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Molecular Medicine Volume 12

Articles from this Volume

Runkuan Yang, Tomoyuki Harada, Kevin P Mollen, Jose M Prince, Ryan M. Levy, Joshua A Englert, Margot Gallowitsch-Puerta, LiHong Ya G Harbrecht, Timothy R Billiar, and Mitchell P Fink

Trauma is the fifth leading cause of death among people of all ages living in the United States and the leading cause of death among people under 45 years of age.  Intestinal barrier dysfunction frequently occurs following hemorrhagic shock and resuscitation, potentially as a result of dysregulation of the pro-inflammatory cytokine high mobility group B1 (HMGB1).  Yang et al. (105-114)provide data that treatment with anti-HMGB1 antibodies improved survival in a rodent model of hemorrhagic shock and resuscitation as well as diminished the development of hyperpermeability of the gut.  Human trauma victims exhibited higher plasma concentrations of HMGB1 compared with control subjects. These data support the notion that HMGB1 is a mediator of hemorrhagic shock and resuscitation-induced gut barrier dysfunction and suggest that anti-HMGB1 antibodies warrant further study as a therapeutic to ameliorate the morbidity of hemorrhagic shock and resuscitation in trauma patients.

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Posted by Leah Caracappa on Jun 2, 2006 12:00 AM CDT
Valeria R Mas, Daniel G Maluf, Kellie J Archer, Kenneth Yanek, Bridgette Williams, and Robert A Fisher

Liver transplantation is a curative treatment for early stages of one of the most common liver cancers in the world, hepatocellular carcinoma (HCC). Preoperative evaluation, to determine the prognosis of the disease and establish the best therapeutic options for the patient is critical. On pages 97-104, Mas et al. use microarray technology to show a distinctive pattern of gene expression between early and advanced hepatitis C virus-HCC. These results suggest that gene expression profiling could improve pre-liver transplant staging and be an ancillary tool for better selecting HCC patient candidates for liver transplantation.

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Posted by Leah Caracappa on Jun 1, 2006 12:00 AM CDT
Jose M Prince, Ryan M Levy, John Bartels, Arie Baratt, John M Kane, III, Claudio Lagoa, Jonathan Rubin, Judy Day, Joyce Wei, Mitchell P. Fink,Sanna M Goyert, Gilles Clermont,Timothy R Billiar, and Yoram Vodovotz

The inflammatory phenotype of genetically modified mice is complex, and the role of Gram-negative lipopolysaccharide (LPS) in acute inflammation induced by surgical trauma is both complex and controversial.  Here, Prince et al. (88-96) sought to determine if a mathematical model of acute inflammation could elucidate both the phenotype of CD14- deficient mice following LPS administration and the role of LPS in trauma/hemorrhage-induced inflammation.  A mathematical model calibrated in wild type mice subjected to LPS was re-calibrated in CD14-deficient mice, revealing several specific differences at both the cellular and molecular levels.  These models suggest that LPS-CD14 responses do not play a role in inflammation in surgical trauma and demonstrate a novel use of combined in silico and in vivo methods to elucidate the complex inflammatory phenotype of genetically modified animals.

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Posted by Leah Caracappa on May 2, 2006 12:00 AM CDT
Yong-Qiang Jiang,Hai-Rong Wang,Han-Ping Li,Huai-Jie Hao,Yu-Ling Zheng, and Jun Gu

Hepatocellular carcinoma (HCC) is among the most common and fatal malignancies worldwide with a mortality rate greater than ninety-four percent. Studies have shown that generating specific monoclonal and genetically engineered antibodies can improve tumor targeting. However, HCC has been unresponsive to these therapies due to the high molecular weight, low tissue penetration and poor cellular uptake of the antibodies. Here, Jiang et al. (81-87) isolate a small peptide, which when fused to the superantigen toxic shock syndrome toxin-1 (TSST-1) binds to hepatoma cells in vitro with higher affinity than TSST-1 alone. Additionally, the fusion protein achieves more significant tumor inhibition through T lymphocyte activation than TSST-1 alone both in vitro and in vivo. These results indicate that this peptide and its potential derivatives may be developed into highly specific cancer therapeutic agents.

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Posted by Leah Caracappa on May 1, 2006 12:00 AM CDT
Serhat Erbayraktar, Nihal de Lanerolle, Alain de Lotbinière, Jonathan P S. Knisely, Zubeyde Erbayraktar, Osman Yilmaz, Anthony Cerami, Thomas R Coleman, and Michael Brines

Gamma knife radiosurgery is a non-invasive treatment for brain tumors and vascular malformation. Although the non-invasive nature of this technique minimizes tissue damage associated with conventional surgery, even low-dose radiation initiates acute and chronic injury with potential morbidity and mortality. The increased longevity following radiation therapy necessitate the identification of methods to prevent radiotherapy-induced collateral tissue damage. Erbayraktar et al. have developed carbamylated erythropoietin (CEPO), which reduces inflammation and promotes healing without the negative hematopoietic activity of erythropoietin (EPO). On pages 74-80, Erbayraktar et al. demonstrate that CEPO given in advance of and for a short time following necrotizing gamma irradiation significantly reduces both the acute behavioral abnormalities and the ultimate extent of necrosis following high-dose radiation injury. These findings extend the types of injury for which administration of a tissue-protective cytokine, such as CEPO, may provide a benefit.

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Posted by Leah Caracappa on Apr 2, 2006 12:00 AM CST
Rui Zheng, George Pan,Bjoern, M Thobe, Mashkoor A.Choudhry, Takeshi Matsutani, T S Anantha Samy, Shih-Ching Kang, Kirby I. Bland, and Irshad H Chaudry

Hypoxia, a major consequence of trauma and hemorrhage, incites an adverse proinflammatory cytokine response in young male mice, but not in proestrus female mice. In humans, males exhibit a higher trauma-related mortality rate when compared with females. Although this etiology is not well understood, elevated plasma levels of the proinflammatory cytokine IL-6 are a reasonably accurate predictor of mortality. In order to further understand the dimorphic immune response seen in males and proestrus females subsequent to hypoxia, Zheng et al. (65-73) have explored the signaling cascade responsible for the release of proinflammatory cytokines such as IL-6 and TNF. Their results indicate that a TLR4-dependent mechanism activates innate immune responses in mice following hypoxia. Additionally, the regulation of MyD88 and Src in Kupffer cells appear different in males and proestrus females. These results correlate with gender dimorphic IL-6 release. Taken together these data demonstrate that gender dimorphism is evident in the intracellular signaling cascades that regulate the innate immune response following hypoxia.

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Posted by Leah Caracappa on Apr 1, 2006 12:00 AM CST
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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Posted by MolMed Editor on Mar 3, 2006 12:00 AM CST
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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Posted by MolMed Editor on Mar 2, 2006 12:00 AM CST
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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Posted by MolMed Editor on Mar 1, 2006 12:00 AM CST
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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Posted by MolMed Editor on Feb 2, 2006 12:00 AM CST
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