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1.  FJU-C4, a New 2-Pyridone Compound, Attenuates Lipopolysaccharide-Induced Systemic Inflammation via p38MAPK and NF-κB in Mice 
PLoS ONE  2013;8(12):e82877.
Despite advances in antibiotic therapy and intensive care, the mortality caused by systemic inflammatory response syndrome and severe sepsis remains high. The use of anti-inflammatory agents to attenuate inflammatory response during acute systemic inflammatory reactions may improve survival rates. Here we show that a newly synthesized 2-pyridone compound (FJU-C4) can suppress the expression of late inflammatory mediators such as iNOS and COX-2 in murine macrophages. The pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6, were dose-dependently suppressed by FJU-C4 both in mRNA and protein levels. In addition, the expression of TNFα was inhibited from as early as 2 hours after exposure to LPS stimulation. The production of mature pro-inflammatory cytokines was also suppressed by pretreatment with FJU-C4 in either cell culture medium or mice serum when stimulated by LPS. FJU-C4 prolongs mouse survival and prevents mouse death from LPS-induced systemic inflammation when the dose of FJU-C4 is over 5 mg/kg. The activities of ERK, JNK, and p38MAPK were induced by LPS stimulation on murine macrophage cell line, but only p38MAPK signaling was dramatically suppressed by pretreatment with the FJU-C4 compound in a dose-dependent manner. NF-κB activation also was suppressed by FJU-C4 compound. These findings suggest that the FJU-C4 compound may act as a promising therapeutic agent against inflammatory diseases by inhibiting the p38MAPK and NF-κB signaling pathway.
doi:10.1371/journal.pone.0082877
PMCID: PMC3871526  PMID: 24376600
2.  The ability of LCRMP-1 to promote cancer invasion by enhancing filopodia formation is antagonized by CRMP-1 
The Journal of Clinical Investigation  2011;121(8):3189-3205.
Metastasis is a predominant cause of death in patients with cancer. It is a complex multistep process that needs to be better understood if we are to develop new approaches to managing tumor metastasis. Tumor cell invasion of the local stroma is suppressed by collapsin response mediator protein-1 (CRMP-1). Recently, we identified a long isoform of CRMP-1 (LCRMP-1), expression of which correlates with cancer cell invasiveness and poor clinical outcome in patients with non-small-cell lung cancer (NSCLC). Here, we report that LCRMP-1 overexpression in noninvasive human cell lines enhanced filopodia formation, cancer cell migration, and invasion via stabilization of actin. This effect required a highly conserved N-terminal region of LCRMP-1 as well as the WASP family verprolin-homologous protein-1/actin nucleation pathway (WAVE-1/actin nucleation pathway). Furthermore, LCRMP-1 appeared to act downstream of Cdc42, a Rho family protein known to be involved in actin rearrangement. In addition, LCRMP-1 associated with CRMP-1, which downregulated cancer cell metastasis by interrupting the association of LCRMP-1 and WAVE-1. Finally, we found that high-level expression of LCRMP-1 and low-level expression of CRMP-1 were associated with lymph node metastasis and poor survival in patients with NSCLC. In sum, we show that LCRMP-1 and CRMP-1 have opposing functions in regulating cancer cell invasion and metastasis and propose that this pathway may serve as a potential anticancer target.
doi:10.1172/JCI42975
PMCID: PMC3148721  PMID: 21747164
3.  Trends and predictors of changes in pulmonary function after treatment for pulmonary tuberculosis 
Clinics  2011;66(4):549-556.
OBJECTIVES:
The present study aimed to investigate the trends in changes in pulmonary function and the risk factors for pulmonary function deterioration in patients with pulmonary tuberculosis after completing treatment.
INTRODUCTION:
Patients usually have pulmonary function abnormalities after completing treatment for pulmonary tuberculosis. The time course for changes in pulmonary function and the risk factors for deterioration have not been well studied.
METHODS:
A total of 115 patients with 162 pulmonary function results were analyzed. We retrieved demographic and clinical data, radiographic scores, bacteriological data, and pulmonary function data. A generalized additive model with a locally weighted scatterplot smoothing technique was used to evaluate the trends in changes in pulmonary function. A generalized estimating equation model was used to determine the risk factors associated with deterioration of pulmonary function.
