Recurrent somatic ASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the ...genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.
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► ASXL1 mutations are loss-of-function mutations ► ASXL1 loss results in a genome-wide reduction in H3K27me3 occupancy ► ASXL1 interacts with the PRC2 complex and is important for PRC2 recruitment ► ASXL1 collaborates with co-occurring oncogenes in vivo to promote leukemogenesis
Objective
Despite 90 % of glioblastoma (GBM) recurrences occurring in the peritumoral brain zone (PBZ), its contribution in patient survival is poorly understood. The current study leverages ...computerized texture (i.e. radiomic) analysis to evaluate the efficacy of PBZ features from pre-operative MRI in predicting long- (>18 months) versus short-term (<7 months) survival in GBM.
Methods
Sixty-five patient examinations (29 short-term, 36 long-term) with gadolinium-contrast T
1w
, FLAIR and T
2w
sequences from the Cancer Imaging Archive were employed. An expert manually segmented each study as: enhancing lesion, PBZ and tumour necrosis. 402 radiomic features (capturing co-occurrence, grey-level dependence and directional gradients) were obtained for each region. Evaluation was performed using threefold cross-validation, such that a subset of studies was used to select the most predictive features, and the remaining subset was used to evaluate their efficacy in predicting survival.
Results
A subset of ten radiomic ‘peritumoral’ MRI features, suggestive of intensity heterogeneity and textural patterns, was found to be predictive of survival (
p
= 1.47 × 10
-5
) as compared to features from enhancing tumour, necrotic regions and known clinical factors.
Conclusion
Our preliminary analysis suggests that radiomic features from the PBZ on routine pre-operative MRI may be predictive of long- versus short-term survival in GBM.
Key Points
•
Radiomic features from peritumoral regions can capture glioblastoma heterogeneity to predict outcome.
•
Peritumoral radiomics along with clinical factors are highly predictive of glioblastoma outcome.
•
Identifying prognostic markers can assist in making personalized therapy decisions in glioblastoma.
Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute ...myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.
Understanding the mechanism of light‐induced halide segregation in mixed‐halide perovskites is essential for their application in multijunction solar cells. Here, photoluminescence spectroscopy is ...used to uncover how both increases in temperature and light intensity can counteract the halide segregation process. It is observed that, with increasing temperature, halide segregation in CH3NH3Pb(Br0.4I0.6)3 first accelerates toward ≈290 K, before slowing down again toward higher temperatures. Such reversal is attributed to the trade‐off between the temperature activation of segregation, for example through enhanced ionic migration, and its inhibition by entropic factors. High light intensities meanwhile can also reverse halide segregation; however, this is found to be only a transient process that abates on the time scale of minutes. Overall, these observations pave the way for a more complete model of halide segregation and aid the development of highly efficient and stable perovskite multijunction and concentrator photovoltaics.
Light‐induced halide segregation is a major barrier to the implementation of mixed‐halide perovskites in tandem solar cells. Increasing temperature from 125 K kinetically enhances halide segregation up to 290 K, but higher temperatures are found to hinder it owing to entropic remixing. Increasing the incident light intensity can also induce remixing, but this effect is transient.
Abstract
Mixed halide perovskites can provide optimal bandgaps for tandem solar cells which are key to improved cost-efficiencies, but can still suffer from detrimental illumination-induced phase ...segregation. Here we employ optical-pump terahertz-probe spectroscopy to investigate the impact of halide segregation on the charge-carrier dynamics and transport properties of mixed halide perovskite films. We reveal that, surprisingly, halide segregation results in negligible impact to the THz charge-carrier mobilities, and that charge carriers within the I-rich phase are not strongly localised. We further demonstrate enhanced lattice anharmonicity in the segregated I-rich domains, which is likely to support ionic migration. These phonon anharmonicity effects also serve as evidence of a remarkably fast, picosecond charge funnelling into the narrow-bandgap I-rich domains. Our analysis demonstrates how minimal structural transformations during phase segregation have a dramatic effect on the charge-carrier dynamics as a result of charge funnelling. We suggest that because such enhanced recombination is radiative, performance losses may be mitigated by deployment of careful light management strategies in solar cells.
Photovoltaic devices based on metal halide perovskites are rapidly improving in efficiency. Once the Shockley-Queisser limit is reached, charge-carrier extraction will be limited only by radiative ...bimolecular recombination of electrons with holes. Yet, this fundamental process, and its link with material stoichiometry, is still poorly understood. Here we show that bimolecular charge-carrier recombination in methylammonium lead triiodide perovskite can be fully explained as the inverse process of absorption. By correctly accounting for contributions to the absorption from excitons and electron-hole continuum states, we are able to utilise the van Roosbroeck-Shockley relation to determine bimolecular recombination rate constants from absorption spectra. We show that the sharpening of photon, electron and hole distribution functions significantly enhances bimolecular charge recombination as the temperature is lowered, mirroring trends in transient spectroscopy. Our findings provide vital understanding of band-to-band recombination processes in this hybrid perovskite, which comprise direct, fully radiative transitions between thermalized electrons and holes.
