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Therapeutic Potential and Challenges of Targeting Receptor Tyrosine Kinase ROR1 with Monoclonal Antibodies in B-Cell Malignancies
Jiahui Yang,Sivasubramanian Baskar,Ka Yin Kwong,Michael G. Kennedy,Adrian Wiestner,Christoph Rader
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0021018
Abstract: Based on its selective cell surface expression in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), receptor tyrosine kinase ROR1 has recently emerged as a promising target for therapeutic monoclonal antibodies (mAbs). To further assess the suitability of ROR1 for targeted therapy of CLL and MCL, a panel of mAbs was generated and its therapeutic utility was investigated.
VASCo: computation and visualization of annotated protein surface contacts
Georg Steinkellner, Robert Rader, Gerhard G Thallinger, Christoph Kratky, Karl Gruber
BMC Bioinformatics , 2009, DOI: 10.1186/1471-2105-10-32
Abstract: VASCo is a program package for the calculation of protein surface properties and the visualization of annotated surfaces. Special emphasis is laid on protein-protein interactions, which are calculated based on surface point distances. The same approach is used to compare surfaces of two aligned molecules. Molecular properties such as electrostatic potential or hydrophobicity are mapped onto these surface points. Molecular surfaces and the corresponding properties are calculated using well established programs integrated into the package, as well as using custom developed programs. The modular package can easily be extended to include new properties for annotation. The output of the program is most conveniently displayed in PyMOL using a custom-made plug-in.VASCo supplements other available protein contact visualisation tools and provides additional information on biological interactions as well as on crystal contacts. The tool provides a unique feature to compare surfaces of two aligned molecules based on point distances and thereby facilitates the visualization and analysis of surface differences.Knowledge on protein-protein interactions is essential for understanding many processes in living cells. These interactions are mediated through the respective molecular surfaces and are governed by the properties of the amino acid residues and atoms, which form these surfaces, as well as more distributed properties such as hydrophobicity and electrostatic potential. Structural data from crystallographic analyses deposited in the Protein Data Bank (PDB) [1,2] contain a vast amount of information on protein-protein contacts, including "biological" contacts which are also present in solution as well as contacts necessary for crystal formation. Several programs are available which allow the calculation and analysis of surface properties, e.g. to predict hotspots for protein interaction [3-5]. However, these programs are not designed to calculate, analyze and visualize actual
Selection of Apoptotic Cell Specific Human Antibodies from Adult Bone Marrow
Caroline Gr?nwall, Edgar D. Charles, Lynn B. Dustin, Christoph Rader, Gregg J. Silverman
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095999
Abstract: Autoreactive antibodies that recognize neo-determinants on apoptotic cells in mice have been proposed to have protective, homeostatic and immunoregulatory properties, although our knowledge about the equivalent antibodies in humans has been much more limited. In the current study, human monoclonal antibodies with binding specificity for apoptotic cells were isolated from the bone marrow of healthy adults using phage display technology. These antibodies were shown to recognize phosphorylcholine (PC)-associated neo-determinants. Interestingly, three of the four identified apoptotic cell-specific antibody clones were encoded by VH3 region rearrangements with germline or nearly germline configuration without evidence of somatic hypermutation. Importantly, the different identified antibody clones had diverse heavy chain CDR3 and deduced binding surfaces as suggested by structure modeling. This may suggest a potentially great heterogeneity in human antibodies recognizing PC-related epitopes on apoptotic cells. To re-construct the postulated structural format of the parental anti-PC antibody, the dominant clone was also expressed as a recombinant human polymeric IgM, which revealed a substantially increased binding reactivity, with dose-dependent and antigen-inhibitable binding of apoptotic cells. Our findings may have implication for improved prognostic testing and therapeutic interventions in human inflammatory disease.
Restricted Cell Surface Expression of Receptor Tyrosine Kinase ROR1 in Pediatric B-Lineage Acute Lymphoblastic Leukemia Suggests Targetability with Therapeutic Monoclonal Antibodies
Hema Dave, Miriam R. Anver, Donna O. Butcher, Patrick Brown, Javed Khan, Alan S. Wayne, Sivasubramanian Baskar, Christoph Rader
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052655
Abstract: Background Despite high cure rates for pediatric B-lineage acute lymphoblastic leukemia (B-ALL), short-term and long-term toxicities and chemoresistance are shortcomings of standard chemotherapy. Immunotherapy and chemoimmunotherapy based on monoclonal antibodies (mAbs) that target cell surface antigens with restricted expression in pediatric B-ALL may offer the potential to reduce toxicities and prevent or overcome chemoresistance. The receptor tyrosine kinase ROR1 has emerged as a candidate for mAb targeting in select B-cell malignancies. Methodology and Principal Findings Using flow cytometry, Western blotting, immunohistochemistry, and confocal immunofluorescence microscopy, we analyzed the cell surface expression of ROR1 across major pediatric ALL subtypes represented by 14 cell lines and 56 primary blasts at diagnosis or relapse as well as in normal adult and pediatric tissues. Cell surface ROR1 expression was found in 45% of pediatric ALL patients, all of which were B-ALL, and was not limited to any particular genotype. All cell lines and primary blasts with E2A-PBX1 translocation and a portion of patients with other high risk genotypes, such as MLL rearrangement, expressed cell surface ROR1. Importantly, cell surface ROR1 expression was found in many of the pediatric B-ALL patients with multiply relapsed and refractory disease and normal karyotype or low risk cytogenetics, such as hyperdiploidy. Notably, cell surface ROR1 was virtually absent in normal adult and pediatric tissues. Conclusions and Significance Collectively, this study suggests that ROR1 merits preclinical and clinical investigations as a novel target for mAb-based therapies in pediatric B-ALL. We propose cell surface expression of ROR1 detected by flow cytometry as primary inclusion criterion for pediatric B-ALL patients in future clinical trials of ROR1-targeted therapies.
