September-October 2008 l Vol 14 l No 9-10

Commentary
Protein Complex, Gene, and Regulatory Modules in Cancer Heterogeneity
Nikolaos A Papanikolaou and Athanasios G Papavassiliou
Page 543 l View article: PDF (76 KB) HTML

Research Articles
Episode-Specific Differential Gene Expression of Peripheral Blood Mononuclear Cells in Rapid Cycling Supports Novel Treatment Approaches
Martin Begemann, Derya Sargin, Moritz J Rossner, Claudia Bartels, Fabian Theis, Sven P Wichert, Nike Stender, Benjamin Fisher, Swetlana Sperling, Sabina Stawicki, Anne Wiedl, Peter Falkai, Klaus-Armin Nave, and Hannelore Ehrenreich
Rapid cycling syndrome, characterized by at least four episodes of depression or mania per year, is present in 10-30% of the bipolar population. The molecular mechanisms underlying bipolar disorder remain unknown. Begemann et al. (546-552) hypothesized cycling alterations in brain function may be reflected in systemic changes with a molecular genetic basis. Molecular signatures of manic and depressed states in peripheral blood, while not disease-inducing, may shed light on similar cyclic alterations in the brain. The authors examined peripheral gene expression in an individual during recurrent stages of disease. Dysregulated gene transcripts included genes involved in the synthesis and metabolism of prostaglandin D2. Prostaglandins, associated with inflammation, are also known to induce hibernation in certain animals. Based on this finding the authors conducted a clinical experiment, treating the patient with a cyclooxygenase inhibitor celecoxib (off-label). In contrast to prior pharmacological attempts to treat this patient (over 17 years), targeting prostaglandin synthesis resulted in a reduced clinical severity rating of both depressed and manic phases. This encouraging result is compatible with a mediator role of prostaglandins in this psychiatric disease.
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Supplementary Data: PDF (300 KB)

Temporal Cytokine Profiles in Severely Burned Patients: A Comparison of Adults and Children
Celeste C Finnerty, Marc G Jeschke, David N Herndon, Richard Garnelli, Nicole Gibran, Matthew Klein, Geoff Silver, Brett Arnoldo, Daniel Remick, Ronald G Tompkins, and the Investigators of the Inflammation and the Host Response Glue Grant
The severe hypermetabolic response following burn injury correlates with age and may be a major contributor to higher morbidity and mortality rates observed in adult burn patients compared with children. Finnerty et al. (553-560) hypothesized the factor linking age and morbidity was the inflammatory response. The authors compared plasma cytokine profiles following a severe burn in adults and children. Findings show cytokine profiles in pediatric patients differ compared with those in adult patients. These results may provide insight with respect to the higher morbidity rate in adults and suggest children and adults may benefit from different post-burn therapeutic interventions. 
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HSP70 Is Associated with Endothelial Activation in Placental Vascular Diseases
Yanxia Liu, Nannan Li, Li You, Xin Liu, Hongyan Li, and Xin Yang
The placenta plays a pivotal role in the acceptance of the fetal-placental unit by the maternal immune system.  Placental vascular disease (PVD) induces complications in human pregnancy such as preeclampsia and fetal intrauterine growth restriction.  Endothelial cell injury and activation in the placenta occur during PVD and in this work Liu et al. (561-566) investigated risk factors and signal transcription pathways involved.  Results indicate heat shock protein 70 may mediate endothelial activation and play a role in PVD pathogenesis.
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Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling
William R Parrish, Mauricio Rosas-Ballina, Margot Gallowitsch-Puerta, Mahendar Ochani, Kanta Ochani, Li-Hong Yang, LaQueta Hudson, Xinchun Lin, Narev Patel, Sarah M Johnson, Sangeeta Chavan, Richard S Goldstein, Christopher J Czura, Edmund J Miller, Yousef Al-Abed, Kevin J Tracey, and Valentin A Pavlov
Excessive proinflammatory cytokine production and release into circulation by immune cells is associated with septic shock, sepsis and other disorders. Exacerbated release of proinflammatory cytokines and lethality during endotoxemia and sepsis can be controlled by the efferent vagus nerve-based “cholinergic antiinflammatory pathway.”  The α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) is an essential component of this pathway. Choline, an essential nutrient, is a selective natural α7nAChR agonist. Parrish et al. (567-574) studied the antiinflammatory potential of choline in models of endotoxemia and sepsis. The data characterize the antiinflammatory efficacy of choline and demonstrate the modulation of the proinflammatory cytokine tumor necrosis factor release by choline requires α7nAChR-mediated signaling. These results suggest choline may have therapeutic potential in the treatment of sepsis and other inflammatory disorders.
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Genome-Wide Association Scan Identifies Candidate Polymorphisms Associated with Differential Response to Anti-TNF Treatment in Rheumatoid Arthritis
Chunyu Liu, Franak Batliwalla, Wentian Li, Annette Lee, Ronenn Roubenoff, Evan Beckman, Houman Khalili, Aarti Damle, Marlena Kern, Richard Furie, Josée Dupuis, Robert M Plenge, Marieke JH Coenen, Timothy W Behrens, John P Carulli, and Peter K Gregersen
Tumor necrosis factor (TNF) is a key regulator of the inflammatory cascade in rheumatoid arthritis (RA) and several other inflammatory diseases. TNF antagonists have been approved by the FDA to treat arthritis and their therapeutic utility is well established.  However, efficacy in patients is unpredictable with approximately one third of patients exhibiting minimal or no response. Therefore, the prediction of response to anti-TNF treatment for RA is a pressing clinical problem. Liu et al. (575-581) conducted a genome wide association study on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of the Autoimmune Biomarkers Collaborative Network (ABCoN). Several SNPs show significant association with the change in disease activity score (DAS28) observed in RA patients over a 14-week period of treatment. While additional data sets are necessary to replicate and support this data, these results suggest SNP analysis may be useful to predict response to anti-TNF therapy.
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Supplementary Data l View PDF (88 KB)