RESULTS:
The median interval between the end of anti-tuberculosis treatment and the pulmonary function test was 16 months (range: 0 to 112 months). The nadir of pulmonary function occurred approximately 18 months after the completion of the treatment. The risk factors associated with pulmonary function deterioration included smear-positive disease, extensive pulmonary involvement prior to anti-tuberculosis treatment, prolonged anti-tuberculosis treatment, and reduced radiographic improvement after treatment.
CONCLUSIONS:
After the completion of anti-tuberculosis TB treatment, several risk factors predicted pulmonary function deterioration. For patients with significant respiratory symptoms and multiple risk factors, the pulmonary function test should be followed up to monitor the progression of functional impairment, especially within the first 18 months after the completion of anti-tuberculosis treatment.
doi:10.1590/S1807-59322011000400005
PMCID: PMC3095809  PMID: 21655745
completion of treatment; disease extent; pulmonary function; pulmonary tuberculosis
4.  Role of the renin‐angiotensin system in ventilator‐induced lung injury: an in vivo study in a rat model 
Thorax  2007;62(6):527-535.
Background
Injurious mechanical ventilation can cause a pro‐inflammatory reaction in the lungs. Recent evidence suggests an association of the renin‐angiotensin system (RAS) with lung inflammation. A study was undertaken to investigate the pathogenic role of the RAS in ventilator‐induced lung injury (VILI) and to determine whether VILI can be attenuated by angiotensin converting enzyme (ACE) inhibition.
Methods
Male Sprague‐Dawley rats were mechanically ventilated for 4 h with low (7 ml/kg) or high (40 ml/kg) tidal volumes; non‐ventilated rats were used as controls. Lung injury and inflammation were measured by the lung injury score, protein leakage, myeloperoxidase activity, pro‐inflammatory cytokine levels and nuclear factor (NF)‐κB activity. Expression of the RAS components was also assessed. Some rats were pretreated with the ACE inhibitor captopril (10 mg/kg) for 3 days or received a concomitant infusion with losartan or PD123319 (type 1 or type 2 angiotensin II receptor antagonist) during mechanical ventilation to assess possible protective effects on VILI.
Results
In the high‐volume group (n = 6) the lung injury score, bronchoalveolar lavage fluid protein concentration, pro‐inflammatory cytokines and NF‐κB activities were significantly increased compared with controls (n = 6). Lung tissue angiotensin II levels and mRNA levels of angiotensinogen and type 1 and type 2 angiotensin II receptors were also significantly increased in the high‐volume group. Pretreatment with captopril or concomitant infusion with losartan or PD123319 in the high‐volume group attenuated the lung injury and inflammation (n = 6 for each group).
Conclusions
The RAS is involved in the pathogenesis of ventilator‐induced lung injury. ACE inhibitor or angiotensin receptor antagonists can attenuate VILI in this rat model.
doi:10.1136/thx.2006.061945
PMCID: PMC2117227  PMID: 17234658
5.  Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-κB pathways 
Journal of medicinal chemistry  2009;52(7):1903-1911.
Tylophorine and related natural compounds exhibit potent antitumor activities. We previously showed that PBT-1, a synthetic C9-substituted phenanthrene-based tylophorine (PBT) derivative, significantly inhibits growth of various cancer cells. In this study, we further explored the mechanisms and potential of PBT-1 as an anticancer agent. PBT-1 dose-dependently suppressed colony formation, induced cell cycle G2/M arrest and apoptosis. DNA microarray and pathway analysis showed that PBT-1 activated the apoptosis pathway and mitogen-activated protein kinase signaling. In contrast, PBT-1 suppressed the nuclear factor kappaB (NF-κB) pathway and focal adhesion. We further confirmed that PBT-1 suppressed Akt activation accelerated RelA degradation via IκB kinase-α, and downregulated NF-κB target gene expression. The reciprocal recruitment of RelA and RelB on COX-2 promoter region led to downregulation of transcriptional activity. We conclude that PBT-1 induces cell cycle G2/M arrest and apoptosis by inactivating Akt and by inhibiting the NF-κB signaling pathway. PBT-1 may be a good drug candidate for anticancer chemotherapy.
doi:10.1021/jm801344j
PMCID: PMC2670969  PMID: 19284764
Phenanthrene-based tylophorine derivatives; apoptosis; cell cycle arrest; NF-κB; lung cancer
6.  Infection Control and SARS Transmission among Healthcare Workers, Taiwan 
Emerging Infectious Diseases  2004;10(5):895-898.
