Publications

Transcriptomic Characterization of the Human Insular Cortex and Claustrum.

Front Neuroanat. 2019;13:94

Authors: Ibrahim C, Le Foll B, French L

Abstract
The insular cortex has been linked to a multitude of functions. In contrast, the nearby claustrum is a densely connected subcortical region with unclear function. To view the insula-claustrum region from the molecular perspective we analyzed the transcriptomic profile of these areas in six adult and four fetal human brains. We identified marker genes with specific expression and performed transcriptome-wide tests for enrichment of biological processes, molecular functions, and cellular components. In addition, specific insular and claustral expression of genes pertaining to diseases, addiction, and depression was tested. At the anatomical level, we used brain-wide analyses to determine the specificity of our results and to determine the transcriptomic similarity of the insula-claustrum region. We found UCMA to be the most significantly enriched gene in the insular cortex and confirmed specific expression of NR4A2, NTNG2, and LXN in the claustrum. Furthermore, the insula was found to have enriched expression of genes associated with mood disorders, learning, cardiac muscle contraction, oxygen transport, glutamate and dopamine signaling. Specific expression in the claustrum was enriched for genes pertaining to human immunodeficiency virus (HIV), severe intellectual disability, epileptic encephalopathy, intracellular transport, spine development, and macroautophagy. We tested for enrichment of genes related to addiction and depression, but they were generally not highly specific to the insula-claustrum region. Exceptions include high insular expression of genes linked to cocaine abuse and genes associated with ever smoking in the claustrum. Brain-wide, we find that markers of the adult claustrum are most specifically expressed in the fetal and adult insula. Altogether, our results provide a novel molecular perspective on the unique properties of the insula and claustrum.

PMID: 31827426 [PubMed]

The deubiquitinase USP7 stabilizes Maf proteins to promote myeloma cell survival.

J Biol Chem. 2019 Dec 10;:

Authors: He Y, Wang S, Tong J, Jiang S, Yang Y, Zhang Z, Xu Y, Zeng Y, Cao B, Moran MF, Mao X

Abstract
The Maf proteins including c-Maf, MafA and MafB are critical transcription factors in myelomagenesis. Previous studies demonstrated that Maf proteins are processed by the ubiquitin-proteasome pathway but the mechanisms remain elusive. The present study applied mass spectrometry to identify MafB ubiquitination-associated proteins and found that the ubiquitin-specific protease USP7 was present in the MafB interactome. Moreover, USP7 also interacted with c-Maf and MafA and blocked their polyubiquitination and degradation. Consistently, knockdown of USP7 resulted in Maf protein degradation along with increased polyubiquitination levels. The action of USP7 thus promoted Maf transcriptional activity as evidenced by luciferase assays and by the upregulation of the expression of Maf-modulated genes. Furthermore, USP7 was upregulated in myeloma cells and it was negatively associated with the survival of myeloma patients. USP7 promoted myeloma cell survival, and when it was inhibited by its specific inhibitor P5091, myeloma cell lines underwent apoptosis. These results therefore demonstrated that USP7 is a deubiquitinase of Maf proteins and promotes MM cell survival in association with Maf stability. Given the significance of USP7 and Maf proteins in myeloma genesis, targeting the USP7/Maf axle is a potential strategy to the precision therapy of MM.

PMID: 31822558 [PubMed - as supplied by publisher]

Effectiveness of the Genomics ADvISER decision aid for the selection of secondary findings from genomic sequencing: a randomized clinical trial.

