| 1. |
- Advani, Jayshree, et al.
(författare)
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Rise of Clinical Microbial Proteogenomics : A Multiomics Approach to Nontuberculous Mycobacterium-The Case of Mycobacterium abscessus UC22
- 2018
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Ingår i: Omics. - : MARY ANN LIEBERT, INC. - 1536-2310 .- 1557-8100. ; 23:1, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Nontuberculous mycobacterial (NTM) species present a major challenge for global health with serious clinical manifestations ranging from pulmonary to skin infections. Multiomics research and its applications toward clinical microbial proteogenomics offer veritable potentials in this context. For example, the Mycobacterium abscessus, a highly pathogenic NTM, causes bronchopulmonary infection and chronic pulmonary disease. The rough variant of the M. abscessus UC22 strain is extremely virulent and causes lung upper lobe fibrocavitary disease. Although several whole-genome next-generation sequencing studies have characterized the genes in the smooth variant of M. abscessus, a reference genome sequence for the rough variant was generated only recently and calls for further clinical applications. We carried out whole-genome sequencing and proteomic analysis for a clinical isolate of M. abscessus UC22 strain obtained from a pulmonary tuberculosis patient. We identified 5506 single-nucleotide variations (SNVs), 63 insertions, and 76 deletions compared with the reference genome. Using a high-resolution LC-MS/MS-based approach (liquid chromatography tandem mass spectrometry), we obtained protein coding evidence for 3601 proteins, representing 71% of the total predicted genes in this genome. Application of proteogenomic approach further revealed seven novel protein-coding genes and enabled refinement of six computationally derived gene models. We also identified 30 variant peptides corresponding to 16 SNVs known to be associated with drug resistance. These new observations offer promise for clinical applications of microbial proteogenomics and next-generation sequencing, and provide a resource for future global health applications for NTM species.
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| 2. |
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| 3. |
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| 4. |
- Cavalli, Marco, et al.
(författare)
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A Multi-Omics Approach to Liver Diseases : Integration of Single Nuclei Transcriptomics with Proteomics and HiCap Bulk Data in Human Liver
- 2020
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Ingår i: Omics. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 24:4, s. 180-194
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Tidskriftsartikel (refereegranskat)abstract
- The liver is the largest solid organ and a primary metabolic hub. In recent years, intact cell nuclei were used to perform single-nuclei RNA-seq (snRNA-seq) for tissues difficult to dissociate and for flash-frozen archived tissue samples to discover unknown and rare cell subpopulations. In this study, we performed snRNA-seq of a liver sample to identify subpopulations of cells based on nuclear transcriptomics. In 4282 single nuclei, we detected, on average, 1377 active genes and we identified seven major cell types. We integrated data from 94,286 distal interactions (p < 0.05) for 7682 promoters from a targeted chromosome conformation capture technique (HiCap) and mass spectrometry proteomics for the same liver sample. We observed a reasonable correlation between proteomics and in silico bulk snRNA-seq (r = 0.47) using tissue-independent gene-specific protein abundancy estimation factors. We specifically looked at genes of medical importance. The DPYD gene is involved in the pharmacogenetics of fluoropyrimidine toxicity and some of its variants are analyzed for clinical purposes. We identified a new putative polymorphic regulatory element, which may contribute to variation in toxicity. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and we investigated all known risk genes. We identified a complex regulatory landscape for the SLC2A2 gene with 16 candidate enhancers. Three of them harbor somatic motif breaking and other mutations in HCC in the Pan Cancer Analysis of Whole Genomes dataset and are candidates to contribute to malignancy. Our results highlight the potential of a multi-omics approach in the study of human diseases.
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| 5. |
- Cavalli, Marco, et al.