This study found infrequent transmission of severe acute respiratory syndrome (SARS) coronavirus to healthcare workers involved in the care of the first five case-patients in Taiwan, despite a substantial number of unprotected exposures. Nonetheless, given that SARS has been highly transmissible on some occasions, we still recommend strict precautions.
doi:10.3201/eid1005.030777
PMCID: PMC3323237  PMID: 15200825
Infection-control measures; serologic assays; SARS-CoV
7.  Microbiologic Characteristics, Serologic Responses, and Clinical Manifestations in Severe Acute Respiratory Syndrome, Taiwan1 
Emerging Infectious Diseases  2003;9(9):1163-1167.
The genome of one Taiwanese severe acute respiratory syndrome-associated coronavirus (SARS-CoV) strain (TW1) was 29,729 nt in length. Viral RNA may persist for some time in patients who seroconvert, and some patients may lack an antibody response (immunoglobulin G) to SARS-CoV >21 days after illness onset. An upsurge of antibody response was associated with the aggravation of respiratory failure.
doi:10.3201/eid0909.030367
PMCID: PMC3016775  PMID: 14519257
8.  A Prospective, Molecular Epidemiology Study of EGFR Mutations in Asian Patients with Advanced Non–Small-Cell Lung Cancer of Adenocarcinoma Histology (PIONEER) 
Journal of Thoracic Oncology  2014;9(2):154-162.
Introduction:
PIONEER (NCT01185314) was a prospective, multinational, epidemiological study of epidermal growth factor receptor (EGFR) mutations in patients from Asia with newly diagnosed advanced lung adenocarcinoma.
Methods:
Eligible patients (aged ≥20 years) had untreated stage IIIB/IV adenocarcinoma. The EGFR mutation status (primary end point: positive, negative, or undetermined) of tumor samples (biopsy, surgical specimen, or cytology) was determined (Scorpion amplification refractory mutation system). EGFR mutation frequency was calculated and compared between demographic and clinical subgroups.
Results:
Of 1482 patients from seven Asian regions, 43.4% of patients were female, median age was 60 years (range, 17–94), and 52.6% of patients were never-smokers. EGFR mutation status was evaluable in tumors from 1450 patients (97.8%) (746 [51.4%] positive; 704 [48.6%] negative). Country, sex, ethnicity, smoking status, pack-years (all p < 0.001), disease stage (p = 0.009), and histology type (p = 0.016) correlated significantly with EGFR mutation frequency. Mutation frequency was 61.1% in females, 44.0% in males; lower in patients from India (22.2%) compared with other areas (47.2%–64.2%); highest among never-smokers (60.7%); and decreased as pack-year number increased (>0–10 pack-years, 57.9%; >50 pack-years, 31.4%) (similar trend by sex). Ethnic group (p < 0.001) and pack-years (p < 0.001) had statistically significant associations with mutation frequency (multivariate analysis); sex was not significant when adjusted for smoking status.
Conclusion:
PIONEER is the first prospective study to confirm high EGFR mutation frequency (51.4% overall) in tumors from Asian patients with adenocarcinoma. The observed high mutation frequency in demographic/clinical subgroups compared with white populations suggests that mutation testing should be considered for all patients with stage IIIB/IV adenocarcinoma, even males and regular smokers, among Asian populations.
doi:10.1097/JTO.0000000000000033
PMCID: PMC4132036  PMID: 24419411
Epidermal growth factor receptor mutation; epidemiology; Asian; Adenocarcinoma; Non–small-cell lung cancer
9.  The Antitumor Agent PBT-1 Directly Targets HSP90 and hnRNP A2/B1 and Inhibits Lung Adenocarcinoma Growth and Metastasis 
Journal of Medicinal Chemistry  2014;57(3):677-685.
Natural products are the major sources of currently available anticancer drugs. We recently reported that phenanthrene-based tylophorine derivative-1 (PBT-1) may be a potential antitumor agent for lung adenocarcinoma. We therefore examined the direct targets of PBT-1 and their effects in inhibiting lung adenocarcinoma. We found that PBT-1 reduced the level of Slug and inhibits the migration, invasion, and filopodia formation of lung adenocarcinoma CL1-5 cells in vitro. In addition, PBT-1 displayed in vivo antitumor and antimetastasis activities against subcutaneous and orthotopic xenografts of CL1-5 cells in nude mice. Chemical proteomics showed that heat shock protein 90 (HSP90) and heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) bound PBT-1 in CL1-5 cells. Inhibition of HSP90 and hnRNP A2/B1 reduced the activation of AKT and Slug expression. Taken together, these findings suggest that PBT-1 binds to HSP90 and/or hnRNP A2/B1 and initiates antitumor activities by affecting Slug- and AKT-mediated metastasis and tumorigenesis.
doi:10.1021/jm401686b
PMCID: PMC3983378  PMID: 24428777
10.  FOXF1 mediates mesenchymal stem cell fusion-induced reprogramming of lung cancer cells 
Oncotarget  2014;5(19):9514-9529.
