Glioma progression is shaped by genetic evolution and microenvironment interactions.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Mitochondrial genome fragmentation is correlated with increased rates of molecular evolution.

While mitochondrial genome content and organization is quite diverse across all Eukaryotes, most bilaterian animal mitochondrial genomes (mitogenomes) exhibit highly conserved gene content and organisation, with genes typically encoded on a single circular chromosome. However, many species of parasitic lice (Insecta: Phthiraptera) are among the notable exceptions, having mitogenomes fragmented into multiple circular chromosomes. To better understand the process of mitogenome fragmentation, we conducted a large-scale genomic study of a major group of lice, Amblycera, with extensive taxon sampling. Analyses of the evolution of mitogenome structure across a phylogenomic tree of 90 samples from 53 genera revealed evidence for multiple independent origins of mitogenome fragmentation, some inferred to have occurred less than five million years ago. We leveraged these many independent origins of fragmentation to compare the rates of DNA substitution and gene rearrangement, specifically contrasting branches with fragmented and non-fragmented mitogenomes. We found that lineages with fragmented mitochondrial genomes had significantly higher rates of mitochondrial sequence evolution. In addition, lineages with fragmented mitochondrial genomes were more likely to have mitogenome gene rearrangements than those with single-chromosome mitochondrial genomes. By combining phylogenomics and mitochondrial genomics we provide a detailed portrait of mitogenome evolution across this group of insects with a remarkably unstable mitogenome structure, identifying processes of molecular evolution that are correlated with mitogenome fragmentation.

Longitudinal molecular trajectories of diffuse glioma in adults.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

On Demand Bioorthogonal Switching of an Antibody-Conjugated SPECT Probe to a Cytotoxic Payload: from Imaging to Therapy.

Antibody-drug conjugates (ADCs) for the treatment of cancer aim to achieve selective delivery of a cytotoxic payload to tumor cells while sparing normal tissue. In vivo, multiple tumor-dependent and -independent processes act on ADCs and their released payloads to impact tumor-versus-normal delivery, often resulting in a poor therapeutic window. An ADC with a labeled payload would make synchronous correlations between distribution and tissue-specific pharmacological effects possible, empowering preclinical and clinical efforts to improve tumor-selective delivery; however, few methods to label small molecules without destroying their pharmacological activity exist. Herein, we present a bioorthogonal switch approach that allows a radiolabel attached to an ADC payload to be removed tracelessly at will. We exemplify this approach with a potent DNA-damaging agent, the pyrrolobenzodiazepine (PBD) dimer, delivered as an antibody conjugate targeted to lung tumor cells. The radiometal chelating group, DOTA, was attached via a novel trans-cyclooctene (TCO)-caged self-immolative para-aminobenzyl (PAB) linker to the PBD, stably attenuating payload activity and allowing tracking of biodistribution in tumor-bearing mice via SPECT-CT imaging (live) or gamma counting (post-mortem). Following TCO-PAB-DOTA reaction with tetrazines optimized for extra- and intracellular reactivity, the label was removed to reveal the unmodified PBD dimer capable of inducing potent tumor cell killing in vitro and in mouse xenografts. The switchable antibody radio-drug conjugate (ArDC) we describe integrates, but decouples, the two functions of a theranostic given that it can serve as a diagnostic for payload delivery in the labeled state, but can be switched on demand to a therapeutic agent (an ADC).

Chromosome-Aware Phylogenomics of Assassin Bugs (Hemiptera: Reduvioidea) Elucidates Ancient Gene Conflict.

Though the phylogenetic signal of loci on sex chromosomes can differ from those on autosomes, chromosomal-level genome assemblies for nonvertebrates are still relatively scarce and conservation of chromosomal gene content across deep phylogenetic scales has therefore remained largely unexplored. We here assemble a uniquely large and diverse set of samples (17 anchored hybrid enrichment, 24 RNA-seq, and 70 whole-genome sequencing samples of variable depth) for the medically important assassin bugs (Reduvioidea). We assess the performance of genes based on multiple features (e.g., nucleotide vs. amino acid, nuclear vs. mitochondrial, and autosomal vs. X chromosomal) and employ different methods (concatenation and coalescence analyses) to reconstruct the unresolved phylogeny of this diverse (∼7,000 spp.) and old (>180 Ma) group. Our results show that genes on the X chromosome are more likely to have discordant phylogenies than those on autosomes. We find that the X chromosome conflict is driven by high gene substitution rates that impact the accuracy of phylogenetic inference. However, gene tree clustering showed strong conflict even after discounting variable third codon positions. Alternative topologies were not particularly enriched for sex chromosome loci, but spread across the genome. We conclude that binning genes to autosomal or sex chromosomes may result in a more accurate picture of the complex evolutionary history of a clade.

