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Molecular Medicine Volume 12

Articles from this Volume

Jimena V Lavandera, Victoria E Parera, Alcira Batlle, and Ana María Buzaleh

Porphyrias are a group of inherited or acquired metabolic disorders which result from decreased enzymatic activity in the heme pathway, clinically manifested by acute attacks and/or cutaneous symptomatology. Cytochrome P-450 (CYP) enzymes including CYP2D6, participate in the metabolism of some porphyrinogenic drugs leading to the de-regulation of heme biosynthesis. The presence of CYP2D6 polymorphisms in porphyric patients could influence the triggering of the disease if these individuals received a precipitating agent that is metabolized by CYP2D6. To investigate the CYP2D6 polymorphisms in porphpyric patients, Lavandera et al.(259-263) analyzed healthy and porphyric subjects and individuals with high iron levels. Results indicated that the CYP2D6*3 and CYP2D6*4 alleles might also have a significant influence on the individual susceptibility to foreign substances and the triggering of porphyria. Predictive genotyping for CYP2D6 in porphyric patients holds promise as a method to improve the clinical efficacy of drug therapy and to personalize drug administration for these patients.

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Posted by Leah Caracappa on Oct 5, 2006 12:00 AM CDT
Zhenzhong Zheng and Zhengxiang Liu

Cardiovascular disease is the leading cause of death in the United States for both men and women.  Ischemic heart disease, resulting in decreased oxygen flow to the heart, develops as a result of coronary artery lesion formation.  In many cases additional vessels develop as an adaptive response to ameliorate the function of the damaged heart, raising the possibility that therapeutic angiogenesis may be beneficial in the treatment of ischemia. CD151 is a potent growth factor that promotes neovascularization and angiogenesis in vitro, but its activity in vivo has not been tested.  Here, Zheng et al. (214-220) used a model of myocardial infarction (MI) in rats to determine if and by what mechanism CD151 promoted neovascularization after MI.  Results confirm that CD151 can promote neovascularization and improve ventricular function in a rat model of MI.  Further, results indicate that CD151 elicits these beneficial effects by activating the P13K pathway without effecting ischemia-induced expression of vascular endothelial growth factor (VEGF), another well-known pro-angiogenic factor.  These results suggest that CD151 may be a potential therapeutic reagent for treating ischemia by inducing angiogensis.

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Posted by Leah Caracappa on Oct 4, 2006 12:00 AM CDT
Tiziano Baroni, Catia Bellucci, Cinzia Lilli, Furio Pezzetti, Francesco Carinci, Ennio Becchetti, Paolo Carinci, Giordano Stabellini, Mario Calvitti, Eleonora Lumare, and Maria Bodo

Craniofacial malformations and orofacial clefting are the most commonly occurring birth defects in humans.  Failure of the facial processes or palatal shelves to fuse properly results in clefts of the lip and/or palate. The palatogenesis process is modulated by a complex interplay of various molecules and growth factors, and normal orofacial development depends on its proper execution.  At pharmacological doses, retinoic acid (RA) induces cleft palate in newborns of many species.  Here, Baroni et al. (237-245) compare the effects of RA on fibroblasts isolated from normal and cleft palate subjects.  Results indicate that aberrant interactions between signaling systems as well as receptor expression levels may alter cross-talk required to produce the normal phenotype in humans. These conclusions extend previous findings and contribute a more detailed picture of cleft lip and palate formation which may lead to the identification of therapeutic targets.

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Posted by Leah Caracappa on Oct 3, 2006 12:00 AM CDT
Hua Xiong, Ling Li, Qin-Chuan Liang, Hui-Jie Bian, Juan Tang, Qin Zhang, Li Mi, and Zhi-Nan Chen

Colorectal cancer has been treated with chemotherapy for over 50 years. While initial responses to chemotherapeutic regiments are frequently positive, their duration is often brief and the majority of patients die shortly after relapse. In contrast to chemotherapies, antibody-based therapies can be designed to target specific tumor cells. Monoclonal antibodies have shown promising results in phase I and II clinical trials, however, treatment for human colorectal cancer is still inadequate and the discovery of new treatments is necessary. Xiong et al. (229-236) present in vitro and in vivo characteristics of the chimeric antibody hCAb. Results illustrate that hCAb has high specificity for human colorectal cancer and does not react with normal cells. The antigenic target for hCAb is expressed stably and homogenously by colorectal cancer cells and is not highly detected in serum of cancer patients, thus avoiding antibody immunodepletion). These data indicate hCAb is a promising new anti-cancer agent which may also be used in radioimmunotherapy.