Genet Med. 2019 Dec 11;:

Authors: Bombard Y, Clausen M, Shickh S, Mighton C, Casalino S, Kim THM, Muir SM, Carlsson L, Baxter N, Scheer A, Elser C, Eisen A, Panchal S, Graham T, Aronson M, Piccinin C, Mancuso T, Semotiuk K, Evans M, Carroll JC, Offit K, Robson M, Hamilton JG, Glogowski E, Schrader K, Kim RH, Lerner-Ellis J, Thorpe KE, Laupacis A, Incidental Genomics Study Team

Abstract
PURPOSE: To evaluate the effectiveness of the Genomics ADvISER (www.genomicsadviser.com) decision aid (DA) for selection of secondary findings (SF), compared with genetic counseling alone.
METHODS: A randomized controlled trial (RCT) was conducted to evaluate whether the Genomics ADvISER is superior to genetic counseling when hypothetically selecting SF. Participants were randomized to use the DA followed by discussion with a genetic counselor, or to genetic counseling alone. Surveys were administered at baseline and post-intervention. Primary outcome was decisional conflict. Secondary outcomes were knowledge, preparation for, and satisfaction with decision-making, anxiety, and length of counseling session.
RESULTS: Participants (n = 133) were predominantly White/European (74%), female (90%), and ≥50 years old (60%). Decisional conflict (mean difference 0.05; P = 0.60), preparation for decision-making (0.17; P = 0.95), satisfaction with decision (-2.18; P = 0.06), anxiety (0.72; P = 0.56), and knowledge of sequencing limitations (0.14; P = 0.70) did not significantly differ between groups. However, intervention participants had significantly higher knowledge of SF (0.39; P < 0.001) and sequencing benefits (0.97; P = 0.01), and significantly shorter counseling time (24.40 minutes less; P < 0.001) CONCLUSIONS: The Genomics ADvISER did not decrease decisional conflict but reduced counseling time and improved knowledge. This decision aid could serve as an educational tool, reducing in-clinic time and potentially health care costs.

PMID: 31822848 [PubMed - as supplied by publisher]

Podocyte GSK3α is important for autophagy and its loss detrimental for glomerular function.

FASEB Bioadv. 2019 Aug;1(8):498-510

Authors: Hurcombe JA, Lay AC, Ni L, Barrington AF, Woodgett JR, Quaggin SE, Welsh GI, Coward RJ

Abstract
Podocytes are key cells in maintaining the integrity of the glomerular filtration barrier and preventing albuminuria. Glycogen synthase kinase 3 (GSK3) is a multi-functional serine/threonine kinase existing as two distinct but related isoforms (α and β). In the podocyte it has previously been reported that inhibition of the β isoform is beneficial in attenuating a variety of glomerular disease models but loss of both isoforms is catastrophic. However, it is not known what the role of GSK3α is in these cells. We now show that GSK3α is present and dynamically modulated in podocytes. When GSK3α is transgenically knocked down specifically in the podocytes of mice it causes mild but significant albuminuria by 6-weeks of life. Its loss also does not protect in models of diabetic or Adriamycin-induced nephropathy. In vitro deletion of podocyte GSK3α causes cell death and impaired autophagic flux suggesting it is important for this key cellular process. Collectively this work shows that GSK3α is important for podocyte health and that augmenting its function may be beneficial in treating glomerular disease.

PMID: 31825015 [PubMed]

Decoupling Analysis of Water Footprint and Economic Growth: A Case Study of Beijing-Tianjin-Hebei Region from 2004 to 2017.

Int J Environ Res Public Health. 2019 Dec 03;16(23):

Authors: Kong Y, He W, Yuan L, Shen J, An M, Degefu DM, Gao X, Zhang Z, Sun F, Wan Z

Abstract
The Beijing-Tianji-Hebei region (BTHR) is economically developed and densely populated, but its water resources are extremely scarce. A clear understanding of the decoupling relationship between water footprint and economic growth is conducive to facilitating and realizing the coordinated development of water resources and economic growth in this region. This study calculated the water footprint and other related indicators of BTHR from 2004 to 2017, and objectively evaluated the utilization of water resources in the region. Then, logarithmic mean divisia index (LMDI) method was applied to study the driving factors that resulted in the change of water footprint and their respective effects. Finally, Tapio decoupling model was used to research the decoupling relationships between water footprint and economic growth, and between the driving factors of water footprint and economic growth. There are three main results in this research. (1) The water utilization efficiency in BTHR continues to improve, and the water footprint shows a gradually increasing trend during the research period, among which the agricultural water footprint accounts for a relatively high proportion. (2) The change of water footprint can be attributed to efficiency effect, economic effect, and population effect. Furthermore, efficiency effect is the decisive factor of water footprint reduction and economic effect is the main factor of water footprint increase, while population effect plays a weak role in promoting the increase in water footprint. (3) The decoupling status between water footprint and economic growth show a weak decoupling in most years, while the status between water footprint intensity and economic growth always remains strong decoupling. Moreover, population size and economic growth always show an expansive coupling state. In sum, it is advisable for policy makers to improve water utilization efficiency, especially agricultural irrigation efficiency, to raise residents' awareness of water conservation, and increase the import of water-intensive products, so as to alleviate water shortage and realize the coordinated development of water resources and economic growth in BTHR.