(författare)
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The Thioesterase ACOT1 as a Regulator of Lipid Metabolism in Type 2 Diabetes Detected in a Multi-Omics Study of Human Liver
- 2021
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Ingår i: Omics. - : Mary Ann Liebert. - 1536-2310 .- 1557-8100. ; 25:10, s. 652-659
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is characterized by pathophysiological alterations in lipid metabolism. One strategy to understand the molecular mechanisms behind these abnormalities is to identify cis-regulatory elements (CREs) located in chromatin-accessible regions of the genome that regulate key genes. In this study we integrated assay for transposase-accessible chromatin followed by sequencing (ATAC-seq) data, widely used to decode chromatin accessibility, with multi-omics data and publicly available CRE databases to identify candidate CREs associated with T2D for further experimental validations. We performed high-sensitive ATAC-seq in nine human liver samples from normal and T2D donors, and identified a set of differentially accessible regions (DARs). We identified seven DARs including a candidate enhancer for the ACOT1 gene that regulates the balance of acyl-CoA and free fatty acids (FFAs) in the cytoplasm. The relevance of ACOT1 regulation in T2D was supported by the analysis of transcriptomics and proteomics data in liver tissue. Long-chain acyl-CoA thioesterases (ACOTs) are a group of enzymes that hydrolyze acyl-CoA esters to FFAs and coenzyme A. ACOTs have been associated with regulation of triglyceride levels, fatty acid oxidation, mitochondrial function, and insulin signaling, linking their regulation to the pathogenesis of T2D. Our strategy integrating chromatin accessibility with DNA binding and other types of omics provides novel insights on the role of genetic regulation in T2D and is extendable to other complex multifactorial diseases.
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| 6. |
- Clish, Clary B., et al.
(författare)
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Integrative biological analysis of the APOE*3-leiden transgenic mouse
- 2004
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Ingår i: Omics. - : Mary Ann Liebert. - 1536-2310 .- 1557-8100. ; 8:1, s. 3-13
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Tidskriftsartikel (refereegranskat)abstract
- Integrative (or systems biology) is a new approach to analyzing biological entities as integrated systems of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. Here, we demonstrate the application of intregrative biological analysis to a mammalian disease model, the apolipoprotein E3-Leiden (APO*E3) transgenic mouse. Mice selected for the study were fed a normal chow diet and sacrificed at 9 weeks of age-conditions under which they develop only mild type I and II atherosclerotic lesions. Hepatic mRNA expression analysis showed a 25% decrease in APO A1 and a 43% increase in liver fatty acid binding protein expression between transgenic and wild type control mice, while there was no change in PPAR-alpha expression. On-line high performance liquid chromatography-mass spectrometry quantitative profiling of tryptic digests of soluble liver proteins and liver lipids, coupled with principle component analysis, enabled rapid identification of early protein and metabolite markers of disease pathology. These included a 44% increase in L-FABP in transgenic animals compared to controls, as well as an increase in triglycerides and select bioactive lysophosphatidylcholine species. A correlation analysis of identified genes, proteins, and lipids was used to construct an interaction network. Taken together, these results indicate that integrative biology is a powerful tool for rapid identification of early markers and key components of pathophysiologic processes, and constitute the first application of this approach to a mammalian system.
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| 7. |
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| 8. |
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| 9. |
- Davidov, Eugene, et al.
(författare)
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Methods for the differential integrative omic analysis of plasma from a transgenic disease animal model
- 2004
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Ingår i: Omics. - : Mary Ann Liebert. - 1536-2310 .- 1557-8100. ; 8:4, s. 267-288
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Tidskriftsartikel (refereegranskat)abstract
- Multitiered quantitative analysis of biological systems is rapidly becoming the desired approach to study hierarchical functional interactions between proteins and metabolites. We describe here a novel systematic approach to analyze organisms with complex metabolic regulatory networks. By using precise analytical methods to measure biochemical constituents and their relative abundance in whole plasma of transgenic ApoE*3-Leiden mice and an isogenic wild-type control group, simultaneous snapshots of metabolic and protein states were obtained. Novel data processing and multivariate analysis tools such as Impurity Resolution Software (IMPRESS) and Windows-based linear fit program (WINLIN) were used to compare protein and metabolic profiles in parallel. Canonical correlations of the resulting data show quantitative relationships between heterogeneous components in the TG animals. These results, obtained solely from whole plasma analysis allowed us, in a rapid manner, to corroborate previous findings as well as find new events pertaining to dominant and peripheral events in lipoprotein metabolism of a genetically modified mammalian organism in relation to ApoE3, a key mediator of lipoprotein metabolism.
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| 10. |
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| 11. |
- Elo, Laura L., et al.