Metabolism of new drug modalities research advances - 2023 year in review.

With contributions from colleagues across academia and industry, we have put together the annual reviews of research advances on drug biotransformation and bioactivation since 2016 led by Cyrus Khojasteh. While traditional small molecules and biologics are still predominant in drug discovery, we start to notice a paradigm shift toward new drug modalities (NDMs) including but not limited to peptide and oligonucleotide therapeutics, protein degraders (heterobifunctional degraders and molecule glues), conjugated drugs and covalent inhibitors. The readers can learn more on each new drug modality from several recent comprehensive reviews (Blanco et al. 2022; Hillebrand et al. 2024; Phuna et al. 2024). Based on this trend, we put together this stand-alone review branched from our previous efforts (Baillie et al. 2016; Khojasteh et al. 2023) with a focus on the metabolism of NDMs. We collected 11 articles which exemplify recent discoveries and perspectives in this field.

Bioactivation and reactivity research advances-2023 year in review.

Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.

Parasite escape mechanisms drive morphological diversification in avian lice.

Organisms that have repeatedly evolved similar morphologies owing to the same selective pressures provide excellent cases in which to examine specific morphological changes and their relevance to the ecology and evolution of taxa. Hosts of permanent parasites act as an independent evolutionary experiment, as parasites on these hosts are thought to be undergoing similar selective pressures. Parasitic feather lice have repeatedly diversified into convergent ecomorphs in different microhabitats on their avian hosts. We quantified specific morphological characters to determine (i) which traits are associated with each ecomorph, (ii) the quantitative differences between these ecomorphs, and (iii) if there is evidence of displacement among co-occurring lice as might be expected under louse-louse competition on the host. We used nano-computed tomography scan data of 89 specimens, belonging to four repeatedly evolved ecomorphs, to examine their mandibular muscle volume, limb length and three-dimensional head shape data. Here, we find evidence that lice repeatedly evolve similar morphologies as a mechanism to escape host defences, but also diverge into different ecomorphs related to the way they escape these defences. Lice that co-occur with other genera on a host exhibit greater morphological divergence, indicating a potential role of competition in evolutionary divergence.

An Integrated Hepatocyte Stability Assay for Simultaneous Metabolic Stability Assessment and Metabolite Profiling.

The determination of metabolic stability is critical for drug discovery programs, allowing for the optimization of chemical entities and compound prioritization. As such, it is common to perform high-volume in vitro metabolic stability experiments early in the lead optimization process to understand metabolic liabilities. Additional metabolite identification experiments are subsequently performed for a more comprehensive understanding of the metabolic clearance routes to aid medicinal chemists in the structural design of compounds. Collectively, these experiments require extensive sample preparation and a substantial amount of time and resources. To overcome the challenges, a high-throughput integrated assay for simultaneous hepatocyte metabolic stability assessment and metabolite profiling was developed. This assay platform consists of four parts: 1) an automated liquid-handling system for sample preparation and incubation, 2) a liquid chromatography and high-resolution mass spectrometry-based system to simultaneously monitor the parent compound depletion and metabolite formation, 3) an automated data analysis and report system for hepatic clearance assessment; and 4) streamlined autobatch processing for software-based metabolite profiling. The assay platform was evaluated using eight control compounds with various metabolic rates and biotransformation routes in hepatocytes across three species. Multiple sample preparation and data analysis steps were evaluated and validated for accuracy, repeatability, and metabolite coverage. The combined utility of an automated liquid-handling instrument, a high-resolution mass spectrometer, and multiple streamlined data processing software improves the process of these highly demanding screening assays and allows for simultaneous determination of metabolic stability and metabolite profiles for more efficient lead optimization during early drug discovery. SIGNIFICANCE STATEMENT: Metabolic stability assessment and metabolite profiling are pivotal in drug discovery to fully comprehend metabolic liabilities for chemical entity optimization and lead selection. Process of these assays can be repetitive and resource demanding. Here, we developed an integrated hepatocyte stability assay that combines automation, high-resolution mass spectrometers, and batch-processing software to improve and combine the workflow of these assays. The integrated approach allows simultaneous metabolic stability assessment and metabolite profiling, significantly accelerating screening and lead optimization in a resource-effective manner.

