| 1. |
- Heffeter, P., et al.
(författare)
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Ribonucleotide Reductase as One Important Target of [Tris(1,10- phenanthroline)lanthanum(III)] Trithiocyanate (KP772)
- 2009
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Ingår i: Current Cancer Drug Targets. - : Bentham Science Publishers Ltd.. - 1568-0096 .- 1873-5576. ; 9:5, s. 595-607
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Tidskriftsartikel (refereegranskat)abstract
- KP772 is a new lanthanum complex containing three 1,10-phenathroline molecules. Recently, we have demonstrated that the promising in vitro and in vivo anticancer properties of KP772 are based on p53-independent G(0)G(1) arrest and apoptosis induction. A National Cancer Institute (NCI) screen revealed significant correlation of KP772 activity with that of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU). Consequently, this study aimed to investigate whether KP772 targets DNA synthesis in tumor cells by RR inhibition. Indeed, KP772 treatment led to significant reduction of cytidine incorporation paralleled by a decrease of deoxynucleoside triphosphate (dNTP) pools. This strongly indicates disruption of RR activity. Moreover, KP772 protected against oxidative stress, suggesting that this drug might interfere with RR by interaction with the tyrosyl radical in subunit R2. Additionally, several observations (e.g. increase of transferrin receptor expression and protective effect of iron preloading) indicate that KP772 interferes with cellular iron homeostasis. Accordingly, co-incubation of Fe(II) with KP772 led to generation of a coloured iron complex (Fe-KP772) in cell free systems. In electron paramagnetic resonance (EPR) measurements of mouse R2 subunits, KP772 disrupted the tyrosyl radical while Fe-KP772 had no significant effects. Moreover, coincubation of KP772 with iron-loaded R2 led to formation of Fe-KP772 suggesting chelation of RR-bound Fe(II). Summarizing, our data prove that KP772 inhibits RR by targeting the iron centre of the R2 subunit. As also Fe-KP772 as well as free lanthanum exert significant -though less pronounced- cytotoxic/static activities, additional mechanisms are likely to synergise with RR inhibition in the promising anticancer activity of KP772.
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| 2. |
- Mahdavi, Ardeshir, et al.
(författare)
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The role of occupants in buildings’ energy performance gap: Myth or reality?
- 2021
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Ingår i: Sustainability. - : MDPI AG. - 2071-1050. ; 13:6
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Forskningsöversikt (refereegranskat)abstract
- Buildings’ expected (projected, simulated) energy use frequently does not match actual observations. This is commonly referred to as the energy performance gap. As such, many factors can contribute to the disagreement between expectations and observations. These include, for in-stance, uncertainty about buildings’ geometry, construction, systems, and weather conditions. However, the role of occupants in the energy performance gap has recently attracted much atten-tion. It has even been suggested that occupants are the main cause of the energy performance gap. This, in turn, has led to suggestions that better models of occupant behavior can reduce the energy performance gap. The present effort aims at the review and evaluation of the evidence for such claims. To this end, a systematic literature search was conducted and relevant publications were identified and reviewed in detail. The review entailed the categorization of the studies according to the scope and strength of the evidence for occupants’ role in the energy performance gap. Moreover, deployed calculation and monitoring methods, normalization procedures, and reported causes and magnitudes of the energy performance gap were documented and evaluated. The results suggest that the role of occupants as significant or exclusive contributors to the energy performance gap is not sufficiently substantiated by evidence.
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| 3. |
- Malik, Rainer, et al.
(författare)
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Low-frequency and common genetic variation in ischemic stroke : The METASTROKE collaboration
- 2016
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Ingår i: Neurology. - 1526-632X. ; 86:13, s. 26-1217
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes.METHODS: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes.RESULTS: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5).CONCLUSIONS: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
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| 4. |
- Mylrea-Foley, Bronacha, et al.
(författare)
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Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise : the TRUFFLE 2 randomised trial protocol
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years.Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (>= 4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire.Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy.
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| 5. |
- Pleijel, Agneta, et al.
(författare)
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Agneta Pleijel, Torgny Lindgren, Gertrude Stein, Ingo Schulze, Heinrich Böll, Reflection on Argentine identity, Filmöversättning och språklekar
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- InnehållRed: InledningAgneta Pleijel: Varför litteraturen?Maria Bergom-Larsson: Lord Nevermore – Europa genom den kvinnliga blickenSverker Ek: ”Utan berättelser förtorkar tiden”. Kring Agneta Pleijels roman Lord NevermoreAstrid Seeberger: Om mörkret kring människorna som bör skingras. Agneta Pleijels sökande efter sanningen – om den nu finnsIngela Pehrson Berger: ”Jag avbildar inte världen sådan som vi ser den.” Konsten som tema i fyra berättelser av Torgny LindgrenIngemar Haag: Om sanning och lögn i självbiografisk mening. Gertrude Steins The Autobiography of Alice B. Toklas och Evererybody’s AutobiographKatharina Strohkirch: Der gejagte Jäger. Emsige Erwerbslosigkeit in Ingo Schulzes CalcuttaThorsten M. Päplow: Heinrich Bölls Irländsk dagbok. Ett exempel på potentialen hos reselitteraturDébora Rottenberg: Identity rewritten: the representation of Indians and Britons in Argentine novels taking place in Tierra del FuegoThorsten Schröter: På spaning efter den wit som flytt: dubbning och textning av språklekar i film
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| 6. |
- Ries, Alexander, et al.
(författare)
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Primary and hTERT-Transduced Mesothelioma-Associated Fibroblasts but Not Primary or hTERT-Transduced Mesothelial Cells Stimulate Growth of Human Mesothelioma Cells
- 2023
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Ingår i: Cells. - 2073-4409. ; 12:15
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Tidskriftsartikel (refereegranskat)abstract
- Pleural mesothelioma (PM) is an aggressive malignancy that develops in a unique tumor microenvironment (TME). However, cell models for studying the TME in PM are still limited. Here, we have generated and characterized novel human telomerase reverse transcriptase (hTERT)-transduced mesothelial cell and mesothelioma-associated fibroblast (Meso-CAF) models and investigated their impact on PM cell growth. Pleural mesothelial cells and Meso-CAFs were isolated from tissue of pneumothorax and PM patients, respectively. Stable expression of hTERT was induced by retroviral transduction. Primary and hTERT-transduced cells were compared with respect to doubling times, hTERT expression and activity levels, telomere lengths, proteomes, and the impact of conditioned media (CM) on PM cell growth. All transduced derivatives exhibited elevated hTERT expression and activity, and increased mean telomere lengths. Cell morphology remained unchanged, and the proteomes were similar to the corresponding primary cells. Of note, the CM of primary and hTERT-transduced Meso-CAFs stimulated PM cell growth to the same extent, while CM derived from mesothelial cells had no stimulating effect, irrespective of hTERT expression. In conclusion, all new hTERT-transduced cell models closely resemble their primary counterparts and, hence, represent valuable tools to investigate cellular interactions within the TME of PM.
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