Publications by authors named "Michael D Taylor"

509 Publications

Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer.

Nat Commun 2021 09 2;12(1):5238. Epub 2021 Sep 2.

Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada.

The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.
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http://dx.doi.org/10.1038/s41467-021-25467-wDOI Listing
September 2021

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Acta Neuropathol 2021 Aug 18. Epub 2021 Aug 18.

Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.
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http://dx.doi.org/10.1007/s00401-021-02358-4DOI Listing
August 2021

Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse.

Neuro Oncol 2021 Jul 17. Epub 2021 Jul 17.

Newcastle University Centre for Cancer, Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK.

Background: <5% of medulloblastoma patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations suggested significant genetic divergence of the relapsed disease.

Methods: We undertook large-scale integrated characterization of the molecular features of rMB - molecular subgroup, novel subtypes, copy number variation (CNV) and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n=107), alongside an independent reference cohort sampled at diagnosis (n=282). rMB events were investigated for association with outcome post-relapse in clinically-annotated patients (n=54).

Results: Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. MBSHH Non-infant displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (e.g. CDK amplifications) and novel (e.g. USH2A mutations) events. Importantly, many hallmark features of medulloblastoma were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (e.g. SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (e.g. DNA damage-signaling) and specific events (e.g. 3p loss) predicted survival post-relapse.

Conclusions: rMB is defined by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.
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http://dx.doi.org/10.1093/neuonc/noab178DOI Listing
July 2021

Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma.

Genome Med 2021 Jun 21;13(1):103. Epub 2021 Jun 21.

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.

Background: Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects.

Methods: We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB.

Results: Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB.

Conclusions: Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.
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http://dx.doi.org/10.1186/s13073-021-00920-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215804PMC
June 2021

Spatial concordance of DNA methylation classification in diffuse glioma.

Neuro Oncol 2021 May 28. Epub 2021 May 28.

Department of Neurosurgery, Amsterdam UMC, Vrije Universiteit, and Brain Tumor Centre, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Background: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence.

Methods: We used neuronavigation to acquire 133 image-guided and spatially-separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast enhanced T1 weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a three-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites.

Results: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account.

Conclusion: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.
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http://dx.doi.org/10.1093/neuonc/noab134DOI Listing
May 2021

Impact of Major Residual Lesions on Outcomes After Surgery for Congenital Heart Disease.

J Am Coll Cardiol 2021 May;77(19):2382-2394

Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

Background: Many factors affect outcomes after congenital cardiac surgery.

Objectives: The RLS (Residual Lesion Score) study explored the impact of severity of residual lesions on post-operative outcomes across operations of varying complexity.

Methods: In a prospective, multicenter, observational study, 17 sites enrolled 1,149 infants undergoing 5 common operations: tetralogy of Fallot repair (n = 250), complete atrioventricular septal defect repair (n = 249), arterial switch operation (n = 251), coarctation or interrupted arch with ventricular septal defect (VSD) repair (n = 150), and Norwood operation (n = 249). The RLS was assigned based on post-operative echocardiography and clinical events: RLS 1 (trivial or no residual lesions), RLS 2 (minor residual lesions), or RLS 3 (reintervention for or major residual lesions before discharge). The primary outcome was days alive and out of hospital within 30 post-operative days (60 for Norwood). Secondary outcomes assessed post-operative course, including major medical events and days in hospital.

Results: RLS 3 (vs. RLS 1) was an independent risk factor for fewer days alive and out of hospital (p ≤ 0.008) and longer post-operative hospital stay (p ≤ 0.02) for all 5 operations, and for all secondary outcomes after coarctation or interrupted arch with VSD repair and Norwood (p ≤ 0.03). Outcomes for RLS 1 versus 2 did not differ consistently. RLS alone explained 5% (tetralogy of Fallot repair) to 20% (Norwood) of variation in the primary outcome.

Conclusions: Adjusting for pre-operative factors, residual lesions after congenital cardiac surgery impacted in-hospital outcomes across operative complexity with greatest impact following complex operations. Minor residual lesions had minimal impact. These findings may provide guidance for surgeons when considering short-term risks and benefits of returning to bypass to repair residual lesions.
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http://dx.doi.org/10.1016/j.jacc.2021.03.304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245007PMC
May 2021

Commentary: Maybe it is better to be a lefty.

