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- DuttaRoy, Smita, 1971, et al.
(författare)
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The effects of age on circulating vascular markers and cardiac prognostic markers, before and after 2 months home-based high-frequency exercise training in patients with stable coronary artery disease
- 2014
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Ingår i: European Heart Journal. European Society of Cardiology, 30 August - 3 September 2014, Barcelona. - 0195-668X .- 1522-9645. ; 35:Supplement: 1
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: Vascular endothelial growth factor (VEGF) and stromal derived factor (SDF-1) play an important role in angiogenesis. Relaxin-2 (Rlx-2) has both angiogenic and vasodilatory properties, while endothelin-1 (ET-1) is a potent vasocontrictor.VEGF, SDF-1 and Rlx-2-levels have shown to be positively modulated by exercise training, while the effect of exercise on (Rlx-2) is not known. Age is a known risk factor for morbidity and mortality in coronary artery disease (CAD). We wanted to investigate how age affects levels of these vascular factors and known prognostic cardiac markers before and after high frequency exercise training (HFE), in patients with CAD. Methods: Patients with stable CAD (age 48-80 years) were randomized to HFE (aerobic exercise 70% of max, 30 minutes, 5 times/week and resistance exercise 3 times/week), performed at home for 8 weeks, or usual lifestyle (ctrl). Serum and plasma was collected from 21 controls and 24 HFE-patients and analyzed at baseline and after 8 weeks. VEGF, SDF-1, Rlx-2 and ET-1were analyzed with enzymelinked immunoadsorbent assay (ELISA). TnT and NT-pro-BNP were analyzed on Cobas e602 (Roche). Correlation was calculated using the statistical software Graph Pad Prism 6. Pearson’s r was calculated to determine correlation between the factors prior to exercise, while Spearman’s r was used for the analysis on the exercise induced effects of the HFE-group. The exercise-induced effect on cardiac biomarkers was determined by comparing % change (from baseline to 8 weeks) between HFE and Ctrl using Mann-Whitney U-test. Results: At baseline, there was a significant positive correlation between age and TnT (r=0.38, p<0.05) and a non-significant positive correlation between age and NT-proBNP (r=0.36, p=0.06), while no correlation was found between age and levels of vascular markers (VEGF r=-0,14, SDF-1 r=-0,13, ET-1 r=0,08, Rlx-2 r=0,06, p=ns for all). As we have previously shown, home-based HFE decreased VEGF (2,6+29% (ctrl) and -3,9 +13% (HFE), p<0,05), but the other studied factors were not significantly affected. We found no correlation between age and changes in cardiac markers after exercise. Conclusions: Elderly patients with stable CAD have higher levels of TnT and NT-proBNP, indicating a higher degree of underlying CAD. This may also reflect their higher mortality in CAD. HFE-training may lower VEGF in patients with stable CAD. Interestingly, there seems to be no difference in the respone response to exercise in cardiac biomarkers, between younger and older CAD patients
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| 4. |
- Hijazi, Ziad
(författare)
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New Risk Markers in Atrial Fibrillation
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atrial fibrillation (AF) confers an independent increased risk of stroke and death. The stroke risk is very heterogeneous and current risk stratification models based on clinical variables, such as the CHADS2 and CHA2DS2VASc score, only offer a modest discriminating value.The aims of this thesis were to study cardiac biomarkers, cardiac troponin and natriuretic peptides e.g. N-terminal prohormone-B-type natriuretic peptide (NT-proBNP), and describe levels in AF patients, investigate the association with stroke or systemic embolism, cardiovascular event, major bleeding and mortality, and to assess how levels of cardiac biomarkers change over time. Cardiac troponin was analyzed with contemporary assays and high sensitivity assays. The study populations consisted of patients with atrial fibrillation and one risk factor for stroke included in the RE-LY (n=6189) and the ARISTOTLE (n=14892) biomarker substudies. Median follow-up time was 2.2 years and 1.9 years, respectively. In a subset of participants (n=2514) data from repeated measurements was available at three months.Cardiac troponin was detectable in 57.0% with the contemporary assay and 99.4% with the high sensitivity assay. NT-proBNP was elevated in approximately three quarters of the participants. In Cox models adjusted for established risk factors the cardiac biomarkers levels was independently associated with stroke or systemic embolism, cardiovascular events, and mortality. Only cardiac troponin was associated with major bleeding. In ROC analyses the prediction of stroke or systemic embolism, cardiovascular events, and mortality increased significantly by addition of cardiac troponin or NT-proBNP to the models. Persistent detectable cardiac troponin (contemporary assay) and elevated NT-proBNP levels were found in a large number of participants. Persistent detectable or elevated levels conferred significantly higher risk for stroke or systemic embolism, cardiovascular events, and mortality. By using both cardiac biomarkers simultaneously the risk stratification improved even further for all outcomes.In conclusion the analyses for the first time display that elevation of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke, cardiovascular events and mortality. Persistent elevation of troponin and NT-proBNP indicate a worse prognosis than transient elevations or no elevations of either marker. The cardiac biomarkers added substantial improvements to existing risk stratification models.
