| 31. |
- Cheung, BB, et al.
(author)
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A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma
- 2021
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In: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 40:13, s. 2367-2381
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Journal article (peer-reviewed)abstract
- Histone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Effects of drug combinations on cell viability, proliferation, apoptosis and colony forming were assessed in a panel of neuroblastoma cell lines. Treatment with SAHA and SE486-11 increased MYCN ubiquitination and degradation, and markedly inhibited tumorigenesis in neuroblastoma xenografts, and, MYCN transgenic zebrafish and mice. The combination reduced ubiquitin-specific protease 5 (USP5) levels and increased unanchored polyubiquitin chains. Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination. SAHA and SE486-11 directly bound to USP5 and the drug combination exhibited a 100-fold higher binding to USP5 than individual drugs alone in microscale thermophoresis assays. MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells. Thus, USP5 acts as an oncogenic cofactor with MYCN in neuroblastoma and the novel combination of HDAC inhibitor with SE486-11 represents a novel therapeutic approach for the treatment of MYCN-driven neuroblastoma.
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| 32. |
- Dussex, Nicolas, et al.
(author)
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A genome-wide investigation of adaptive signatures in protein-coding genes related to tool behaviour in New Caledonian and Hawaiian crows
- 2021
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In: Molecular Ecology. - : John Wiley & Sons. - 0962-1083 .- 1365-294X. ; 30:4, s. 973-986
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Journal article (peer-reviewed)abstract
- Very few animals habitually manufacture and use tools. It has been suggested that advanced tool behaviour co-evolves with a suite of behavioural, morphological and life history traits. In fact, there are indications for such an adaptive complex in tool-using crows (genus Corvus species). Here, we sequenced the genomes of two habitually tool-using and ten non-tool-using crow species to search for genomic signatures associated with a tool-using lifestyle. Using comparative genomic and population genetic approaches, we screened for signals of selection in protein-coding genes in the tool-using New Caledonian and Hawaiian crows. While we detected signals of recent selection in New Caledonian crows near genes associated with bill morphology, our data indicate that genetic changes in these two lineages are surprisingly subtle, with little evidence at present for convergence. We explore the biological explanations for these findings, such as the relative roles of gene regulation and protein-coding changes, as well as the possibility that statistical power to detect selection in recently diverged lineages may have been insufficient. Our study contributes to a growing body of literature aiming to decipher the genetic basis of recently evolved complex behaviour.
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| 33. |
- James, Sarah-Naomi, et al.
(author)
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A population-based study of head injury, cognitive function and pathological markers.
- 2021
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In: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 8:4, s. 842-856
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Journal article (peer-reviewed)abstract
- To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals.Participants (n=502, age=69-71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18 F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer's disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15years prior to the scan (ii) anytime up to age 71.Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15years prior (16%, n=80) performed worse on cognitive tests at age 69-71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p>0.01).Having a LOC HI aged 50's and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).
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| 34. |
- Leeksma, AC, et al.
(author)
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Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: a multi-center study
- 2021
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In: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 106:1, s. 87-97
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Journal article (peer-reviewed)abstract
- Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p<0.01) were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided in three distinct prognostic subgroups based on the number of CNAs. Only high genomic complexity (high-GC), defined as ≥5 CNAs emerged as an independent adverse prognosticator on multivariable analysis for time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and performed at least as well in terms of risk stratification compared to simultaneous chromosome banding analysis as determined in 122 patients. Our findings highlight genomic array as an accurate tool for CLL risk stratification.
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| 35. |
- Parker, Thomas C., et al.
(author)
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Rhizosphere allocation by canopy-forming species dominates soil CO2 efflux in a subarctic landscape
- 2020
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In: New Phytologist. - : John Wiley & Sons. - 0028-646X .- 1469-8137. ; 227:6, s. 1818-1830
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Journal article (peer-reviewed)abstract
- In arctic ecosystems, climate change has increased plant productivity. As arctic carbon (C) stocks predominantly are located belowground, the effects of greater plant productivity on soil C storage will significantly determine the net sink/source potential of these ecosystems, but vegetation controls on soil CO2 efflux remain poorly resolved.In order to identify the role of canopy‐forming species in belowground C dynamics, we conducted a girdling experiment with plots distributed across 1 km2 of treeline birch (Betula pubescens ) forest and willow (Salix lapponum ) patches in northern Sweden and quantified the contribution of canopy vegetation to soil CO2 fluxes and belowground productivity.Girdling birches reduced total soil CO2 efflux in the peak growing season by 53%, which is double the expected amount, given that trees contribute only half of the total leaf area in the forest. Root and mycorrhizal mycelial production also decreased substantially. At peak season, willow shrubs contributed 38% to soil CO2 efflux in their patches.Our findings indicate that C, recently fixed by trees and tall shrubs, makes a substantial contribution to soil respiration. It is critically important that these processes are taken into consideration in the context of a greening arctic because productivity and ecosystem C sequestration are not synonymous.
