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Molecular Medicine Volume 12

Articles from this Volume

Michele Barone, Daniela Spano, Maria D’Apolito, Marta Centra, Carla Lasalandra, Mario Capasso, Alfredo Di Leo, Stefano Volinia, Diego Arcelli, Natalia Rosso, Antonio Francavilla, Claudio Tiribelli, and Achille Iolascon

Hepatitis B virus (HBV) is one of the major etiological factors responsible for the development of hepatocellular carcinoma (HCC).  The vast majority of HCC worldwide is attributed to HBV or hepatitis C virus infection.  However, the specific mechanism by which HBV induces hepatocarcinogenesis remains unclear.  In order to study the early events leading up to liver cancer, Barone et al. (115-123) examined the gene expression profiles of three month old wild type mice and transgenic mice, containing HBV sequences.  The transgenic mice exhibited 45 significantly differentially expressed genes, specifically, the up-regulation of the anti-apoptotic gene NuprI and the down-regulation of the pro-apoptotic gene Bnip3.  These results are supported by in vitro analysis.  These findings can begin to unravel the molecular mechanisms of hepatitis B virus induced hepatocellular carcinoma.

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Posted by MolMed Editor on Jun 3, 2006 12:00 AM CDT
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