The Ubiquitin-Proteasome Pathway Mediates Gelsolin Protein Downregulation in Pancreatic Cancer
Xiao-Guang Ni, Lu Zhou, Gui-Qi Wang, Shang-Mei Liu, Xiao-Feng Bai, Fang Liu,  Maikel P Peppelenbosch, and Ping Zhao
Pancreatic cancer is a virulent malignancy with an overall five-year survival rate of only 3-5%.  Despite this poor prognosis, relatively little is known regarding the mechanisms involved in this disease. Pancreatic tumor cells characteristically display a disturbed cytoskeleton and in this work, Ni et al. (582-589) compared proteomes from pancreatic cancer samples with controls. The gelsolin protein, capable of severing and capping actin filament cytoskeletal structural proteins, was diminished in the cancerous samples. Gelsolin mRNA was not downregulated in cancerous samples, suggesting posttranscriptional mechanisms may mediate low gelsolin protein levels. Further investigation into gelsolin degradation in cancer progression may have clinical significance in diagnosis, treatment and prognosis of pancreatic and other cancers.
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Protective Effects of Epigallocatechin Gallate on Colon Preneoplastic Lesions Induced by 2-Amino-3-Methylimidazo[4,5-f]Quinoline in Mice
Jun-Hua Yuan, Yan-Qing Li, and Xiao-Yun Yang
Colorectal cancer causes significant mortality in Western countries and is the second most common fatal cancer site. Epigallocatechin gallate (EGCG), an active ingredient in green tea, exhibits anti-carcinogenic effects. Yuan et al. (590-598) investigated the potential of EGCG in the prevention of early morphological alterations of colon carcinogenesis. Results indicate that dose-response administration of EGCG results in increasing preventive effects in an animal model of colon cancer. This EGCG polyphenol from green tea may offer an effective and inexpensive preventive strategy for patients predisposed to colon cancer.
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Identification of Marker Genes for Differential Diagnosis of Chronic Fatigue Syndrome
Takuya Saiki, Tomoko Kawai, Kyoko Morita, Masayuki Ohta, Toshiro Saito, Kazuhito Rokutan, and Nobutaro Ban
Chronic fatigue syndrome (CFS) is a clinically defined condition characterized by long-lasting disabling fatigue. The mechanisms involved in CFS remain unknown and therefore biomarkers for pathological fatigue assessment do not exist. Saiki et al. (599-607) compared gene expression profiles from CFS subjects with control subjects and identified nine differentially regulated genes in CFS. This expression profile was subsequently tested in additional CFS and non-CFS subjects with long lasting fatigue, correctly classifying over 90% of CFS and non-CFS patients. These results suggest this gene cluster may be useful in detecting pathological responses in CFS patients and for differential diagnosis of this syndrome.
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Immune Dysregulation and Tumor-Associated Gene Changes in Recurrent Respiratory Papillomatosis: A Paired Microarray Analysis
James A DeVoti, David W Rosenthal, Rong Wu, Allan L Abramson, Bettie M Steinberg, and Vincent R Bonagura
Recurrent respiratory papillomatosis (RRP) is primarily caused by human papillomavirus types 6 and 11. The viruses induce benign tumor growth in the larynx causing significant morbidity and occasionally mortality. Standard treatment is repeated surgery to remove papillomas that, because of their location in the airway, cause significant morbidity and on occasion mortality. The interval between surgical intervention varies between patients, ranging from 3 weeks to several years.  In order to identify novel targets for future therapy, DeVoti et al. (608-617) established transcriptional profiles for actively growing papillomas. Results support the role of a systemic TH2-like adaptive immune response in RRP, suggest a role for altered innate immunity and identify novel targets for future therapeutic interventions in RRP.
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Supplementary Data l View PDF (36 KB)

