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- Handelsman, Yehuda, et al.
(författare)
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Impact of dronedarone on patients with atrial fibrillation and diabetes : A sub-analysis of the ATHENA and EURIDIS/ADONIS studies
- 2022
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Ingår i: Journal of Diabetes and its Complications. - : Elsevier BV. - 1056-8727. ; 36:7
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Tidskriftsartikel (refereegranskat)abstract
- Aim: This post hoc analysis evaluated efficacy and safety of dronedarone in atrial fibrillation (AF) and atrial flutter (AFL) patients with/without diabetes. Methods: Patients were categorized according to baseline diabetes status. Time-to-event analyses were performed using Kaplan-Meier method. Hazard-ratios were assessed using Cox models. Results: 945/4628 (dronedarone = 482; placebo = 463) patients in ATHENA and 215/1237 (dronedarone = 148; placebo = 67) patients in EURIDIS/ADONIS studies had diabetes. In ATHENA, there were higher rates of CV hospitalization/death in patients with diabetes (39.5%) than without diabetes (34.7%). Incidence of first CV hospitalization/death was lower in patients with diabetes treated with dronedarone (35.1%) than placebo (44.1%), and time to this event was longer in those treated with dronedarone than placebo (log-rank p = 0.005). Median AF/AFL recurrence time was longer in patients treated with dronedarone than placebo in patients with diabetes (ATHENA: 722 vs 527 days, log-rank p = 0.004; EURIDIS/ADONIS: 100 vs 23 days, log-rank p = 0.15) or without diabetes (ATHENA: 741 vs 492 days, log-rank p < 0.0001; EURIDIS/ADONIS: 120 vs 59 days, log-rank p = 0.0002). Occurrence of any treatment-related adverse events with dronedarone was similar for patients with/without diabetes and was comparable to placebo. Conclusions: Dronedarone reduced incidence of CV hospitalization/death, AF/AFL recurrence and increased time to these events in AF/AFL patients with/without diabetes. Trial registration: Not applicable, as it was a post hoc analysis. This article is based on previously conducted studies (ATHENA: NCT00174785, EURIDIS: NCT00259428, and ADONIS: NCT00259376).
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- Kardos, Marty, et al.
(författare)
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Whole-genome resequencing uncovers molecular signatures of natural and sexual selection in wild bighorn sheep
- 2015
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Ingår i: Molecular Ecology. - : Wiley. - 0962-1083 .- 1365-294X. ; 24:22, s. 5616-5632
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Tidskriftsartikel (refereegranskat)abstract
- The identification of genes influencing fitness is central to our understanding of the genetic basis of adaptation and how it shapes phenotypic variation in wild populations. Here, we used whole-genome resequencing of wild Rocky Mountain bighorn sheep (Ovis canadensis) to >50-fold coverage to identify 2.8 million single nucleotide polymorphisms (SNPs) and genomic regions bearing signatures of directional selection (i.e. selective sweeps). A comparison of SNP diversity between the X chromosome and the autosomes indicated that bighorn males had a dramatically reduced long-term effective population size compared to females. This probably reflects a long history of intense sexual selection mediated by male-male competition for mates. Selective sweep scans based on heterozygosity and nucleotide diversity revealed evidence for a selective sweep shared across multiple populations at RXFP2, a gene that strongly affects horn size in domestic ungulates. The massive horns carried by bighorn rams appear to have evolved in part via strong positive selection at RXFP2. We identified evidence for selection within individual populations at genes affecting early body growth and cellular response to hypoxia; however, these must be interpreted more cautiously as genetic drift is strong within local populations and may have caused false positives. These results represent a rare example of strong genomic signatures of selection identified at genes with known function in wild populations of a nonmodel species. Our results also showcase the value of reference genome assemblies from agricultural or model species for studies of the genomic basis of adaptation in closely related wild taxa.
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- Mujovic, Nebojsa, et al.
