Since the completion of the first human genome sequence and the advent of next generation sequencing technologies, remarkable progress has been made in understanding the genetic basis of cancer. ...These studies have mainly defined genetic changes as either causal, providing a selective advantage to the cancer cell (a driver mutation) or consequential with no selective advantage (not directly causal, a passenger mutation). A vast unresolved question is how a primary cancer cell becomes metastatic and what are the molecular events that underpin this process. However, extensive sequencing efforts indicate that mutation may not be a causal factor for primary to metastatic transition. On the other hand, epigenetic changes are dynamic in nature and therefore potentially play an important role in determining metastatic phenotypes and this area of research is just starting to be appreciated. Unlike genetic studies, current limitations in studying epigenetic events in cancer metastasis include a lack of conceptual understanding and an analytical framework for identifying putative driver and passenger epigenetic changes. In this review, we discuss the key concepts involved in understanding the role of epigenetic alterations in the metastatic cascade. We particularly focus on driver epigenetic events, and we describe analytical approaches and biological frameworks for distinguishing between “epi-driver” and “epi-passenger” events in metastasis. Finally, we suggest potential directions for future research in this important area of cancer research.
Epi-completely Regular Topological Spaces AlShammari, Ibtesam Eid
European journal of pure and applied mathematics,
10/2022, Letnik:
15, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The purpose of this work is to introduce and study a new topological property called epi-complete-regularity. A space (X, T ) is called an epi-completely-regular space if there exists a topology T′ ...on X which is coarser than T such that (X, T′) is Tychonoff. This new property is investigated and some examples are presented in this work to illustrate its relationships with other kinds of normality and complete-regularity.
Purpose
A segmented k‐space blipped‐controlled aliasing in parallel imaging (skipped‐CAIPI) sampling strategy for EPI is proposed, which allows for a flexible choice of EPI factor and phase encode ...bandwidth independent of the controlled aliasing in parallel imaging (CAIPI) sampling pattern.
Theory and Methods
With previously proposed approaches, exactly two EPI trajectories were possible given a specific CAIPI pattern, either with slice gradient blips (blipped‐CAIPI) or following a shot‐selective CAIPI approach (higher resolution). Recently, interleaved multi‐shot segmentation along shot‐selective CAIPI trajectories has been applied for high‐resolution anatomical imaging. For more flexibility and a broader range of applications, we propose segmentation along any blipped‐CAIPI trajectory. Thus, all EPI factors and phase encode bandwidths available with traditional segmented EPI can be combined with controlled aliasing.
Results
Temporal SNR maps of moderate‐to‐high‐resolution time series acquisitions at varying undersampling factors demonstrate beneficial sampling alternatives to blipped‐CAIPI or shot‐selective CAIPI. Rapid high‐resolution scans furthermore demonstrate SNR‐efficient and motion‐robust structural imaging with almost arbitrary EPI factor and minimal noise penalty.
Conclusion
Skipped‐CAIPI sampling increases protocol flexibility for high spatiotemporal resolution EPI. In terms of SNR and efficiency, high‐resolution functional or structural scans benefit vastly from a free choice of the CAIPI pattern. Even at moderate resolutions, the independence of sampling pattern, TE, and image matrix size is valuable for optimized functional protocol design. Although demonstrated with 3D‐EPI, skipped‐CAIPI is also applicable with simultaneous multislice EPI.
•CotA laccase from Bacillus licheniformis was capable of degrading aflatoxin B1.•CotA-mediated AFB1 degradation was achieved in the absence of redox mediators.•AFB1 was transformed into aflatoxin Q1 ...and epi-aflatoxin Q1.•AFQ1 and epi-AFQ1 were almost non-toxic to human liver cells L-02.
In the present study, the CotA protein from Bacillus licheniformis ANSB821 was cloned and expressed in Escherichia coli. Apart from the laccase activities, we found that the recombinant CotA could effectively oxidize aflatoxin B1 in the absence of redox mediators. The Km, Kcat and Vmax values of the recombinant CotA towards aflatoxin B1 were 60.62 μM, 0.03 s−1 and 10.08 μg min−1 mg−1, respectively. CotA-mediated aflatoxin B1 degradation products were purified and identified to be aflatoxin Q1 and epi-aflatoxin Q1. The treatment of human liver cells L-02 with aflatoxin Q1 and epi-aflatoxin Q1 did not suppress cell viability and induce apoptosis. Molecular docking simulation revealed that hydrogen bonds and van der Waals interaction played an important role in aflatoxin B1-CotA stability. These findings in the current study are promising for a possible application of CotA as a novel aflatoxin oxidase in degrading AFB1 in food.
