The cancer translational research informatics platform

<p>Abstract</p> <p>Background</p> <p>Despite the pressing need for the creation of applications that facilitate the aggregation of clinical and molecular data, most current applications are proprietary and lack the necessary compliance with standards that would allow for cross-institutional data exchange. In line with its mission of accelerating research discoveries and improving patient outcomes by linking networks of researchers, physicians, and patients focused on cancer research, caBIG (cancer Biomedical Informatics Grid™) has sponsored the creation of the caTRIP (Cancer Translational Research Informatics Platform) tool, with the purpose of aggregating clinical and molecular data in a repository that is user-friendly, easily accessible, as well as compliant with regulatory requirements of privacy and security.</p> <p>Results</p> <p>caTRIP has been developed as an N-tier architecture, with three primary tiers: domain services, the distributed query engine, and the graphical user interface, primarily making use of the caGrid infrastructure to ensure compatibility with other tools currently developed by caBIG. The application interface was designed so that users can construct queries using either the Simple Interface via drop-down menus or the Advanced Interface for more sophisticated searching strategies to using drag-and-drop. Furthermore, the application addresses the security concerns of authentication, authorization, and delegation, as well as an automated honest broker service for deidentifying data.</p> <p>Conclusion</p> <p>Currently being deployed at Duke University and a few other centers, we expect that caTRIP will make a significant contribution to further the development of translational research through the facilitation of its data exchange and storage processes.</p

Role of Fibronectin in the Adhesion of Acinetobacter baumannii to Host Cells

Adhesion to host cells is an initial and important step in Acinetobacter baumannii pathogenesis. However, there is relatively little information on the mechanisms by which A. baumannii binds to and interacts with host cells. Adherence to extracellular matrix proteins, such as fibronectin, affords pathogens with a mechanism to invade epithelial cells. Here, we found that A. baumannii adheres more avidly to immobilized fibronectin than to control protein. Free fibronectin used as a competitor resulted in dose-dependent decreased binding of A. baumannii to fibronectin. Three outer membrane preparations (OMPs) were identified as fibronectin binding proteins (FBPs): OMPA, TonB-dependent copper receptor, and 34 kDa OMP. Moreover, we demonstrated that fibronectin inhibition and neutralization by specific antibody prevented significantly the adhesion of A. baumannii to human lung epithelial cells (A549 cells). Similarly, A. baumannii OMPA neutralization by specific antibody decreased significantly the adhesion of A. baumannii to A549 cells. These data indicate that FBPs are key adhesins that mediate binding of A. baumannii to human lung epithelial cells through interaction with fibronectin on the surface of these host cells

The descriptive content of names as predicate modifiers

In this paper I argue that descriptive content associated with a proper name can serve as a truth-conditionally relevant adjunct and be an additional contribution of the name to the truth-conditions. Definite descriptions the so-and-so associated by speakers with a proper name can be used as qualifying prepositional phrases as so-and-so, so sentences containing a proper name NN is doing something could be understood as NN is doing something as NN (which means as so-and-so). Used as an adjunct, the descriptive content of a proper name expresses the additional circumstances of an action (a manner, reason, goal, time or purpose) and constitute a part of a predicate. I argue that qualifying prepositional phrases should be analyzed as predicate modifiers and propose a formal representation of modified predicates. The additional truth-conditional relevance of the descriptive content of a proper name helps to explain the phenomenon of the substitution failure of coreferential names in simple sentences

Active and Passive Immunization Protects against Lethal, Extreme Drug Resistant-Acinetobacter baumannii Infection

Extreme-drug-resistant (XDR) Acinetobacter baumannii is a rapidly emerging pathogen causing infections with unacceptably high mortality rates due to inadequate available treatment. New methods to prevent and treat such infections are a critical unmet medical need. To conduct a rational vaccine discovery program, OmpA was identified as the primary target of humoral immune response after intravenous infection by A. baumannii in mice. OmpA was >99% conserved at the amino acid level across clinical isolates harvested between 1951 and 2009 from cerebrospinal fluid, blood, lung, and wound infections, including carbapenem-resistant isolates, and was ≥89% conserved among other sequenced strains, but had minimal homology to the human proteome. Vaccination of diabetic mice with recombinant OmpA (rOmpA) with aluminum hydroxide adjuvant markedly improved survival and reduced tissue bacterial burden in mice infected intravenously. Vaccination induced high titers of anti-OmpA antibodies, the levels of which correlated with survival in mice. Passive transfer with immune sera recapitulated protection. Immune sera did not enhance complement-mediated killing but did enhance opsonophagocytic killing of A. baumannii. These results define active and passive immunization strategies to prevent and treat highly lethal, XDR A. baumannii infections

Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis

Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non–cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte–mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity

The effects of exercise and weight loss in overweight patients with hip osteoarthritis: design of a prospective cohort study

