Jan-Mar 2006 l Vol 12 l No 1-3

Matriptase: Potent Proteolysis on the Cell Surface
Karin List, Thomas H Bugge, and Roman Szabo
Matriptase, a type II transmembrane serine protease and its cognate transmembrane inhibitor, hepatocyte growth factor activator inhibitor (HAI)-1 play physiological roles in the epithelium, epidermis, and hair follicle growth.  Matriptase and HAI expression are frequently dysregulated in human cancer and when unopposed by HAI-1, matriptase promotes carcinogenesis and metastatic dissemination in animal models.  In an invited review, List et al. (pages 1-7) describe the biochemistry, physiology, and pathology of this complex cell surface serine protease.
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Selective Inhibition of the Human tie-1 Promoter with Triplex-Forming Oligonucleotides Targeted to Ets Binding Sites
Peter W Hewett, Emma L Daft, Charles A Laughton, Shakil Ahmad, Asif Ahmed, and J Clifford Murray
Angigogenesis is essential for the growth of tumors and the development of hematological metastases.   Tie receptors, which are up-regulated during angigogeneis, play a fundamental role in vascular remodeling.  Inhibition of Tie receptors disrupts angigogenesis and can subsequently prevent tumor growth.  Hewett et al. (pages 8-16) provide evidence that an anti-gene approach, which targets Ets binding sites can selectively inhibit Tie-1 gene promoter activity in endothelial cells.  As similar Ets binding sites are important in the regulation of several endothelial restricted genes, this approach may have broad therapeutic potential for cancer and pathologies involving endothelial cell proliferation and dysfunction.
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Phytosphingosine Stimulates the Differentiation of Human Keratinocytes and Inhibits TPA-Induced Inflammatory Epidermal Hyperplasia in Hairless Mouse Skin
Sujong Kim, Il Hong, Jung Sun Hwang, Jin Kyu Choi, Ho Sik Rho, Duck Hee Kim, Ihseop Chang, Seung Hun Lee, Mi-Ock Lee, Jae Sung Hwang
Psoriasis and atopic dermatitis are chronic skin conditions resulting in dry, scaly skin patches for which there is no cure.  These conditions are characterized by hyperproliferation and aberrant differentiation of keratinocytes as well as infiltration of inflammatory cells to the site.  Phytosphingosine (PS) is an activator for peroxisome proliferator-activated receptors (PPARs), which function in skin barrier homeostasis by regulating cell growth, terminal differentiation, and inflammatory response.  In a mouse model of irritant contact dermatitis PS reduces epidermal thickening, edema, and infiltration of inflammatory cells into the dermis.  Kim et al. (pages 17-24) provide insight to the multiple regulatory roles of PS in epidermal homeostasis and indicate the potential use of PS as a therapeutic agent for the treatment of inflammatory and hyperproliferative cutaneous diseases.
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Peeling Off the Hidden Genetic Heterogeneities of Cancers Based on Disease-Relevant Functional Modules
Jian-zhen Xu, Zheng Guo, Min Zhang, Xia Li, Yong-jin Li, and Shao-qi Rao
Current characterization of human diseases lumps together molecularly distinct diseases with the same phenotypes, such as cancers.  Morphological or pre-treatment characteristics do not completely account for clinical behaviors of complex diseases such as cancers; for example, patients with the similar phenotypes often show different responses to drug treatment and have different prognoses.  On pages 25-33, Xu et al. define a putative computational disease module and validate its ability to correctly partition samples in two large cancer datasets, which results in highly accurate partitions corresponding with clinical phenotypes.  Additionally, the application of a disease module to a dataset of diffuse large B-cell lymphomas (DLBCL) predicted two different five-year rates which correlated with survival.  This computational strategy is a promising approach for understanding the modular mechanisms of complex human diseases such as cancers.
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Supplement 1 PDF, Supplement 2 PDF, Supplement 3 PDF, Supplement 4 PDF,

Predifferentiated Embryonic Stem Cells Prevent Chronic Pain Behaviors and Restore Sensory Function Following Spinal Cord Injury in Mice
Wesley A Hendricks, Elena S Pak, J Paul Owensby, Kristie J Menta, Margarita Glazova, Justin Moretto, Sarah Hollis, Kori L Brewer, and Alexander K Murashov
Chronic central pain occurs in the majority of patients following spinal cord injury and is severely compromising, in both adjustment following injury and the patients' quality of life. Numerous therapies have been explored, however, adverse side effects, the potential for addiction or tolerance to pharmacological modalities, and the ineffectiveness of these agents for severe chronic central pain leads to a need for more efficacious and safer long-term approaches. Using a mouse model of spinal cord injury, Hendricks et al. (pages 34-46) show that pre-differentiated embryonic stem cells act in a neuroprotective manner and provide antinociceptive and therapeutic effects following excitotoxic spinal cord injury.
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Effect of Hepatitis C Virus Core Protein on the Molecular Profiling of Human B Lymphocytes
Chuan-ging Wu, Anuradha Budhu, Sheng Chen, Xiaoling Zhou, Nicholas C. Popescu, Kristoffer Valerie, and Xin Wei Wang
Hepatitis C Virus (HCV) is the major cause of cirrhosis and can potentially lead to hepatocellular carcinoma.  HCV can infect and replicate in B lymphocytes. However, how HCV induces B cell lymphoproliferative disorders, and whether HCV core protein plays a role in B cell immunity, is still unclear.  As described on pages 47-53, Wu et al. used gene expression profiling to explore the molecular effects of HCV core protein on human B cells.  Several clusters of differentially expressed genes were identified in human B lymphocytes expressing HCV core protein, suggesting a potential impairment of antigen processing and presentation.  These findings may provide insights into hepatitis C virus infection in B lymphocytes.
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