Oncology Research 19(3-4) Abstracts

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Oncology Research, Vol. 19, pp. 105–110, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587641
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Methylation Markers: A Potential Force Driving Cancer Diagnostics Forward

Surabhi Khandige,* Vikram V. Shanbhogue,† Sanjiban Chakrabarty,* and Satyamoorthy Kapettu*

*Manipal Life Sciences Center, Manipal University, Manipal, Karnataka, India
†Kasturba Medical College, Manipal University, Manipal, Karnataka, India

Epigenetics, transcending genetics, genomics, and molecular biology, is now poised to be the avant-garde beacon of biological science. The rise of DNA methylation studies marks a new dawn in the field of epigenetics, which only a few decades ago was largely underestimated, but is now a dynamic area of research challenging and revising traditional paradigms of gene expression and behavior. Cancer research enjoys a major share of this attention to DNA methylation and it has been widely accepted for some time now that cancer is as much an epigenetic phenomenon as it is genetic. Epigenetic lesions and perturbations are acquired during the life of an individual and accumulate with aging and represent the flip side of the same coin that bears genetic mutations. Both events, either individually or in cooperation, result in the development and progression of cancer. Epigenetic research and the hunt for strong methylation markers has been ably mitigated by new and improved high throughput technology that has improved the efficacy and enabled the rapid progress of biomarker evaluation and validation. This review looks into some of the recent strides in biomarker research dealing exclusively with methylation markers and the potential key they may hold to the resilient door shut tight on cancer diagnostics and treatment.

Key words: Epigenetics; Methylation markers; Diagnosis; Prognosis; Primary cancer

Address correspondence to Surabhi Khandige, Manipal Life Sciences Center, Department of Biotechnology, Manipal University, Manipal 576104, Karnataka, India. Tel: +91 820 2574607; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 111–114, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587687
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

A Fully Integrated and Automated Detection System for Single Nucleotide Polymorphisms of UGT1A1 and CYP2C19

Norio Ureshino,*† Naoko Aragane,* Tomomi Nakamura,* Masaru Ide,* Sakiko Mochinaga,‡ Noriyasu Fukushima,* Shinichiro Hayashi,* Eizaburo Sueoka,*§ and Shinya Kimura*

*Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
†Department of Medical Oncology, Saga Prefectural Hospital Koseikan, Saga, Japan
‡Department of Pharmacy, Saga University Hospital, Saga, Japan
§Department of Transfusion Medicine, Saga University Hospital, Saga, Japan

The need for examinations of single nucleotide polymorphisms (SNPs) on drug metabolizing enzymes is accelerating. Especially, SNPs of UTG1A1 and CYP2C19 are important for patients who are treated with irinotecan and proton pump inhibitors, respectively. Thus, a method for the rapid, fully automated, and accurate measurement of these SNPs is desired. We genotyped 109 Japanese volunteers for UGT1A1*6, UGT1A1*28, CYP2C19*2, and CYP2C19*3 with the quenching probe (QP) method. Only 90 min after whole blood was applied, QP method enabled to detect these SNPs automatically. The results obtained by QP method were absolutely identical to those examined by the conventional direct sequencing. These findings indicate that the QP method will enable point-of-care testing in clinical laboratories and patient-oriented therapy with its convenience and speed for patients who are treated with irinotecan or proton pump inhibitors.

Key words: Single nucleotide polymorphism; Quenching probe; Direct sequencing; UTG1A1; CYP2C19

Address correspondence to Shinya Kimura, M.D., Ph.D., Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. Tel: +81-952-34-2353; Fax: +81-952-34-2017; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 115–123, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587722
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

KITENIN Is Associated With Activation of AP-1 Target Genes via MAPK Cascades Signaling in Human Hepatocellular Carcinoma Progression

Sung-Bum Cho,* Young-Lan Park,* Su-Jin Park,* Seon-Young Park,* Wan-Sik Lee,* Chang-Hwan Park,* Sung-Kyu Choi,* Young-Hye Heo,† Yang-Seok Koh,† Chul-Kyoon Cho,† Ik-Joo Chung,* Kyeong-Keun Kim,‡ Seewan Kim,§ and Young-Eun Joo*

*Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
†Department of Surgery, Chonnam National University Medical School, Gwangju, Korea
‡Department of Pharmacology, Chonnam National University Medical School, Gwangju, Korea
§Korean Minjok Leadership Academy, Gangwon-do, Korea

KITENIN promotes cancer cell migration and invasion in vitro and cancer metastasis in mouse cancer models, including colon and head and neck cancers. The purposes of this study were to observe the effect of KITENIN on tumor cell behaviors of human hepatocellular carcinoma (HCC) cells and to evaluate its expression in human HCC tissues. To functionally characterize KITENIN in human HCC, we depleted its expression in human HCC cell lines, HepG2 and Huh7, by using small interfering RNA (siRNA). Invasion and proliferation assays were performed. The activator protein-1 (AP-1) transcriptional activity and expression of AP-1 target genes were evaluated by AP-1 luciferase reporter assay and RT-PCR. The contribution of mitogen-activated protein kinase (MAPK) cascade signaling involved in AP-1 activation was assessed by Western blotting. We evaluated the expression of KITENIN and AP-1 target genes at mRNA levels by RTPCR in human HCC tissues and paired normal hepatic mucosa of the same patients taken by surgery. Knockdown of KITENIN in HepG2 and Huh7 cells resulted in a significant reduction of tumor cell invasion. The tumor cell proliferation was significantly decreased in the KITENIN knocked down Huh7 cells compared to the negative control. The mRNA expressions of MMP-3 and COX-2 were decreased in KITENIN knocked down Huh7 cells. The mRNA expression of MMP-1 was decreased in KITENIN knocked down HepG2 cells. The AP-1 transcriptional activity in Huh7 cells was significantly decreased by knockdown of KITENIN. The JNK and ERK1/2 phosphorylations were decreased in KITENIN knocked down HepG2 and the p38 phosphorylation was decreased in KITENIN knocked down Huh7 cells. The mRNA expressions of KITENIN, MMP-1, and MMP-3 were significantly upregulated in human HCC tissues compared to paired normal mucosa. These results indicate that KITENIN is associated with activation of AP-1 target genes via MAPK cascades signaling in human HCC progression.

Key words: KITENIN; Hepatocellular carcinoma; AP-1; MAPK

Address correspondence to Young-Eun Joo, M.D., Department of Internal Medicine, Chonnam National University Medical School, 8 Hak-Dong, Dong-ku, Gwangju, 501-757, Korea. Tel: 82-62-220-6296; Fax: 82-62-225-8578; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 125–130, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587768
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

iASPP Is Important for Bladder Cancer Cell Proliferation

Tao Liu,* Lin Li,† WenFeng Yang,‡ Hui Jia,§ MingKai Xu,¶ JianBin Bi,* ZeLiang Li,* XianKui Liu,* ZhenHua Li,* HongWei Jing,* and ChuiZe Kong*

*Department of Urology, The First affiliated Hospital, China Medical University, Heping District, Shenyang, P. R. China
†Department of Rehabilitation, Guangdong General Hospital, Dongshan District, Guangzhou, Guangdong, P. R. China
‡Department of Urology, Handan Central Hospital, Hebei, P. R. China
§Department of Seven-year, China Medical University, Heping District, Shenyang, P. R. China
¶Institute of Applied of Ecology, Chinese Academy of Sciences, Shenhe District, Shenyang, Liaoning, P. R. China

Inhibitor of apoptosis stimulatory protein phosphatase (iASPP) is a key inhibitor of p53 conserved from worm to human and is associated with cell proliferation and carcinogenesis in a variety of human cancers. Because iASPP is important for tumor cell apoptosis, it is a potential target for cancer gene therapy. However, it is still not clear whether iASPP is relevant to p53-deficient human bladder cancer. In the present study, iASPP was knocked down in bladder carcinoma 5637 and T24 cells (p53 defective) by lentiviral-mediated interfering short hairpin RNAs (siRNAs). MTT assay, BrdU incorporation assay, and colony formation assay were performed to investigate the role of iASPP on cell proliferation. It was suggested that iASPP knockdown led to cell growth deceleration and slow colony formation. A positive relationship between expression of iASPP and bladder cancer proliferation was found. The expression of iASPP may be critical for proliferation of bladder cancer cells. Our study indicates iASPP could be an important target for therapy in bladder cancer.

