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Different Targets (different + target)
Selected AbstractsMaking Efficient Use of Patients in Designing Phase III Trials Investigating Simultaneously a Set of Targeted Therapies with Different TargetsBIOMETRICAL JOURNAL, Issue 6 2006Werner Vach Abstract Targeted therapies are a recent development in cancer treatment research. As these therapies can only be administered to patients with certain individual characteristics, it is a straightforward idea to investigate several of such therapies simultaneously in a given patient population in order to compare each targeted therapy with the current standard therapy. This raises the question how patients satisfying several characteristics should be handled. We consider in this paper several designs to allocate treatments in a random manner to these patients, such that the evaluation of each single targeted therapy can be based on a simple comparison of patients receiving the targeted therapies versus those receiving the standard therapy within a well defined subgroup of patients satisfying the corresponding characteristic. We show how one can ensure that patients with several characteristics can contribute simultaneously to the evaluation of several targeted therapies and that this is the key point for an efficient use of the patients available. We further discuss some ethical and practical issues in applying the new designs and outline strategies to evaluate the overall effect of all targeted therapies together. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Accelerating botulism therapeutic product development in the Department of Defense,DRUG DEVELOPMENT RESEARCH, Issue 4 2009Andrea M. Stahl Abstract Coordinated small-molecule drug discovery research efforts for the treatment of botulism by the public sector, especially the U.S. Department of Defense (DoD) and Department of Health and Human Services (DHHS), began in the 1990s and represent a significant resource investment. Organization of an effective botulism therapeutic drug program, however, presents formidable technical and logistical challenges. Seven distinct BoNT serotypes are known, each representing a different target. Moreover, BoNT exerts its action inside peripheral cholinergic neurons, and some serotypes may persist functionally within nerve cells for weeks or months. Clinical botulism occurs infrequently, and the effectiveness of prolonged mechanical ventilation to treat poisoning further limits experimental drug testing. The efficacy of experimental compounds must be extrapolated from disparate cell- or tissue-based or rodent models. Numerous compounds with moderate efficacy in experimental laboratory assays have been reported, but may not possess the necessary safety, efficacy, and pharmacokinetic profile to support therapeutic development. To mitigate these challenges, we propose product development tools to assist in management of the BoNT portfolio and to clearly define the desired therapeutic product. Establishing a target product profile (TPP) is proposed to guide public sector managers toward critical aspects of the desired therapeutic product. Additional product development tools to assist in shaping research portfolios and to inform decisions regarding lead candidates to pursue are also discussed. Product development tools that facilitate the characterization of the ideal therapeutic product, and assist in the maintenance of a robust portfolio, will ameliorate the inherent financial risk in drug development for treating BoNT intoxication. Drug Dev Res 70:303,326, 2009. Published 2009 Wiley-Liss, Inc. [source] A cryptic lysis gene near the start of the Q, replicase gene in the +1 frameGENES TO CELLS, Issue 10 2004Tohru Nishihara The maturation/lysis (A2) protein encoded by the group B single-stranded RNA bacteriophage Q, mediates lysis of host Escherichia coli cells. We found a frameshift mutation in the replicase (,-subunit) gene of Q, cDNA causes cell lysis. The mutant has a single base deletion 73 nucleotides (nt) 3, from the start of the replicase gene with consequent translation termination at a stop codon 129,131 nt further 3,. The 43-amino acid C-terminal part of the 67-amino acid product encoded by what in WT (wild-type) is the +1 frame, is rich in basic amino acids This 67-aa protein can mediate cell lysis whose characteristics indicate that the protein may cause lysis by a different mechanism and via a different target, than that caused by the A2 maturation/lysis protein. Synthesis of a counterpart of the newly discovered lysis product in wild-type phage infection would require a hypothetical ribosomal frameshifting event. The lysis gene of group A RNA phages is also short, 75 codons in MS2, and partially overlaps the first part of their equivalently located replicase gene, raising significant evolutionary implications for the present finding. [source] Analysis