PMID: 31816978 [PubMed - in process]

Author Correction: Nanopore native RNA sequencing of a human poly(A) transcriptome.

Nat Methods. 2019 Dec 09;:

Authors: Workman RE, Tang AD, Tang PS, Jain M, Tyson JR, Razaghi R, Zuzarte PC, Gilpatrick T, Payne A, Quick J, Sadowski N, Holmes N, de Jesus JG, Jones KL, Soulette CM, Snutch TP, Loman N, Paten B, Loose M, Simpson JT, Olsen HE, Brooks AN, Akeson M, Timp W

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31819268 [PubMed - as supplied by publisher]

Association between side effects and blood microRNA expression levels and their targeted pathways in patients with major depressive disorder treated by a selective serotonin reuptake inhibitor, escitalopram: a CAN-BIND-1 report.

Int J Neuropsychopharmacol. 2019 Dec 10;:

Authors: Yrondi A, Fiori LM, Frey BN, Lam RW, MacQueen GM, Milev R, Müller DJ, Foster JA, Kennedy SH, Turecki G

Abstract
INTRODUCTION: Antidepressant drugs are effective therapies for Major Depressive Disorder (MDD); however, they are frequently associated with side effects. Although there is some evidence for a relationship between genetic variation and side effects, little is known regarding the role of dynamic molecular factors as moderators of side effect. The aim of this study is to assess microRNA (miRNA) changes associated with side effects during escitalopram treatment, and their downstream effects on target gene expression.
METHODS: 160 patients with MDD from the CAN-BIND -1 cohort were included. Side effects were assessed with the Toronto Side Effect Scale after 2 weeks of treatment with escitalopram. We assessed the relationship between side effects and changes in peripheral expression of miRNAs between baseline and week 2. For miRNAs whose expression changed, we used target prediction algorithms to identify putative messenger RNA (mRNA) targets and assessed their expression.
RESULTS: Nausea was experienced by 42.5% of patients. We identified 45 miRNAs whose expression changed upon initiation of escitalopram treatment, of which 10 displayed a negative association with intensity of nausea (miR15b-5p, miR17-5p, miR20a-5p, miR20b-5p, miR103a-3p, miR103b, miR106a-5p, miR182-5p, miR185-5p and miR660-5p). Additionally, we found negative associations between 4 miRNAs (miR20a-5p, miR106a-5p, miR185-5p, miR660-5p) and mRNA targets. The expression of the miR185-5p target, CAMK2δ was significantly decreased [log 2 mean= -0.048 (0.233)] between weeks 0 and 2 (p=0.01)].
CONCLUSIONS: We identified an overexpression of miR185-5p during escitalopram treatment of MDD, which was negatively associated with intensity of nausea, and identified a potential mRNA target which may mediate this effect.

PMID: 31819986 [PubMed - as supplied by publisher]

Baseline Characteristics of the VANISH Cohort.

Circ Heart Fail. 2019 Dec;12(12):e006231

Authors: Axelsson Raja A, Shi L, Day SM, Russell M, Zahka K, Lever H, Colan SD, Margossian R, Hall EK, Becker J, Jefferies JL, Patel AR, Choudhury L, Murphy AM, Canter C, Bach R, Taylor M, Mestroni L, Wheeler MT, Benson L, Owens AT, Rossano J, Lin KY, Pahl E, Pereira AC, Bundgaard H, Lewis GD, Vargas JD, Cirino AL, McMurray JJV, MacRae CA, Solomon SD, Orav EJ, Braunwald E, Ho CY

Abstract
BACKGROUND: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers.
METHODS: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy.
RESULTS: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required.
CONCLUSIONS: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.