The meteoric rise of the field of perovskite solar cells has been fueled by the ease with which a wide range of high‐quality materials can be fabricated via simple solution processing methods. ...However, to date, little effort has been devoted to understanding the precursor solutions, and the role of additives such as hydrohalic acids upon film crystallization and final optoelectronic quality. Here, a direct link between the colloids concentration present in the HC(NH2)20.83Cs0.17Pb(Br0.2I0.8)3 precursor solution and the nucleation and growth stages of the thin film formation is established. Using dynamic light scattering analysis, the dissolution of colloids over a time span triggered by the addition of hydrohalic acids is monitored. These colloids appear to provide nucleation sites for the perovskite crystallization, which critically impacts morphology, crystal quality, and optoelectronic properties. Via 2D X‐ray diffraction, highly ordered and textured crystals for films prepared from solutions with lower colloidal concentrations are observed. This increase in material quality allows for a reduction in microstrain along with a twofold increase in charge‐carrier mobilities leading to values exceeding 20 cm2 V−1 s−1. Using a solution with an optimized colloidal concentration, devices that reach current–voltage measured power conversion efficiency of 18.8% and stabilized efficiency of 17.9% are fabricated.
The dissolution of colloids that are present in the formamidinium–cesium perovskite (HC(NH2)20.83Cs0.17Pb(Br0.2I0.8)3) precursor solution is triggered with the addition of hydrohalic acids. Dynamic light scattering intensity measurement shows the gradual dissolution of these colloids over a period of time. These colloids impact the morphology, crystal quality, and optoelectronic properties of the perovskite, leading to improvements in solar‐cell efficiency.
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Articular cartilage is a remarkable tissue whose sophisticated composition and architecture allow it to withstand complex stresses within the joint. Once injured, cartilage lacks the ...capacity to self-repair, and injuries often progress to joint wide osteoarthritis (OA) resulting in debilitating pain and loss of mobility. Current palliative and surgical management provides short-term symptom relief, but almost always progresses to further deterioration in the long term. A number of bioactive factors, including drugs, corticosteroids, and growth factors, have been utilized in the clinic, in clinical trials, or in emerging research studies to alleviate the inflamed joint environment or to promote new cartilage tissue formation. However, these therapies remain limited in their duration and effectiveness. For this reason, current efforts are focused on improving the localization, retention, and activity of these bioactive factors. The purpose of this review is to highlight recent advances in drug delivery for the treatment of damaged or degenerated cartilage. First, we summarize material and modification techniques to improve the delivery of these factors to damaged tissue and enhance their retention and action within the joint environment. Second, we discuss recent studies using novel methods to promote new cartilage formation via biofactor delivery, that have potential for improving future long-term clinical outcomes. Lastly, we review the emerging field of orthobiologics, using delivered and endogenous cells as drug-delivering “factories” to preserve and restore joint health. Enhancing drug delivery systems can improve both restorative and regenerative treatments for damaged cartilage.
Articular cartilage is a remarkable and sophisticated tissue that tolerates complex stresses within the joint. When injured, cartilage cannot self-repair, and these injuries often progress to joint-wide osteoarthritis, causing patients debilitating pain and loss of mobility. Current palliative and surgical treatments only provide short-term symptomatic relief and are limited with regards to efficiency and efficacy. Bioactive factors, such as drugs and growth factors, can improve outcomes to either stabilize the degenerated environment or regenerate replacement tissue. This review highlights recent advances and novel techniques to enhance the delivery, localization, retention, and activity of these factors, providing an overview of the cartilage drug delivery field that can guide future research in restorative and regenerative treatments for damaged cartilage.
The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II was developed to reflect a more current dataset and evidence-based improvements in cardiac surgery. In the United States, The ...Society of Thoracic Surgeons (STS) risk score is more accepted owing to relatively high predictive value despite less user friendliness and inapplicability to some cardiac surgeries. We compared the precision of EuroSCORE II with EuroSCORE I and the STS risk score for operative mortality.
Data were collected prospectively for all cardiac surgery patients at a single center since 2001 (N = 11,788). A secondary analysis for patients with cardiac surgery not accommodated by the STS model compared only EuroSCORE II and I (N = 5,880). Receiver-operating characteristic analyses were performed for operative mortality to determine the discriminative ability for each score.
Observed operative mortality was 1.8%. Mean predicted mortality for STS risk score, EuroSCORE II, and EuroSCORE I was 2.7%, 3.3%, and 7.8%, respectively. The discriminative ability for operative mortality by area under the curve for EuroSCORE II, EuroSCORE I, and STS risk score was 0.844, 0.819, and 0.846, respectively. In secondary analyses comparing EuroSCORE II with EuroSCORE I, risk scores were correlated (rs = 0.83, p < 0.001). However, for operative mortality (observed, 4%), EuroSCORE II had better absolute prediction and discriminative ability (expected, 5.8%; area under the curve 0.754) than EuroSCORE I (expected, 12.5%; area under the curve 0.688).
EuroSCORE II had better predictive discrimination for operative mortality than EuroSCORE I, which greatly overestimated this risk. EuroSCORE II fared well compared with the STS risk score. The inclusive nature of EuroSCORE II for numerous procedures provides more flexibility than the STS score for complex procedures. EuroSCORE II should be considered for calculating risk score for complex cardiac surgical patients.
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