of Nanocrystalline and Microcrystalline ZnO Sintering Using Master Sintering CurvesJOURNAL OF THE AMERICAN CERAMIC SOCIETY, Issue 6 2006Kevin G. Ewsuk Master sintering curves were constructed for dry-pressed compacts composed of either a nanocrystalline or a microcrystalline ZnO powder using constant heating rate dilatometry data and an experimentally determined apparent activation energy for densification of 268±25 and 296±21 kJ/mol, respectively. The calculated activation energies for densification are consistent with one another, and with values reported in the literature for ZnO densification by grain boundary diffusion. Grain boundary diffusion appears to be the single dominant mechanism controlling intermediate-stage densification in both the nanocrystalline and the microcrystalline ZnO during sintering from 65% to 90% of the theoretical density (TD). Based on both the consistency of the calculated activation energy as a function of density and the narrow dispersion of the sintering data about the master sintering curve (MSC) for the nanocrystalline ZnO, there is no evidence of either significantly enhanced surface diffusion or grain growth during sintering relative to the microcrystalline ZnO. The MSC constructed for the nanocrystalline ZnO was used to design time,temperature profiles to successfully achieve four different target sintered densities on the MSC, demonstrating the applicability of the MSC theory to nanocrystalline ceramic sintering. The most significant difference in sintering behavior between the two ZnO powders is the enhanced densification in the nanocrystalline ZnO powder at shorter times and lower temperatures. This difference is attributed to a scaling (i.e., particle size) effect. [source] Abundance of intrinsic disorder in SV-IV, a multifunctional androgen-dependent protein secreted from rat seminal vesicleFEBS JOURNAL, Issue 4 2008Silvia Vilasi The potent immunomodulatory, anti-inflammatory and procoagulant properties of protein no. 4 secreted from the rat seminal vesicle epithelium (SV-IV) have previously been found to be modulated by a supramolecular monomer,trimer equilibrium. More structural details that integrate experimental data into a predictive framework have recently been reported. Unfortunately, homology modelling and fold-recognition strategies were not successful in creating a theoretical model of the structural organization of SV-IV. It was inferred that the global structure of SV-IV is not similar to that of any protein of known three-dimensional structure. Reversing the classical approach to the sequence,structure,function paradigm, in this paper we report novel information obtained by comparing the physicochemical parameters of SV-IV with two datasets composed of intrinsically unfolded and ideally globular proteins. In addition, we analyse the SV-IV sequence by several publicly available disorder-oriented predictors. Overall, disorder predictions and a re-examination of existing experimental data strongly suggest that SV-IV needs large plasticity to efficiently interact with the different targets that characterize its multifaceted biological function, and should therefore be better classified as an intrinsically disordered protein. [source] Parental depression, parenting behaviours, and behaviour problems in young children,INFANT AND CHILD DEVELOPMENT, Issue 4 2009Melissa Middleton Abstract In the past, research has demonstrated that parental depression and parenting practices are related. More recently, there has been an increase in research examining child outcomes as they are related to maternal and paternal psychopathology. To continue with this line of research, this study examined the relationships among mothers' and fathers' symptoms of depression, characteristics of their parenting practices, and their ratings of their young children's internalizing and externalizing behaviour problems. The results of this study demonstrated that these variables are related significantly. Further, the results of this study suggested that mothers' parenting, particularly their limit setting with their young children, is an important predictor of their ratings of their young children's externalizing behaviour problems in the context of their own symptoms of depression. A different pattern of relationships may be present for fathers, as both their symptoms of depression and their parenting characteristics predicted their ratings of their young children's externalizing behaviour problems. Such findings were not supported for young children's internalizing behaviour problems. These findings suggested that interventions should have different targets for mothers and fathers. Copyright © 2009 John Wiley & Sons, Ltd. [source] Measuring Counterproductivity: Development and Initial Validation of a German Self-Report QuestionnaireINTERNATIONAL JOURNAL OF SELECTION AND ASSESSMENT, Issue 1-2 2002Bernd Marcus This article