Several reports suggest that malignant cells generate phenotypic diversity through fusion with various types of stromal cells within the tumor microenvironment. Mesenchymal stem cell (MSC) is one of the critical components in the tumor microenvironment and a promising fusogenic candidate, but the underlying functions of MSC fusion with malignant cell have not been fully examined. Here, we demonstrate that MSCs fuse spontaneously with lung cancer cells, and the latter is reprogrammed to slow growth and stem-like state. Transcriptome profiles reveal that lung cancer cells are reprogrammed to a more benign state upon MSC fusion. We further identified FOXF1 as a reprogramming mediator that contributes not only to the reprogramming toward stemness but also to the p21-regulated growth suppression in fusion progeny. Collectively, MSC fusion does not enhance the intrinsic malignancy of lung cancer cells. The anti-malignant effects of MSC fusion-induced reprogramming on lung cancer cells were accomplished by complementation of tumorigenic defects, including restoration of p21 function and normal terminal differentiation pathways as well as up-regulation of FOXF1, a putative tumor suppressor. Such fusion process raises the therapeutic potential that MSC fusion can be utilized to reverse cellular phenotypes in cancer.
PMCID: PMC4253450  PMID: 25237908
cell fusion; mesenchymal stem cell; lung cancer cell; reprogramming; FOXF1; p21
11.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
doi:10.1038/ng.2456
PMCID: PMC4169232  PMID: 23143601
12.  GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug 
Oncogene  2013;33(24):3172-3182.
Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer (NSCLC). GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the C-terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion, and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.
doi:10.1038/onc.2013.279
PMCID: PMC4096338  PMID: 23851495
GSK3β; Slug; CHIP; post-translational modification
13.  Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers 
Cancer research  2013;73(13):4028-4038.
To identify the genetic factors that influence overall survival in never smokers who have non-small cell lung cancer (NSCLC), we performed a consistency meta-analysis study utilizing genome-wide association approaches for overall survival in 327 never smoker NSCLC patients from the MD Anderson Cancer Center and 293 cases from the Mayo Clinic. We then performed a two-pronged validation of the top 25 variants that included additional validation in 1,256 NSCLC patients from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a p-value of 10−6. Two variants of these 25 were also significant in the Taiwanese population: rs6901416 (HR:1.44, 95%CI:1.01-2.06) and rs10766739 (HR:1.23, 95%CI:1.00-1.51). These loci resulted in a reduction in median survival time of at least 8 and 5 months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biological mechanism for a subset of these observed associations.
doi:10.1158/0008-5472.CAN-12-4033
PMCID: PMC3719971  PMID: 23704207
14.  Chronic obstructive pulmonary disease treated with inhaled medium- or high-dose corticosteroids: a prospective and randomized study focusing on clinical efficacy and the risk of pneumonia 
Purpose
Complications of pneumonia development in patients with chronic obstructive pulmonary disease (COPD) receiving inhaled corticosteroid (ICS) therapy have been documented. The aim of this study was to focus on clinical efficacy and the incidence of pneumonia between COPD patients receiving medium and high doses of ICS.
Patients and methods
This prospective, randomized study included COPD patients identified from three tertiary medical centers from 2010 to 2012. The patients were randomized into two groups: high dose (HD; fluticasone 1,000 μg + salmeterol 100 μg/day) and medium dose (MD; fluticasone 500 μg + salmeterol 100 μg/day). Lung function with forced expiratory volume in 1 second (FEV1), forced vital capacity, and COPD-assessment test (CAT) were checked every 2 months. The frequency of acute exacerbations and number of pneumonia events were measured. The duration of the study period was 1 year.
