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Tanja Proctor Katrin Jensen Meinhard Kieser 《Biometrical journal. Biometrische Zeitschrift》2020,62(3):777-789
Individualized therapies for patients with biomarkers are moving more and more into the focus of research interest when developing new treatments. Hereby, the term individualized (or targeted) therapy denotes a treatment specifically developed for biomarker-positive patients. A network meta-analysis model for a binary endpoint combining the evidence for a targeted therapy from individual patient data with the evidence for a non-targeted therapy from aggregate data is presented and investigated. The biomarker status of the patients is either available at patient-level in individual patient data or at study-level in aggregate data. Both types of biomarker information have to be included. The evidence synthesis model follows a Bayesian approach and applies a meta-regression to the studies with aggregate data. In a simulation study, we address three treatment arms, one of them investigating a targeted therapy. The bias and the root-mean-square error of the treatment effect estimate for the subgroup of biomarker-positive patients based on studies with aggregate data are investigated. Thereby, the meta-regression approach is compared to approaches applying alternative solutions. The regression approach has a surprisingly small bias even in the presence of few studies. By contrast, the root-mean-square error is relatively greater. An illustrative example is provided demonstrating implementation of the presented network meta-analysis model in a clinical setting. 相似文献
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SA Carrasco 《New Zealand journal of zoology.》2013,40(1):32-45
This study combined morphological and morphometric information on egg clutches, egg capsules and paralarvae of two sympatric coastal octopuses from New Zealand waters, Octopus huttoni and Pinnoctopus cordiformis, to provide species-specific traits to identify their early life stages obtained from field surveys. Eggs of O. huttoni (2.5 mm length; 1 mm width) were entwined with one another forming strings that ranged from 11 to 25.8 mm in length. Eggs of P. cordiformis (6.4 mm length; 1.5 mm width) were significantly bigger than those of O. huttoni and were grouped in small clusters of about seven eggs. Paralarvae O. huttoni and P. cordiformis differed in hatching size (1.4 mm versus 3.1 mm mantle length), number of suckers per arm (four versus eight), number of lamellae per outer demibranch (five versus ten) and arrangements of chromatophores in the body surface (29 to 59 versus 91 to 179), respectively. The morphological traits described in hatchlings from the laboratory allowed comparisons with field-collected paralarvae, suggesting that such characters were reliable species-specific patterns to enable a consistent differentiation between the early life stages of these two sympatric species, even in the absence of the brooding female. 相似文献
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Elizabeth A. Proctor Pradeep Kota Stephen J. Demarest Justin A. Caravella Nikolay V. Dokholyan 《Proteins》2013,81(5):884-895
The ability to generate and design antibodies recognizing specific targets has revolutionized the pharmaceutical industry and medical imaging. Engineering antibody therapeutics in some cases requires modifying their constant domains to enable new and altered interactions. Engineering novel specificities into antibody constant domains has proved challenging due to the complexity of inter‐domain interactions. Covarying networks of residues that tend to cluster on the protein surface and near binding sites have been identified in some proteins. However, the underlying role these networks play in the protein resulting in their conservation remains unclear in most cases. Resolving their role is crucial, because residues in these networks are not viable design targets if their role is to maintain the fold of the protein. Conversely, these networks of residues are ideal candidates for manipulating specificity if they are primarily involved in binding, such as the myriad interdomain interactions maintained within antibodies. Here, we identify networks of evolutionarily‐related residues in C‐class antibody domains by evaluating covariation, a measure of propensity with which residue pairs vary dependently during evolution. We computationally test whether mutation of residues in these networks affects stability of the folded antibody domain, determining their viability as design candidates. We find that members of covarying networks cluster at domain‐domain interfaces, and that mutations to these residues are diverse and frequent during evolution, precluding their importance to domain stability. These results indicate that networks of covarying residues exist in antibody domains for functional reasons unrelated to thermodynamic stability, making them ideal targets for antibody design. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