describes the development and initial construct validation of a comprehensive self-report measure of workplace counterproductivity. The instrument contains subscales for different targets of counterproductivity (organizational and interpersonal deviance, Robinson and Bennett 1995) as well as for different forms of manifestation (absenteeism, substance use, aggression, and theft, respectively) An empirical study (N = 174), conducted in one manufacturing and one retail organization, confirmed the intended internal structure by means of confirmatory factor analysis. Counterproductivity may best be described as a higher-order behavioural construct loading on subdimensions carrying unique variance. In addition, an examination of outside variables showed that the best predictor of counterproductivity was self-control, followed by integrity, whereas cognitive ability was largely unrelated to the construct. The opposite pattern of correlations occurred for productive performance behaviours, indicating that counterproductivity is a unique construct within the performance domain. Differences and similarities between the present measure and a recent independent development by Bennett and Robinson (2000) are discussed, along with conclusions for future research on the topic. [source] Vakzinationstherapie kutaner T-Zell-LymphomeJOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 12 2002Vaccination therapy for cutaneous T-cell lymphoma primary cutaneous T cell lymphomas (CTCL); vaccination; antigenic targets Zusammenfassung: Primär kutane T-Zell-Lymphome (CTCL) sind definiert als klonale Proliferation hautinfiltrierender T-Lymphozyten. Unabhängig von der Heterogenität dieser Krankheitsgruppe besteht derzeit keine kurative Therapiemöglichkeit, was zur Entwicklung verschiedener Behandlungsstrategien, einschließlich der Vakzination, führte. Dieser Artikel gibt eine Übersicht über den Entwicklungsstand der Vakzinationstherapie für Lymphome mit besonderer Rücksicht auf die CTCL. Da bisher kein universelles Tumorantigen identifiziert wurde, sind verschiedenste antigene Agenzien (komplette Tumorzellen, Idiotypen, Cancer/Testis-Antigene, Proteine aus tumorassoziierten Mutationen und Mimotope) hinsichtlich ihrer Eignung für die Vakzinationstherapie von CTCL untersucht worden. Die antigene Information dieser Präparationen kann dem körpereigenen Immunsystem über verschiedene Wege (Carrier) dargeboten werden, bisher sind dazu mit Tumorzellen fusionierte dendritische Zellen, Idiotyp-Proteine oder -Peptide sowie DNA- und RNA-Präparationen eingesetzt worden. Da die verwendeten Antigene allesamt schwache Immunogene darstellen, sind Adjuvanzien (dendritische Zellen, immunogene Peptide, Oligonukleotide, Zytokine, virale Vektoren) notwendig, um eine suffiziente Antigenpräsentation und Aktivierung des Immunsystems zu erreichen. Erste klinische Daten bestätigen die prinzipielle Wirksamkeit einer Vakzinationstherapie bei CTCL. Die große Anzahl bisher verwendeter Antigene, Carrier, Adjuvanzien und Applikationsschemen macht die Identifizierung eines optimalen Protokolls jedoch nahezu unmöglich. Da auch die Wechselwirkungen zwischen Lymphom und Immunsystem sehr komplex und nicht vollständig verstanden sind, ist bis zur Einführung der Vakzinationstherapie in die klinische Praxis noch großer Forschungsaufwand nötig. Summary: Primary cutaneous T,cell lymphomas (CTCL) are defined as clonal proliferation of skin-infiltrating T lymphocytes. Despite their heterogeneity, CTCL are generally incurable, which lead to the development of various treatment strategies including vaccination. Here, the attempts to vaccinate against lymphoma will be reviewed with special emphasis on CTCL. Since an universal tumour antigen is not available so far, different targets, including whole tumour cells, idiotypes, cancer/testis antigens, proteins derived from tumour-associated mutations, and mimotopes, have been investigated for their applicability in CTCL vaccination. The antigenic information can be delivered in different ways. So far, tumour cells fused to dendritic cells, idiotypic proteins/peptides and DNA/RNA preparations have been applied in lymphoma. Since most targets are weak immunogens, adjuvants and other helpers, including dendritic cells, immunogenic peptides and oligonucleotides, cytokines, and viral vectors, are required to enable proper presentation of the antigens and sufficient activation of the immune system. Although first data from CTCL patients prove the suitability of vaccination in CTCL therapy, the number of available antigens, carriers, adjuvants and application schemes creates a multitude of vaccine formulations and identification of the best-suited approach difficult. Furthermore, the relationship between lymphoma and the host immune system is complex and still not completely understood. In consequence, CTCL vaccination requires a lot of research to be done before its