(författare)
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Improving identification of differentially expressed genes by integrative analysis of Affymetrix and Illumina arrays
- 2006
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Ingår i: Omics. - : Mary Ann Liebert. - 1536-2310 .- 1557-8100. ; 10:3, s. 369-380
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Tidskriftsartikel (refereegranskat)abstract
- Together with the widely used Affymetrix microarrays, the recently introduced Illumina platform has become a cost-effective alternative for genome-wide studies. To efficiently use data from both array platforms, there is a pressing need for methods that allow systematic integration of multiple datasets, especially when the number of samples is small. To address these needs, we introduce a meta-analytic procedure for combining Affymetrix and Illumina data in the context of detecting differentially expressed genes between the platforms. We first investigate the effect of different expression change estimation procedures within the platforms on the agreement of the most differentially expressed genes. Using the best estimation methods, we then show the benefits of the integrative analysis in producing reproducible results across bootstrap samples. In particular, we demonstrate its biological relevance in identifying small but consistent changes during T helper 2 cell differentiation.
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| 12. |
- Günther, Torsten, et al.
(författare)
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Where in the genome are significant single nucleotide polymorphisms from genome-wide association studies located?
- 2011
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Ingår i: Omics. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 15:7-8, s. 507-12
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Tidskriftsartikel (refereegranskat)abstract
- Recent technological progress has permitted the efficient performance of genome-wide association studies (GWAS) to map genetic variants associated with common diseases. Here, we analyzed 2,893 single nucleotide polymorphisms (SNPs) that have been identified in 593 published GWAS as associated with a disease phenotype with respect to their genomic location. In absolute numbers, most significant SNPs are located in intergenic regions and introns. When compared to their representation on the chips, there is essentially overrepresentation of nonsynonymous coding SNPs (nsSNPs), synonymous coding SNPs, and SNPs in untranscribed regions upstream of genes among the disease associated SNPs. A Gene Ontology term analysis showed that genes putatively causing a phenotype often code for membrane associated proteins or signal transduction genes.
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| 13. |
- Hatta, Fazleen H M, et al.
(författare)
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Differences in CYP2C9 Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine : Role of Ethnicity, Genotype, Smoking, Age, and Sex
- 2015
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Ingår i: Omics. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 19:6, s. 346-353
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Tidskriftsartikel (refereegranskat)abstract
- Global personalized medicine demands the characterization of person-to-person and between-population differences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is subject to modulation by both genetic and environmental factors. CYP2C9 genotype-based dose recommendations (e.g., for warfarin) is advocated. However, the overall contribution of genotype for variation in enzyme activity may differ between populations. We evaluated the importance of ethnicity, genotype, smoking, body weight, age, and sex for CYP2C9 enzyme activity. CYP2C9 genotype and phenotype was determined in 148 Swedes and 146 Koreans using losartan as a probe. CYP2C9 enzyme activity was assessed using urinary losartan/metabolite E-3174 ratio. The frequency of CYP2C9 defective variant alleles (*2 and *3) was significantly higher in Swedes (10.8% and 12.5%) than in Koreans (0% and 5.8%). In matched genotypes, CYP2C9 enzyme activity was significantly lower in Swedes compared to Koreans (p<0.0001). In a univariate analysis, age, weight, ethnicity, genotype, and smoking were significant predictors of CYP2C9 phenotype. A stepwise multivariate analysis indicated ethnicity, genotype, and smoking remained as significant predictors of CYP2C9 enzyme activity, accounting for 50% of the total variance. In both study populations, CYP2C9 genotype was a significant predictor of CYP2C9 enzyme activity, but its contribution in explaining the total variance was lower in Koreans (26.6%) than Swedes (40%). In conclusion, we report significantly lower CYP2C9 enzyme activity in Swedes compared to Koreans, partly but not exclusively due to CYP2C9 pharmacogenetic variations. Ethnicity and environment factors need to be considered together with genotype for population-specific dose optimization and global personalized medicine.
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| 14. |
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| 15. |
- Jamialahmadi, Oveis, et al.
(författare)
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Cellular Genome-Scale Metabolic Modeling Identifies New Potential Drug Targets Against Hepatocellular Carcinoma.