(författare)
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Persistency of left atrial linear lesions after radiofrequency catheter ablation for atrial fibrillation : Data from an invasive follow-up electrophysiology study
- 2017
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Ingår i: Cardiovascular Electrophysiology. - : WILEY. - 1045-3873 .- 1540-8167. ; 28:12, s. 1403-1414
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data on the roof line (RL) and mitral isthmus line (MIL) reconnections after atrial fibrillation (AF) catheter ablation (CA) are scarce.Objective: We studied the RL andMIL completeness and localization of reconnection sites in consecutive patients after their first-ever AF-CA.Methods: We prospectively included 41 consecutive AF patients who underwent predefined lesion sets of two circumferential lines (CLs) for ipsilateral pulmonary vein isolation (PVI) combinedwith a RL and lateral MIL. Three months after CA, all patients underwent invasive follow-up procedure for line persistency evaluation, irrespective of clinical outcome.Results: At the time of index ablation, PVI-CLs, RL, and MIL was completed in 41 (100%), 39 (95%), and 34 (83%) of patients, respectively. At the 3-month follow-up procedure, reconnections of PVI-CLs, RL, and MIL were found in 61% (25/41), 28% (11/39), and 24% (8/34) of patients, respectively. The 3-month reconnections were located commonly in the anterior and posterior PVI-CL segments, and rarely in the right third of RL and in the posterior part of MIL. The 3-month reconnections were rarely seen at the sites of acute reconnections during index procedure (6%, 20%, and 25% of the PVI-CL segments, RL segments, and MIL segments, respectively).Conclusions: To our knowledge, this is the first study systematically investigating the reconnection of standardized left atrium linear lesions such as RL and MIL after RF-CA for AF in consecutive patients. The RL and MIL 3-month reconnection rates were relatively low (28% and 24%), with poor anatomical concordance between the sites with acute and 3-month reconnections.
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- Siegel, T. P., et al.
(författare)
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Mass Spectrometry Imaging and Integration with Other Imaging Modalities for Greater Molecular Understanding of Biological Tissues
- 2018
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Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 20:6, s. 888-901
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Forskningsöversikt (refereegranskat)abstract
- Over the last two decades, mass spectrometry imaging (MSI) has been increasingly employed to investigate the spatial distribution of a wide variety of molecules in complex biological samples. MSI has demonstrated its potential in numerous applications from drug discovery, disease state evaluation through proteomic and/or metabolomic studies. Significant technological and methodological advancements have addressed natural limitations of the techniques, i.e., increased spatial resolution, increased detection sensitivity especially for large molecules, higher throughput analysis and data management. One of the next major evolutions of MSI is linked to the introduction of imaging mass cytometry (IMC). IMC is a multiplexed method for tissue phenotyping, imaging signalling pathway or cell marker assessment, at sub-cellular resolution (1m). It uses MSI to simultaneously detect and quantify up to 30 different antibodies within a tissue section. The combination of MSI with other molecular imaging techniques can also provide highly relevant complementary information to explore new scientific fields. Traditionally, classical histology (especially haematoxylin and eosin-stained sections) is overlaid with molecular profiles obtained by MSI. Thus, MSI-based molecular histology provides a snapshot of a tissue microenvironment and enables the correlation of drugs, metabolites, lipids, peptides or proteins with histological/pathological features or tissue substructures. Recently, many examples combining MSI with other imaging modalities such as fluorescence, confocal Raman spectroscopy and MRI have emerged. For instance, brain pathophysiology has been studied using both MRI and MSI, establishing correlations between in and ex vivo molecular imaging techniques. Endogenous metabolite and small peptide modulation were evaluated depending on disease state. Here, we review advanced hot topics' in MSI development and explore the combination of MSI with established molecular imaging techniques to improve our understanding of biological and pathophysiological processes.
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- Strittmatter, Nicole, et al.
(författare)
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Method To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging
- 2022
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 94:3, s. 1795-1803
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Tidskriftsartikel (refereegranskat)abstract
- Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.
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