Key words: iASPP; RNA interference; Bladder cancer; Proliferation

Address correspondence to Dr. ChuiZe Kong, Department of Urology, The First Affiliated Hospital, China Medical University, Heping District, Shenyang 110001, P. R. China. Tel. +86-24-83283433; Fax: +86-24-83283433; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 131–139, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587803
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

The Cyclooxygenase-2 Inhibitor Celecoxib Attenuates Hepatocellular Carcinoma Growth and c-Met Expression in an Orthotopic Mouse Model

Jibin Yin,* Bingrong Liu,* Baoxin Li,† Zhaojun Liu,* Xinyu Xie,‡ Zhiwu Lv,* Shanling Gao,* and Jingming Guang*

*The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
†Department of Pharmacology, Harbin Medical University, Harbin, Heilingjiang, China
‡Beijing Chuiyangliu Hospital, Beijing, China

To demonstrate in vivo tumor growth inhibition, the liver cancer cell lines HepG2, BEL7402, and SMMC7721 were independently inoculated into the livers of 45 6-week-old nude mice. After 24 h, mice were randomly divided into celecoxib (intragastric celecoxib suspension, 300 mg/kg), negative control (equal volume intragastric saline), and positive control (intraperitoneal injection of 6 mg/kg doxorubicin) and treated once per day for 3 days. Body weights, tumor diameters, and tumor expressions of proliferating cell nuclear antigen (PCNA) and c-Met were determined at 23 days posttreatments. Significant increases in body weight were observed in celecoxib- or doxorubicin-treated mice compared to saline-treated animals and tumor growth was significantly attenuated, accompanied by downregulation of tumor PCNA expression (p < 0.01). Weight gain, attenuated tumor growth, and reduced PCNA expression were similar following celecoxib or doxorubicin treatment. Celecoxib also significantly reduced c-Met expression in HepG2- and BEL7402-induced tumors, but not SMMC7721-induced tumors (p < 0.05). In conclusion, celecoxib effectively suppressed the in vivo growth of liver cancer in an orthotopic tumor model. Celecoxib also inhibited tumor cell PCNA expression independent of changes in c-Met expression, with some variability between different implanted cell lines. This preclinical demonstration of celecoxib efficacy and safety provides a foundation for future clinical investigations involving use of this agent alone or as a component of chemotherapeutic regimens for treatment of HCC.

Key words: Celecoxib; c-Met tyrosine kinase; Doxorubicin; Hepatocellular carcinoma; Hepatocyte growth factor receptor; Orthotopic mouse model; Proliferating cell nuclear antigen

Address correspondence to Bingrong Liu, Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Heilongjiang 150086, China. Tel: 86-13313695959; Fax: 86-451-86605980; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 141–147, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587849
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Enhanced PPAR-γ Expression May Correlate With the Development of Barrett’s Esophagus and Esophageal Adenocarcinoma

Wen Wang,*1 Rong Wang,*1 Zhijian Zhang,* Dazhou Li,* and Yinghao Yu†

*Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, Fuzhou, China
†Department of Pathology, Fuzhou General Hospital of Nanjing Command, Fuzhou, China

PPAR-γ is known to have a growth-suppressive effect in different cancers. In this study, we investigated the role of PPAR-γ  in the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We used immunohistochemistry and real-time PCR to analyze differences in PPAR-γ  protein and mRNA expression levels in samples of normal esophageal squamous epithelium (n = 75), BE (n = 50), and EA (n = 25). Immunoreactivity with antibodies against PPAR-γ  was confined to the nuclei of goblet cells and surface glandular epithelium in BE samples. We found significantly lower levels of expression of PPAR-γ  protein (p < 0.01) in normal esophageal squamous epithelium when compared to BE and EA samples. PPAR-γ  protein levels showed an increasing trend from normal esophageal squamous epithelium < BE samples < EA samples (p < 0.01). PPAR-γ  mRNA expression levels in BE and EA samples were 5.9130-fold (p < 0.01) and 2.0314-fold (p < 0.01) higher than that of normal esophageal squamous epithelium, respectively. There was a trend towards increased expression of PPAR-γ  with decreasing levels of differentiation. Increased PPAR-γ  expression may play an important role in the development and progression from normal cells to BE and EA.

