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1.  Immunotherapy of hepatoma with a monoclonal antibody against murine endoglin 
AIM: To explore the capability of a monoclonal antibody (mAb) against murine endoglin to inhibit tumor angiogenesis and suppression of hepatoma growth in murine models.
METHODS: A monoclonal antibody against murine endoglin was purified by affinity chromatography and passively transfused through tail veins in two murine hepatoma models. Tumor volume and survival time were observed at three-day intervals for 48 d. Microvessels in tumor tissues were detected by immunohistochemistry against CD31, and angiogenesis in vivo was determined by alginate encapsulated assay. In addition, tumor cell apoptosis was detected by TUNEL assay.
RESULTS: Passive immunotherapy with anti-endoglin mAb could effectively suppress tumor growth, and prolonged the survival time of hepatoma-bearing mice. Angiogenesis was apparently inhibited within the tumor tissues, and the vascularization of alginate beads was also reduced in the mice passively transfused with anti-endoglin mAb. In addition, increased apoptotic cells were observed within the tumor tissues from the mice passively transfused with anti-endoglin mAb.
CONCLUSION: Passive immunotherapy with anti-endoglin mAb effectively inhibits tumor growth via inhibiting tumor angiogenesis and increasing tumor cell apoptosis, which may be highly correlated with the blockage of endoglin-related signal pathway induced by anti-endoglin mAb.
PMCID: PMC4146767  PMID: 17552032
Monoclonal antibody; Endoglin; Passive immunotherapy; Tumor angiogenesis; Apoptosis
2.  Risk Factors for Invasive Cryptococcus neoformans Diseases: A Case-Control Study 
PLoS ONE  2015;10(3):e0119090.
Cryptococcus neoformans is a ubiquitous environmental fungus that can cause life-threatening meningitis and fungemia, often in the presence of acquired immunodeficiency syndrome (AIDS), liver cirrhosis, diabetes mellitus, or other medical conditions. To distinguish risk factors from comorbidities, we performed a hospital-based, density-sampled, matched case-control study.
All new-onset cryptococcal meningitis cases and cryptococcemia cases at a university hospital in Taiwan from 2002–2010 were retrospectively identified from the computerized inpatient registry and were included in this study. Controls were selected from those hospitalized patients not experiencing cryptococcal meningitis or cryptococcemia. Controls and cases were matched by admission date, age, and gender. Conditional logistic regression was used to analyze the risk factors.
A total of 101 patients with cryptococcal meningitis (266 controls) and 47 patients with cryptococcemia (188 controls), of whom 32 patients had both cryptococcal meningitis and cryptococcemia, were included in this study. Multivariate regression analysis showed that AIDS (adjusted odds ratio [aOR] = 181.4; p < 0.001), decompensated liver cirrhosis (aOR = 8.5; p = 0.008), and cell-mediated immunity (CMI)-suppressive regimens without calcineurin inhibitors (CAs) (aOR = 15.9; p < 0.001) were independent risk factors for cryptococcal meningitis. Moreover, AIDS (aOR = 216.3, p < 0.001), decompensated liver cirrhosis (aOR = 23.8; p < 0.001), CMI-suppressive regimens without CAs (aOR = 7.3; p = 0.034), and autoimmune diseases (aOR = 9.3; p = 0.038) were independent risk factors for developing cryptococcemia. On the other hand, diabetes mellitus and other medical conditions were not found to be risk factors for cryptococcal meningitis or cryptococcemia.
The findings confirm AIDS, decompensated liver cirrhosis, CMI-suppressive regimens without CAs, and autoimmune diseases are risk factors for invasive C. neoformans diseases.
PMCID: PMC4352003  PMID: 25747471
3.  Overexpression of Arachis hypogaea AREB1 Gene Enhances Drought Tolerance by Modulating ROS Scavenging and Maintaining Endogenous ABA Content 
AhAREB1 (Arachis hypogaea Abscisic-acid Response Element Binding Protein 1) is a member of the basic domain leucine zipper (bZIP)-type transcription factor in peanut. Previously, we found that expression of AhAREB1 was specifically induced by abscisic acid (ABA), dehydration and drought. To understand the drought defense mechanism regulated by AhAREB1, transgenic Arabidopsis overexpressing AhAREB1 was conducted in wild-type (WT), and a complementation experiment was employed to ABA non-sensitivity mutant abi5 (abscisic acid-insensitive 5). Constitutive expression of AhAREB1 confers water stress tolerance and is highly sensitive to exogenous ABA. Microarray and further real-time PCR analysis revealed that drought stress, reactive oxygen species (ROS) scavenging, ABA synthesis/metabolism-related genes and others were regulated in transgenic Arabidopsis overexpressing AhAREB1. Accordingly, low level of ROS, but higher ABA content was detected in the transgenic Arabidopsis plants’ overexpression of AhAREB1. Taken together, it was concluded that AhAREB1 modulates ROS accumulation and endogenous ABA level to improve drought tolerance in transgenic Arabidopsis.