- 2022
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Ingår i: Omics : a journal of integrative biology. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 26:12, s. 671-682
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Tidskriftsartikel (refereegranskat)abstract
- Genome-scale metabolic modeling (GEM) is one of the key approaches to unpack cancer metabolism and for discovery of new drug targets. In this study, we report the Transcriptional Regulated Flux Balance Analysis-CORE (TRFBA-), an algorithm for GEM using key growth-correlated reactions using hepatocellular carcinoma (HCC), an important global health burden, as a case study. We generated a HepG2 cell-specific GEM by integrating this cell line transcriptomic data with a generic human metabolic model to forecast potential drug targets for HCC. A total of 108 essential genes for growth were predicted by the TRFBA-CORE. These genes were enriched for metabolic pathways involved in cholesterol, sterol, and steroid biosynthesis. Furthermore, we silenced a predicted essential gene, 11-beta dehydrogenase hydroxysteroid type 2 (HSD11B2), in HepG2 cells resulting in a reduction in cell viability. To further identify novel potential drug targets in HCC, we examined the effect of nine drugs targeting the essential genes, and observed that most drugs inhibited the growth of HepG2 cells. Some of these drugs in this model performed better than Sorafenib, the first-line therapeutic against HCC. A HepG2 cell-specific GEM highlights sterol metabolism to be essential for cell growth. HSD11B2 downregulation results in lower cell growth. Most of the compounds, selected by drug repurposing approach, show a significant inhibitory effect on cell growth in a wide range of concentrations. These findings offer new molecular leads for drug discovery for hepatic cancer while also illustrating the importance of GEM and drug repurposing in cancer therapeutics innovation.
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| 16. |
- Larsson, O, et al.
(författare)
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Comparative microarray analysis
- 2006
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Ingår i: Omics : a journal of integrative biology. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 10:3, s. 381-397
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Tidskriftsartikel (refereegranskat)
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| 17. |
- Nilsson, Emil K., et al.
(författare)
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Epigenomics of Total Acute Sleep Deprivation in Relation to Genome-Wide DNA Methylation Profiles and RNA Expression
- 2016
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Ingår i: Omics. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 20:6, s. 334-342
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Tidskriftsartikel (refereegranskat)abstract
- Despite an established link between sleep deprivation and epigenetic processes in humans, it remains unclear to what extent sleep deprivation modulates DNA methylation. We performed a within-subject randomized blinded study with 16 healthy subjects to examine the effect of one night of total sleep deprivation (TSD) on the genome-wide methylation profile in blood compared with that in normal sleep. Genome-wide differences in methylation between both conditions were assessed by applying a paired regression model that corrected for monocyte subpopulations. In addition, the correlations between the methylation of genes detected to be modulated by TSD and gene expression were examined in a separate, publicly available cohort of 10 healthy male donors (E-GEOD-49065). Sleep deprivation significantly affected the DNA methylation profile both independently and in dependency of shifts in monocyte composition. Our study detected differential methylation of 269 probes. Notably, one CpG site was located 69 bp upstream of ING5, which has been shown to be differentially expressed after sleep deprivation. Gene set enrichment analysis detected the Notch and Wnt signaling pathways to be enriched among the differentially methylated genes. These results provide evidence that total acute sleep deprivation alters the methylation profile in healthy human subjects. This is, to our knowledge, the first study that systematically investigated the impact of total acute sleep deprivation on genome-wide DNA methylation profiles in blood and related the epigenomic findings to the expression data.
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| 18. |
- Sachdeva, Cheryl, et al.
(författare)
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In silicoPotential of Approved Antimalarial Drugs for Repurposing Against COVID-19
- 2020
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Ingår i: Omics. - : MARY ANN LIEBERT, INC. - 1536-2310 .- 1557-8100. ; 24:10, s. 568-580
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Tidskriftsartikel (refereegranskat)abstract
- Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on thein silicopotential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (M-Pro) using the Schrodinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. Thein silicoapproach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, furtherin vitroandin vivostudies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.
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| 19. |
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| 20. |
- Thysell, Elin, et al.