Authors:
Michael D Taylor

J Thorac Cardiovasc Surg 2021 Mar 5. Epub 2021 Mar 5.

The Heart Institute - Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.03.007DOI Listing
March 2021

The transcriptional landscape of Shh medulloblastoma.

Nat Commun 2021 03 19;12(1):1749. Epub 2021 Mar 19.

Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-021-21883-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979819PMC
March 2021

Non-invasive left ventricular myocardial work indices in healthy adolescents at rest.

Int J Cardiovasc Imaging 2021 Aug 15;37(8):2429-2438. Epub 2021 Mar 15.

The Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.

Global myocardial work (GMW) provides a metric of left ventricular (LV) function and energy consumption. Its non-invasive assessment by echocardiography correlates with invasive measures and normal values have been reported in healthy adults. We aimed to establish normal values in a healthy adolescent population. Fifty-two healthy adolescents (mean age = 14.5 ± 2.0 years, range 11-19 years, 62% male) with normal echocardiograms were included. Brachial cuff blood pressure was obtained immediately following apical imaging in the supine position. Post-processing of echocardiograms for speckle tracking strain measurement and derivation of global myocardial work indices from LV pressure-strain loops was performed. The mean global work index (GWI) was 1802.0 ± 264.4 mmHg% with mean global work efficiency of 95.5 ± 1.1%. The mean global constructive work (GCW) was 2054.5 ± 297.3 mmHg%, and the mean global wasted work 83.8 ± 28.1 mmHg%. On multivariable analysis, there were significant associations between both GWI and GCW with systolic blood pressure (β coefficient = 0.57, p < 0.001; β coefficient = 0.67, p < 0.001 respectively) and LV global longitudinal strain (GLS) (β coefficient = - 0.56, p < 0.001; β coefficient = - 0.52, p < 0.001 respectively). There were no associations with any of the work indices with age, sex, body surface area, heart rate or LV ejection fraction. This study provides echocardiographic reference ranges for non-invasive indices of GMW in normal adolescents.
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http://dx.doi.org/10.1007/s10554-021-02218-yDOI Listing
August 2021

Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q.

Neuro Oncol 2021 08;23(8):1360-1370

Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Within PF-EPN-A, 1q gain is a marker of poor prognosis, however, it is unclear if within PF-EPN-A additional cytogenetic events exist which can refine risk stratification.

Methods: Five independent non-overlapping cohorts of PF-EPN-A were analyzed applying genome-wide methylation arrays for chromosomal and clinical variables predictive of survival.

Results: Across all cohorts, 663 PF-EPN-A were identified. The most common broad copy number event was 1q gain (18.9%), followed by 6q loss (8.6%), 9p gain (6.5%), and 22q loss (6.8%). Within 1q gain tumors, there was significant enrichment for 6q loss (17.7%), 10q loss (16.9%), and 16q loss (15.3%). The 5-year progression-free survival (PFS) was strikingly worse in those patients with 6q loss, with a 5-year PFS of 50% (95% CI 45%-55%) for balanced tumors, compared with 32% (95% CI 24%-44%) for 1q gain only, 7.3% (95% CI 2.0%-27%) for 6q loss only and 0 for both 1q gain and 6q loss (P = 1.65 × 10-13). After accounting for treatment, 6q loss remained the most significant independent predictor of survival in PF-EPN-A but is not in PF-EPN-B. Distant relapses were more common in 1q gain irrespective of 6q loss. RNA sequencing comparing 6q loss to 6q balanced PF-EPN-A suggests that 6q loss forms a biologically distinct group.

Conclusions: We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.
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http://dx.doi.org/10.1093/neuonc/noab034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328032PMC
August 2021

Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition.

Cancer Discov 2021 Jun 9;11(6):1454-1467. Epub 2021 Feb 9.

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair-deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for mutations ( = 10). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition and . Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies. SIGNIFICANCE: Tumors harboring a single driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406556PMC
June 2021

Rapid cardiac MRI protocol for cardiac assessment in paediatric and young adult patients undergoing haematopoietic stem cell transplant: a feasibility study.