Four-dimensional flow MRI for quantitative assessment of cerebrospinal fluid dynamics: Status and opportunities.

Neurological disorders can manifest with altered neurofluid dynamics in different compartments of the central nervous system. These include alterations in cerebral blood flow, cerebrospinal fluid (CSF) flow, and tissue biomechanics. Noninvasive quantitative assessment of neurofluid flow and tissue motion is feasible with phase contrast magnetic resonance imaging (PC MRI). While two-dimensional (2D) PC MRI is routinely utilized in research and clinical settings to assess flow dynamics through a single imaging slice, comprehensive neurofluid dynamic assessment can be limited or impractical. Recently, four-dimensional (4D) flow MRI (or time-resolved three-dimensional PC with three-directional velocity encoding) has emerged as a powerful extension of 2D PC, allowing for large volumetric coverage of fluid velocities at high spatiotemporal resolution within clinically reasonable scan times. Yet, most 4D flow studies have focused on blood flow imaging. Characterizing CSF flow dynamics with 4D flow (i.e., 4D CSF flow) is of high interest to understand normal brain and spine physiology, but also to study neurological disorders such as dysfunctional brain metabolite waste clearance, where CSF dynamics appear to play an important role. However, 4D CSF flow imaging is challenged by the long T1 time of CSF and slower velocities compared with blood flow, which can result in longer scan times from low flip angles and extended motion-sensitive gradients, hindering clinical adoption. In this work, we review the state of 4D CSF flow MRI including challenges, novel solutions from current research and ongoing needs, examples of clinical and research applications, and discuss an outlook on the future of 4D CSF flow.

Cotyledon-Specific Flow Evaluation of Rhesus Macaque Placental Injury Using Ferumoxytol Dynamic Contrast-Enhanced MRI.

BACKGROUND: Recently, dynamic contrast-enhanced (DCE) MRI with ferumoxytol as contrast agent has recently been introduced for the noninvasive assessment of placental structure and function throughout. However, it has not been demonstrated under pathological conditions. PURPOSE: To measure cotyledon-specific rhesus macaque maternal placental blood flow using ferumoxytol DCE MRI in a novel animal model for local placental injury. STUDY TYPE: Prospective animal model. SUBJECTS: Placental injections of Tisseel (three with 0.5 mL and two with 1.5 mL), monocyte chemoattractant protein 1 (three with 100 µg), and three with saline as controls were performed in a total of 11 rhesus macaque pregnancies at approximate gestational day (GD 101). DCE MRI scans were performed prior (GD 100) and after (GD 115 and GD 145) the injection (term = GD 165). FIELD STRENGTH/SEQUENCE: 3 T, T1-weighted spoiled gradient echo sequence (product sequence, DISCO). ASSESSMENT: Source images were inspected for motion artefacts from the mother or fetus. Placenta segmentation and DCE processing were performed for the dynamic image series to measure cotyledon specific volume, flow, and normalized flow. Overall placental histopathology was conducted for controls, Tisseel, and MCP-1 animals and regions of tissue infarctions and necrosis were documented. Visual inspections for potential necrotic tissue were conducted for the two Tisseelx3 animals. STATISTICAL TESTS: Wilcoxon rank sum test, significance level P < 0.05. RESULTS: No motion artefacts were observed. For the group treated with 1.5 mL of Tisseel, significantly lower cotyledon volume, flow, and normalized flow per cotyledon were observed for the third gestational time point of imaging (day ~145), with mean normalized flow of 0.53 minute-1 . Preliminary histopathological analysis shows areas of tissue necrosis from a selected cotyledon in one Tisseel-treated (single dose) animal and both Tisseelx3 (triple dose) animals. DATA CONCLUSION: This study demonstrates the feasibility of cotyledon-specific functional analysis at multiple gestational time points and injury detection in a placental rhesus macaque model through ferumoxytol-enhanced DCE MRI. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 2.

