University of Louisville

About: University of Louisville is a education organization based out in Louisville, Kentucky, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 24600 authors who have published 49248 publications receiving 1573346 citations. The organization is also known as: UofL.

Lessons learned from the Sunbelt Melanoma Trial

Abstract: The Sunbelt Melanoma Trial is an ongoing multicenter prospective randomized trial that involves 79 centers and over 3600 patients from across the United States and Canada. This is one of the first large randomized studies to incorporate molecular staging using reverse transcriptase polymerase chain reaction (RT-PCR). While the results related to the primary endpoints of the study are not yet available, several analyses have shed light on many aspects of sentinel lymph node (SLN) biopsy and melanoma prognostic factors. In particular, we have developed a practical definition of sentinel nodes based on the degree of radioactivity. We have established the low rate of postoperative complications associated with SLN biopsy as compared to complete lymph node dissection. We have identified factors that predict the presence of SLN metastases. In contrast, we have been unable to identify factors that indicate a low risk of non-sentinel node metastases in patients with a positive sentinel node, suggesting that completion lymphadenectomy is appropriate for such patients. We have further established the value of identifying interval or in-transit sentinel nodes, which can be the only site of nodal metastasis. We have evaluated the particular challenges associated with SLN biopsy of head and neck melanomas, have evaluated the patterns of early recurrence, and have identified an interesting correlation between increasing patient age and a number of prognostic factors. Future analyses will evaluate the benefit of early therapeutic lymphadenectomy and early institution of adjuvant interferon alfa-2b therapy, as well as the validity of molecular staging.

Hydroxychloroquine Reverses Thrombogenic Properties of Antiphospholipid Antibodies in Mice

Abstract: Background Previous studies have demonstrated that human monoclonal and polyclonal anticardiolipin antibodies have thrombogenic properties in vivo. Using such a model in which these antibodies have been shown to increase both the size of an induced thrombus and the duration of time in which such a clot lasts, we investigated whether hydroxychloroquine alters the dynamics of such thrombus formation. Methods and Results Three groups of nine mice were injected with purified immunoglobulin G (IgG) from a patient with the antiphospholipid syndrome (IgG-APS) and then fed with hydroxychloroquine at various doses (100, 6, and 3 mg/kg body wt). Three control groups of mice were also studied, including mice injected with IgG-APS and then fed with placebo, as well as two other groups injected with IgG from normal human serum and fed either hydroxychloroquine or placebo. A standardized thrombogenic injury was subsequently induced in the femoral vein of each mouse and the area (size) of thrombus measured as well as th...

Meeting Report: Hazard Assessment for Nanoparticles—Report from an Interdisciplinary Workshop

Abstract: Close to 400 manufacturer-identified nanotechnology-based consumer products are now on the market (Woodrow Wilson International Center for Scholars 2007). Using increasingly sophisticated levels of control over the assembly of atoms and molecules to form substances and devices, nanotech companies are exploiting the size-dependent properties of nanostructured materials for applications ranging from cosmetics to fuel cells (Colvin 2003). Yet our understanding of the potential toxicity of nanoparticles remains rudimentary (Colvin 2003; Oberdorster et al. 2005b). To determine whether the unique chemical and physical properties of new nanoparticles result in specific toxicologic properties, the nanotechnology community needs new ways of evaluating hazard and ultimately assessing risk (Nel et al. 2006). These new strategies must also consider the complexities inherent to studies of chemical mixtures. This workshop’s assessment of the novel aspects of nanotoxicology built on knowledge gained from prior workshops. In 2004, scientists from many different areas of research came together in Gainesville, Florida, to discuss the emerging field of nanotoxicology (Bucher et al. 2004). They described the challenges facing toxicologists in rigorously characterizing the new materials and in understanding how nanostructures might differentially influence toxicity. This theme was further elaborated in a seminal article by Oberdorster et al. (2005a), which provides a general framework for evaluating the toxicity of engineered nanoparticles. More detailed questions regarding exactly how to evaluate the potential health impact of engineered nanoparticles remain. This report captures some of the critical information that is still needed to understand the human health impact of engineered nanoparticles and defines mechanisms to begin to acquire this information. Building on the insight from those previous meetings and published articles—that the structure of nanoparticles brings many new challenges to toxicological evaluation—workshop participants were asked to identify both factors that make nanoparticles different and information specific to these differences that is needed to assess nanoparticle hazards. The group was further charged with making recommendations on how to gather and use that additional information to evaluate health hazards associated with these scale-specific properties. Because of the short duration of this workshop, the scope was limited to consideration of toxic properties of nanoparticles. A full evaluation of human health risks will require development of sufficient techniques for assessing exposure to nanoparticles in addition to consideration of toxicity. E. Silbergeld of Johns Hopkins University opened the workshop with a presentation that explored ways of thinking about and evaluating the potential hazards of nanoparticles. She emphasized focus on the nanoscale interactions that take place in the normal functioning of biological systems in order to understand the positive and negative effects that engineered nanoparticles could have on humans. For example, because the immune system functions through nanoscale intercellular communications, Lynch et al. (2006) hypothesized that engineered nanoparticles can disrupt these processes with deleterious end results. Specifically, they considered unique interactions between native proteins and the highly curved surfaces of nanoparticles, speculating that the protein shape could be modified after binding. This deformation could expose amino acid residues that are normally buried in the core of the protein, and the immune system would then recognize these newly exposed residues as “cryptic epitopes” and mount an unwanted immune response. A 2005 study by Zhao et al. (2005) predicted that DNA repair, another vital biological system that operates at the nanoscale, is also susceptible to modification by nanoparticles. Specifically, this study found through computer modeling that the association in water between C60 and DNA is stronger than the association between two C60 molecules. Therefore, when DNA is damaged, fullerenes can occupy the damaged site, possibly impeding the self-repairing processes of the double-strand DNA and thus negatively impacting the structure, stability, and biological functions of DNA molecules. These unique interactions between nanoparticles and biological systems afford great promise for medicinal applications, but the unintended consequences could be harmful. We know, for instance, that natural and unintentionally produced ultrafine particulate matter, which is in the same size range as engineered nanoparticles, can carry a broad range of compounds, including polycyclic aromatic hydrocarbons, endotoxin, metals, and other toxic chemicals. These complexes can then damage biological systems (Penn et al. 2005; Schwarze et al. 2006). Gutierrez-Castillo et al. (2006) found that particulate matter with chemicals adsorbed to the surface can damage DNA. These examples suggest that the myriad possible interactions between nanoparticles and harmful environmental chemicals may lead to unique exposures and health risks. Conventional knowledge about exposure assessment, fate and transport, and current computer models is not necessarily applicable to nanoparticles. But alternative methods such as toxicogenomic technologies, lower-order animal and in vitro testing, and ultimately the development of structure activity models could prove useful, providing more rapid testing than traditional animal toxicology tests and allowing for explicit experimental design based on mechanism. The development of alternative methods is an ambitious but necessary goal if the large and growing numbers of nanoparticles are to be adequately assessed for toxicity. Silbergeld ended her presentation with a charge for the group: to frame its dialogue both to inform the industry on how to look before leaping into the production of new nanoparticles and to provide guidance for those who have already taken that leap.