Cardiol Young 2021 Jun 28;31(6):973-978. Epub 2021 Jan 28.

Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Background: Haematopoietic stem cell transplantation is an important and effective treatment strategy for many malignancies, marrow failure syndromes, and immunodeficiencies in children, adolescents, and young adults. Despite advances in supportive care, patients undergoing transplant are at increased risk to develop cardiovascular co-morbidities.

Methods: This study was performed as a feasibility study of a rapid cardiac MRI protocol to substitute for echocardiography in the assessment of left ventricular size and function, pericardial effusion, and right ventricular hypertension.

Results: A total of 13 patients were enrolled for the study (age 17.5 ± 7.7 years, 77% male, 77% white). Mean study time was 13.2 ± 5.6 minutes for MRI and 18.8 ± 5.7 minutes for echocardiogram (p = 0.064). Correlation between left ventricular ejection fraction by MRI and echocardiogram was good (ICC 0.76; 95% CI 0.47, 0.92). None of the patients had documented right ventricular hypertension. Patients were given a survey regarding their experiences, with the majority both perceiving that the echocardiogram took longer (7/13) and indicating they would prefer the MRI if given a choice (10/13).

Conclusion: A rapid cardiac MRI protocol was shown feasible to substitute for echocardiogram in the assessment of key factors prior to or in follow-up after haematopoietic stem cell transplantation.
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http://dx.doi.org/10.1017/S1047951120004990DOI Listing
June 2021

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

J Clin Oncol 2021 03 27;39(7):807-821. Epub 2021 Jan 27.

Division of Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX.

Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors.

Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing.

Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving , , and . Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms.

Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.
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http://dx.doi.org/10.1200/JCO.20.01359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078396PMC
March 2021

HARP-I: A Harmonic Phase Interpolation Method for the Estimation of Motion From Tagged MR Images.

IEEE Trans Med Imaging 2021 04 1;40(4):1240-1252. Epub 2021 Apr 1.

We proposed a novel method called HARP-I, which enhances the estimation of motion from tagged Magnetic Resonance Imaging (MRI). The harmonic phase of the images is unwrapped and treated as noisy measurements of reference coordinates on a deformed domain, obtaining motion with high accuracy using Radial Basis Functions interpolations. Results were compared against Shortest Path HARP Refinement (SP-HR) and Sine-wave Modeling (SinMod), two harmonic image-based techniques for motion estimation from tagged images. HARP-I showed a favorable similarity with both methods under noise-free conditions, whereas a more robust performance was found in the presence of noise. Cardiac strain was better estimated using HARP-I at almost any motion level, giving strain maps with less artifacts. Additionally, HARP-I showed better temporal consistency as a new method was developed to fix phase jumps between frames. In conclusion, HARP-I showed to be a robust method for the estimation of motion and strain under ideal and non-ideal conditions.
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http://dx.doi.org/10.1109/TMI.2021.3051092DOI Listing
April 2021

Single-cell chromatin accessibility profiling of glioblastoma identifies an invasive cancer stem cell population associated with lower survival.

Elife 2021 Jan 11;10. Epub 2021 Jan 11.

Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumors, such as glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary human GBMs harbor a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In-depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival, in line with the higher invasive properties of Invasive state GSCs compared to Reactive and Constructive GSCs as shown by in vitro and in vivo assays. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.
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http://dx.doi.org/10.7554/eLife.64090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847307PMC
January 2021

Modeling human brain tumors in flies, worms, and zebrafish: From proof of principle to novel therapeutic targets.

Neuro Oncol 2021 05;23(5):718-731

Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada.

For decades, cell biologists and cancer researchers have taken advantage of non-murine species to increase our understanding of the molecular processes that drive normal cell and tissue development, and when perturbed, cause cancer. The advent of whole-genome sequencing has revealed the high genetic homology of these organisms to humans. Seminal studies in non-murine organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio identified many of the signaling pathways involved in cancer. Studies in these organisms offer distinct advantages over mammalian cell or murine systems. Compared to murine models, these three species have shorter lifespans, are less resource intense, and are amenable to high-throughput drug and RNA interference screening to test a myriad of promising drugs against novel targets. In this review, we introduce species-specific breeding strategies, highlight the advantages of modeling brain tumors in each non-mammalian species, and underscore the successes attributed to scientific investigation using these models. We conclude with an optimistic proposal that discoveries in the fields of cancer research, and in particular neuro-oncology, may be expedited using these powerful screening tools and strategies.
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http://dx.doi.org/10.1093/neuonc/noaa306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099479PMC
May 2021

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Cancer Discov 2021 May 18;11(5):1176-1191. Epub 2020 Dec 18.