False lumen hemodynamics and partial thrombosis in chronic aortic dissection of the descending aorta.

OBJECTIVES: Partial thrombosis of the false lumen (FL) in patients with chronic aortic dissection (AD) of the descending aorta has been associated with poor outcomes. Meanwhile, the fluid dynamic and biomechanical characteristics associated with partial thrombosis remain to be elucidated. This retrospective, single-center study tested the association between FL fluid dynamics and biomechanics and the presence and extent of FL thrombus. METHODS: Patients with chronic non-thrombosed or partially thrombosed FLs in the descending aorta after an aortic dissection underwent computed tomography angiography, cardiovascular magnetic resonance (CMR) angiography, and a 4D flow CMR study. A comprehensive quantitative analysis was performed to test the association between FL thrombus presence and extent (percentage of FL with thrombus) and FL anatomy (diameter, entry tear location and size), fluid dynamics (inflow, rotational flow, wall shear stress, kinetic energy, and flow acceleration and stasis), and biomechanics (pulse wave velocity). RESULTS: Sixty-eight patients were included. In multivariate logistic regression FL kinetic energy (p = 0.038) discriminated the 33 patients with partial FL thrombosis from the 35 patients with no thrombosis. Similarly, in separated multivariate linear correlations kinetic energy (p = 0.006) and FL inflow (p = 0.002) were independently related to the extent of the thrombus. FL vortexes, flow acceleration and stasis, wall shear stress, and pulse wave velocity showed limited associations with thrombus presence and extent. CONCLUSION: In patients with chronic descending aorta dissection, false lumen kinetic energy is related to the presence and extent of false lumen thrombus. CLINICAL RELEVANCE STATEMENT: In patients with chronic aortic dissection of the descending aorta, false lumen hemodynamic parameters are closely linked with the presence and extent of false lumen thrombosis, and these non-invasive measures might be important in patient management. KEY POINTS: • Partial false lumen thrombosis has been associated with aortic growth in patients with chronic descending aortic dissection; therefore, the identification of prothrombotic flow conditions is desirable. • The presence of partial false lumen thrombosis as well as its extent was related with false lumen kinetic energy. • The assessment of false lumen hemodynamics may be important in the management of patients with chronic aortic dissection of the descending aorta.

Rate of oophorectomy in pediatric ovarian torsion: risk factors and change over time.

PURPOSE: The management of ovarian torsion in pediatric patients has evolved over time. Ovarian salvage is currently recommended given concerns for fertility preservation and the low likelihood of malignancy. Studies have shown that the incidence of oophorectomy is higher amongst pediatric surgeons in comparison to gynecologists. Using a national database, this study examined how the surgical management of ovarian torsion has evolved. METHODS: Children with a discharge diagnosis of ovarian torsion (ICD-9 code 620.5, ICD-10 code N835X) and procedure codes for oophorectomy (CCS code 119) were identified within the KID database from 2003, 2006, 2009, 2012, 2016, and 2019. Diagnosis of ovarian pathology was based upon ICD-9 and ICD-10 codes at the time of discharge. RESULTS: A total of 7008 patients, ages 1-20, had a discharge diagnosis of ovarian torsion. Of those patients, 2,597 (37.1%) were diagnosed with an ovarian cyst, 1560 (22.2%) were diagnosed with a benign ovarian neoplasm, and 30 (0.4%) were diagnosed with a malignant neoplasm. There was a decreased risk of oophorectomy in urban-teaching versus rural hospitals (OR: 0.64, p < 0.001). The rate of oophorectomy has decreased overtime. However, patients with benign or malignant neoplasms were more likely to undergo oophorectomy than those without a diagnosis (OR: 2.03, p < 0.001; 4.82, p < 0.001). CONCLUSION: The rate of oophorectomy amongst children with ovarian torsion has decreased over time. Yet, despite improvements, oophorectomy is common amongst patients with benign ovarian neoplasms and those treated at rural hospitals. Continued education is needed to optimize patient care in all clinical scenarios. LEVEL OF EVIDENCE: IV.

Helicobacter pylori Chronic-Stage Inflammation Undergoes Fluctuations That Are Altered in tlpA Mutants.