PMID: 31813281 [PubMed - in process]

Precision Health Resource of Control iPSC Lines for Versatile Multilineage Differentiation.

Stem Cell Reports. 2019 Nov 27;:

Authors: Hildebrandt MR, Reuter MS, Wei W, Tayebi N, Liu J, Sharmin S, Mulder J, Lesperance LS, Brauer PM, Mok RSF, Kinnear C, Piekna A, Romm A, Howe J, Pasceri P, Meng G, Rozycki M, Rodrigues DC, Martinez EC, Szego MJ, Zúñiga-Pflücker JC, Anderson MK, Prescott SA, Rosenblum ND, Kamath BM, Mital S, Scherer SW, Ellis J

Abstract
Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users demonstrated versatility by generating kidney organoids, T lymphocytes, and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole-genome sequencing-based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harbored at least one pre-existing or acquired variant with cardiac, neurological, or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cells from six tissues for disease modeling, and variant-preferred healthy control lines were identified for specific disease settings.

PMID: 31813827 [PubMed - as supplied by publisher]

Sex-Based Differences in Cortical and Subcortical Development in 436 Individuals Aged 4-54 Years.

Cereb Cortex. 2019 Dec 09;:

Authors: Duerden EG, Chakravarty MM, Lerch JP, Taylor MJ

Abstract
Sex-based differences in brain development have long been established in ex vivo studies. Recent in vivo studies using magnetic resonance imaging (MRI) have offered considerable insight into sex-based variations in brain maturation. However, reports of sex-based differences in cortical volumes and thickness are inconsistent. We examined brain maturation in a cross-sectional, single-site cohort of 436 individuals (201 [46%] males) aged 4-54 years (median = 16 years). Cortical thickness, cortical surface area, subcortical surface area, volumes of the cerebral cortex, white matter (WM), cortical and subcortical gray matter (GM), including the thalamic subnuclei, basal ganglia, and hippocampi were calculated using automatic segmentation pipelines. Subcortical structures demonstrated distinct curvilinear trajectories from the cortex, in both volumetric maturation and surface-area expansion in relation to age. Surface-area analysis indicated that dorsal regions of the thalamus, globus pallidus and striatum, regions demonstrating structural connectivity with frontoparietal cortices, exhibited extensive expansion with age, and were inversely related to changes seen in cortical maturation, which contracted with age. Furthermore, surface-area expansion was more robust in males in comparison to females. Age- and sex-related maturational changes may reflect alterations in dendritic and synaptic architecture known to occur during development from early childhood through to mid-adulthood.

PMID: 31814003 [PubMed - as supplied by publisher]

The basic residues in the Orai1 channel inner pore promote opening of the outer hydrophobic gate.

J Gen Physiol. 2020 Jan 06;152(1):

Authors: Yamashita M, Ing CE, Yeung PS, Maneshi MM, Pomès R, Prakriya M

Abstract
Store-operated Orai1 channels regulate a wide range of cellular functions from gene expression to cell proliferation. Previous studies have shown that gating of Orai1 channels is regulated by the outer pore residues V102 and F99, which together function as a hydrophobic gate to block ion conduction in resting channels. Opening of this gate occurs through a conformational change that moves F99 away from the permeation pathway, leading to pore hydration and ion conduction. In addition to this outer hydrophobic gate, several studies have postulated the presence of an inner gate formed by the basic residues R91, K87, and R83 in the inner pore. These positively charged residues were suggested to block ion conduction in closed channels via mechanisms involving either electrostatic repulsion or steric occlusion by a bound anion plug. However, in contrast to this model, here we find that neutralization of the basic residues dose-dependently abolishes both STIM1-mediated and STIM1-independent activation of Orai1 channels. Molecular dynamics simulations show that loss of the basic residues dehydrates the pore around the hydrophobic gate and stabilizes the pore in a closed configuration. Likewise, the severe combined immunodeficiency mutation, Orai1 R91W, closes the channel by dewetting the hydrophobic stretch of the pore and stabilizing F99 in a pore-facing configuration. Loss of STIM1-gating in R91W and in the other basic residue mutants is rescued by a V102A mutation, which restores pore hydration at the hydrophobic gate to repermit ion conduction. These results indicate that the inner pore basic residues facilitate opening of the principal outer hydrophobic gate through a long-range effect involving hydration of the outer pore.

