Unstable states in QED of strong magnetic fields

We question the use of stable asymptotic scattering states in QED of strong magnetic fields. To correctly describe excited Landau states and photons above the pair creation threshold the asymptotic fields are chosen as generalized Licht fields. In this way the off-shell behavior of unstable particles is automatically taken into account, and the resonant divergences that occur in scattering cross sections in the presence of a strong external magnetic field are avoided. While in a limiting case the conventional electron propagator with Breit-Wigner form is obtained, in this formalism it is also possible to calculate $S$-matrix elements with external unstable particles.Comment: Revtex, 7 pages. To appear in Phys. Rev. D53(2

Evidence that Localized Variation in Primate Sequence Divergence Arises from an Influence of Nucleosome Placement on DNA Repair

Understanding the origins of localized substitution rate heterogeneity has important implications for identifying functional genomic sequences. Outside of gene regions, the origins of rate heterogeneity remain unclear. Experimental studies establish that chromatin compaction affects rates of both DNA lesion formation and repair. A functional association between chromatin status and 5-methyl-cytosine also exists. These suggest that both the total rate and the type of substitution will be affected by chromatin status. Regular positioning of nucleosomes, the building block of chromatin, further predicts that substitution rate and type should vary spatially in an oscillating manner. We addressed chromatin's influence on substitution rate and type in primates. Matched numbers of sites were sampled from Dnase I hypersensitive (DHS) and closed chromatin control flank (Flank). Likelihood ratio tests revealed significant excesses of total and of transition substitutions in Flank compared with matched DHS for both intergenic and intronic samples. An additional excess of CpG transitions was evident for the intergenic, but not intronic, regions. Fluctuation in substitution rate along ∼1,800 primate promoters was measured using phylogenetic footprinting. Significant positive correlations were evident between the substitution rate and a nucleosome score from resting human T-cells, with up to ∼50% of the variance in substitution rate accounted for. Using signal processing techniques, a dominant oscillation at ∼200 bp was evident in both the substitution rate and the nucleosome score. Our results support a role for differential DNA repair rates between open and closed chromatin in the spatial distribution of rate heterogeneity

MRl of Prostate Cancer Antigen Expression for Diagnosis and lmmunotherapy

BACKGROUND: Tumor antigen (TA)-targeted monoclonal antibody (mAb) immunotherapy can be effective for the treatment of a broad range of cancer etiologies; however, these approaches have demonstrated variable clinical efficacy for the treatment of patients with prostate cancer (PCa). An obstacle currently impeding translational progress has been the inability to quantify the mAb dose that reaches the tumor site and binds to the targeted TAs. The coupling of mAb to nanoparticle-based magnetic resonance imaging (MRI) probes should permit in vivo measurement of patient-specific biodistributions; these measurements could facilitate future development of novel dosimetry paradigms wherein mAb dose is titrated to optimize outcomes for individual patients. METHODS: The prostate stem cell antigen (PSCA) is broadly expressed on the surface of prostate cancer (PCa) cells. Anti-human PSCA monoclonal antibodies (mAb 7F5) were bound to Au/Fe(3)O(4) (GoldMag) nanoparticles (mAb 7F5@GoldMag) to serve as PSCA-specific theragnostic MRI probe permitting visualization of mAb biodistribution in vivo. First, the antibody immobilization efficiency of the GoldMag particles and the efficacy for PSCA-specific binding was assessed. Next, PC-3 (prostate cancer with PSCA over-expression) and SMMC-7721 (hepatoma cells without PSCA expression) tumor-bearing mice were injected with mAb 7F5@GoldMag for MRI. MRI probe biodistributions were assessed at increasing time intervals post-infusion; therapy response was evaluated with serial tumor volume measurements. RESULTS: Targeted binding of the mAb 7F5@GoldMag probes to PC-3 cells was verified using optical images and MRI; selective binding was not observed for SMMC-7721 tumors. The immunotherapeutic efficacy of the mAb 7F5@GoldMag in PC-3 tumor-bearing mice was verified with significant inhibition of tumor growth compared to untreated control animals. CONCLUSION: Our promising results suggest the feasibility of using mAb 7F5@GoldMag probes as a novel paradigm for the detection and immunotherapeutic treatment of PCa. We optimistically anticipate that the approaches have the potential to be translated into the clinical settings

Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity

‘There is a Time to be Born and a Time to Die’ (Ecclesiastes 3:2a): Jewish Perspectives on Euthanasia