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Ecosystem engineers affect other species by changing physical environments. Such changes may influence movement of organisms, particularly belowground where soil permeability can restrict dispersal. We investigated whether earthworms, iconic ecosystem engineers, influence microarthropod movement. Our experiment tested whether movement is affected by tunnels (i.e., burrows), earthworm excreta (mucus, castings), or earthworms themselves. Earthworm burrows form tunnel networks that may facilitate movement. This effect may be enhanced by excreta, which could provide resources for microarthropods moving along the network. Earthworms may also promote movement via phoresy. Conversely, negative effects could occur if earthworms alter predator-prey relationships or change competitive interactions between microarthropods. We used microcosms consisting of a box connecting a “source” container in which microarthropods were present and a “destination” container filled with autoclaved soil. Treatments were set up within the boxes, which also contained autoclaved soil, as follows: 1) control with no burrows; 2) artificial burrows with no excreta; 3) abandoned burrows with excreta but no earthworms; and 4) earthworms (Lumbricus rubellus) present in burrows. Half of the replicates were sampled once after eight days, while the other half were sampled repeatedly to examine movement over time. Rather than performing classical pairwise comparisons to test our hypotheses, we used AICc to assess support for three competing models (presence of tunnels, excreta, and earthworms). More individuals of Collembola, Mesostigmata, and all microarthropods together dispersed when tunnels were present. Models that included excreta and earthworms were less well supported. Total numbers of dispersing Oribatida and Prostigmata+Astigmata were not well explained by any models tested. Further research is needed to examine the impact of soil structure and ecosystem engineering on movement belowground, as the substantial increase in movement of some microarthropods when corridors were present suggests these factors can strongly affect colonization and community assembly. 相似文献
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Anthony E. Glenn C. Britton Davis Minglu Gao Scott E. Gold Trevor R. Mitchell Robert H. Proctor Jane E. Stewart Maurice E. Snook 《PloS one》2016,11(1)
Microbes encounter a broad spectrum of antimicrobial compounds in their environments and often possess metabolic strategies to detoxify such xenobiotics. We have previously shown that Fusarium verticillioides, a fungal pathogen of maize known for its production of fumonisin mycotoxins, possesses two unlinked loci, FDB1 and FDB2, necessary for detoxification of antimicrobial compounds produced by maize, including the γ-lactam 2-benzoxazolinone (BOA). In support of these earlier studies, microarray analysis of F. verticillioides exposed to BOA identified the induction of multiple genes at FDB1 and FDB2, indicating the loci consist of gene clusters. One of the FDB1 cluster genes encoded a protein having domain homology to the metallo-β-lactamase (MBL) superfamily. Deletion of this gene (MBL1) rendered F. verticillioides incapable of metabolizing BOA and thus unable to grow on BOA-amended media. Deletion of other FDB1 cluster genes, in particular AMD1 and DLH1, did not affect BOA degradation. Phylogenetic analyses and topology testing of the FDB1 and FDB2 cluster genes suggested two horizontal transfer events among fungi, one being transfer of FDB1 from Fusarium to Colletotrichum, and the second being transfer of the FDB2 cluster from Fusarium to Aspergillus. Together, the results suggest that plant-derived xenobiotics have exerted evolutionary pressure on these fungi, leading to horizontal transfer of genes that enhance fitness or virulence. 相似文献
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A hidden aggregation‐prone structure in the heart of hypoxia inducible factor prolyl hydroxylase
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Hamid Hadi‐Alijanvand Elizabeth A. Proctor Feng Ding Nikolay V. Dokholyan Ali A. Moosavi‐Movahedi 《Proteins》2016,84(5):611-623
Prolyl hydroxylase domain‐containing protein 2 (PHD2), as one of the most important regulators of angiogenesis and metastasis of cancer cells, is a promising target for cancer therapy drug design. Progressive studies imply that abnormality in PHD2 function may be due to misfolding. Therefore, study of the PHD2 unfolding pathway paves the way for a better understanding of the influence of PHD2 mutations and cancer cell metabolites on the protein folding pathway. We study the unfolding of the PHD2 catalytic domain using differential scanning calorimetry (DSC), fluorescence spectroscopy, and discrete molecular dynamics simulations (DMD). Using computational and experimental techniques, we find that PHD2 undergoes four transitions along the thermal unfolding pathway. To illustrate PHD2 unfolding events in atomic detail, we utilize DMD simulations. Analysis of computational results indicates an intermediate species in the PHD2 unfolding pathway that may enhance aggregation propensity, explaining mutation‐independent PHD2 malfunction. Proteins 2016; 84:611–623. © 2016 Wiley Periodicals, Inc. 相似文献
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Endothelial progenitor cells (EPC) participate in revascularization and angiogenesis. EPC can be cultured in vitro from mononuclear cells of peripheral blood, umbilical cord blood or bone marrow; they also can be transdifferentiated from mesenchymal stem cells (MSC). We isolated EPCs from Wharton's jelly (WJ) using two methods. The first method was by obtaining MSC from WJ and characterizing them by flow cytometry and their adipogenic and osteogenic differentiation, then applying endothelial growth differentiating media. The second method was by direct culture of cells derived from WJ into endothelial differentiating media. EPCs were characterized by morphology, Dil-LDL uptake/UEA-1 immunostaining and testing the expression of endothelial markers by flow cytometry and RT-PCR. We found that MSC derived from WJ differentiated into endothelial-like cells using simple culture conditions with endothelium induction agents in the medium. 相似文献