Surface Expression of Bcl-2 in Chronic Lymphocytic Leukemia and Other B-Cell Leukemias and Lymphomas Without a Breakpoint t(14;18)
Brian A McCarthy, Erin Boyle, Xue Ping Wang, Dorothy Guzowski, Santanu Paul, Rosa Catera, Joshua Trott, Xiao-jie Yan, Carlo M Croce, Rajendra Damle, Sophia Yancopoulos, Bradley T Messmer, Martin Lesser, Steven L Allen, Kanti R Rai, and Nicholas Chiorazzi
Bcl-2 has been widely studied in oncology since its discovery in follicular lymphoma cells. Bcl-2 can locate as an integral mitochondrial membrane component where its primary role is to block apoptosis by maintaining membrane integrity. In this work, McCarthy et al. (618-627) demonstrate the presence of Bcl-2 on the surface membrane of human chronic lymphocytic leukemia B cells. Although the function of cell surface-associated Bcl-2 is not clear, its appearance primarily on cells undergoing apoptosis suggests a relationship between surface membrane re-localization and the apoptotic process.
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Supplementary Data l Figures 1-4 l PDF (4.9 MB)

Burn Injury-Induced Alterations in Wound Inflammation and Healing Are Associated with Suppressed Hypoxia Inducible Factor 1-α Expression
Martin G Schwacha, Eike Nickel, and TanJanika Daniel
A major complication associated with burn injury is delayed wound healing. Although burn patient care has improved, problems develop which are often associated with the healing process. While healing of the burn injury site is essential, healing of distal injury sites caused by surgical interventions and other processes are also important. In this work, Schwacha et al. (628-633) explored the mechanisms of distal wound healing and found that reduced levels of hypoxia inducible factor (HIF)-1α contribute to the impaired wound-healing response post-burn. 
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Viability-Dependent Promoting Action of Adult Neural Precursors in Spinal Cord Injury
Daniele Bottai, Laura Madaschi, Anna M Di Giulio, and Alfredo Gorio
There currently is no therapy for spinal cord injury, leaving patients permanently disabled. The observation that neural stem cells (NSCs) may be useful for treating degenerative brain conditions prompted Bottai et al. (634-644) to assess the effects of adult NSC transplantation in a model of spinal cord injury (SCI). NSCs administered either by intravenous injection or direct transplantation into the spinal cord significantly improved recovery of hind limb function and attenuated degeneration. Intravenous administration of NSCs yielded a more significant recovery compared with intraspinal administration. These results indicate adult NSC cellular therapy via intravenous administration may represent a useful treatment for spinal cord injury.
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Review Articles
No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation
Steven C Gribar, Ward M Richardson, Chhinder P Sodhi, and David J Hackam
Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. Disease occurs when the intestinal epithelial barrier breaks down. However, the mechanisms leading to barrier breakdown and subsequent inflammation are controversial. Gribar et al. (645-659) review recent work on this topic and identify essential areas for further study.
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