Purpose
Single‐shot (SS) EPI is widely used for clinical DWI. This study aims to develop an end‐to‐end deep learning–based method with a novel loss function in an improved network structure to ...simultaneously increase the resolution and correct distortions for SS‐EPI DWI.
Theory and Methods
Point‐spread‐function (PSF)–encoded EPI can provide high‐resolution, distortion‐free DWI images. A distorted image from SS‐EPI can be described as the convolution between a PSF function with a distortion‐free image. The deconvolution process to recover the distortion‐free image can be achieved with a convolution neural network, which also learns the mapping function between low‐resolution SS‐EPI and high‐resolution reference PSF‐EPI to achieve superresolution. To suppress the oversmoothing effect, we proposed a modified generative adversarial network structure, in which a dense net with gradient map guidance and a multilevel fusion block was used as the generator. A fractional anisotropy loss was proposed to utilize the diffusion anisotropy information among diffusion directions. In vivo brain DWI data were used to test the proposed method.
Results
The results show that distortion‐corrected high‐resolution DWI images with restored structural details can be obtained from low‐resolution SS‐EPI images by taking advantage of the high‐resolution anatomical images. Additionally, the proposed network can improve the quantitative accuracy of diffusion metrics compared with previously reported networks.
Conclusion
Using high‐resolution, distortion‐free EPI‐DWI images as references, a deep learning–based method to simultaneously increase the perceived resolution and correct distortions for low‐resolution SS‐EPI was proposed. The results show that DWI image quality and diffusion metrics can be improved.
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► Recent advances of simultaneous multi-slice echo planar imaging are reviewed. ► Improved with blipped controlled aliasing (blipped-CAIPI). ► Neuroimaging of brain connectivity with ...fMRI and diffusion MRI. ► Faster whole brain measurement of diffusion for axonal tractography. ► Faster imaging improves statistical definition of networks in resting state fMRI.
The recent advancement of simultaneous multi-slice imaging using multiband excitation has dramatically reduced the scan time of the brain. The evolution of this parallel imaging technique began over a decade ago and through recent sequence improvements has reduced the acquisition time of multi-slice EPI by over ten fold. This technique has recently become extremely useful for (i) functional MRI studies improving the statistical definition of neuronal networks, and (ii) diffusion based fiber tractography to visualize structural connections in the human brain. Several applications and evaluations are underway which show promise for this family of fast imaging sequences.
Purpose
To introduce wave‐encoded acquisition and reconstruction techniques for highly accelerated EPI with reduced g‐factor penalty and image artifacts.
Theory and Methods
Wave‐EPI involves ...application of sinusoidal gradients during the EPI readout, which spreads the aliasing in all spatial directions, thereby taking better advantage of 3D coil sensitivity profiles. The amount of voxel spreading that can be achieved by the wave gradients during the short EPI readout period is constrained by the slew rate of the gradient coils and peripheral nerve stimulation monitor. We propose to use a “half‐cycle” sinusoidal gradient to increase the amount of voxel spreading that can be achieved while respecting the slew and stimulation constraints. Extending wave‐EPI to multi‐shot acquisition minimizes geometric distortion and voxel blurring at high in‐plane resolutions, while structured low‐rank regularization mitigates shot‐to‐shot phase variations. To address gradient imperfections, we propose to use different point spread functions for the k‐space lines with positive and negative polarities, which are calibrated with a FLEET‐based reference scan.
Results
Wave‐EPI enabled whole‐brain single‐shot gradient‐echo (GE) and multi‐shot spin‐echo (SE) EPI acquisitions at high acceleration factors at 3T and was combined with g‐Slider encoding to boost the SNR level in 1 mm isotropic diffusion imaging. Relative to blipped‐CAIPI, wave‐EPI reduced average and maximum g‐factors by up to 1.21‐ and 1.37‐fold at Rin × Rsms = 3 × 3, respectively.
Conclusion
Wave‐EPI allows highly accelerated single‐ and multi‐shot EPI with reduced g‐factor and artifacts and may facilitate clinical and neuroscientific applications of EPI by improving the spatial and temporal resolution in functional and diffusion imaging.