breakthrough. [source] Use of Cr K, radiation to enhance the signal from anomalous scatterers including sulfurJOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 3-2 2000Witek Kwiatkowski The anomalous signals from scatterers such as sulfur (S) and arsenic (As) were compared in diffraction data sets collected from an X-ray source with three different targets, Au, Cu and Cr, on a multi-target rotating anode. HIV-1 integrase crystals served as the test case for this study. The crystalline specimen of HIV-1 integrase contains in each protein molecule two As atoms, each covalently bound to a cysteine S atom, and two additional S atoms derived from methionine. It was found that the Cr K, radiation gave the clearest peaks in anomalous difference Fourier maps, although the signal-to-noise ratios of the anomalous signal for the Cu K, and Cr K, data were similar but better than that for Au L,. This result was in spite of the fourfold higher flux from the Cu anode versus the Cr anode. For all three X-ray wavelengths, anomalous difference Fourier maps calculated with bias-removed phases derived from the known atomic model revealed clear peaks at the two As sites. However, only in the map calculated using the Cr K, data were both peaks of the expected ellipsoidal shape, enveloping the As atom and the adjacent S atom. None of the S sites was apparent in difference maps calculated using the Au L, data. The ability to enhance the S-derived anomalous signal using Cr K, radiation has particularly useful applications in the structure determination of proteins, for example in resolving ambiguities in the chain tracing of a protein with numerous disulfide bonds and in assigning amino acid identities. Additionally, anomalous difference Patterson maps calculated from the Cr K, data were sufficiently clear to identify the As-related peaks. These results form the groundwork for in-house phase determination with the multi-wavelength anomalous diffraction method. [source] Role of annexin A6 isoforms in catecholamine secretion by PC12 cells: Distinct influence on calcium responseJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2010Paulina Podszywalow-Bartnicka Abstract Noradrenaline and adrenaline are secreted by adrenal medulla chromaffin cells via exocytosis. Exocytosis of catecholamines occurs after cell stimulation with various endogenous activators such as nicotine or after depolarization of the plasma membrane and is regulated by calcium ions. Cytosolic [Ca2+] increases in response to cell excitation and triggers a signal-initiated secretion. Annexins are known to participate in the regulation of membrane dynamics and are also considered to be involved in vesicular trafficking. Some experimental evidence suggests that annexins may participate in Ca2+ -regulated catecholamine secretion. In this report the effect of annexin A6 (AnxA6) isoforms 1 and 2 on catecholamine secretion has been described. Overexpression of AnxA6 isoforms and AnxA6 knock-down in PC12 cells were accompanied by almost complete inhibition or a 20% enhancement of dopamine secretion, respectively. AnxA6-1 and AnxA6-2 overexpression reduced ,[Ca2+]c upon depolarization by 32% and 58%, respectively, while AnxA6 knock-down increased ,[Ca2+]c by 44%. The mechanism of AnxA6 action on Ca2+ signalling is not well understood. Experimental evidence suggests that two AnxA6 isoforms interact with different targets engaged in regulation of calcium homeostasis in PC12 cells. J. Cell. Biochem. 111: 168,178, 2010. © 2010 Wiley-Liss, Inc. [source] Photothermal and accompanied phenomena of selective nanophotothermolysis with gold nanoparticles and laser pulsesLASER PHYSICS LETTERS, Issue 11 2008V.K. Pustovalov Abstract In medical applications of laser and nanotechnology to diagnosis and treat cancer or microorganisms, understanding of lased-induced photothermal (PT) and accompanied phenomena around nanoparticles are crucial for optimization and bringing this promising technology to bedside. We analyzed the main Ptbased effects in and around gold nanoparticles under action of short (nano-, pico-, and femtosecond) laser pulses with focus on photoacoustic effects due to the thermal expansion of nanoparticles and liquid around them, thermal protein denaturation, explosive liquid vaporization, melting and evaporation of nanoparticle, optical breakdown initiated by nanoparticles and accompanied to shock waves and explosion (fragmentation) of gold nanoparticles. Characteristic parameters for these processes such as the temperature and pressures levels, and laser intensity thresholds among others are summarized to provide basis for comparison of different mechanisms of selective nanophotothermolysis and diagnostics of different targets (e.g., cancer cells, bacteria, viruses). (© 2008 by Astro Ltd., Published exclusively by WILEY-VCH Verlag GmbH & Co. KGaA) [source] Ancient Weapons for Attack and Defense: the Pore-forming