Results
In total, 237 COPD patients were randomized into the two treatment arms (115 in the HD group, 122 in the MD group). The FEV1 level was significantly improved in the patients in the HD group compared with those in the MD group (HD 103.9±26.6 mL versus MD 51.4±19.7 mL, P<0.01) at the end of the study. CAT scores were markedly improved in patients using an HD compared to those using an MD (HD 13±5 versus MD 16±7, P=0.05). There was a significant difference in the percentage of annual rates in acute exacerbations (HD 0.16 versus MD 0.34, P<0.01) between the two groups. The incidence of pneumonia was similar in the two groups (HD 0.08 versus MD 0.10, P=0.38).
Conclusion
COPD patients treated with high doses of ICS had more treatment benefits and no significant increases in the incidence in pneumonia. Higher-dose ICS treatment may be suitable for COPD therapy.
doi:10.2147/DDDT.S63100
PMCID: PMC4044992
chronic obstructive pulmonary disease; pneumonia; inhaled corticosteroids
15.  MicroRNA-133a Suppresses Multiple Oncogenic Membrane Receptors and Cell Invasion in Non-Small Cell Lung Carcinoma 
PLoS ONE  2014;9(5):e96765.
Non-small cell lung cancers (NSCLCs) cause high mortality worldwide, and the cancer progression can be activated by several genetic events causing receptor dysregulation, including mutation or amplification. MicroRNAs are a group of small non-coding RNA molecules that function in gene silencing and have emerged as the fine-tuning regulators during cancer progression. MiR-133a is known as a key regulator in skeletal and cardiac myogenesis, and it acts as a tumor suppressor in various cancers. This study demonstrates that miR-133a expression negatively correlates with cell invasiveness in both transformed normal bronchial epithelial cells and lung cancer cell lines. The oncogenic receptors in lung cancer cells, including insulin-like growth factor 1 receptor (IGF-1R), TGF-beta receptor type-1 (TGFBR1), and epidermal growth factor receptor (EGFR), are direct targets of miR-133a. MiR-133a can inhibit cell invasiveness and cell growth through suppressing the expressions of IGF-1R, TGFBR1 and EGFR, which then influences the downstream signaling in lung cancer cell lines. The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines. In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells. Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels. In summary, we identified the tumor suppressor role of miR-133a in lung cancer outcome prognosis, and we demonstrated that it targets several membrane receptors, which generally produce an activating signaling network during the progression of lung cancer.
doi:10.1371/journal.pone.0096765
PMCID: PMC4016005  PMID: 24816813
16.  Long-term booster schedules with AS03A-adjuvanted heterologous H5N1 vaccines induces rapid and broad immune responses in Asian adults 
BMC Infectious Diseases  2014;14:142.
Background
The pandemic potential of avian influenza A/H5N1 should not be overlooked, and the continued development of vaccines against these highly pathogenic viruses is a public health priority.
Methods
This open-label extension booster study followed a Phase III study of 1206 adults who had received two 3.75 μg doses of primary AS03A-adjuvanted or non-adjuvanted H5N1 split-virus vaccine (A/Vietnam/1194/2004; clade 1) (NCT00449670). The aim of the extension study was to evaluate different timings for heterologous AS03A-adjuvanted booster vaccination (A/Indonesia/5/2005; clade 2.1) given at Month 6, 12, or 36 post-primary vaccination. Immunogenicity was assessed 21 days after each booster vaccination and the persistence of immune responses against the primary vaccine strain (A/Vietnam) and the booster strain (A/Indonesia) was evaluated up to Month 48 post-primary vaccination. Reactogenicity and safety were also assessed.
Results
After booster vaccination given at Month 6, HI antibody responses to primary vaccine, and booster vaccine strains were markedly higher with one dose of AS03A-H5N1 booster vaccine in the AS03A-adjuvanted primary vaccine group compared with two doses of booster vaccine in the non-adjuvanted primary vaccine group. HI antibody responses were robust against the primary and booster vaccine strains 21 days after boosting at Month 12 or 36. At Month 48, in subjects boosted at Month 6, 12, or 36, HI antibody titers of ≥1:40 against the booster strain persisted in 39.2%, 61.2%, and 95.6% of subjects, respectively. Neutralizing antibody responses and cell-mediated immune responses also showed that AS03A-H5N1 heterologous booster vaccination elicited robust immune responses within 21 days of boosting at Month 6, 12, or 36 post-primary vaccination. The booster vaccine was well tolerated, and no safety concerns were raised.