Endothelial Lipase Concentrations Are Increased in Metabolic Syndrome and Associated with Coronary Atherosclerosis.
PLOS Medicine , 2005,
Abstract: BACKGROUND: Endothelial lipase (EL), a new member of the lipase family, has been shown to modulate high-density lipoprotein (HDL-C) metabolism and atherosclerosis in mouse models. We hypothesized that EL concentrations would be associated with decreased HDL-C and increased atherosclerosis in humans. METHODS AND FINDINGS: Healthy individuals with a family history of premature coronary heart disease (n = 858) were recruited as part of the Study of the Inherited Risk of Atherosclerosis. Blood was drawn in the fasting state before and, in a subgroup (n = 510), after administration of a single dose of intravenous heparin. Plasma lipids were measured enzymatically, lipoprotein subclasses were assessed by nuclear magnetic resonance, and coronary artery calcification (CAC) was quantified by electron beam computed tomography. Plasma EL mass was measured using a newly developed enzyme-linked immunosorbent assay. Median EL mass in pre-heparin plasma was 442 (interquartile range = 324-617) ng/ml. Median post-heparin mass was approximately 3-fold higher, 1,313 (888-1,927) ng/ml. The correlation between pre-heparin EL mass and post-heparin EL mass was 0.46 (p < 0.001). EL mass concentrations in both pre- and post-heparin plasma significantly correlated with all NCEP ATPIII-defined metabolic syndrome factors: waist circumference (r = 0.28 and 0.22, respectively, p < 0.001 for each), blood pressure (r = 0.18 and 0.24, p < 0.001 for each), triglycerides (r = 0.22, p < 0.001; and 0.13, p = 0.004), HDL cholesterol (r = -0.11, p = 0.002; and -0.18, p < 0.001), and fasting glucose (r = 0.11 and 0.16, p = 0.001 for both). EL mass in both routine (odds ratio [OR] = 1.67, p = 0.01) and post-heparin (OR = 2.42, p = 0.003) plasma was associated with CAC as determined by ordinal regression after adjustment for age, gender, waist circumference, vasoactive medications, hormone replacement therapy (women), and established cardiovascular risk factors. CONCLUSIONS: We report, to our knowledge for the first time, that human plasma EL concentrations, in both post-heparin and routine pre-heparin plasma, are significantly associated with metabolic syndrome features and with subclinical atherosclerosis. EL may be a pro-atherogenic factor in humans, especially in overweight individuals and those with metabolic syndrome.
Glassiness in Simple Liquids
Ziv Rader,Moshe Schwartz
Physics , 2007, DOI: 10.1016/j.physa.2007.11.032
Abstract: In previous work the parameter of glassiness was introduced to distinguish between a liquid and a glass, using a formal analogy with the quantum Bose system. The glassiness is defined in such a way that it is unity in a frozen system and less than one in a liquid. In the present letter we revise first the results obtained for the glassiness in a hard sphere liquid as a function of the density. Then we investigate the influence of an attractive potential by obtaining the glassiness as a function of the density, temperature and the attractive tail when a square well potential is added to the hard core.
Exploring Historical and Emerging Phishing Techniques and Mitigating the Associated Security Risks
Marc Rader,Shawon Rahman
Computer Science , 2015, DOI: 10.5121/ijnsa.2013.5402
Abstract: Organizations invest heavily in technical controls for their Information Assurance (IA) infrastructure. These technical controls mitigate and reduce the risk of damage caused by outsider attacks. Most organizations rely on training to mitigate and reduce risk of non-technical attacks such as social engineering. Organizations lump IA training into small modules that personnel typically rush through because the training programs lack enough depth and creativity to keep a trainee engaged. The key to retaining knowledge is making the information memorable. This paper describes common and emerging attack vectors and how to lower and mitigate the associated risks.
Apolipoprotein E and Coronary Disease: A Puzzling Paradox
Muredach Reilly,Daniel J Rader
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030258
The Role of High Density Lipoproteins in Thrombosis
Marina Cuchel,Daniel J. Rader
The Scientific World Journal , 2002, DOI: 10.1100/tsw.2002.85
Establishing Payment Hubs—Unwind the Spaghetti?  [PDF]
Christoph Markert
American Journal of Industrial and Business Management (AJIBM) , 2014, DOI: 10.4236/ajibm.2014.44024

Banks and financial services providers are facing a more and more competitive business within the retail banking as well as corporate market. Increasing productivity and efficiency by decreasing operational costs is very often one milestone on the strategic business roadmap of a bank or financial services providers. The payment area is usually seen as a cost intensive, but necessary part of the business and information technology (IT) landscape. Many banks and financial services providers do still follow a best-of-breed approach within the system payments landscape, which ends up in high operational and maintenance costs as different payment processing platforms are serving different business purposes. The establishment of a single globally centralized payment hub cannot be only the solution for the ending of a heterogeneous payment processing landscape, but also for supporting the strategic management roadmap by decreasing system complexity and increasing the efficiency of the payment platforms and thus decreasing operational and maintenance IT costs. Furthermore it can support banks to establish a far more flexible technological implementation approach for an entire core banking transformation program. This paper is analyzing the challenges and issues banks and financial services providers are facing with the establishment of payment hubs in their enterprise system landscape from a management as well as IT point of view.

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