BACKGROUND: Hip osteoarthritis (OA) is recognised as a substantial source of disability, with pain and loss of function as principal symptoms. An aging society and a growing number of overweight people, which is considered a risk factor for OA, contribute to the growing number of cases of hip OA. In knee OA patients, exercise as a single treatment is proven to be very effective towards counteracting pain and physical functionality, but the combination of weight loss and exercise is demonstrated to be even more effective. Exercise as a treatment for hip OA patients is also effective, however evidence is lacking for the combination of weight loss and exercise. Consequently, the aim of this study is to get a first impression of the potential effectiveness of exercise and weight loss in overweight patients suffering from hip OA. METHODS/DESIGN: This is a prospective cohort study. Patients aged 25 or older, overweight (BMI > 25) or obese (BMI > 30), with clinical and radiographic evidence of OA of the hip and able to attend exercise sessions will be included. The intervention is an 8-month exercise and weight-loss lifestyle program. Main goal is to increase aerobic capacity, lose weight and stimulate a low-calorie and active lifestyle. Primary outcome is self-reported physical functioning. Secondary outcomes include pain, stiffness, health-related quality of life and habitual activity level. Weight loss in kilograms and percentage of fat-free mass will also be measured. DISCUSSION: The results of this study will give a first impression of potential effectiveness of exercise and weight loss as a combination program for patients with OA of the hip. Once this program is proven to be effective it may lead to postponing the moment of total hip replacement. TRIAL REGISTRATION NUMBER: NTR1053

Integrative mapping analysis of chicken microchromosome 16 organization

<p>Abstract</p> <p>Background</p> <p>The chicken karyotype is composed of 39 chromosome pairs, of which 9 still remain totally absent from the current genome sequence assembly, despite international efforts towards complete coverage. Some others are only very partially sequenced, amongst which microchromosome 16 (GGA16), particularly under-represented, with only 433 kb assembled for a full estimated size of 9 to 11 Mb. Besides the obvious need of full genome coverage with genetic markers for QTL (Quantitative Trait Loci) mapping and major genes identification studies, there is a major interest in the detailed study of this chromosome because it carries the two genetically independent <it>MHC </it>complexes <it>B </it>and <it>Y</it>. In addition, GGA16 carries the ribosomal RNA (<it>rRNA</it>) genes cluster, also known as the <it>NOR </it>(nucleolus organizer region). The purpose of the present study is to construct and present high resolution integrated maps of GGA16 to refine its organization and improve its coverage with genetic markers.</p> <p>Results</p> <p>We developed 79 STS (Sequence Tagged Site) markers to build a physical RH (radiation hybrid) map and 34 genetic markers to extend the genetic map of GGA16. We screened a BAC (Bacterial Artificial Chromosome) library with markers for the <it>MHC-B</it>, <it>MHC-Y </it>and <it>rRNA </it>complexes. Selected clones were used to perform high resolution FISH (Fluorescent <it>In Situ </it>Hybridization) mapping on giant meiotic lampbrush chromosomes, allowing meiotic mapping in addition to the confirmation of the order of the three clusters along the chromosome. A region with high recombination rates and containing PO41 repeated elements separates the two <it>MHC </it>complexes.</p> <p>Conclusions</p> <p>The three complementary mapping strategies used refine greatly our knowledge of chicken microchromosome 16 organisation. The characterisation of the recombination hotspots separating the two <it>MHC </it>complexes demonstrates the presence of PO41 repetitive sequences both in tandem and inverted orientation. However, this region still needs to be studied in more detail.</p

Assessment of behavioral change in a child psychiatric inpatient program

A behavioral rating scale, the Devereux Child Behavior Scale, was used to assess change in 55 children who were patients in a child psychiatric inpatient unit for an average of 3.9 months. The children were rated by unit staff on admission and at discharge, and by their parents prior to admission and at three and six months after discharge. The ratings indicate that the children did make statistically significant positive behavioral changes while in the hospital and that they continued to change up to six months post-discharge. Staff tended to rate the children as less disturbed than the parents but both groups of raters indicated significant change by their ratings.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43952/1/10578_2004_Article_BF00706168.pd

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

5-α reductase inhibitors and prostate cancer prevention: where do we turn now?

With the lifetime risk of being diagnosed with prostate cancer so great, an effective chemopreventive agent could have a profound impact on the lives of men. Despite decades of searching for such an agent, physicians still do not have an approved drug to offer their patients. In this article, we outline current strategies for preventing prostate cancer in general, with a focus on the 5-α-reductase inhibitors (5-ARIs) finasteride and dutasteride. We discuss the two landmark randomized, controlled trials of finasteride and dutasteride, highlighting the controversies stemming from the results, and address the issue of 5-ARI use, including reasons why providers may be hesitant to use these agents for chemoprevention. We further discuss the recent US Food and Drug Administration ruling against the proposed new indication for dutasteride and the change to the labeling of finasteride, both of which were intended to permit physicians to use the drugs for chemoprevention. Finally, we discuss future directions for 5-ARI research