PMCID: PMC3709814  PMID: 23783278
AhAREB1; transcription factor; drought stress; Arachis hypogaea
4.  Toxicarioside A Inhibits Tumor Growth and Angiogenesis: Involvement of TGF-β/Endoglin Signaling 
PLoS ONE  2012;7(11):e50351.
Toxicarioside A is a cardenolide isolated mainly from plants and animals. Emerging evidence demonstrate that cardenolides not only have cardiac effects but also anticancer effects. In this study, we used in vivo models to investigate the antitumor activities of toxicarioside A and the potential mechanisms behind them. Murine colorectal carcinoma (CT26) and Lewis lung carcinoma (LL/2) models were established in syngeneic BALB/c and C57BL/6 mice, respectively. We found that the optimum effective dose of toxicarioside A treatment significantly suppressed tumor growth and angiogenesis in CT and LL/2 tumor models in vivo. Northern and Western blot analysis showed significant inhibition of endoglin expression in toxicarioside A-treated human umbilical vein endothelial cells (HUVECs) in vitro and tumor tissues in vivo. Toxicarioside A treatment significantly inhibited cell proliferation, migration and invasion, but did not cause significant cell apoptosis and affected other membrane protein (such as CD31 and MHC I) expression. In addition, TGF-β expression was also significantly inhibited in CT26 and LL/2 tumor cells treated with toxicarioside A. Western blot analysis indicated that Smad1 and phosphorylated Smad1 but not Smad2/3 and phosphorylated Smad2/3 were attenuated in HUVECs treated with toxicarioside A. Smad1 and Smad2/3 signaling remained unchanged in CT26 and LL/2 tumor cells treated with toxicarioside A. Endoglin knockout by small interfering RNA against endoglin induced alternations in Smad1 and Smad2/3 signaling in HUVECs. Our results indicate that toxicarioside A suppresses tumor growth through inhibition of endoglin-related tumor angiogenesis, which involves in the endoglin/TGF-β signal pathway.
PMCID: PMC3508932  PMID: 23209720
5.  Inverse Association between Methylation of Human Papillomavirus Type 16 DNA and Risk of Cervical Intraepithelial Neoplasia Grades 2 or 3 
PLoS ONE  2011;6(8):e23897.
The clinical relevance of human papillomavirus type 16 (HPV16) DNA methylation has not been well documented, although its role in modulation of viral transcription is recognized.
Study subjects were 211 women attending Planned Parenthood clinics in Western Washington for routine Papanicolaou screening who were HPV16 positive at the screening and/or subsequent colposcopy visit. Methylation of 11 CpG dinucleotides in the 3′ end of the long control region of the HPV16 genome was examined by sequencing the cloned polymerase chain reaction products. The association between risk of CIN2/3 and degree of CpG methylation was estimated using a logistic regression model.
CIN2/3 was histologically confirmed in 94 (44.5%) of 211 HPV16 positive women. The likelihood of being diagnosed as CIN2/3 increased significantly with decreasing numbers of methylated CpGs (meCpGs) in the 3′ end of the long control region (Pfor trend = 0.003). After adjusting for HPV16 variants, number of HPV16-positive visits, current smoking status and lifetime number of male sex partners, the odds ratio for the association of CIN2/3 with ≥4 meCpGs was 0.31 (95% confidence interval, 0.12–0.79). The proportion of ≥4 meCpGs decreased appreciably as the severity of the cervical lesion increased (Pfor trend = 0.001). The inverse association remained similar when CIN3 was used as the clinical endpoint. Although not statistically significant, the ≥4 meCpGs-related risk reduction was more substantial among current, as compared to noncurrent, smokers.
Results suggest that degree of the viral genome methylation is related to the outcome of an HPV16 cervical infection.