Department of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223607PMC
May 2021

A novel method of donor‒recipient size matching in pediatric heart transplantation: A total cardiac volume‒predictive model.

J Heart Lung Transplant 2021 02 4;40(2):158-165. Epub 2020 Dec 4.

Cincinnati Children's Hospital Medical Center - Heart Institute, Cincinnati, Ohio.

Background: The pediatric heart transplant community uses weight-based donor-to-recipient size matching almost exclusively, despite no evidence to validate weight as a reliable surrogate of cardiac size. Donor size mismatch is the second most common reason for the refusal of donor hearts in current practice (∼30% of all refusals). Whereas case-by-case segmentation of total cardiac volume (TCV) by computed tomography (CT) for direct virtual transplantation is an attractive option, it remains limited by the unavailability of donor chest CT. We sought to establish a predictive model for donor TCV on the basis of anthropomorphic and chest X-ray (CXR) cardiac measures.

Methods: Banked imaging studies from 141 subjects with normal CT chest angiograms were obtained and segmented using 3-dimensional modeling to derive TCV. CXR data were available for 62 of those subjects. A total of 3 predictive models of TCV were fit through multiple linear regression using the following variables: Model A (weight only); Model B (weight, height, sex, and age); Model C (weight, height, sex, age, and 1-view anteroposterior CXR maximal horizontal cardiac width).

Results: Model C provided the most accurate prediction of TCV (optimism corrected R = 0.99, testing set R = 0.98, mean absolute percentage error [MAPE] = 8.6%) and outperformed Model A (optimism corrected R = 0.94, testing set R = 0.94, MAPE = 16.1%) and Model B (optimism corrected R = 0.97, testing set R = 0.97, MAPE = 11.1%).

Conclusions: TCV can be predicted accurately using readily available anthropometrics and a 1-view CXR from donor candidates. This simple and scalable method of TCV estimation may provide a reliable and consistent method to improve donor size matching.
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http://dx.doi.org/10.1016/j.healun.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855742PMC
February 2021

Activated leukocyte cell adhesion molecule expression correlates with the WNT subgroup in medulloblastoma and is involved in regulating tumor cell proliferation and invasion.

PLoS One 2020 3;15(12):e0243272. Epub 2020 Dec 3.

Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Cluster of differentiation (CD) 166 or activated leukocyte cell adhesion molecule (ALCAM) is a transmembrane molecule known to be an intercellular adhesion factor. The expression and function of ALCAM in medulloblastoma (MB), a pediatric brain tumor with highly advanced molecular genetics, remains unclear. Therefore, this study aimed to clarify the significance and functional role of ALCAM expression in MB. ALCAM expression in 45 patients with MB was evaluated by immunohistochemical analysis of formalin-fixed paraffin-embedded clinical specimens and the relationship between ALCAM expression and pathological type/molecular subgroup, such as WNT, SHH, Group 3, and Group 4, was examined. Eight ALCAM positive (18%), seven partially positive (16%), and 30 negative (67%) cases were detected. All seven cases of the WNT molecular subgroup were ALCAM positive and ALCAM expression strongly correlated with this subgroup (P < 0.0001). In addition, functional studies using MB cell lines revealed ALCAM expression affected proliferation and migration as a positive regulator in vitro. However, ALCAM silencing did not affect survival or the formation of leptomeningeal dissemination in an orthotopic mouse model, but did induce a malignant phenotype with increased tumor cell invasion at the dissemination sites (P = 0.0029). In conclusion, our results revealed that ALCAM exhibited highly specific expression in the WNT subgroup of MB. Furthermore, we demonstrated that the cell kinetics of MB cell lines can be altered by the expression of ALCAM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243272PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714159PMC
January 2021

Artificial intelligence for automatic cerebral ventricle segmentation and volume calculation: a clinical tool for the evaluation of pediatric hydrocephalus.