(författare)
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Reliable Profile Detection in Comparative Metabolomics
- 2007
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Ingår i: Omics. - : Mary Ann Liebert. - 1536-2310 .- 1557-8100. ; 11:2, s. 209-224
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Tidskriftsartikel (refereegranskat)abstract
- A strategy for processing of metabolomic GC/MS data is presented. By considering the relationship between quantity and quality of detected profiles, representative data suitable for multiple sample comparisons and metabolite identification was generated. Design of experiments (DOE) and multivariate analysis was used to relate the changes in settings of the hierarchical multivariate curve resolution (H-MCR) method to quantitative and qualitative characteristics of the output data. These characteristics included number of resolved profiles, chromatographic quality in terms of reproducibility between analytical replicates, and spectral quality defined by purity and number of spectra containing structural information. The strategy was exemplified in two datasets: one containing 119 common metabolites, 18 of which were varied according to a DOE protocol; and one consisting of rat urine samples from control rats and rats exposed to a liver toxin. It was shown that the performance of the data processing could be optimized to produce metabolite data of high quality that allowed reliable sample comparisons and metabolite identification. This is a general approach applicable to any type of data processing where the important processing parameters are known and relevant output data characteristics can be defined. The results imply that this type of data quality optimization should be carried out as an integral step of data processing to ensure high quality data for further modeling and biological evaluation. Within metabolomics, this degree of optimization will be of high importance to generate models and extract biomarkers or biomarker patterns of biological or clinical relevance.
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| 21. |
- Vongsangnak, Wanwipa, 1982, et al.
(författare)
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Analysis of Genome-Wide Coexpression and Coevolution of Aspergillus oryzae and Aspergillus niger
- 2010
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Ingår i: OMICS A Journal of Integrative Biology. - : Mary Ann Liebert Inc. - 1536-2310 .- 1557-8100. ; 14:2, s. 165-175
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Tidskriftsartikel (refereegranskat)abstract
- Analysis of coexpressed genes in response to different perturbations at the genome-level can provide new insight into global regulatory structures. Here we performed integrated data analysis for a crossspecies comparative investigation by exploring genomes and transcriptional coexpression profiles in Aspergillus oryzae and Aspergillus niger. Based on our analysis of conserved coexpressed genes, fatty acid catabolism via beta-oxidation, fatty acid transport, the glyoxylate bypass, and peroxisomal biogenesis were identified as core coevolved pathways between the two species. The occurrence of coexpression patterns, allowed for identification of DNA regulatory motifs and putative corresponding transcription factors, and we hereby show that comparative transcriptome analysis between two closely related fungi allows for identification of how genes involved in the utilization of fatty acids, peroxisomal biogenesis, and the glyoxylate bypass are regulated. Interestingly, "CCTCGG'' was identified as a core binding site for the putative FarA and FarB transcription factors that govern the underlined biological processes. Phylogeny and domain architecture analysis of amino acid sequences of FarA and FarB in eight species of aspergilli, clearly indicate that these proteins are evolutionarily conserved across Aspergillus species as well as they are conserved in other fungi.
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| 22. |
- Wingren, Christer, et al.
(författare)
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Antibody microarrays: Current status and key technological advances
- 2006
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Ingår i: OMICS: A Journal of Integrative Biology. - : Mary Ann Liebert Inc. - 1557-8100 .- 1536-2310. ; 10:3, s. 411-427
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Forskningsöversikt (refereegranskat)abstract
- Antibody-based microarrays are among the novel classes of rapidly evolving proteomic technologies that holds great promise in biomedicine. Miniaturized microarrays (< 1 cm(2)) can be printed with thousands of individual antibodies carrying the desired specificities, and with biological sample (e.g., an entire proteome) added, virtually any specifically bound analytes can be detected. While consuming only minute amounts (
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| 23. |
- Zieba, Agata, et al.
(författare)
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The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling
- 2015
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Ingår i: Omics. - : MARY ANN LIEBERT, INC. - 1536-2310 .- 1557-8100. ; 19:11, s. 659-668
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Tidskriftsartikel (refereegranskat)abstract
- The human uterus includes the complex endometrial mucosa, the endometrium that undergoes dynamic, hormone-dependent alterations throughout the life of fertile females. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to analyze gene expression patterns in the normal endometrium. Human endometrial tissues from five women were used for deep sequencing (RNA-Seq). The mRNA and protein expression data from the endometrium were compared to 31 (RNA) and 44 (protein) other normal tissue types, to identify genes with elevated expression in the endometrium and to localize the expression of corresponding proteins at a cellular resolution. Based on the expression levels of transcripts, we could classify all putative human protein coding genes into categories defined by expression patterns and found altogether 101 genes that showed an elevated pattern of expression in the endometrium, with only four genes showing more than five-fold higher expression levels in the endometrium compared to other tissues. In conclusion, our analysis based on transcriptomics and antibody-based protein profiling reports here comprehensive lists of genes with elevated expression levels in the endometrium, providing important starting points for a better molecular understanding of human reproductive biology and disease.