Conclusions
In Asian adults primed with two doses of AS03A-adjuvanted H5N1 pandemic influenza vaccine, strong cross-clade anamnestic antibody responses were observed after one dose of AS03A-H5N1 heterologous booster vaccine given at Month 6, 12, or 36 after priming, suggesting that AS03A-adjuvanted H5N1 vaccines may provide highly flexible prime–boost schedules. Although immunogenicity decreased with time, vaccinated populations could potentially be protected for up to three years after vaccination, which is likely to far exceed the peak of the a pandemic.
doi:10.1186/1471-2334-14-142
PMCID: PMC4008266  PMID: 24628789
H5N1; Pandemic influenza; AS03A-adjuvant; Prime–boost
17.  Overcoming EGFR T790M-based Tyrosine Kinase Inhibitor Resistance with an Allele-specific DNAzyme 
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the main therapeutic agents used to treat non–small-cell lung cancer patients harboring EGFR-activating mutations. However, most of these patients will eventually develop resistance, 50% of which are due to a secondary mutation at T790M in the EGFR. In this paper, we describe the development of an allele-specific DNAzyme, DzT, that can specifically silence EGFR T790M mutant messenger RNA while leaving wild-type EGFR intact. Allele-specific silencing of EGFR T790M expression and downstream signaling by DzT triggered apoptosis in non–small-cell lung cancer cells harboring this mutant. Adding a cholesterol-triethylene glycol group on the 3′-end of DzT (cDzT) improved drug efficacy, increasing inhibitory effect on cell viability from 46 to 79% in T790M/L858R-harboring H1975TM/LR non–small-cell lung cancer cells, without loss of allele specificity. Combined treatment with cDzT and BIBW-2992, a second-generation EGFR-tyrosine kinase inhibitor, synergistically inhibited EGFR downstream signaling and suppressed the growth of xenograft tumors derived from H1975TM/LR cells. Collectively, these results indicate that the allele-specific DNAzyme, DzT, may provide an alternative treatment for non–small-cell lung cancer that is capable of overcoming EGFR T790M mutant-based tyrosine kinase inhibitor resistance.
doi:10.1038/mtna.2014.3
PMCID: PMC3982196  PMID: 24594844
DNAzyme; EGFR T790M; NSCLC; TKI
18.  Antitumor Agents 295. E-ring Hydroxylated Antofine and Cryptopleurine Analogs as Antiproliferative Agents: Design, Synthesis, and Mechanistic Studies 
Journal of medicinal chemistry  2012;55(15):6751-6761.
Various E-ring hydroxylated antofine and cryptopleurine analogs were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of non-small cell lung cancer (NSCLC) cell lines, in which it showed impressive antiproliferative activity. Mechanistic studies revealed that 13b is able to down-regulate HSP90 and β-catenin in A549 lung adenocarcinoma cells in a dose-dependent manner, suggesting a potential use for treating Hedgehog pathway-driven tumorigenesis.
doi:10.1021/jm3001218
PMCID: PMC3422873  PMID: 22823514
19.  Rapid single cell detection of Staphylococcus aureus by aptamer-conjugated gold nanoparticles 
Scientific Reports  2013;3:1863.
Staphylococcus aureus is one of the most important human pathogens, causing more than 500,000 infections in the United States each year. Traditional methods for bacterial culture and identification take several days, wasting precious time for patients who are suffering severe bacterial infections. Numerous nucleic acid-based detection methods have been introduced to address this deficiency; however, the costs and requirement for expensive equipment may limit the widespread use of such technologies. Thus, there is an unmet demand of new platform technology to improve the bacterial detection and identification in clinical practice. In this study, we developed a rapid, ultra-sensitive, low cost, and non-polymerase chain reaction (PCR)-based method for bacterial identification. Using this method, which measures the resonance light-scattering signal of aptamer-conjugated gold nanoparticles, we successfully detected single S. aureus cell within 1.5 hours. This new platform technology may have potential to develop a rapid and sensitive bacterial testing at point-of-care.
doi:10.1038/srep01863
PMCID: PMC3659324  PMID: 23689505
20.  The Motor Protein KIF14 Inhibits Tumor Growth and Cancer Metastasis in Lung Adenocarcinoma 
PLoS ONE  2013;8(4):e61664.