Key words: Barrett’s esophagus; Esophageal adenocarcinoma; Peroxisome proliferator-activated receptor-γ  (PPAR-γ); Immunohistochemistry; Clinicopathology

1These authors provided equal contribution to this study.
Address correspondence to Wen Wang, Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, No. 156, Xi’er Huan North Road, Fuzhou, 350025, China. Tel: +86-0591-22859371; Fax: +86-0591-24937074; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 149–163, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587885
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Arsenic Trioxide Induces Apoptosis of Burkitt Lymphoma Cell Lines Through Multiple Apoptotic Pathways and Triggers Antiangiogenesis

Hui-min Li,* Yi Long,§1 Chen Qing,‡1 Meijia Yu,†1 Zhi-hui Li,†¶ Xue-mei Zhang,* Xiao-jin Li,† Ya-Juan Chen,‡ Yan-li Zhang,‡ and Yang Liang#

*Department of Hematology, The First Affiliated Hospital of Kunming Medical College, Kunming, Yunnan Province, China
†Department of Hematology, The Fourth Affiliated Hospital of Kunming Medical College, Kunming, Yunnan Province, China
‡Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical College, Kunming, Yunnan Province, China
§Department of Hematology, Yan’an Hospital, Kunming, Yunnan Province, China
¶Department of Hematology, Daopei Hospital, Beijing, China
#Department of Hematology, Kunming General Hospital of the Chinese People’s Liberation Army, Kunming, Yunnan Province, China

Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) and it appears to be one of the most common childhood cancers in equatorial areas. Unprecedented gains have been made in the cure rates for BL during the past two decades and these reflect steady improvements in treatment protocols and a multidisciplinary approach to patient care. However, the life-threatening side effects associated with conventional treatment urge us to explore new strategies. Arsenic trioxide (ATO), a natural product that has improved the prognosis of acute promyelocytic leukemia (APL) from highly fatal to highly curable, has also been proven to be effective in treating BL cell lines through multiple pathways in our study. Our data indicates that ATO can inhibit the proliferation of BL cell lines through 1) arresting the cell cycle; 2) decreasing the respiratory function and transmembrane potential of mitochondrial; and 3) downregulating the expressions of Survivin, Bcl-2, MCL-1, and VEGF. We therefore suggest that dissecting the pharmaceutical mechanism of ATO at the molecular and cellular levels may be a good strategy to explore the value of traditional natural products in treating high malignant Burkitt lymphoma.

Key words: Burkitt lymphoma; Arsenic trioxide; Survivin; Bcl-2; MCL-1; VEGF

1These authors provided equal contribution to this work.
Address correspondence to Hui-min Li, M.D., Department of Hematology, The First Affiliated Hospital of Kunming Medical College, 295 Xi Chang Road, Kunming, Yunnan Province, P. R. China, 650031. Tel: 86-13150754535; Fax: 86-871-5510167; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Yang Liang, M.D., Ph.D., Department of Hematology, Kunming General Hospital of the Chinese People’s Liberation Army, 212 Da Guan Road, Kunming, Yunnan Province, China, 650032. Tel: 86-13888386043; Fax: 86-871-5510167; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 165–169, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587920
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Association of TP53 Intron 3, 16 bp Duplication Polymorphism With Esophageal and Gastric Cancer Susceptibility in Kashmir Valley

Manzoor Ahmad Malik,* Kokil Sharma,* Shivangi Goel,* Showkat Ali Zargar,† and Balraj Mittal*

*Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
†Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Kashmir, India