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| 24. |
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| 25. |
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| 26. |
- Rapp-Ricciardi, Max, 1964, et al.
(författare)
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Designed Mentorship, Career Development, Learning and Psychological Growth across Generations: A Study of a Mentoring Program in an International Industrial Company
- 2016
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Ingår i: Omics. - 1536-2310. ; 2:4, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was: 1) to evaluate workplace mentoring programs from the perspectives of the mentors and protégés. 2) to compare the evolution of three mentoring programs 3) to contribute to the development of the theoretical field of mentorship. Qualitative and quantitative methods were used and data was collected during a five year period at an international company. The results showed that the majority of the mentors and protégés were satisfied mainly with how the mentoring programs provided personal growth and learning. The separation between junior employees and senior employees in the mentoring programs has decreased over the years concomitant with a strengthening of organizational culture. It was noted not only that the protégés need to be inspired, but also that mentors need inspiration as well. Resilient relationship between mentors and protégés may occur only if the gain is mutual over time. One conclusion pertains to the necessity of designing mentor programs that will contribute to the mentors’ as well as the protégées’ development. A model is presented that indicates how this development may be accomplished.
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| 27. |
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| 28. |
- Doran, Michael G., et al.
(författare)
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Cabozantinib Resolves Bone Scans in Tumor-Naive Mice Harboring Skeletal Injuries
- 2014
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Ingår i: Molecular Imaging. - : SAGE Publications. - 1535-3508 .- 1536-0121. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The receptor tyrosine kinase inhibitor cabozantinib (XL184, BMS-907351 Cometriq) has displayed impressive clinical activity against several indications, culminating in its recent approval for medullary thyroid cancer. Among malignancies with tropism for the bone (prostate, breast), one striking feature of early clinical reports about this drug has been the rapid and complete resolution of bone scans, a phenomenon almost never observed even among therapies already shown to confer survival benefit. In castration-resistant prostate cancer, not all conventional response indicators change as dramatically posttreatment, raising the possibility that cabozantinib may impair the ability of bone-seeking radionuclides to integrate within the remodeling bone. To test this hypothesis, we surgically induced bone remodeling via physical insult in non-tumor-bearing mice and performed F-18-sodium fluoride (F-18-NaF) positron emission tomographic (PET) and technetium 99m-methylene diphosphonate (Tc-99m-MDP) single-photon emission computed tomographic (SPECT) scans pre- and posttreatment with cabozantinib and related inhibitors. A consistent reduction in the accumulation of either radiotracer at the site of bone remodeling was observed in animals treated with cabozantinib. Given that cabozantinib is known to inhibit several receptor tyrosine kinases, we drugged animals with various permutations of more selective inhibitors to attempt to refine the molecular basis of bone scan resolution. Neither the vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib, the MET inhibitor crizotinib, nor the combination was capable of inhibiting F-18-NaF accumulation at known bioactive doses. In summary, although the mechanism by which cabozantinib suppresses radionuclide incorporation into foci undergoing bone remodeling remains unknown, that this phenomenon occurs in tumor-naive models indicates that caution should be exercised in interpreting the clinical significance of this event.
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| 29. |
- Eriksson, Olof, et al.
