January-February 2008 l Vol 14 l No 1-2

Editorial
Editorial
Margot Gallowitsch-Puerta
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Research Articles
Neoplastic Transformation of Human Small Airway Epithelial Cells Induced by Arsenic
Gengyun Wen, Gloria M Calaf, Michael A Partridge, Carlos Echiburú-Chau, Yongliang Zhao, Sarah Huang, Yunfei Chai, Bingyan Li, Burong Hu, and Tom K Hei
Arsenic is a trace element found naturally in the environment and has been recognized as a human carcinogen for over 100 years.  Chronic exposure to arsenic results in liver injury, peripheral neuropathy, keratosis and an increased incidence of cancer of the lung, skin, bladder and liver.  In an effort to understand the mechanisms by which arsenic causes cancer, scientists have attempted to develop animal models of arsenic-induced carcinogenesis. However, animals have been remarkably resistant to arsenic-induced cancers and, consequently, in vitro studies have become important as a means of studying arsenic-derived carcinogenic mechanisms.  Many in vitro models have been established using virus and gene incorporation, however, these processes affect genomic stability and intracellular signaling, which may facilitate increased transformation.  In this work, Wen et al. (2-10) established an in vitro arsenic induced transformation model by using H-TERT immortalized human small airway epithelial cells that exhibit characteristics of normal cells.  This work provides the opportunity to study phenotypic and molecular carcinogenic processes induced by arsenic in a more normal cell type.
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Insulin Decreases Inflammatory Signal Transcription Factor Expression in Primary Human Liver Cells After LPS Challenge
Marc G Jeschke, Dagmar Klein, Wolfgang E Thasler, Ulrich Bolder, Hans-Jürgen Schlitt, Karl-Walter Jauch, and Thomas S Weiss
Hepatic homeostasis is essential for survival in critically ill and burned patients.  Insulin administration improves survival and decreases infections in patients; in this study, Jeschke et al. (11-19) investigated whether primary human hepatocytes undergo a stress response and if this response could be altered by insulin administration.  Results indicate that insulin administration decreases hepatic cytokine expression in a dose dependent manner.   There was no difference in glucose concentration or cellular metabolism suggesting insulin’s beneficial effects may be due to a direct anti-inflammatory effect.  The authors conclude that primary hepatocyte cultures may be used as an in vitro model to study hepatocyte stress responses.  This work advances understanding of the molecular mechanisms involved in the protective effect of insulin in critically ill and burned patients.
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Valproic Acid Sensitizes Chronic Lymphocytic Leukemia Cells to Apoptosis and Restores the Balance Between Pro- and Antiapoptotic Proteins
Imke Bokelmann and Ulrich Mahlknecht
Chronic lymphocytic leukemia (CLL) is one of the most common leukemias in adults in the developed world.  Despite significant advances in cancer treatment, CLL remains incurable.  Accepted treatment regimens are neither curative nor associated with prolonged survival.  CLL cells exhibit impaired apoptosis leading to increased survival of circulating cells.  Valproic acid (VPA) belongs to a relatively new class of agents used for anticancer therapy.  These agents induce apoptosis in malignant cells by upregulation of proapoptotic and repression of antiapoptotic genes.  In this study, Bokelmann and Mahlknecht (20-27) further elucidate the effects of VPA on apoptosis in primary CLL cells.  Their results provide new insights into the pathogenesis of apoptosis mediated by VPA, which in the future may be of use on its own or in combination with other drugs for the treatment of CLL.
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The Antithrombotic Effect of Angiotensin-(1-7) Involves Mas-Mediated NO Release from Platelets
Rodrigo Araújo Fraga-Silva, Sergio Veloso Brant Pinheiro, Andrey Christian Costa Gonçalves, Nathalia Alenina, Michael Bader, and Robson Augusto Souza Santos
Platelets play a critical role in hemostasis and thrombosis.  Platelets become activated, adhere to injured blood vessel walls and aggregate.  This process may result in the formation of an occlusive thrombus leading to heart attacks, stroke and peripheral vascular disease.  Angiotensin-(1-7) is a member of the renin-angiotensin system and exhibits antithrombotic activity.  The mechanism has yet to be elucidated but may involve Mas, a G protein-coupled receptor for angiotensin-(1-7).  Fraga-Silva et al. (28-35) evaluated the participation of platelets and Mas receptor-related mechanisms in antithrombotic activity.  Data show that the antithrombotic effect of angiotensin-(1-7) is Mas-dependent, involves Mas-mediated NO release from platelets and is functionally important in hemostasis.  These results suggest that the angiotensin-(1-7)-Mas axis should be considered as a putative target for development of a new class of drugs used in the treatment of thrombotic diseases.