Polypeptides of Pathogenic Enteric and Free-living Amoeboid Protozoa,THE JOURNAL OF EUKARYOTIC MICROBIOLOGY, Issue 5 2004MATTHIAS LEIPPE ABSTRACT Pore-forming polypeptides have been purified from several amoeboid protozoans that are well-known human pathogens. Obligate enteric parasites, such as Entamoeba histolytica, and free-living but potentially highly pathogenic species, such as Naegleria fowleri, contain these cytolytic molecules inside cytoplasmic granules. Comprehensive functional and structural studies have been conducted that include isolation of the proteins from their natural sources, monitoring of their biological activity towards different targets, and molecular cloning of the genes of their precursors. In the case of the most prominent member of the protein family, with respect to protozoans, the three-dimensional structure of amoebapore A was solved recently. The amoebic pore-forming polypeptides can rapidly perforate human cells. The antibacterial activity of amoebapores and of related polypetides from free-living protozoa points to a more vital function of these molecules: inside the digestive vacuoles they combat growth of phagocytosed bacteria which are killed when their cytoplasmic membranes are permeabilized. The concommitant activity of these proteins towards host cells may be due to a coincidental selection for an efficient effector molecule. Nonetheless, several lines of evidence indicate that these factors are involved in pathogenesis of fatal diseases induced by amoeboid protozoa. [source] Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer's diseaseANAESTHESIA, Issue 4 2010V. Fodale Summary With longevity, postoperative cognitive decline in the elderly has emerged as a major health concern for which several factors have been implicated, one of the most recent being the role of anaesthetics. Interactions of anaesthetic agents and different targets have been studied at the molecular, cellular and structural anatomical levels. Recent in vitro nuclear magnetic resonance spectroscopy studies have shown that several anaesthetics act on the oligomerisation of amyloid , peptide. Uncontrolled production, oligomerisation and deposition of amyloid , peptide, with subsequent development of amyloid plaques, are fundamental steps in the generation of Alzheimer's disease. Amyloid , peptide is naturally present in the central nervous system, and is found at higher tissue concentrations in the elderly. We argue that administering certain general anaesthetics to elderly patients may worsen amyloid , peptide oligomerisation and deposition and thus increase the risk of developing postoperative cognitive dysfunction. The aim of this review is to highlight the clinical aspects of postoperative cognitive dysfunction and to find plausible links between possible anaesthetic effects and the molecular pathological mechanism of Alzheimer's disease. It is hoped that our hypothesis will stimulate further enquiry, especially triggering research into elucidating those anaesthetics that may be more suitable when cognitive dysfunction is a particular concern. [source] Selection and mass spectrometry characterization of peptides targeting semiconductor surfacesBIOTECHNOLOGY & BIOENGINEERING, Issue 6 2009Elias Estephan Abstract We report on elaboration of 12-mer peptides that reveal specific recognition for the following semiconductor (SC) surfaces: GaAs(100), InAs(100), GaN(0001), ZnSe(100), ZnTe(100), GaAs(111)A, GaSb(100), CdSe(100). A M13 bacteriophage library was used to screen 109 different 12-mer peptides against these substrates to finally isolate, in maximum six amplification cycles, peptides that bind to the target surfaces. The specific peptides for the InAs and ZnSe surfaces were obtained. Contrary, for the other SC surfaces several peptides with high affinities have been isolated. Aiming for a better specificity, when the phage display has been conducted through six cycles, the screening procedure got dominated by a phage present in the M13 bacteriophage library and the SVSVGMKPSPRP peptide has been selected for different SCs. The high amplification potential of this phage has been observed previously with different targets. Thus, precaution should be undertaken in defining adhesion peptides with the phage display technique and real affinity of the obtained biolinkers should be studied with other methods. We employed mass spectrometry (MALDI-TOF/TOF) to demonstrate the preferential attachment (or not) of the SVSVGMKPSPRP peptide to the different SC surfaces. This allows us to define a realistic selection of the expressed peptides presenting affinity for the studied eight SC surfaces. We demonstrate that with increasing the dielectric constants of the employed solvents, adhesion of the SVSVGMKPSPRP peptide onto GaN(0001) is hindered. Biotechnol. Bioeng. 2009; 104: 1121,1131. © 2009 Wiley Periodicals, Inc. [source] | ||||||||||||||||