The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase-to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P = 0.0158 and <0.0001, respectively), and the protein levels were also inversely correlated with metastasis (P<0.0001). The overexpression of KIF14 in lung adenocarcinoma cells inhibited anchorage-independent growth in vitro and xenograft tumor growth in vivo. The overexpression and silencing of KIF14 also inhibited or enhanced cancer cell migration, invasion and adhesion to the extracellular matrix proteins laminin and collagen IV. Furthermore, we detected the adhesion molecules cadherin 11 (CDH11) and melanoma cell adhesion molecule (MCAM) as cargo on KIF14. The overexpression and silencing of KIF14 enhanced or reduced the recruitment of CDH11 in the membrane fraction, suggesting that KIF14 might act through recruiting adhesion molecules to the cell membrane and modulating cell adhesive, migratory and invasive properties. Thus, KIF14 might inhibit tumor growth and cancer metastasis in lung adenocarcinomas.
doi:10.1371/journal.pone.0061664
PMCID: PMC3633961  PMID: 23626713
21.  Genome-wide analysis of three-way interplay among gene expression, cancer cell invasion and anti-cancer compound sensitivity 
BMC Medicine  2013;11:106.
Background
Chemosensitivity and tumor metastasis are two primary issues in cancer management. Cancer cells often exhibit a wide range of sensitivity to anti-cancer compounds. To gain insight on the genetic mechanism of drug sensitivity, one powerful approach is to employ the panel of 60 human cancer cell lines developed by the National Cancer Institute (NCI). Cancer cells also show a broad range of invasion ability. However, a genome-wide portrait on the contributing molecular factors to invasion heterogeneity is lacking.
Methods
Our lab performed an invasion assay on the NCI-60 panel. We identified invasion-associated (IA) genes by correlating our invasion profiling data with the Affymetrix gene expression data on NCI-60. We then employed the recently released chemosensitivity data of 99 anti-cancer drugs of known mechanism to investigate the gene-drug correlation, focusing on the IA genes. Afterwards, we collected data from four independent drug-testing experiments to validate our findings on compound response prediction. Finally, we obtained published clinical and molecular data from two recent adjuvant chemotherapy cohorts, one on lung cancer and one on breast cancer, to test the performance of our gene signature for patient outcome prediction.
Results
First, we found 633 IA genes from the invasion-gene expression correlation study. Then, for each of the 99 drugs, we obtained a subset of IA genes whose expression levels correlated with drug-sensitivity profiles. We identified a set of eight genes (EGFR, ITGA3, MYLK, RAI14, AHNAK, GLS, IL32 and NNMT) showing significant gene-drug correlation with paclitaxel, docetaxel, erlotinib, everolimus and dasatinib. This eight-gene signature (derived from NCI-60) for chemosensitivity prediction was validated by a total of 107 independent drug tests on 78 tumor cell lines, most of which were outside of the NCI-60 panel. The eight-gene signature predicted relapse-free survival for the lung and breast cancer patients (log-rank P = 0.0263; 0.00021). Multivariate Cox regression yielded a hazard ratio of our signature of 5.33 (95% CI = 1.76 to 16.1) and 1.81 (95% CI = 1.19 to 2.76) respectively. The eight-gene signature features the cancer hallmark epidermal growth factor receptor (EGFR) and genes involved in cell adhesion, migration, invasion, tumor growth and progression.
Conclusions
Our study sheds light on the intricate three-way interplay among gene expression, invasion and compound-sensitivity. We report the finding of a unique signature that predicts chemotherapy survival for both lung and breast cancer. Augmenting the NCI-60 model with in vitro characterization of important phenotype-like invasion potential is a cost-effective approach to power the genomic chemosensitivity analysis.
doi:10.1186/1741-7015-11-106
PMCID: PMC3635895  PMID: 23590835
NCI-60; Invasion; Metastasis; Microarray; Chemotherapy
22.  Apoptosis-associated biomarkers in tuberculosis: promising for diagnosis and prognosis prediction 
Background
Apoptosis-associated biomarkers are rarely studied, especially their role in predicting the development of tuberculosis (TB) from latent TB infection and in prognostication.
Methods
Patients with TB and interferon-gamma release assay (IGRA)-positive and IGRA-negative family contacts were evaluated to analyze changes in apoptosis-associated serum biomarkers, which included decoy receptor 3 (DcR3), prostaglandin 2 (PGE2), and lipoxin. The prognostic implications of these serum biomarkers were also analyzed.