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| 5. |
- Isaksson, Helena, 1978-
(författare)
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Clinical studies of RNA as a prognostic and diagnostic marker for disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Technologies for RNA detection are evolving rapidly and gives an op-portunity for discovery of new markers for early detection of complex diseases. Today in clinical work we rely on signs and symptoms in com-bination with the measurement of protein levels for diagnosis. The quick turnaround time of mRNA synthesis may provide an earlier diagnostic signal than protein-based biomarkers assays, in acute dramatic condi-tions such as acute mesenteric ischemia (AMI), for early detection of cancer, as prognostic tool in cancer treatment and as an aid in difficult diagnosis of unknown origin.The main goals of this thesis was to apply a whole genome approach to study different complex diseases to evaluate the applicability of RNA as a diagnostic or prognostic marker for disease, preferably from an easily accessible source such as peripheral blood. This was investigated in an animal model with induced AMI, a cohort of ovarian cancer patients and in a single-patient study of a girl with a severe inflammatory syn-drome.Through this thesis we have gained insight into how gene expression is regulated in ischemic intestinal tissue.We found that a peripheral blood test can distinguish between ovarian cancer patients with or without residual tumour mass after surgery with the help of expression analysis of six genes. We also found that gene expressions of three genes can predict overall survival in peripheral whole blood from ovarian cancer patients. And that gene expression profiles indeed can significantly distinguish between two groups of high and low risk ovarian cancer. In the single-patient study, we tried but failed to device a successful treatment before it was too late. Neverthe-less, the things we learned and the case studies that were published may serve as a diagnostic tool for clinicians facing similar syndromes.
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| 6. |
- Löwbeer, Christian, et al.
(författare)
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Energiomsättning, diabetes och lipoproteinrubbningar
- 2018. - 10
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Ingår i: Laurells klinisk kemi i praktisk medicin. - Lund : Studentlitteratur AB. - 9789144119748 ; , s. 345-414
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Sabouri, Nasim, 1978-
(författare)
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Structure of eukaryotic DNA polymerase epsilon and lesion bypass capability
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- To transfer the information in the genome from mother cell to daughter cell, the DNA replication must be carried out only once and with very high fidelity prior to every cell division. In yeast there are several different DNA polymerases involved in DNA replication and/or DNA repair. The two replicative DNA polymerases, DNA polymerase delta (Pol delta) and DNA polymerase epsilon (Pol epsilon), which both include a proofreading 3´→5´exonuclease activity, can replicate and proofread the genome with a very high degree of accuracy. The aim of this thesis was to gain a better understanding of how the enigmatic DNA polymerase epsilon participates in DNA transactions. To investigate whether Pol epsilon or Pol delta is responsible for the synthesis of DNA on the lagging strand, the processing and assembly of Okazaki fragments was studied. Pol delta was found to have a unique property called “idling” which, together with the flap-endonuclease (FEN1), maintained a ligatable nick for DNA ligase I. In contrast, Pol epsilon was found to lack the ability to “idle” and interact functionally with FEN-1, indicating that Pol epsilon is not involved in processing Okazaki fragments. Together with previous genetic studies, it was concluded that Pol delta is the preferred lagging strand polymerase, leaving Pol epsilon to carry out some other function. The structure of Pol epsilon was determined by cryo-electron microscopy, to a resolution of ~20 Å. Pol epsilon is composed of a globular “head” domain consisting of the large catalytic subunit Pol2p, and a “tail” domain, consisting of the small subunits Dpb2p, Dpb3p, and Dpb4p. The two separable domains were found to be connected by a flexible hinge. Interestingly, the high intrinsic processivity of Pol epsilon depends on the interaction between the tail domain and double-stranded DNA. As a replicative DNA polymerase, Pol epsilon encounters different lesions in DNA. It was shown that Pol epsilon can perform translesion synthesis (TLS) through a model abasic site in the absence of external processivity clamps under single-hit conditions. The lesion bypass was dependent of the sequence on the template and also on a proper interaction of the “tail”domain with the primer-template. Yeast cells treated with a DNA damaging agent and devoid of all TLS polymerases showed improved survival rates in the presence of elevated levels of dNTPs. These genetic results suggested that replicative polymerases may be engaged in the bypass of some DNA lesions. In vitro, Pol epsilon was found to bypass 8-OxoG at elevated dNTP levels. Together, the in vitro and in vivo results suggest that the replicative polymerases may be engaged in bypass of less bulky DNA lesions at elevated dNTP levels. In conclusion, the low-resolution structure presented represents the first structural characterization of a eukaryotic multi-subunit DNA polymerase. The replicative DNA polymerase Pol epsilon can perform translesion synthesis due to an interaction between the tail domain and double-stranded DNA. Pol epsilon may also bypass less bulky DNA lesions when there are elevated dNTP concentrations in vivo.