Reviewing the publications of prominent American rabbis who have (extensively) published on Jewish biomedical ethics, this article highlights Orthodox, Conservative and Reform opinions on a most pressing contemporary bioethical issue: euthanasia. Reviewing their opinions against the background of the halachic character of Jewish (biomedical) ethics, this article shows how from one traditional Jewish textual source diverse, even contradictory, opinions emerge through different interpretations. In this way, in the Jewish debate on euthanasia the specific methodology of Jewish (bio)ethical reasoning comes forward as well as a diversity of opinion within Judaism and its branches

LabKey Server: An open source platform for scientific data integration, analysis and collaboration

<p>Abstract</p> <p>Background</p> <p>Broad-based collaborations are becoming increasingly common among disease researchers. For example, the Global HIV Enterprise has united cross-disciplinary consortia to speed progress towards HIV vaccines through coordinated research across the boundaries of institutions, continents and specialties. New, end-to-end software tools for data and specimen management are necessary to achieve the ambitious goals of such alliances. These tools must enable researchers to organize and integrate heterogeneous data early in the discovery process, standardize processes, gain new insights into pooled data and collaborate securely.</p> <p>Results</p> <p>To meet these needs, we enhanced the LabKey Server platform, formerly known as CPAS. This freely available, open source software is maintained by professional engineers who use commercially proven practices for software development and maintenance. Recent enhancements support: (i) Submitting specimens requests across collaborating organizations (ii) Graphically defining new experimental data types, metadata and wizards for data collection (iii) Transitioning experimental results from a multiplicity of spreadsheets to custom tables in a shared database (iv) Securely organizing, integrating, analyzing, visualizing and sharing diverse data types, from clinical records to specimens to complex assays (v) Interacting dynamically with external data sources (vi) Tracking study participants and cohorts over time (vii) Developing custom interfaces using client libraries (viii) Authoring custom visualizations in a built-in R scripting environment.</p> <p>Diverse research organizations have adopted and adapted LabKey Server, including consortia within the Global HIV Enterprise. Atlas is an installation of LabKey Server that has been tailored to serve these consortia. It is in production use and demonstrates the core capabilities of LabKey Server. Atlas now has over 2,800 active user accounts originating from approximately 36 countries and 350 organizations. It tracks roughly 27,000 assay runs, 860,000 specimen vials and 1,300,000 vial transfers.</p> <p>Conclusions</p> <p>Sharing data, analysis tools and infrastructure can speed the efforts of large research consortia by enhancing efficiency and enabling new insights. The Atlas installation of LabKey Server demonstrates the utility of the LabKey platform for collaborative research. Stable, supported builds of LabKey Server are freely available for download at <url>http://www.labkey.org</url>. Documentation and source code are available under the Apache License 2.0.</p

Managing medical research data with a Web-Interfacing Repository Manager.

This paper describes the Web-Interfacing Repository Manager (WIRM), a perl toolkit for managing and deploying multimedia data, which is built entirely from free, platform-independent components. The WIRM consists of an object-relational API layered over a relational database, with built-in support for file management and CGI programming. The basic underlying data structure for all WIRM data is the repository object, a perl associative array whose values are bound to a row of a table in the relational database. Based on our experience implementing a target application (the Brain Mapper Console), we describe five stages through which a system passes as it evolves from a primitive file hierarchy to a full-fledged repository console

A Web-based repository manager for brain mapping data.

The Web provides a rapid prototyping environment for building platform-independent graphical user interfaces. A Web-based console can be implemented as a suite of CGI scripts that generate HTML code, manipulate files, execute system commands, and invoke external tools. Often these tools share data by reading and writing flat files, which must be explicitly maintained by the CGI programmer. In a repository system, meta-data about each file object are maintained in a database, and access to all data is regulated by a layer of control services. This paper describes the design and implementation of a Web-based Repository Manager (WRM), which provides an application programmer's interface for controlling applications, generating HTML documents, handling Web forms, and managing multi-media data. The WRM is being used to develop a console for the Brain Mapping Framework, a system for visualizing cortical stimulation data obtained during neurosurgery

Enabling clinicians, researchers, and educators to build custom web-based biomedical information systems.

We describe an open-source toolkit that enables clinicians, researchers, and educators to build their own web-based biomedical information systems. The Web Interfacing Repository Manager (Wirm) is a high-level application server aimed at medical professionals, allowing them to create individually tailored systems for managing their multimedia data and knowledge. We provide an overview of the features of Wirm, explaining how they meet the requirements for supporting biomedical information management, and describe four applications that are currently being developed with Wirm: MyPACS, a teaching file authoring system for radiologists, Fathom, an experiment management system for natural language processing, the Digital Anatomist Repository, an image archiving tool for medical schools, and Ontolog, a browser for medical vocabularies