(författare)
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[C-11] Carfentanil Binds Preferentially to mu-Opioid Receptor Subtype 1 Compared to Subtype 2
- 2015
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Ingår i: Molecular Imaging. - : SAGE Publications. - 1535-3508 .- 1536-0121. ; 14, s. 476-483
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Tidskriftsartikel (refereegranskat)abstract
- The positron emission tomography (PET) ligand [C-11] carfentanil is a selective agonist for mu-opioid receptors and has been used for studying mu-opioid receptors in the human brain. However, it is unknown if [C-11] carfentanil binding differentiates between subtype receptors mu(1) and mu(2). In this study, we investigated whether mu(1) and mu(2) can be studied separately through receptor subtype-selective inhibition of [C-11] carfentanil by pharmacologic intervention. [C-11] Carfentanil binding characteristics on rat brain sections were assessed either alone or in the presence of the mu-receptor inhibitor cyprodime or the mu(1)-specific inhibitor naloxonazine. [C-11] Carfentanil binding in the living rat brain was similarly studied by small animal PET/computed tomography during baseline conditions or following displacement by cyprodime or naloxonazine. Autoradiography binding studies on rat brain sections demonstrated that [C-11] carfentanil has higher affinity and binding potential for mu(1) than for mu(2). [C-11] Carfentanil binding to mu(2) in vivo could not be detected following specific blocking of mu(1), as predicted from the low binding potential for mu(2) as measured in vitro. [C-11] Carfentanil binding is preferential for mu(1) compared to mu(2) in vitro and in vivo. Clinical studies employing [C-11] carfentanil are therefore likely biased to measure mu(1) rather than mu(2).
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| 30. |
- Honarvar, Hadis, et al.
(författare)
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Position for site-specific attachment of a DOTA chelator to synthetic affibody molecules has a different influence on the targeting properties of 68Ga-Compared to 111in-labeled conjugates
- 2014
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Ingår i: Molecular Imaging. - : SAGE Publications. - 1535-3508 .- 1536-0121. ; 13:10
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules, small (7 kDa) scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET), providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT). The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the Cterminus. The biodistribution of 68Ga-and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers, and the influence was more pronounced for 68Ga-labeled Affibody molecules than for the 111In-labeled counterparts. The best 68Ga-labeled variant was 68Ga-[DOTA-A1]-ZHER2:S1, which provided a tumor uptake of 13 ± 1 %ID/g and a tumor to blood ratio of 39 ± 12 at 2 hours after injection. 111In-[DOTA-A1]-ZHER2:S1 and 111In-[DOTA-K58]-ZHER2:S1 were equally good at this time point, providing a tumor uptake of 15 to 16 %ID/g and a tumor to blood ratio in the range of 60 to 80. In conclusion, the selection of the best position for a chelator in Affibody molecules can be used for optimization of their imaging properties. This may be important for the development of Affibody-based and other protein-based imaging probes.
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| 31. |
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| 32. |
- Zhang, Deyou, Postdoc, 1991-, et al.
(författare)
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IRS Assisted Federated Learning: A Broadband Over-the-Air Aggregation Approach
- 2023
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Ingår i: IEEE Transactions on Wireless Communications. - 1536-1276 .- 1558-2248.
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Tidskriftsartikel (refereegranskat)abstract
- We consider a broadband over-the-air computation empowered model aggregation approach for wireless federated learning (FL) systems and propose to leverage an intelligent reflecting surface (IRS) to combat wireless fading and noise. We first investigate the conventional node-selection based framework, where a few edge nodes are dropped in model aggregation to control the aggregation error. We analyze the performance of this node-selection based framework and derive an upper bound on its performance loss, which is shown to be related to the selected edge nodes. Then, we seek to minimize the mean-squared error (MSE) between the desired global gradient parameters and the actually received ones by optimizing the selected edge nodes, their transmit equalization coefficients, the IRS phase shifts, and the receive factors of the cloud server. By resorting to the matrix lifting technique and difference-of-convex programming, we successfully transform the formulated optimization problem into a convex one and solve it using off-the-shelf solvers. To improve learning performance, we further propose a weight-selection based FL framework. In such a framework, we assign each edge node a proper weight coefficient in model aggregation instead of discarding any of them to reduce the aggregation error, i.e., amplitude alignment of the received local gradient parameters from different edge nodes is not required. We also analyze the performance of this weight-selection based framework and derive an upper bound on its performance loss, followed by minimizing the MSE via optimizing the weight coefficients of the edge nodes, their transmit equalization coefficients, the IRS phase shifts, and the receive factors of the cloud server. Furthermore, we use the MNIST dataset for simulations to evaluate the performance of both node-selection and weight-selection based FL frameworks.
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