the remote community. Our findings suggest that weight control efforts may produce more beneficial effects in CHD prevention in young adults than in older adults.
doi:10.1136/bmjopen-2013-004042
PMCID: PMC3845075  PMID: 24282250
NUTRITION & DIETETICS; EPIDEMIOLOGY
20.  Hedgehog Signaling Regulates Bladder Cancer Growth And Tumorigenicity 
Cancer research  2012;72(17):10.1158/0008-5472.CAN-11-4123.
The role of HEDGEHOG (HH) signaling in bladder cancer remains controversial. The gene encoding the HH receptor and negative regulator PATCHED1 (PTCH1) resides on a region of chromosome 9q, one copy of which is frequently lost in bladder cancer. Inconsistent with PTCH1 functioning as a classic tumor suppressor gene, loss-of-function mutations in the remaining copy of PTCH1 are not commonly found. Here, we provide direct evidence for a critical role of HH signaling in bladder carcinogenesis. We show that transformed human urothelial cells and many urothelial carcinoma (UC) cell lines exhibit constitutive HH signaling, which is required for their growth and tumorigenic properties. Surprisingly, rather than originating from loss of PTCH1, the constitutive HH activity observed in UC cell lines was HH ligand-dependent. Consistent with this finding, increased levels of HH and the HH target gene product GLI1 were found in resected human primary bladder tumors. Furthermore, based on the difference in intrinsic HH dependence of UC cell lines, a gene expression signature was identified that correlated with bladder cancer progression. Our findings therefore indicate that therapeutic targeting of the HH signaling pathway may be beneficial in the clinical management of bladder cancer.
doi:10.1158/0008-5472.CAN-11-4123
PMCID: PMC3809830  PMID: 22815529
Hedgehog signaling; bladder cancer; urothelial carcinoma; HEDGEHOG; GLI
21.  Hedgehog-Producing Cancer Cells Respond to and Require Autocrine Hedgehog Activity 
Cancer research  2011;71(13):10.1158/0008-5472.CAN-10-2313.
A number of Smoothened (SMO) pathway antagonists are currently undergoing clinical trials as anti-cancer agents. These drugs are proposed to attenuate tumor growth solely through inhibition of Hedgehog (HH), which is produced in tumor cells but acts on tumor stromal cells. The pivotal argument underlying this model is that the growth inhibitory properties of SMO antagonists on HH-producing cancer cells are due to their off-target effects. Here we show that the tumorigenic properties of such lung cancer cells depend on their intrinsic level of HH activity. Notably, reducing HH signaling in these tumor cells decreases HH target gene expression. Taken together, these results question the dogma that autocrine HH signaling plays no role in HH-dependent cancers, and does so without using SMO antagonists.
doi:10.1158/0008-5472.CAN-10-2313
PMCID: PMC3809996  PMID: 21565978
Hedgehog; cancer; non-small cell lung carcinoma (NSCLC); autocrine
22.  Ubiquitin ligase A20 regulates p53 protein in human colon epithelial cells 
Background
Intestinal polyps may further develop into colon cancer; the pathogenesis is not clear. The p53 gene is an important anti-cancer gene in the body, which is suppressed in cancer. The ubiquitin E3 ligase A20 (A20) plays a role in regulating the activities of epithelial cells. This study was designed to investigate the role of the colon polyp epithelium-derived A20 in the pathogenesis of colon cancer.
Results
Eighty-eight colon cancer patients and 136 colon polyp patients were recruited into this study. Human colon cancer tissue, the epithelium of adenomas polyp and hyperplastic polyp showed high levels of A20, which had a positive correlation with the cancerous tendency of colon polyps. The levels of A20 were much higher in the adenomas and hyperplastic polyps than that in the inflammatory polyps; the latter showed less cancerous tendency. A20 bound p53 to form complexes in colon cancer tissue and colon polyps. Over expression of A20 suppresses P53 protein levels in the HEK293 cells.