J Neurosurg Pediatr 2020 Dec 1:1-8. Epub 2020 Dec 1.

3Department of Radiology, Stanford University School of Medicine.

Objective: Imaging evaluation of the cerebral ventricles is important for clinical decision-making in pediatric hydrocephalus. Although quantitative measurements of ventricular size, over time, can facilitate objective comparison, automated tools for calculating ventricular volume are not structured for clinical use. The authors aimed to develop a fully automated deep learning (DL) model for pediatric cerebral ventricle segmentation and volume calculation for widespread clinical implementation across multiple hospitals.

Methods: The study cohort consisted of 200 children with obstructive hydrocephalus from four pediatric hospitals, along with 199 controls. Manual ventricle segmentation and volume calculation values served as "ground truth" data. An encoder-decoder convolutional neural network architecture, in which T2-weighted MR images were used as input, automatically delineated the ventricles and output volumetric measurements. On a held-out test set, segmentation accuracy was assessed using the Dice similarity coefficient (0 to 1) and volume calculation was assessed using linear regression. Model generalizability was evaluated on an external MRI data set from a fifth hospital. The DL model performance was compared against FreeSurfer research segmentation software.

Results: Model segmentation performed with an overall Dice score of 0.901 (0.946 in hydrocephalus, 0.856 in controls). The model generalized to external MR images from a fifth pediatric hospital with a Dice score of 0.926. The model was more accurate than FreeSurfer, with faster operating times (1.48 seconds per scan).

Conclusions: The authors present a DL model for automatic ventricle segmentation and volume calculation that is more accurate and rapid than currently available methods. With near-immediate volumetric output and reliable performance across institutional scanner types, this model can be adapted to the real-time clinical evaluation of hydrocephalus and improve clinician workflow.
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http://dx.doi.org/10.3171/2020.6.PEDS20251DOI Listing
December 2020

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Cell 2020 12 30;183(6):1617-1633.e22. Epub 2020 Nov 30.

Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
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http://dx.doi.org/10.1016/j.cell.2020.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791404PMC
December 2020

GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.

J Neuropathol Exp Neurol 2021 01;80(2):129-136

Department of Pathology, Brain Research Institute, Niigata University.

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.
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http://dx.doi.org/10.1093/jnen/nlaa141DOI Listing
January 2021

The Transition from Quiescent to Activated States in Human Hematopoietic Stem Cells Is Governed by Dynamic 3D Genome Reorganization.

Cell Stem Cell 2021 03 25;28(3):488-501.e10. Epub 2020 Nov 25.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. Electronic address:

Lifelong blood production requires long-term hematopoietic stem cells (LT-HSCs), marked by stemness states involving quiescence and self-renewal, to transition into activated short-term HSCs (ST-HSCs) with reduced stemness. As few transcriptional changes underlie this transition, we used single-cell and bulk assay for transposase-accessible chromatin sequencing (ATAC-seq) on human HSCs and hematopoietic stem and progenitor cell (HSPC) subsets to uncover chromatin accessibility signatures, one including LT-HSCs (LT/HSPC signature) and another excluding LT-HSCs (activated HSPC [Act/HSPC] signature). These signatures inversely correlated during early hematopoietic commitment and differentiation. The Act/HSPC signature contains CCCTC-binding factor (CTCF) binding sites mediating 351 chromatin interactions engaged in ST-HSCs, but not LT-HSCs, enclosing multiple stemness pathway genes active in LT-HSCs and repressed in ST-HSCs. CTCF silencing derepressed stemness genes, restraining quiescent LT-HSCs from transitioning to activated ST-HSCs. Hence, 3D chromatin interactions centrally mediated by CTCF endow a gatekeeper function that governs the earliest fate transitions HSCs make by coordinating disparate stemness pathways linked to quiescence and self-renewal.
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http://dx.doi.org/10.1016/j.stem.2020.11.001DOI Listing
March 2021

Left Ventricular Magnetic Resonance Imaging Strain Predicts the Onset of Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

Circ Cardiovasc Imaging 2020 11 16;13(11):e011526. Epub 2020 Nov 16.