PMCID: PMC3161083  PMID: 21887341
6.  Nanoparticles for biomedical imaging 
Expert opinion on drug delivery  2009;6(11):1175-1194.
Synthetic nanoparticles are emerging as versatile tools in biomedical applications, particularly in the area of biomedical imaging. Nanoparticles 1 – 100 nm in diameter have dimensions comparable to biological functional units. Diverse surface chemistries, unique magnetic properties, tunable absorption and emission properties, and recent advances in the synthesis and engineering of various nanoparticles suggest their potential as probes for early detection of diseases such as cancer. Surface functionalization has expanded further the potential of nanoparticles as probes for molecular imaging.
To summarize emerging research of nanoparticles for biomedical imaging with increased selectivity and reduced nonspecific uptake with increased spatial resolution containing stabilizers conjugated with targeting ligands.
This review summarizes recent technological advances in the synthesis of various nanoparticle probes, and surveys methods to improve the targeting of nanoparticles for their application in biomedical imaging.
Structural design of nanomaterials for biomedical imaging continues to expand and diversify. Synthetic methods have aimed to control the size and surface characteristics of nanoparticles to control distribution, half-life and elimination. Although molecular imaging applications using nanoparticles are advancing into clinical applications, challenges such as storage stability and long-term toxicology should continue to be addressed.
PMCID: PMC3097035  PMID: 19743894
biomedical imaging; molecular imaging; nanoparticle synthesis; surface modification; targeting
7.  RNA interference against interleukin-5 attenuates airway inflammation and hyperresponsiveness in an asthma model*  
Interleukin-5 (IL-5) accompanies the development of airway inflammation and hyperresponsiveness through the activation of eosinophils. Therefore, interference of IL-5 expression in lung tissue seems to be an accepted approach in asthma therapy. In this study, we designed a small interfering RNA (siRNA) to inhibit the expression of IL-5. The siRNAs against IL-5 were constructed in a lentivirus expressing system, and 1.5×106 IFU (inclusion-forming unit) lentiviruses were administered intratracheally to ovalbumin (OVA)-sensitized murine asthmatic models. Our results show that lentivirus-delivered siRNA against IL-5 efficiently inhibited the IL-5 messenger ribonucleic acid (mRNA) expression and significantly attenuated the inflammation in lung tissue. Significant decrease of eosinophils and inflammatory cells were found in peripheral blood, bronchoalveolar lavage fluid (BALF), and lung tissue. In addition, significant inhibition of airway hyperresponsiveness (AHR) was found in the mice treated with siRNA against IL-5. These observations demonstrate that siRNA delivered by means of the lentivirus system is possibly an efficacious therapeutic approach for asthma.
PMCID: PMC2613959  PMID: 19198019
Interleukin-5 (IL-5); Small interfering RNA (siRNA); Airway hyperresponsiveness (AHR); Allergy; Lentivirus
8.  A fusion protein containing murine vascular endothelial growth factor and tissue factor induces thrombogenesis and suppression of tumor growth in a colon carcinoma model*  
Induction of tumor vasculature occlusion by targeting a thrombogen to newly formed blood vessels in tumor tissues represents an intriguing approach to the eradication of primary solid tumors. In the current study, we construct and express a fusion protein containing vascular endothelial growth factor (VEGF) and tissue factor (TF) to explore whether this fusion protein has the capability of inhibiting tumor growth in a colon carcinoma model. The murine cDNA of VEGF A and TF were amplified by reverse transcriptase polymerase chain reaction (RT-PCR), and then cloned into prokaryotic expression plasmid pQE30 with a linker. The expression product recombinant VEGF-TF (rVEGF-TF) was purified and proved to have comparable enzyme activity to a commercial TF and the capability of specific binding to tumor vessels. Significant decrease of tumor growth was found in the mice administered with rVEGF-TF on Day 6 after initiated rVEGF-TF treatment (P<0.05), and the tumor masses in 2 of 10 mice were almost disappeared on Day 14 after the first treatment. In addition, valid thrombogenesis and tumor necrosis were observed in the tumor tissues injected with rVEGF-TF. Our results demonstrate that occlusion of tumor vasculature with rVEGF-TF is potentially an effective approach for cancer therapy.
PMCID: PMC2491689  PMID: 18763309
Thrombogenesis; Vascular endothelial growth factor (VEGF); Tissue factor (TF); Recombinant fusion protein

Results 1-8 (8)