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| 8. |
- Tran, Phong, 1987-
(författare)
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Pathology of dNTP dysregulation
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Deoxyribonucleoside triphosphates (dNTPs) are precursors for DNA replication and repair. Mammalian cells have two distinct biosynthesis pathways to supply dNTPs: de novo and salvage pathways. These pathways are intimately coordinated to maintain optimal dNTP concentrations throughout different phases of the cell cycle, and perturbations in the production of dNTPs could lead to increased, decreased, or imbalanced dNTP pools. In yeasts, changes in both the level and balance of dNTPs increase mutation rates and genome instability. In mammals, elevated mutation rates and genome instability predispose to numerous diseases, including cancer. However, the correlation of dNTP changes with pathology has not been well established in mammals. In this thesis, I present how we addressed this issue using three separate mouse models – one with an increased dNTP pool, one with a decreased dNTP pool, and one with an imbalanced dNTP pool. To modulate dNTP levels in the mice, we deleted or mutated either sterile alpha motif and histidine-aspartic domain containing protein 1 (SAMHD1) or ribonucleotide reductase (RNR) proteins, which are involved in the salvage and de novo pathways, respectively. In the first model, mouse embryos without the SAMHD1 gene showed a slight increase in dNTP levels. A similar increase in dNTPs conferred moderately elevated mutation rates in cultured cancer cells. In the second model, we created a mouse strain carrying a modified allosteric specificity site in a subunit of RNR. Embryos with a heterozygous mutation had a mildly imbalanced dNTP pool. Heterozygous mutant mice showed a shorter lifespan and increased incidence and earlier onset of cancer. In the third model, the de novo dNTP production was inactivated in cardiac and skeletal muscles through the deletion of a gene encoding RNR. The hearts of knockout pups showed significant depletion of dNTPs, leading to aberrant DNA replication. In addition, knockout pups developed anatomic and histologic cardiac abnormalities and impaired cardiac conduction systems. As a result, they died between two and four weeks after birth. Taken together, our studies provide the first empirical evidence that both the de novo and salvage pathways are essential to keeping the dNTP concentration at an optimal range to prevent mutagenesis, carcinogenesis, and mortality.
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| 9. |
- Tsaponina, Olga, 1978-
(författare)
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Regulation of ribonucleotide reductase and the role of dNTP pools in genomic stability in yeast Saccharomyces cerevisiae
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Every living organism is programmed to reproduce and to pass genetic information to descendants. The information has to be carefully copied and accurately transferred to the next generation. Therefore organisms have developed the network of conserved mechanisms to survey the protection and precise transfer of the genetic information. Such mechanisms are called checkpoints and they monitor the correct execution of different cell programs. The DNA damage and the replication blocks are surveyed by the conserved Mec1-Rad53 (human ATM/ATR and Chk2, respectively) protein kinase cascade. Mec1 and Rad53 are essential for survival and when activated orchestrate the multiple cellular responses, including the activation of the ribonucleotide reductase (RNR), to the genotoxic stress. RNR is an enzyme producing all four dNTPs - the building blocks of the DNA - and is instrumental for the maintenance both proper concentration and balance of each of dNTPs. The appropriate concentration of the dNTPs should be strictly regulated since inadequate dNTP production can impede many cellular processes and lead to higher mutation rates and genome instability. Hence RNR activity is regulated at many levels, including allosteric and transcriptional regulation and the inhibition at protein level. In our research, we addressed the question of the transcriptional regulation of RNR and the consequences of dNTP malproduction in the terms of the genomic stability. In yeast S. cerevisiae, four genes encode RNR: 2 genes encode a large subunit (RNR1 and RNR3) and 2 genes encode a small subunit (RNR2 and RNR4). All 4 genes are DNA-damage inducible: transcription of RNR2, RNR3 and RNR4 is regulated via Mec1-Rad53-Dun1 pathway by targeting the transcriptional repressor Crt1 (Rfx1) for degradation; on the contrary, RNR1 gene promoter does not contain Crt1-binding sites and is not regulated through the Mec1-Rad53-Dun1 pathway. Instead, we show that intrastrand cross (X)-link recognition protein (Ixr1) is required for the proper transcription of the RNR1 gene and maintenance of the dNTP pools both during unperturbed cell cycle and after the DNA damage. Thus, we identify the novel regulator of the RNR1 transcription. Next, we show that the depletion of dNTP pools negatively affects genome stability in the hypomorphic mec1 mutants: the hyper-recombination phenotype in those mutants correlates with low dNTP levels. By introducing even lower dNTP levels the hyper-recombination increased even further and conversely all the hyper-recombination phenotypes were suppressed by artificial elevation of dNTP levels. In conclusion, we present Ixr1 as a novel regulator of the RNR activity and provide the evidence of role of dNTP concentration in the genome stability.
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