The Heart Institute (S.S., T.A., S.E.H., C.V., T.D.R., S.W., S.M.L., M.D.T.), Cincinnati Children's Hospital Medical Center, OH.

Background: Early detection of left ventricular (LV) dysfunction before the onset of overt Duchenne muscular dystrophy-associated cardiomyopathy (DMDAC) may direct clinical management to slow onset of dysfunction. We aimed to assess whether LV strain will predict those who develop DMDAC.

Methods: We performed a single center retrospective case control study of patients with Duchenne muscular dystrophy who underwent serial cardiac magnetic resonance between 2006 and 2019. Patients with Duchenne muscular dystrophy with an LV ejection fraction ≥55% on ≥1 cardiac magnetic resonance were identified and grouped into age-matched +DMDAC and -DMDAC. Within 3 years, +DMDAC had a subsequent cardiac magnetic resonance with a decline in LV ejection fraction ≥10% and absolute LV ejection fraction ≤50%. -DMDAC maintained an LV ejection fraction ≥55% on serial cardiac magnetic resonances. Two-dimensional and 3-dimensional global radial strain, global circumferential strain (GCS), and global longitudinal strain were measured using tissue tracking software and their ability to predict DMDAC onset was assessed. Multivariable analysis adjusted for late gadolinium enhancement.

Results: Thirty +DMDAC and 30 age-matched -DMDAC patients were included with a total of 164 studies analyzed. Before DMDAC onset, 2-dimensional global radial strain and GCS were significantly worse in +DMDAC compared with -DMDAC (25.1±6.0 versus 29.0±6.3, =0.011; -15.4%±2.4 versus -17.3%±2.6, =0.003). Three-dimensional GCS and global radial strain had similar findings. Among strain measures, 3-dimensional GCS had the highest area under the curve to predict DMDAC in our cohort. These findings persisted after adjusting for the presence of late gadolinium enhancement.

Conclusions: Reduced global radial strain and GCS may predict those at risk for developing DMDAC before onset of LV dysfunction and its clinical utility warrants further exploration.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011526DOI Listing
November 2020

Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma.

Acta Neuropathol Commun 2020 10 28;8(1):173. Epub 2020 Oct 28.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, USA.

Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case-control data from three studies: a population-based pediatric and adolescent ependymoma case-control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case-control study from Toronto's Hospital for Sick Children and the Children's Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case-control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case-control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12-19 (P = 4.0 × 10), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (OR = 1.67; 95% CI 1.18-2.37; P = 3.97 × 10) and adult-onset ependymoma (P = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94-1.34; P = 0.21), nor with EPN-PF-A (P = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.
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http://dx.doi.org/10.1186/s40478-020-01038-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592366PMC
October 2020

Myocardial fibrosis, diastolic dysfunction and elevated liver stiffness in the Fontan circulation.

Open Heart 2020 10;7(2)

Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Introduction: Single ventricle diastolic dysfunction and hepatic fibrosis are frequently observed in patients with a Fontan circulation. The relationship between adverse haemodynamics and end-organ fibrosis has not been investigated in adolescents and young adults with Fontan circulation.

Methods: Prospective observational study of Fontan patients who had a cardiac catheterisation. Cardiac MRI with T1 mapping was obtained to measure extracellular volume (ECV), a marker of myocardial fibrosis. Hepatic magnetic resonance elastography was performed to assess liver shear stiffness. Serum biomarkers of fibrosis including matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) were measured. Very high ECV was defined as >30% and elevated serum biomarkers as >75th percentile for each biomarker.

Results: 25 Fontan patients (52% female) with mean age of 16.3±6.8 years were included. Mean ECV was 28%±5%. There was a significant correlation between ECV and systemic ventricular end-diastolic pressure (r=0.42, p=0.03) and between ECV and liver stiffness (r=0.45, p=0.05). Patients with elevated ECV demonstrated elevations in MMPs and TIMPs. Similarly, patients with elevated MMPs and TIMPs had greater liver stiffness compared with patients with normal levels of these biomarkers.