Helicobacter pylori colonizes half of the world's population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an 8-month mouse infection time course and comparison of the wild type (WT) and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic-stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from the wild type at some time points. tlpA mutants have equivalent total and gland colonization in late-stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to those by WT. Our results suggest the chronic inflammation setting is dynamic and may be influenced by colonization properties of early infection.

Bioactivation and reactivity research advances - 2022 year in review‡.

With the 50th year mark since the launch of Drug Metabolism and Disposition journal, the field of drug metabolism and bioactivation has advanced exponentially in the past decades (Guengerich 2023).This has, in a major part, been due to the continued advances across the whole spectrum of applied technologies in hardware, software, machine learning (ML), and artificial intelligence (AI). LC-MS platforms continue to evolve to support key applications in the field, and automation is also improving the accuracy, precision, and throughput of these supporting assays. In addition, sample generation and processing is being aided by increased diversity and quality of reagents and bio-matrices so that what is being analyzed is more relevant and translatable. The application of in silico platforms (applied software, ML, and AI) is also making great strides, and in tandem with the more traditional approaches mentioned previously, is significantly advancing our understanding of bioactivation pathways and how these play a role in toxicity. All of this continues to allow the area of bioactivation to evolve in parallel with associated fields to help bring novel or improved medicines to patients with urgent or unmet needs.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.

Biotransformation research advances - 2022 year in review.

This annual review is the eighth of its kind since 2016 (Baillie et al. 2016, Khojasteh et al. 2017, Khojasteh et al. 2018, Khojasteh et al. 2019, Khojasteh et al. 2020, Khojasteh et al. 2021, Khojasteh et al. 2022). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation.

Normative Cerebral Hemodynamics in Middle-aged and Older Adults Using 4D Flow MRI: Initial Analysis of Vascular Aging.

Background Characterizing cerebrovascular hemodynamics in older adults is important for identifying disease and understanding normal neurovascular aging. Four-dimensional (4D) flow MRI allows for a comprehensive assessment of cerebral hemodynamics in a single acquisition. Purpose To establish reference intracranial blood flow and pulsatility index values in a large cross-sectional sample of middle-aged (45-65 years) and older (>65 years) adults and characterize the effect of age and sex on blood flow and pulsatility. Materials and Methods In this retrospective study, patients aged 45-93 years (cognitively unimpaired) underwent cranial 4D flow MRI between March 2010 and March 2020. Blood flow rates and pulsatility indexes from 13 major arteries and four venous sinuses and total cerebral blood flow were collected. Intraobserver and interobserver reproducibility of flow and pulsatility measures was assessed in 30 patients. Descriptive statistics (mean ± SD) of blood flow and pulsatility were tabulated for the entire group and by age and sex. Multiple linear regression and linear mixed-effects models were used to assess the effect of age and sex on total cerebral blood flow and vessel-specific flow and pulsatility, respectively. Results There were 759 patients (mean age, 65 years ± 8 [SD]; 506 female patients) analyzed. For intra- and interobserver reproducibility, median intraclass correlation coefficients were greater than 0.90 for flow and pulsatility measures across all vessels. Regression coefficients ß ± standard error from multiple linear regression showed a 4 mL/min decrease in total cerebral blood flow each year (age ß = -3.94 mL/min per year ± 0.44; P < .001). Mixed effects showed a 1 mL/min average annual decrease in blood flow (age ß = -0.95 mL/min per year ± 0.16; P < .001) and 0.01 arbitrary unit (au) average annual increase in pulsatility over all vessels (age ß = 0.011 au per year ± 0.001; P < .001). No evidence of sex differences was observed for flow (ß = -1.60 mL/min per male patient ± 1.77; P = .37), but pulsatility was higher in female patients (sex ß = -0.018 au per male patient ± 0.008; P = .02). Conclusion Normal reference values for blood flow and pulsatility obtained using four-dimensional flow MRI showed correlations with age. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Steinman in this issue.

Motion compensated self supervised deep learning for highly accelerated 3D ultrashort Echo time pulmonary MRI.

