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| 2. |
- Andersson, Irene, 1978, et al.
(författare)
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Endothelial dysfunction in growth hormone transgenic mice
- 2006
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 110:2, s. 217-25
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Tidskriftsartikel (refereegranskat)abstract
- Acromegaly [overproduction of GH (growth hormone)] is associated with cardiovascular disease. Transgenic mice overexpressing bGH (bovine GH) develop hypertension and hypercholesterolaemia and could be a model for cardiovascular disease in acromegaly. The aims of the present study were to investigate the effects of excess GH on vascular function and to test whether oxidative stress affects endothelial function in bGH transgenic mice. We studied the ACh (acetylcholine)-induced relaxation response in aortic and carotid rings of young (9-11 weeks) and aged (22-24 weeks) female bGH transgenic mice and littermate control mice, without and with the addition of a free radical scavenger {MnTBAP [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride]}. We also measured mRNA levels of eNOS (endothelial nitric oxide synthase) and EC-SOD (extracellular superoxide dismutase). Intracellular superoxide anion production in the vascular wall was estimated using a dihydroethidium probe. Carotid arteries from bGH transgenic mice had an impaired ACh-induced relaxation response (young, 46 +/- 7% compared with 69 +/- 8%; aged, 52 +/- 5% compared with 80 +/- 3%; P < 0.05), whereas endothelial function in aorta was intact in young but impaired in aged bGH transgenic mice. Endothelial dysfunction was corrected by addition of MnTBAP in carotid arteries from young mice and in aortas from aged mice; however, MnTBAP did not correct endothelial dysfunction in carotid arteries from aged bGH transgenic mice. There was no difference in intracellular superoxide anion production between bGH transgenic mice and control mice, whereas mRNA expression of EC-SOD and eNOS was increased in aortas from young bGH transgenic mice compared with control mice (P < 0.05). We interpret these data to suggest that bGH overexpression is associated with a time- and vessel-specific deterioration in endothelial function, initially caused by increased oxidative stress and later by other alterations in vascular function.
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| 3. |
- Carroll, Christopher, et al.
(författare)
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Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation
- 2024
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Ingår i: Cancer Research Communications. - 2767-9764. ; 4:3, s. 691-705
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF2α. We found altered chromatin accessibility, ablated expression of retinoblastoma protein (RB1), and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF2α in stress response by polyploidy suggests a novel avenue for tackling chemotherapy-induced resistance in cancer. Significance: In response to cisplatin treatment, some surviving cancer cells undergo whole-genome duplications without mitosis, which represents a mechanism of drug resistance. This study presents mechanistic data to implicate AP-1 and HIF2α signaling in the formation of this surviving cell phenotype. The results open a new avenue for targeting drug-resistant cells.
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| 4. |
- Collins, Ruairi, et al.
(författare)
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Biochemical discrimination between selenium and sulfur 1 : a single residue provides selenium specificity to human selenocysteine lyase
- 2012
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Ingår i: PLoS One. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- Selenium and sulfur are two closely related basic elements utilized in nature for a vast array of biochemical reactions. While toxic at higher concentrations, selenium is an essential trace element incorporated into selenoproteins as selenocysteine (Sec), the selenium analogue of cysteine (Cys). Sec lyases (SCLs) and Cys desulfurases (CDs) catalyze the removal of selenium or sulfur from Sec or Cys and generally act on both substrates. In contrast, human SCL (hSCL) is specific for Sec although the only difference between Sec and Cys is the identity of a single atom. The chemical basis of this selenium-over-sulfur discrimination is not understood. Here we describe the X-ray crystal structure of hSCL and identify Asp146 as the key residue that provides the Sec specificity. A D146K variant resulted in loss of Sec specificity and appearance of CD activity. A dynamic active site segment also provides the structural prerequisites for direct product delivery of selenide produced by Sec cleavage, thus avoiding release of reactive selenide species into the cell. We thus here define a molecular determinant for enzymatic specificity discrimination between a single selenium versus sulfur atom, elements with very similar chemical properties. Our findings thus provide molecular insights into a key level of control in human selenium and selenoprotein turnover and metabolism.
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| 5. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 6. |
- Hruby, Adela, et al.
(författare)
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Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies
- 2013
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 0022-3166 .- 1541-6100. ; 143:3, s. 345-353
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Tidskriftsartikel (refereegranskat)abstract
- Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (In-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [beta = -0.009 mmol/L (95% CI: -0.013, -0.005), P< 0.0001] and insulin (-0.020 In-pmo/L (95% CI: -0.024, -0.017), P< 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P= 0.03) with glucose, and rs11558471 in SLC30A8and rs3740393 near CNNM2showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted. J. Nutr. 143: 345-353, 2013.
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| 7. |
- Joensuu, Heikki, et al.
(författare)
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Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer The SOLD Randomized Clinical Trial
- 2018
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Ingår i: JAMA Oncology. - : AMER MEDICAL ASSOC. - 2374-2437 .- 2374-2445. ; 4:9, s. 1199-1206
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear.Objective: To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab.Design, Setting, and Participants: Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries.Intervention: Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year.Main Outcomes and Measures: The primary objective was DFS; secondary objectives included distant disease–free survival, overall survival, cardiac DFS, and safety.Results: In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease–free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group.Conclusions and Relevance: Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study.Trial Registration: ClinicalTrials.gov Identifier: NCT00593697
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| 8. |
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| 9. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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