Results
One hundred TB patients and 92 IGRA-negative and 91 IGRA-positive family contacts were recruited. The DcR3 and PGE2 levels decreased from the IGRA-negative group to the IGRA-positive group, and peaked in the TB group. Lipoxin decreased to trough in the TB group. The three apoptosis serum markers and age were independent factors discriminating active TB from latent TB infection. In active TB, older age, co-morbidity, and higher serum DcR3 and monocyte chemotactic protein (MCP)-1 were independently associated with poorer six-month survival.
Conclusion
Apoptosis-associated serum biomarkers change along with the status of Mycobacterium tuberculosis infection. In close contacts with positive IGRA, high DcR3 and PGE2 and low lipoxin may increase the probability of active TB. Older age, co-morbidity, and high DcR3 and MCP-1 levels might be important prognostic factors that warrant further investigation.
doi:10.1186/1471-2334-13-45
PMCID: PMC3566962  PMID: 23356448
Apoptosis; Decoy receptor 3; Latent tuberculosis infection; Lipoxin; Prostaglandin E2; Tuberculosis
24.  Advanced non-small cell lung cancer in patients aged 45 years or younger: outcomes and prognostic factors 
BMC Cancer  2012;12:241.
Background
Lung cancer in young patients (less or equal to 45 years) is uncommon and has clinical characteristics different from that in older patients. We investigated the outcomes and prognostic factors of young patients with advanced non-small cell lung cancer (NSCLC).
Methods
From January 2000 to December 2009, we enrolled patients aged ≤45 years and diagnosed with stage IIIB or IV NSCLC. Their clinical data, including age, gender, performance status, histologic types, disease stages, laboratory data at diagnosis, treatment modalities, and survival were reviewed and analyzed. A Cox proportional hazard model was used to calculate the hazard ratio (HR) and its 95% confidence interval (CI).
Results
A total of 144 patients with advanced NSCLC were included. Female patients were more prevalent (n = 74, 51.4%). Adenocarcinoma was the most common histologic type (n = 119, 82.6%) in both genders (male, n = 54, 77.1%; female, n = 65, 87.8%). Epidermal growth factor receptor (EGFR) sequences were determined using tumor specimens from 58 patients, and 29 showed an EGFR mutation. No significant difference in median survival was found between patient groups with and without the EGFR mutation (798 vs. 708 days, p = 0.65). In multivariate analysis, male gender (HR, 1.70; 95% CI: 1.08-2.68), body mass index (BMI) less than 25 kg/m2 (HR, 2.72; 95% CI: 1.39-5.30), stage IV disease (HR, 2.62; 95% CI: 1.50-4.57), and anemia (HR, 2.08; 95% CI: 1.15-3.77) were associated with a short survival time.
Conclusions
Low BMI, stage IV disease, anemia at diagnosis, and male gender were the negative prognostic factors for young patients with advanced NSCLC.
doi:10.1186/1471-2407-12-241
PMCID: PMC3420246  PMID: 22695392
Lung cancer; Prognosis; Young patients
25.  TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma 
EMBO Molecular Medicine  2012;4(6):472-485.
Trop-2, a cell surface glycoprotein, contains both extracellular epidermal growth factor-like and thyroglobulin type-1 repeat domains. Low TROP2 expression was observed in lung adenocarcinoma tissues as compared with their normal counterparts. The lack of expression could be due to either the loss of heterozygosity (LOH) or hypermethylation of the CpG island DNA of TROP2 upstream promoter region as confirmed by bisulphite sequencing and methylation-specific (MS) polymerase chain reaction (PCR). 5-Aza-2′-deoxycytidine treatment on lung cancer cell (CL) lines, CL1-5 and A549, reversed the hypermethylation status and elevated both TROP2 mRNA and protein expression levels. Enforced expression of TROP2 in the lung CL line H1299 reduced AKT as well as ERK activation and suppressed cell proliferation and colony formation. Conversely, silencing TROP2 with shRNA transfection in the less efficiently tumour-forming cell line H322M enhanced AKT activation and increased tumour growth. Trop-2 could attenuate IGF-1R signalling-mediated AKT/β-catenin and ERK activation through a direct binding of IGF1. In conclusion, inactivation of TROP2 due to LOH or by DNA methylation may play an important role in lung cancer tumourigenicity through losing its suppressive effect on IGF-1R signalling and tumour growth.
doi:10.1002/emmm.201200222
PMCID: PMC3443948  PMID: 22419550
epigenetic; IGF-1R; lung cancer; slug; TROP2

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