January-February 2009 l Vol 15 l No 1-2

Research Articles

Macrophage Migration Inhibitory Factor Promotes Colorectal Cancer
Xing-Xiang He, Ken Chen, Jun Yang, Xiao-Yu Li, Huo-Ye Gan, Cheng-Yong Liu, Thomas R Coleman, and Yousef Al-Abed
Despite advances in colorectal cancer diagnosis and treatment, this disease remains a major cause of cancer deaths worldwide. Approximately half of all patients with colorectal cancer develop liver metastasis and die within 5 years of diagnosis.  A growing body of evidence implicates macrophage migration inhibitory factor (MIF) in tumorigenesis and metastasis.  He et al. investigated whether MIF expression was associated with clinicopathologic features of colorectal carcinoma (CRC) and if neutralization of endogenous MIF using anti-MIF therapeutics could inhibit tumor growth and frequency of colorectal hepatic metastases. Results show that MIF is positively correlated with an increased risk of hepatic metastasis in patients with CRC and may play a direct role in cancer development. These findings suggest that the MIF level in both serum and colorectal tissue may be a useful marker in the diagnosis of colorectal cancer and its metastasis to the liver.
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Rational Optimization of a Bispecific Ligand Trap Targeting EGF Receptor Family Ligands
Pei Jin, Juan Zhang, Malgorzata Beryt, Lisa Turin, Cathleen Brdlik, Ying Feng, Xiaomei Bai, Jim Liu, Brett Jorgenson, and H Michael Shepard
The human epidermal growth factor (EGF) receptor (HER) family members play a role in the development of cancer malignancies. Diversity within the HER family leads to difficultly in the creation of specific therapeutic HER family inhibitors. Jin et al. identified three single amino acid changes in the EGFR and HER3 which create high affinity sequestration of the cognate ligands and may be used as receptor decoys to downregulate aberrant HER family activity. This increased ligand binding improved inhibition of in vitro tumor cell proliferation and tumor suppression in a human non-small cell lung cancer xenograft model. These amino acid substitutions enhance ligand affinity and may enable a pan-specific therapeutic approach for downregulating the HER family in cancer.
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Supplementary Data 

Genome-Wide Association for Nicotine Dependence and Smoking Cessation Success in NIH Research Volunteers
Tomas Drgon, Ivan Montoya, Catherine Johnson, Qing-Rong Liu, Donna Walther, Dean Hamer, and George R Uhl
Vulnerability to dependence on addictive substances, such as nicotine, is a complex trait with strong genetic influences well documented by data from family, adoption, and twin studies. In this work, Drgon et al. report results from a genome-wide association study involving 480 volunteers who reported smoking histories, symptoms of nicotine dependence, and ability to successfully quit smoking outside of a clinical trial. Data from these volunteers support the idea that studies of genes associated with smoking cessation success in clinical trial participants may also apply to smokers who are able to initiate and sustain abstinence outside of clinical trials. This data provides the basis for improved understanding of addiction and for development of personalized prevention and treatment strategies.
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Supplementary Data 

Reversing Established Sepsis in Rats with Human Vasoactive Hormone Adrenomedullin and its Binding Protein
Rongqian Wu, Shinya Higuchi, Weifeng Dong, Youxin Ji, Mian Zhou, Corrado P Marini, Thanjavur S Ravikumar, and Ping Wang
Sepsis remains a critical problem leading to significant morbidity and mortality. Sepsis is the second leading cause of death among patients in noncoronary intensive care units underscoring the urgent unmet need for effective therapies. Early administration of adrenomedullin (AM) and its binding protein (AMBP-1) produce beneficial effects in models of sepsis. In this work, Wu et al. tested whether human AM and human AMBP-1 could exhibit positive effects in a model of sepsis. Results show administration of human AM/AMBP-1 markedly attenuated tissue injury, reduced proinflammatory cytokines, ameliorated intestinal-barrier dysfunction, and improved survival rate. This indicates AM/AMBP-1 could be further developed as a safe and effective therapy for patients with established sepsis.
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Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome
Bristol Sorenson, James F Jones, Suzanne D Vernon, and Mangalathu S Rajeevan
Efforts to identify diagnostic markers for CFS have been hampered because the disorder is identified by self-reported symptoms and exclusionary conditions. Complement activation has been found in subjects with CFS, specifically, increased C4a following exercise. Sorensen et al. investigated the transcriptional control of C4a in CFS subjects post-exercise. C4a generation via the lectin pathway results from C4 cleavage by mannan-binding lectin serine protease 2 (MASP2). Results from Sorensen et al. suggest that MASP2 down-regulation may act as an antiinflammatory acute-phase response in healthy subjects. The elevated level of MASP2 in CFS subjects may account for increased C4a and inflammation-mediated post-exertional malaise in CFS subjects. 
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Review Articles 

Melatonin: An Established Antioxidant Worthy of Use in Clinical Trials
Ahmet Korkmaz, Russel J Reiter, Turgut Topal, Lucien C Manchester, Sukru Oter, and
Dun-Xian Tan
Oxidative stress plays a key role in the pathogenesis of aging and many metabolic diseases. More than half of the American population is aware of antiaging therapies and currently use them in some form. Melatonin, a multifunctional indolamine, is easily synthesized in a pharmacologically pure form, counteracts most pathophysiologic steps, and displays significant beneficial actions against peroxynitrite-induced cellular toxicity. Korkmaz et al. discuss melatonin’s potential for treatment of oxidative stress due to its antioxidative and antiinflammatory properties.
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On the Physiology and Pathophysiology of Antimicrobial Peptides
Roland Pálffy, Roman Gardlik, Michal Behuliak, Ludevit Kadasi, Jan Turna, and Peter Celec
Infectious diseases are the most common cause of death in developing countries. While effective treatments are available for most infections, microbial horizontal gene transfer and the misuse of antibiotics leads to antimicrobial resistance. Antimicrobial peptides, a heterogeneous group of molecules, are part of the basic line of defense in innate immunity. Pálffy et al. review the basic physiology of antimicrobial peptides and their possible therapeutic use against antimicrobial resistance.
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Educational and Social-Ethical Issues in the Pursuit of Molecular Medicine
Panagiotis A Konstantinopoulos, Michalis V Karamouzis, and Athanasios G Papavassiliou
Molecular medicine is transforming everyday clinical practice, providing a more personalized approach to disease prevention, prognosis, and treatment. The successful translation of the
advances of biomedical research in everyday clinical practice depends largely upon our ability to train researchers and health professionals in molecular medicine, and to inform and educate the public. In this mini-review, Konstantinopoulos et al. discuss the educational and social-ethical issues raised by the advances of biomedical research as related to medical practice, outline the implications of molecular medicine, and emphasize the responsibility of academia and the pharmaceutical industry to translate the scientific knowledge to an improved quality of life.
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