Conclusions: In Fontan patients, cardiac magnetic resonance evidence of myocardial fibrosis is associated with diastolic dysfunction, increased liver stiffness and elevated circulating biomarkers of fibrosis. These findings suggest the presence of a profibrotic milieu, with end-organ implications, in some patients with Fontan circulation.
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http://dx.doi.org/10.1136/openhrt-2020-001434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592252PMC
October 2020

Pediatric Myocardial T1 and T2 Value Associations with Age and Heart Rate at 1.5 T.

Pediatr Cardiol 2021 Feb 2;42(2):269-277. Epub 2020 Oct 2.

Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.

The objective of the study was to determine normal global left ventricular reference values for T1 and T2 in children. This is a retrospective study that included healthy subjects, age 5-19 years, who underwent CMR for the indication of pectus excavatum from 2018 to 2019. Linear regression models were used to determine associations of native T1 and T2 values to heart rate, age, and other CMR parameters. 102 patients with a mean age of 14.0 ± 2.4 years were included (range 5.4-18.8). 87 (85%) were males and 15 (15%) were females. The mean global T1 was 1018 ± 25 ms and the mean T2 was 53 ± 3 ms. T1 was negatively correlated with age (r = - 0.39, p < 0.001) and positively correlated with heart rate (r = 0.32, p < 0.001) by univariate analysis. Multivariable analysis showed that age and heart rate were independently associated with T1. T2 demonstrated a weak negative correlation with age (r = - 0.20, p = 0.047) and no correlation with heart rate. There was no difference in T1 (p = 0.23) or T2 (p = 0.52) between genders. This study reports normal pediatric T1 and T2 values at a 1.5 Tesla scanner. T1 was dependent on age and heart rate, while T2 was less dependent on age with no correlation with heart rate.
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http://dx.doi.org/10.1007/s00246-020-02479-9DOI Listing
February 2021

H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone.

Cancer Discov 2020 12 23;10(12):1968-1987. Epub 2020 Sep 23.

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR-Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a osteoblast-like progenitor population toward an myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. SIGNIFICANCE: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710565PMC
December 2020

Variations in native T1 values in patients with Duchenne muscular dystrophy with and without late gadolinium enhancement.

Int J Cardiovasc Imaging 2021 Feb 20;37(2):635-642. Epub 2020 Sep 20.

Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2003, Cincinnati, OH, 45229, USA.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder leading to progressive skeletal and cardiac myopathy. Elevated myocardial T1 values correlate with fibrosis in most disease processes, but DMD skeletal and cardiac histopathology is defined by fibrofatty replacement that may result in a decrease in T1 values, due to the low T1 of fat. The study goal was to assess myocardial T1 values in DMD patients with and without late gadolinium enhancement (LGE). A retrospective analysis was performed on all patients with DMD referred for CMR at our institution from 7/5/2017 to 10/24/2018. T1 measurements were performed using breath-held modified Look Locker inversion recovery (MOLLI) sequences at the basal and mid-ventricular levels. The cohort was separated into patients without the presence of LGE (LGE-) and patients with current or previous LGE (LGE+). A total of 207 CMR studies were analyzed. The LGE- group comprised 88 patients while 119 patients were in the LGE+ group. The LGE+ group was older, had larger indexed LV end-diastolic volume and lower LV ejection fraction (LVEF) compared to the LGE- group. T1 values in the LGE+ group were lower compared to the LGE- group (mid T1 1012 ms vs. 1035 ms; p = 0.002), with 5 CMR studies demonstrating mid T1 values < 900 ms. There was no correlation between mid T1 and LVEF in the LGE- group. In the LGE+ cohort, lower T1 values correlated with worse LVEF (r = 0.34, p = 0.0002). The association between mid T1 values and LVEF remained statistically significant on multivariable analysis when accounting for number of LGE segments, LVEDVi, and age (p = 0.009). This is the largest study assessing native T1 values in patients with DMD. The results demonstrate that patients with LGE had lower T1 values than patients without LGE. In the LGE+ group, lower T1 values correlated with worse LV systolic function. These results are consistent with the evolving recognition of fibrofatty replacement in advanced stages of DMD myopathy. Furthermore, our study supports that there is not a simple linear relationship between increasing T1 values and advancing disease progression reported in most other cardiomyopathies.
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http://dx.doi.org/10.1007/s10554-020-02031-zDOI Listing
February 2021
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