Background and Aims In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines... Show moreBackground and Aims In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4 alpha (HNF4 alpha), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. Approach and Results Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4 alpha, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4 alpha in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4 alpha controls the expression of coagulation factors by binding to their promoters in LPC. HNF4 alpha expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-beta superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4 alpha in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. Conclusions These results highlight a crucial role of the follistatin-controlled activin-HNF4 alpha-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF. Show less
DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >... Show moreDNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated. Show less
Background and purpose: Anatomical changes induce differences between planned and delivered dose. Adaptive radiotherapy (ART) may reduce these differences but the optimal implementation is... Show moreBackground and purpose: Anatomical changes induce differences between planned and delivered dose. Adaptive radiotherapy (ART) may reduce these differences but the optimal implementation is insufficiently clear. The aims of this study were to quantify the difference between planned and delivered dose in HNC patients, assess the consequential difference in normal tissue complication probability (Delta NTCP) and to explore the value of Delta NTCP as an objective selection strategy for ART.Materials and methods: For 52 patients, daily doses were accumulated to estimate the delivered dose. The difference from planned dose was analyzed for CTVs and 9 organs-at-risk (OAR). Delta NTCP was calculated for xerostomia, dysphagia, parotid gland dysfunction and tube feeding dependency at 6 months. ART was deemed necessary if Delta NTCP was >5%. The positive predicted value (PPV) was calculated for identification of ART-patients by clinical judgement, and Delta NTCP at fraction 10 and 15.Results: Delta NTCP >5% was seen five times for dysphagia and twice for the other toxicities. Only 5/9 patients with any Delta NTCP >5% clinically received ART, although ART had been done for 13/52 patients (PPV: 0.38). PPV was 0.86 and 0.75 for accumulated dose at fraction 10 and 15, respectively, using a Delta NTCP cut-off for the allocation of ART of 5%. Using other Delta NTCP cut-offs did not substantially improve PPV. With this cutoff the negative predictive value was 0.93 for Delta NTCP method of fraction 10 and fraction 15, and 0.90 for clinical judgement.Conclusion: To identify patients accurately for ART, NTCP calculations based on the dose differences between planned and delivered dose at fraction 10 are superior to clinical judgement. (C) 2019 Published by Elsevier B.V. Show less
Although the introduction of invasive plant species in a given area causes economic and ecological problems, it still provides an ideal opportunity for ecologists to study evolutionary changes.... Show moreAlthough the introduction of invasive plant species in a given area causes economic and ecological problems, it still provides an ideal opportunity for ecologists to study evolutionary changes. According to the Evolution of Increased Competitive Ability hypothesis and Shifting Defense Hypothesis, the release from specialist herbivores after introduction is expected invasive plants to shift their costly defense against specialist herbivores to cheaper defense against local generalist herbivores. A net gain can be saved to increase plant growth and competitive ability. In this thesis I used Jacobaea vulgaris as a model plant species to study the evolutionary changes in plant anti-herbivore defenses and growth ability. I found that invasive Jacobaea vulgaris populations indeed have evolved better growth and competitive ability, higher chemical defense but decreased structural defense and regrowth ability compare to the native populations. In addition, we show that all studied traits of invasive populations from multiple geographically distinct regions changed toward the same expected direction. It indicates parallel evolution took place in these invasive regions since they all differed significantly in climatic conditions. Such parallel evolution is most likely due to the disappearance of selection pressures from specialist herbivores rather than the adaptation to local abiotic factors after invasion. Show less
A shift in the composition of the herbivore guild in the invasive range is expected to select for plants with a higher competitive ability, a lower regrowth capacity and a lower investment in... Show moreA shift in the composition of the herbivore guild in the invasive range is expected to select for plants with a higher competitive ability, a lower regrowth capacity and a lower investment in defence. We show here that parallel evolution took place in three geographically distinct invasive regions that differed significantly in climatic conditions. This makes it most likely that indeed the shifts in herbivore guilds were causal to the evolutionary changes. We studied competitive ability and regrowth of invasive and native Jacobaea vulgaris using an intraspecific competition set-up with and without herbivory. Without herbivores invasive genotypes have a higher competitive ability than native genotypes. The invasive genotypes were less preferred by the generalist Mamestra brassicae but more preferred by the specialist Tyria jacobaeae, consequently their competitive ability was significantly increased by the first and reduced by the latter. Invasive genotypes showed a lower regrowth ability in both herbivore treatments. Show less