Abstract
Gliomas are the most common central nervous system neoplasm and despite the past significant progress, its diagnostics faces suboptimal classification which impacts patient management. The ...stem cell-like phenotype of various cancers is correlated with the worst overall prognosis. We propose a Stemness prediction model based on gene expression signatures of neural progenitors that can be used to measure the dedifferentiation state (or Stemness) of glioma samples. To built the model, publicly available single-cell RNA sequencing data was used to identify gene expression from the fetal astrocyte (AST) population. Subpopulations of interest were identified through the expression of marker genes. We applied a one-class logistic regression to built the prediction model using the AST population. The model was applied to glioma bulk transcriptomic data to generate an fetal astrocyte stemness index (ASTsi). The ASTsi was able to stratify gliomas based on grade, histology, and molecular subtypes. Grade 4, glioblastoma, IDHwt, and the mitochondrial and proliferative functional subtypes had the highest stemness. When applied to longitudinal samples we observed an increase of ASTsi in IDHmut recurrent and a decrease in IDHwt recurrent tumors, compared to primary samples. Additionally, we applied the model to single-cell RNAseq of adult IDHwt glioblastomas and found clusters of high-stemness cells (ASTsi > 0.8). A differential gene expression combined with pathway analysis between high- and low-stemness cells revealed cell cycle, DNA repair mechanisms and histone modifications upregulated in the high-stemness population. The balance between histone methylation and demethylation may be directly related to the phenotype of these cells. More in-depth analysis of these genes and pathways are being carried out and may provide important information about the oncogenesis and phenotypic characterization of glioma stemness. Our stemness prediction model stratified glioma samples by pathological and molecular features and revealed tumor subpopulations with distinct stemness degree in gliomas IDHwt.
Abstract
Diffuse intrinsic pontine glioma (DIPG) is an infiltrative incurable tumor affecting children. DIPG tumors often harbor a recurrent H3K27M mutation which leads to a global loss of H3K27me2/3 ...and overall DNA hypomethylation, suggesting an important role of the epigenome, and consequent transcriptome in DIPG pathogenesis. To thoroughly characterize the clonal evolution of DIPG, we collected 33 samples from 7 DIPG patients using a multi-region sampling strategy and generated whole-exome and transcriptome sequencing, and DNA methylation profiling data. Using our novel bioinformatics approach, 28 distinct tumor sub-clones were identified and characterized in our cohort of DIPG patients whilst simultaneously interrogating the tumor’s ability to migrate and disseminate. When present, initiating tumor clone (Clone 1) exclusively contained H3K27M with significant DNA methylation changes whereas the divergent clones that arise later in DIPG evolutionary trees were typically driven by the copy number aberrations. Further characterization of DIPG sub-clones identified unique gene expression profiles (i.e. cell migration and angiogenesis programs) that support and enable DIPG dissemination. In this study, we uncovered how DIPG evolves at the genetic, epigenetic, and transcriptional levels in parallel and in doing so, reveal novel evolutionary phenotypes at the sub-clonal level related to the tumor’s behavior. We are further validating these results in single-cell RNA sequencing experiments and gaining further insights into the underlying molecular mechanisms responsible for invasive and aggressive DIPG phenotypes.
Abstract
Glioblastoma (GBM) is the most frequent and malignant adult-type diffuse glioma (WHO grade IV) with a median patient survival of less than 15 months despite multimodal treatment. The poor ...prognosis of GBM, among others, is associated with a tumor-supporting microenvironment characterized by a rather anti-inflammatory state, where the tumor cells have been shown to hijack microglial gene expression profiles. These so-called tumor-associated microglia cells (TAMs) repress normal immune functions, such as phagocytosis and pro-inflammatory cytokine secretion through transcriptional reprogramming, further underlying morphological changes. It is currently starting to emerge that the exceptional cellular plasticity required to orchestrate such microglial reactivity could originate from pre-imposed epigenetic modifications. We thus hypothesize that TAM reprogramming in GBM is controlled by epigenetic mechanisms, and therefore aim to understand if modifications in DNA methylation patterns can lead to pro-tumor transcriptomic and phenotypical changes.Reactive microglia are classically described as either ‘pro-inflammatory’ M1 or ‘anti-inflammatory’ M2 phenotypes, inducable by Lipopolysaccharide (LPS) and Interferon-gamma (IFNɣ) or Interleukin-4 (IL-4), respectively. In a GBM context, microglial cells have been mostly classified as M2, but exhibit heterogeneous features among the M1 to M2 activation spectrum. In this study, we exposed human and murine microglial cell lines to LPS, IFNɣ, IL-4, and GBM-conditioned medium (GBM-CM), followed by morphological assessment, transcript expression and secretome characterization. The onset of activation was followed in time series every 12h to interrogate epigenetic and transcriptomic changes together with protein expression and secretion. After exposure to GBM-CM, microglial cells exhibited a bipolar and more elongated phenotype. We observed significant variations in cytokine production together with a decrease in phagocytosis in LPS-treated microglia, whereas the secretome in GBM-CM was only slightly altered. We furthermore observed differentially methylated regions (DMRs) using the novel Infinium® Mouse Methylation BeadChip, suggesting a role of DNA methylation in microglial reprogramming.
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