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Posted by Leah Caracappa on Oct 2, 2006 12:00 AM CDT
Emese Tóth-Zsámboki, Eszter Horváth, Katarina Vargova, Eszter Pankotai, Kanneganti Murthy, Zsuzsanna Zsengellér, Tamás Bárány, Tamás Pék, Katalin Fekete, Róbert Gábor Kiss, István Préda, Zsombor Lacza, Domokos Gerö, and Csaba Szabó

Coronary reperfusion therapy has been established as a standard for the management of myocardial infarction that affects ventricle contractility. However, reperfusion may trigger tissue damage resulting in injuries such as myocardial stunning, arrhythmias, and microvascular dysfunction. Although the mechanism of reperfusion injury has been extensively studied, limited therapeutic applications have been developed. Poly(ADP-ribose) polymerase (PARP), an abundant nuclear chromatin-bound DNA repair enzyme, plays a key role in myocardial reperfusion injury by inducing mitochondrial dysfunction and necrotic cell death. Here, Toth-Zsamboki et al. (221-228) show that reperfusion-related stress triggers DNA damage, leading to activation of PARP in circulating leukocytes, followed by subsequent activation of anti-apoptosis inducing factor (AIF). These results directly demonstrate PARP activation in human myocardial infarction. These observations have therapeutic implications since PARP inhibitors have recently been developed and have beneficial effects in ischemia/reperfusion models. PARP inhibitors administered prior to reperfusion may provide multiple benefits including myocyte salvage and improved survival in humans suffering from myocardial infarction.

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Posted by Leah Caracappa on Oct 1, 2006 12:00 AM CDT
Catherine H Valentine, Judith Hellman, Laura K Beasley-Topliffe, Aranya Bagchi, and H Shaw Warren

Many studies report that immunoglobulin directed to rough mutant bacteria provide broad protection against challenge with strains of Gram-negative bacteria. Protection was initially thought to occur through binding of immunoglobulin to bacterial lipopolysaccharide (LPS); however, no such observation has been published, raising the question of whether the protection is mediated by binding to bacterial outer membrane proteins. Identification of the protective mechanism would facilitate development of broadly protective human monoclonal antibodies for treating sepsis. Valentine et al. (252-258) tested two bacterial outer membrane proteins, murein lipoprotein (MLP) and peptidoglycan-associated lipoprotein (PAL) to determine if passive immunization directed at them would protect mice from Gram-negative sepsis. Neither monoclonal nor polyclonal IgG directed to MLP or PAL conferred survival protection in three different models of sepsis: cecal ligation and puncture, an infected burn model, and an infected fibrin clot model mimicking peritonitis. These studies suggest that a different mechanism of protection is involved.

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Posted by Leah Caracappa on Sep 4, 2006 12:00 AM CDT
Cristina Lapucci, Diego Pomarè Montin, Massimo Pandolfo, and Matteo Bertelli

Lesch-Nyhan syndrome (LNS) is a rare, recessive, X-linked disorder, and therefore nearly all reported cases occur in males. LNS is caused by a deficiency of the enzyme hypoxanthine-guanine-phosphoribosyltransferase (HPRT) and symptoms include overproduction of uric acid and neurological and behavioral problems. While several screening methods for HPRT enzymatic activity or genetic integrity exist, these approaches are technically challenging and impractical for routine clinical use in healthy LSN carriers. Here, Lapucci et al. (246-251) describe a new approach for the identification of carriers with large deletions in the HPRT gene. This rapid and straightforward diagnostic approach may allow for more definitive detection of LNS carriers possessing larger deletions.

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Posted by Leah Caracappa on Sep 3, 2006 12:00 AM CDT
Shin Hirayama, Takeshi Shiraishi, Takayuki Shirakusa, Takao Higuchi, and Edmund J Miller

In the past decade lung transplantation has become a more widely available therapeutic option. The recent development of preservation solutions and other techniques for organ procurement facilitates more remote organ donation and the increased capability to use marginal donor lungs.  However, preservation-related injury is still unavoidable and can compromise the integrity of candidate organs.  Ischemia-reperfusion injury after transplantation induces substantial tissue inflammatory responses and activation of vascular endothelial cells.  A variety of chemoattractants are release which recruit neutrophils into the lung. During this non-specific insult, neutrophils play a key role through a number of mechanisms including release of reactive oxygen species and proteolytic enzymes.  Here, Hirayama et al. (208-213) sought to determine if neutrophil migration correlated with lung allograft rejection.  Results suggest that neutrophils may play a promoting role in the development of allograft rejection, and blockage of neutrophil migration may suppress acute lung allograft rejection.

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Posted by Leah Caracappa on Sep 2, 2006 12:00 AM CDT
Tobias Hirsch, Sebastian von Peter, Grzegorz Dubin, Dominik Mittler, Frank Jacobsen, Markus Lehnhardt, Elof Eriksson, Hans-Ulrich Steinau, and Lars Steinstraesser

More than 50,000 patients suffering from burn injuries are hospitalized each year in the US. Many of these victims experience wound healing impairment and infection, which remain among the most evident problems in this patient population. Topical treatment of burn wounds with synthetic agents is expensive and ineffective due to high production costs and limited biological half-life. New concepts and therapeutic strategies are needed to improve care and speed recovery. Here, Hirsh et al. (199-207) use adenoviral mediated gene transfer to deliver therapeutic genes into burn wounds to over-express wound healing factors. The authors’ results demonstrate that transient gene transfer to epidermal primary cells and established cell-lines as well as in vivo gene transfer is feasible. The authors conclude that while future studies are necessary, adenoviral transfection holds therapeutic potential as a treatment for chronic and burn wounds.

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Posted by Leah Caracappa on Sep 1, 2006 12:00 AM CDT