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.
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.
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.
Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the ...specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. Our structure-activity relationship study investigates the conjugation of EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction and receptor affinity. Molecular dynamic simulations revealed that the lipid moieties stabilize the peptide-receptor interaction through hydrophobic contacts at the receptor's N-terminus, anchoring the lipopeptide within the CXCR4 binding pocket and maintaining essential receptor interactions. Accordingly, lipidation resulted in increased receptor affinities and antagonistic activities. Additionally, by interacting with human serum albumin lipidated EPI-X4 derivatives displayed sustained stability in human plasma and extended circulation times in vivo. Selected candidates showed significant therapeutic potential in human retinoblastoma cells in vitro and in ovo, with our lead derivative exhibiting higher efficacies compared to its non-lipidated counterpart. This study not only elucidates the optimization trajectory for EPI-X4 derivatives but also underscores the intricate interplay between stability and efficacy, crucial for delineating their translational potential in clinical applications.
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•Lipidated derivatives of EPI-X4 exhibit increased affinity and antagonistic activity towards the CXCR4 receptor.•Lipidated EPI-X4 derivatives exhibit a half-life of >8 h in both blood and plasma.•The lipidated EPI-X4 JM#198 displays a circulation half-life of nearly 4 h in mice.•EPI-X4 JM#198 inhibits retinoblastoma tumor formation in vitro and in ovo.
•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.
Abstract
IDH-mutant low-grade diffuse astrocytomas frequently progress to grade IV astrocytomas with implications for patient prognosis. To better understand this process, we applied whole-genome and ...transcriptome sequencing to matched tumor samples collected before and after progression to grade IV astrocytomas from five patients. All tumors carried an IDH1 mutation. The number of chromosomal rearrangements was increased between 1.3 and 3.5-fold in the tumors upon progression, with the exception of one case, in which the increase was only 1.03-fold. This case exhibited a hypermutation signature caused by homozygous deletion of the MSH2 gene, which encodes a member of the DNA mismatch repair complex. The most common genomic alterations acquired at progression were homozygous deletions in the CDKN2A/ RB1 -pathway or hemizygous deletion of PTEN. Additionally, PDGFRA was amplified in two grade IV tumors, with concordantly increased expression. For one of these cases, a PDGFRA-amplified subclone is likely to be present already in the low-grade astrocytoma. We further detected intrachromosomal rearrangements closeby the genes NRG3 in the progressed tumors as well as in the The Cancer Genome Atlas (TCGA) cohort. The expression of NRG3 decreased with increasing grade in the TCGA cohort and the gene was frequently deleted. Lower NRG3 expression was associated with shorter survival in the TCGA cohort. Several miRNAs showed differential expression upon progression. For two miRNAs the predicted targets were associated with cell cycle regulation and we detected inverse correlation between miRNA and target mRNA expression. While progression seems to occur via different pathways, the predicted outcome for many of the alterations was the inactivation of tumor suppressor genes and further dysregulation of cell proliferation.
Abstract
Glioblastoma (GBM) is the most common form of adult brain tumors and patients diagnosed with GBM face a very dismal prognosis with a median survival rate of 15 months. The challenges in ...treating GBM are many, there is a complex cellular and molecular heterogeneity, both between patients and within individual tumors. In a single tumor, individual cancer cells adopt a variety of stem-like, progenitor-like, and more differentiated phenotypes (a.k.a. cell states). Recent advances in single-cell technology have made it possible to detect this diversity of cellular states, but yet we lack a good explanation for how the states arise and if transitions between states can be exploited to therapeutic ends. We here propose a new computational strategy to measure the differentiation potential of GBM cells, based on the Ising models from statistical mechanics. Originally used to model coupled magnets on a lattice, the Ising models can be generalized to represent the probability of a particular configuration of any system of n variables. We show that the models can be fitted to high-dimensional single cell data in a matter of seconds by solving a convex optimization problem, and that the models help explain cell differentiation in terms of minimization of an energy function of the system. In our on-going work we have fitted the model to single cell data from our previous work on state transitions in GBM (Larsson, Dalmo et al, Molecular Systems Biology 2021) and shown that the predicted differentiation potential of cell states is consistent with the cell state hierarchies derived from lineage tracing experiments. Moving forward, we are now exploring how the Ising models can be used to model state transitions in GBM and to predict the effect of targeted therapy on the cell’s differentiation potential.
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