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Neutrophils in Cystic Fibrosis Display a Distinct Gene Expression Pattern
Minou Adib-Conquy, Thierry Pedron, Anne-France Petit-Bertron, Olivier Tabary, Harriet Corvol, Jacky Jacquot, Annick Clément, and Jean-Marc Cavaillon
Circulating neutrophils from cystic fibrosis patients differ from those of healthy subjects and may reflect mutations or deletions of the cystic fibrosis transmembrane regulator.  This may lead to the disturbance of neutrophils either directly or as a consequence of on-going inflammation or infection.  To investigate the genetic differences between normal and cystic fibrosis neutrophils, Adib-Conquy et al. (36-44) compared gene expression profiles from cystic fibrosis patients with those from healthy subjects.  Analysis showed an upregulation of 62 genes and downregulation of 27 genes in CF patient neutrophils.  These results demonstrate that neutrophils from cystic fibrosis patients display a modified gene expression profile associated with disease.  G-CSF spontaneously released by neutrophils could activate these cells within an autocrine loop.
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Clinical Significance of Telomerase Activity in Peritoneal Disseminated Cells: Gastrointestinal Cancers
Inna L Botchkina, David E Rivadeneira, Kevin Watkins, Martin S Karpeh, and Galina I Botchkina
Gastrointestinal cancers have the highest incidence of all cancers worldwide with over 3 million cases per year and 2.2 million deaths.  The generally asymptomatic onset makes early detection and accurate staging of gastrointestinal cancers difficult.  Despite the multitude of oncogenic pathways and tumor suppressor mechanisms, telomerase has emerged as a valuable cancer marker.  In this work, Botchkina et al. (45-54) evaluated whether telomerase activity could be used as a reliable marker for gastrointestinal cancers in exfoliated/disseminated human epithelial cells.  Results show that real-time quantitative telomeric repeat amplificaton protocol (RTQ-TRAP) assessment of telomerase activity in immunomagnetically sorted peritoneal epithelial cells has both 100% sensitivity and negative predictive value for gastrointestinal cancers.  This method may be considered as a valuable tool and useful addition to current standard diagnostic methods.
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Altered Interleukin-1 Receptor Antagonist And Interleukin-18 mRNA Expression in Myocardial Tissues of Patients with Dilatated Cardiomyopathy
Elena Westphal, Susanne Rohrbach, Michael Buerke, Hagen Behr, Dorothea Darmer, Rolf-Edgar Silber, Karl Werdan, and Harald Loppnow
Proinflammatory cytokines are potent modulators of cardiovascular diseases such as acute myocardial infarction, atherosclerosis and chronic heart failure.  Previous studies have investigated the expression of single members of the interleukin 1 and caspase families; however, expression has not been compared in patients suffering from ischemic or dilated cardiomyopathy.  Westphal et al. (55-63) analyzed the mRNA expression of the IL-1 family members and caspases-1 and -3 in nonfailing human donor heart tissue and in myocardium of patients with ischemic or dilated cardiomyopathy.  Their data provide evidence for an altered ratio of IL-1/IL-1ra in dilated cardiomyopathy patients.  This dysregulation may contribute to pathogenesis and/or progression of heart disease by modulating the otherwise balanced IL-1-mediated functions in cardiovascular cells.
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Review Articles
Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony
Guillaume Monneret, Fabienne Venet, Alexandre Pachot, and Alain Lepape
Septic syndromes represent a major although largely under-recognized healthcare problem worldwide accounting for hundreds of thousands of deaths every year.  Sepsis deeply perturbs immune homeostasis by inducing an initial systemic inflammatory response; an ensuing anti-inflammatory process acts initially as a negative feedback regulator of the inflammatory response, but ultimately becomes deleterious as nearly all immune functions are compromised.  This review (64-78) focuses on immune dysfunctions described in septic patients and on their potential use as markers on a routine standardized basis for prediction of adverse outcome or of occurrence of secondary nosocomial infections.
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Nonviral Vector Gene Modification of Stem Cells for Myocardial Repair
Husnain K Haider, Ibrahim Elmadbouh, Michel Jean-Baptiste, and Muhammad Ashraf
Myocardial infarction is the most common cause of congestive heart failure.  In the US alone, it affects approximately 5 million patients over the age of 65 with staggering economic costs.  Heart transplantation is the gold standard therapeutic intervention, but this approach is hampered by the paucity of donor organs and high risk surgery.  Therapeutic angiogenesis and myogenesis could restore perfusion of ischemic myocardium and improve contractility.  These therapeutic modalities must be considered as complementary rather than competing in order to exploit their advantages for optimal beneficial effects.  The resistant nature of cardiomyocytes to gene transfection can be overcome by ex vivo delivery of therapeutic genes to the heart using genetically modified stem cells. This article (79-86) rovides a critical appreciation of the ex vivo gene delivery approach using genetically modified stem cells to achieve angiomyogenesis for the treatment of infarcted heart.
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