PURPOSE: To investigate motion compensated, self-supervised, model based deep learning (MBDL) as a method to reconstruct free breathing, 3D pulmonary UTE acquisitions. THEORY AND METHODS: A self-supervised eXtra dimension MBDL architecture (XD-MBDL) was developed that combined respiratory states to reconstruct a single high-quality 3D image. Non-rigid motion fields were incorporated into this architecture by estimating motion fields from a lower resolution motion resolved (XD-GRASP) reconstruction. Motion compensated XD-MBDL was evaluated on lung UTE datasets with and without contrast and compared to constrained reconstructions and variants of self-supervised MBDL that do not account for dynamic respiratory states or leverage motion correction. RESULTS: Images reconstructed using XD-MBDL demonstrate improved image quality as measured by apparent SNR (aSNR), contrast to noise ratio (CNR), and visual assessment relative to self-supervised MBDL approaches that do not account for dynamic respiratory states, XD-GRASP and a recently proposed motion compensated iterative reconstruction strategy (iMoCo). Additionally, XD-MBDL reduced reconstruction time relative to both XD-GRASP and iMoCo. CONCLUSION: A method was developed to allow self-supervised MBDL to combine multiple respiratory states to reconstruct a single image. This method was combined with graphics processing unit (GPU)-based image registration to further improve reconstruction quality. This approach showed promising results reconstructing a user-selected respiratory phase from free breathing 3D pulmonary UTE acquisitions.

Accelerated 4D-flow MRI with 3-point encoding enabled by machine learning.

PURPOSE: To investigate the acceleration of 4D-flow MRI using a convolutional neural network (CNN) that produces three directional velocities from three flow encodings, without requiring a fourth reference scan measuring background phase. METHODS: A fully 3D CNN using a U-net architecture was trained in a block-wise fashion to take complex images from three flow encodings and to produce three real-valued images for each velocity component. Using neurovascular 4D-flow scans (n = 144), the CNN was trained to predict velocities computed from four flow encodings by standard reconstruction including correction for residual background phase offsets. Methods to optimize loss functions were investigated, including magnitude, complex difference, and uniform velocity weightings. Subsequently, 3-point encoding was evaluated using cross validation of pixelwise correlation, flow measurements in major arteries, and in experiments with data at differing acceleration rates than the training data. RESULTS: The CNN-produced 3-point velocities showed excellent agreements with the 4-point velocities, both qualitatively in velocity images, in flow rate measures, and quantitatively in regression analysis (slope = 0.96, R2  = 0.992). Optimizing the training to focus on vessel velocities rather than the global velocity error and improved the correlation of velocity within vessels themselves. The lowest error was observed when the loss function used uniform velocity weighting, in which the magnitude-weighted inverse of the velocity frequency uniformly distributed weighting across all velocity ranges. When applied to highly accelerated data, the 3-point network maintained a high correlation with ground truth data and demonstrated a denoising effect. CONCLUSION: The 4D-flow MRI can be accelerated using machine learning requiring only three flow encodings to produce three-directional velocity maps with small errors.

Fat mitigation strategies to improve image quality of radial 4D flow MRI in obese subjects.

PURPOSE: This study addresses the challenges in obtaining abdominal 4D flow MRI of obese patients. We aimed to evaluate spectral saturation and inner volume excitation as methods to mitigating artifacts originating from adipose signals, with the goal of enhancing image quality and improving quantification. METHODS: Radial 4D flow MRI acquisitions with fat mitigation (inner volume excitation [IVE] and intermittent fat saturation [FS]) were compared to a standard slab selective excitation (SSE) in a test-retest study of 15 obese participants. IVE selectively excited a cylindrical region of interest, avoiding contamination from peripheral adipose tissue, while FS globally suppressed fat based on spectral selection. Acquisitions were evaluated qualitatively based on expert ratings and quantitatively based on conservation of mass, test-retest repeatability, and a divergence free quality metric. Errors were evaluated statistically using the absolute and relative errors, regression, and Bland-Altman analysis. RESULTS: IVE demonstrated superior performance quantitatively in the conservation of mass analysis in the portal vein, with higher correlation and lower bias in regression analysis. IVE also produced flow fields with the lowest divergence error and was rated best in overall image quality, delineating small vessels, and producing the least streaking artifacts. Evaluation results did not differ significantly between FS and SSE. Test-retest reproducibility was similarly high for all sequences, with data suggesting biological variations dominate the technical variability. CONCLUSION: IVE improved hemodynamic assessment of radial 4D flow MRI in the abdomen of obese participants while FS did not lead to significant improvements in image quality or flow metrics.