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| 36. |
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| 37. |
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| 38. |
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| 39. |
- Stritzinger, M. D., et al.
(author)
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The Carnegie Supernova Project II : Observations of the luminous red nova AT 2014ej
- 2020
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 639
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Journal article (peer-reviewed)abstract
- We present optical and near-infrared broadband photometry and optical spectra of AT 2014ej from the Carnegie Supernova Project-II. These observations are complemented with data from the CHilean Automatic Supernova sEarch, the Public ESO Spectroscopic Survey of Transient Objects, and from the Backyard Observatory Supernova Search. Observational signatures of AT 2014ej reveal that it is similar to other members of the gap-transient subclass known as luminous red novae (LRNe), including the ubiquitous double-hump light curve and spectral properties similar to that of LRN SN 2017jfs. A medium-dispersion visual-wavelength spectrum of AT 2014ej taken with the Magellan Clay telescope exhibits a P Cygni H alpha feature characterized by a blue velocity at zero intensity of approximate to 110 km s(-1) and a P Cygni minimum velocity of approximate to 70 km s(-1). We attribute this to emission from a circumstellar wind. Inspection of pre-outbust Hubble Space Telescope images yields no conclusive progenitor detection. In comparison with a sample of LRNe from the literature, AT 2014ej lies at the brighter end of the luminosity distribution. Comparison of the ultra-violet, optical, infrared light curves of well-observed LRNe to common-envelope evolution models from the literature indicates that the models underpredict the luminosity of the comparison sample at all phases and also produce inconsistent timescales of the secondary peak. Future efforts to model LRNe should expand upon the current parameter space we explore here and therefore may consider more massive systems and a wider range of dynamical timescales.
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| 40. |
- Tanabe, Sean, et al.
(author)
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Cohort study of electroencephalography markers of amyloid-tau-neurodegeneration pathology.
- 2020
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In: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 2:2
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Journal article (peer-reviewed)abstract
- Electroencephalography signatures of amyloid-β, tau and neurodegenerative pathologies would aid in screening for, tracking progression of, and critically, understanding the pathogenesis of dementia. We hypothesized that slowing of the alpha peak frequency, as a signature of hyperpolarization-activated cyclic nucleotide gated 'pacemaker' channel activity, would correlate with amyloid and tau pathology burden measured by amyloid (Pittsburgh Compound B) and tau (MK-6240) positron emission tomography or CSF biomarkers. We also hypothesized that EEG power would be associated with neurodegeneration (CSF neurofilament light and hippocampal volume). Wakeful high-density EEG data were collected from 53 subjects. Both amyloid-β and tau pathology were associated with slowing in the alpha peak frequency [Pittsburgh Compound B (+) vs. Pittsburgh Compound B (-) subjects, P=0.039 and MK-6240 (+) vs. MK-6240 (-) subjects, P=0.019]. Furthermore, slowing in the peak alpha frequency correlated with CSF Aβ42/40 ratio (r2 = 0.270; P=0.003), phosphoTau (pTau181, r2 = 0.290; P=0.001) and pTau181/Aβ42 (r2 = 0.343; P<0.001). Alpha peak frequency was not associated with neurodegeneration. Higher CSF neurofilament light was associated with lower total EEG power (r2 = 0.136; P=0.018), theta power (r2 = 0.148; P=0.014) and beta power (r2 = 0.216; P=0.002); the latter was also associated with normalized hippocampal volume (r2 = 0.196; P=0.002). Amyloid-tau and neurodegenerative pathologies are associated with distinct electrophysiological signatures that may be useful as mechanistic tools and diagnostic/treatment effect biomarkers in clinical trials.
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