Conclusions
A20 may play an important role in the cancerous tendency of colon polyposis.
doi:10.1186/1423-0127-20-74
PMCID: PMC4021182  PMID: 24099634
Colon; Cancer; Ubiquitin E3 ligase A20; P53 protein; Colon polyp
23.  Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion 
Nature medicine  2013;19(4):465-472.
To understand why cancer vaccine-induced T cells often fail to eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund’s adjuvant (IFA), commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8+ T cells, which accumulated not in tumors but at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, Interferon-γ (IFN-γ) and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of anti-CD40 antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination site sequestration. A non-persisting vaccine formulation shifted T cell localization towards tumors, inducing superior anti-tumor activity while reducing systemic T cell dysfunction and promoting memory formation. Persisting peptide/IFA vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.
doi:10.1038/nm.3105
PMCID: PMC3618499  PMID: 23455713
24.  The correlates of urinary albumin to creatinine ratio (ACR) in a high risk Australian aboriginal community 
BMC Nephrology  2013;14:176.
Background
Albuminuria marks renal disease and cardiovascular risk. It was estimated to contribute 75% of the risk of all-cause natural death in one Aboriginal group. The urine albumin/creatinine ratio (ACR) is commonly used as an index of albuminuria. This study aims to examine the associations between demographic factors, anthropometric index, blood pressure, lipid-protein measurements and other biomarkers and albuminuria in a cross-sectional study in a high-risk Australian Aboriginal population. The models will be evaluated for albuminuria at or above the microalbuminuria threshold, and at or above the “overt albuminuria” threshold with the potential to distinguish associations they have in common and those that differ.
Methods
This was a cross-sectional study of 598 adults aged 18–76 years. All participants were grouped into quartiles by age. Logistic regression models were used to explore the correlates of ACR categories.
Results
The significant correlates were systolic blood pressure (SBP), C-reactive protein (CRP), uric acid, diabetes, gamma-glutamyl transferase (GGT) (marginally significant, p = 0.054) and serum albumin (negative association) for ACR 17+ (mg/g) for men and 25+ for women. Independent correlates were SBP, uric acid, diabetes, total cholesterol, alanine amino transferase (ALT), Cystatin C and serum albumin (negative association) for overt albuminuria; and SBP, CRP and serum albumin only for microalbuminuria.
Conclusions
This is the most detailed modelling of pathologic albuminuria in this setting to date. The somewhat variable association with risk factors suggests that microalbuminuria and overt albuminuria might reflect different as well as shared phenomena.
doi:10.1186/1471-2369-14-176
PMCID: PMC3765271  PMID: 23947772
Albuminuria; Microalbuminuria; Overt albuminuria; ACR; Aboriginal people
25.  SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells 
Oncogene  2012;32(5):589-598.
BCR-ABL transforms bone marrow progenitor cells and promotes genome instability, leading to development of chronic myelogenous leukemia (CML). The tyrosine kinase inhibitor imatinib effectively treats CML, but acquired resistance can develop due to BCR-ABL mutations. Mechanisms for acquisition of BCR-ABL mutations are not fully understood. Using a novel culture model of CML acquired resistance, we show that inhibition of SIRT1 deacetylase by small molecule inhibitors or gene knockdown blocks acquisition of BCR-ABL mutations and relapse of CML cells on tyrosine kinase inhibitors. SIRT1 knockdown also suppresses de novo genetic mutations of HPRT (hypoxanthine phosphoribosyl transferase) gene in CML and non-CML cells upon treatment with DNA damaging agent camptothecin. Although SIRT1 can enhance cellular DNA damage response, it alters functions of DNA repair machineries in CML cells and stimulates activity of error-prone DNA damage repair, in association with acquisition of genetic mutations. These results reveal a previously unrecognized role of SIRT1 for promoting mutation acquisition in cancer, and have implication for targeting SIRT1 to overcome CML drug resistance.
doi:10.1038/onc.2012.83
PMCID: PMC3376246  PMID: 22410779

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