TP53 is one of the major tumor suppressor genes, which is essential for the preservation of genome integrity. Different polymorphic variants of the p53 gene have been demonstrated for their association with several human malignancies. Of these, 16 base pair (bp) duplication in intron 3 of the TP53 gene (PIN3 Ins16bp, rs17878362) is the most extensively studied variant. However, no studies have, so far, investigated the association of this polymorphism with esophageal and gastric cancers. Thus, we aimed to investigate the association of PIN3 Ins16bp polymorphism with esophageal cancer (EC) and gastric cancer (GC) in Kashmir Valley, a northern part of India, where incidence of these cancers is very high. In addition, we also tested other covariates such as smoking/tea consumption as potential confounding factors. We analyzed DNA samples from a total of 243 patients (135 EC and 108 GC patients) and 195 healthy controls for PIN3 Ins16bp polymorphisms using PCR. Data were statistically analyzed using chi-square test and logistic regression models. Results showed that carriers for the PIN3 Ins16bp allele (A2) were associated with increased risk for both EC (OR = 2.31, 95% CI = 1.08–4.97, p = 0.03) and GC (OR = 2.91, 95% CI = 1.28–6.63, p = 0.01). Also, in a recessive model, our results showed that PIN3 Ins16bp A2A2 allele was conferring significant high risk for both EC (OR = 2.18, 95% CI = 1.03–4.59, p = 0.04) and GC (OR = 2.87, 95% CI = 1.29–6.42, p = 0.010). Although smoking (Hukka) and high consumption of salted tea are significant risk factors for both EC and GC, interaction of PIN3 Ins16bp genotypes with these factors did not further modulate the risk of EC and GC. Determination of PIN3 A2A2 genotype may provide a useful genetic marker in predicating high-risk individuals for the development of EC and GC and an early diagnosis.

Key words: Kashmir Valley; Esophageal and gastric cancer; PIN3 Ins16bp polymorphism

Address correspondence to Prof. Balraj Mittal, Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareilly Road, Lucknow-226014, India. Tel: +91-522-2668973, 004-8, ext. 2322; Fax: +91-522-2668017, 2668074; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 19, pp. 171–178, 2011
0965-0407/11 $90.00 + .00
DOI: 10.3727/096504011X12935427587966
E-ISSN 1555-3906
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

The Risk Factors and Prognosis of Bilateral Primary Breast Cancer: A Comparative Study With Unilateral Breast Cancer

Tong Wang,* Hong Liu,* Ke-xin Chen,† Pei Xun,* Hai-xin Li,† and Shou-Ching Tang*‡

*Second Department of Breast Tumor, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
†Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China;
Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
‡Virginia Piper Cancer Institute, Minneapolis, MN, USA

This study was performed to determine the risk factors and evaluate the outcome of bilateral breast cancer (BBC). We reviewed the records of 170 patients with BBC and 1,677 with unilateral breast cancer (UBC), and compared their personal history, histopatholgical characteristics, clinical findings, and treatment, and postoperative follow-up records. The patients with UBC were more likely to develop contralateral cancer with the features including: young age at onset, especially younger than 40, premenopause, late primiparity, breast cancer family history, benign mammary disease history, and a tumor larger than 5 cm (p < 0.05). After adjustment by multivariate analysis, we concluded that breast cancer family history and age at onset younger than 40 years old were the independent risk factors for BBC. There were no significant differences for distant metastasis or overall survival between BBC and UBC (p > 0.05). We observed that 64.1% of the second breast cancer occurred within 5 years after the operation of the first cancer, and medical examination could improve the early diagnosis of the contralateral breast cancer. Contrary to common belief, our study showed that BBC and UBC had similar biological features and prognosis (p > 0.05). The excessive treatment and prophylactic measures may be unnecessary in this seemingly aggressive breast cancer. The patients with UBC younger than 40 or with breast cancer family history should have intensive contralateral breast follow-up, especially within 5 years after in the initial treatment.

Key words: Unilateral breast cancer; Bilateral breast cancer; Prognosis; Treatment and follow-up

Address correspondence to Hong Liu, M.D., Ph.D., Second Department of Breast Tumor, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin, China, 300060. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Shou-Ching Tang, M.D., Ph.D., FACP, FRCPC, Martha Bacon Stimpson Endowed Chair in Medical Oncology, Virginia Piper Cancer Institute and Minnesota Oncology, Mail Route 39602, 800 E., 28th Street, Suite 602, Minneapolis, MN 55404, USA. Tel: (612) 63-2955; Fax: (612) 863-4698; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it