Trade agreements, regulatory sovereignty and democratic legitimacy

Governments increasingly are seeking to use bilateral and regional trade agreements to reduce the cost-increasing effects of differences in product market regulation. They also pursue regulatory cooperation independent of trade agreements. It is important to understand what is being done through bilateral or plurilateral mechanisms to address regulatory differences, and to identify what, if any, role trade agreements can play in supporting international regulatory cooperation. This paper reflects on experience to date in regulatory cooperation and the provisions of recent trade agreements involving advanced economies that have included regulatory cooperation. We argue for a re-thinking by trade officials of the modalities and design of trade negotiations and the incorporation of institutional mechanisms that draw on insights of experimentalist governance approaches to enhance the scope for international regulatory cooperation

Correctness of an STM Haskell implementation

A concurrent implementation of software transactional memory in Concurrent Haskell using a call-by-need functional language with processes and futures is given. The description of the small-step operational semantics is precise and explicit, and employs an early abort of conflicting transactions. A proof of correctness of the implementation is given for a contextual semantics with may- and should-convergence. This implies that our implementation is a correct evaluator for an abstract specification equipped with a big-step semantics

Proteomics in Melanoma Biomarker Discovery: Great Potential, Many Obstacles

The present clinical staging of melanoma stratifies patients into heterogeneous groups, resulting in the application of aggressive therapies to large populations, diluting impact and increasing toxicity. To move to a new era of therapeutic decisions based on highly specific tumor profiling, the discovery and validation of new prognostic and predictive biomarkers in melanoma is critical. Genomic profiling, which is showing promise in other solid tumors, requires fresh tissue from a large number of primary tumors, and thus faces a unique challenge in melanoma. For this and other reasons, proteomics appears to be an ideal choice for the discovery of new melanoma biomarkers. Several approaches to proteomics have been utilized in the search for clinically relevant biomarkers, but to date the results have been relatively limited. This article will review the present work using both tissue and serum proteomics in the search for melanoma biomarkers, highlighting both the relative advantages and disadvantages of each approach. In addition, we review several of the major obstacles that need to be overcome in order to advance the field

Clinical Utility of Serum Autoantibodies Detected by Protein Microarray in Melanoma

Better prognostic and predictive markers in melanoma are needed to select patients for therapy. We utilized a dual-lectin affinity chromatography and a natural protein microarray-based analysis to select a subproteome of target glycoproteins to profile serum antibodies against melanoma associated antigens that may predict nodal positivity. We identified 5 melanoma-associated antigens using this microarray coupled to mass spectrometry; GRP75, GRP94, ASAH1, CTSD and LDHB. We evaluated their predictive value for nodal status adjusting for age, gender, Breslow thickness, mitotic rate and ulceration using standard logistic regression. After adjustment, ASAH1, CTSD and LDHB were significantly negatively associated with nodal status (P = 0.0008) and GRP94 was significantly positively associated (P = 0.014). Our best multivariate model for nodal positivity included Breslow thickness, presence of serum anti-ASAH1, anti-LDHB or anti-CTSD, and presence of serum anti-GRP94, with an area under the ROC curve of 0.869. If validated, these results show promise for selecting clinically node negative patients for SLN biopsy. In addition, there is strong potential for glycoprotein microarray to screen serum autoantibodies that may identify patients at high risk of distant metastases or those likely or unlikely to respond to treatment, and these proteins may serve as targets for intervention

Evaluation of toxicity and neural uptake in vitro and in vivo of superparamagnetic iron oxide nanoparticles

Superparamagnetic iron oxide nanoparticles (SPIO-NPs) have great potential to be used in different pharmaceutical applications, due to their unique and versatile physical and chemical properties. The aim of this study was to quantify in vitro cytotoxicity of dextran 70,000-coated SPIO-NPs labelled/unlabelled with rhodamine 123, in C6 glioma cells and primary hippocampal neural cells. In addition, we analyzed the in vitro and in vivo cellular uptake of labelled SPIO-NPs. The nanoparticles, with average size of 10⁻50 nm and polydispersity index of 0.37, were synthesized using Massart's co-precipitation method. The concentration-dependent cytotoxicity was quantified by using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Intracellular localization of SPIO-NPs was detected by confocal laser microscopy. In vivo confocal neuroimaging (ICON) was performed on male Wistar rats after intravitreal injection followed by ex vivo retina whole mount analysis. When used for in vitro testing concentrations in the range of diagnostic and therapeutic dosages, SPIO-NPs proved to be non-cytotoxic on C6 glioma cells for up to 24 h incubation time. The hippocampal cell culture also did not show impaired viability at low doses after 24 h incubation. Our results indicate that our dextran-coated SPIO-NPs have the potential for in vivo drug delivery applications

Does the Method of Biopsy Affect the Incidence of Sentinel Lymph Node Metastases?

More detailed examination of the sentinel lymph node (SLN) in breast cancer has raised concerns about the clinical significance of micrometastases, specifically isolated tumor cells detected only through immunohistochemical (IHC) staining. It has been suggested that these cells do not carry the same biologic implications as true metastatic foci and may represent artifact. A retrospective institutional review board-approved review was conducted on clinically node-negative breast cancer patients who underwent SLN biopsy (SLNB) between 1997 and 2003. Retrospective analysis of tumor characteristics and the method of the initial diagnostic biopsy were correlated with the presence and nature of metastatic disease in the SLN. Of 537 SLNBs, 123 (23%) were hematoxylin-eosin (H&E) positive. SLN positivity strongly correlated with tumor size (p < 0.001) and tumor grade (p = 0.025), but not with the method of biopsy (needle versus excisional biopsy). Prior to July 2002, we routinely evaluated H&E-negative SLNs with IHC ( n  = 381). Of the 291 H&E-negative patients, 26 had IHC-only detected micrometastases (9%). The likelihood of detecting IHC-only metastases did not correlate with tumor size or grade, but was significantly higher in patients undergoing excisional biopsy than core needle biopsy. While the method of biopsy has no demonstrable effect on the likelihood of finding metastases in the SLN by routine serial sectioning and H&E staining, it may significantly impact the likelihood of finding micrometastases by IHC. IHC should not be used routinely in the evaluation of the SLN and caution should be used when basing treatment decisions (completion axillary lymph node dissection or adjuvant therapy) on IHC-only detected micrometastases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72849/1/j.1075-122X.2006.00179.x.pd