PMID: 31816637 [PubMed - in process]

Predicting Ischemic Risk Using Blood Oxygen Level-Dependent MRI in Children with Moyamoya.

AJNR Am J Neuroradiol. 2019 Dec 05;:

Authors: Dlamini N, Slim M, Kirkham F, Shroff M, Dirks P, Moharir M, MacGregor D, Robertson A, deVeber G, Logan W

Abstract
BACKGROUND AND PURPOSE: Moyamoya is a progressive steno-occlusive arteriopathy. MR imaging assessment of cerebrovascular reactivity can be performed by measuring the blood oxygen level-dependent cerebrovascular reactivity response to vasoactive stimuli. Our objective was to determine whether negative blood oxygen level-dependent cerebrovascular reactivity status is predictive of ischemic events in childhood moyamoya.
MATERIALS AND METHODS: We conducted a retrospective study of a consecutive cohort of children with moyamoya who underwent assessment of blood oxygen level-dependent cerebrovascular reactivity. The charts of patients with written informed consent were reviewed for the occurrence of arterial ischemic stroke, transient ischemic attack, or silent infarcts. We used logistic regression to calculate the OR and 95% CI for ischemic events based on steal status. Hazard ratios for ischemic events based on age at blood oxygen level-dependent cerebrovascular reactivity imaging, sex, and moyamoya etiology were calculated using Cox hazards models.
RESULTS: Thirty-seven children (21 female; median age, 10.7 years; interquartile range, 7.5-14.7 years) were followed for a median of 28.8 months (interquartile range, 13.7-84.1 months). Eleven (30%) had ischemic events, 82% of which were TIA without infarcts. Steal was present in 15 of 16 (93.8%) hemispheres in which ischemic events occurred versus 25 of 58 (43.1%) ischemic-free hemispheres (OR = 19.8; 95% CI, 2.5-160; P = .005). Children with idiopathic moyamoya were at significantly greater risk of ischemic events (hazard ratio, 3.71; 95% CI, 1.1-12.8; P = .037).
CONCLUSIONS: Our study demonstrates that idiopathic moyamoya and the presence of steal are independently associated with ischemic events. The use of blood oxygen level-dependent cerebrovascular reactivity could potentially assist in the selection of patients for revascularization surgery and the direction of therapy in children with moyamoya.

PMID: 31806596 [PubMed - as supplied by publisher]

Rational engineering of 2-deoxyribose-5-phosphate aldolases for the biosynthesis of (R)-1,3-butanediol.

J Biol Chem. 2019 Dec 05;:

Authors: Kim T, Stogios PJ, Khusnutdinova AN, Nemr K, Skarina T, Flick R, Joo JC, Mahadevan R, Savchenko A, Yakunin AF

Abstract
Carbon-carbon bond formation is one of the most important reactions in biocatalysis and organic chemistry. In nature, aldolases catalyze the reversible stereo-selective aldol addition between two carbonyl compounds, making them attractive catalysts for the synthesis of various chemicals. In this work, we identified several 2-deoxyribose-5- phosphate (DRP) aldolases (DERAs) having acetaldehyde condensation activity, which can be used for the biosynthesis of (R)-1,3-butanediol (1,3BDO) in combination with aldo-keto reductases (AKRs). Enzymatic screening of 20 purified DERAs revealed the presence of significant acetaldehyde condensation activity in 12 of the enzymes, with the highest activities in BH1352 from Bacillus halodurans, TM1559 from Thermotoga maritima, and DeoC from Escherichia coli. The crystal structures of BH1352 and TM1559 at 1.40-2.50 Å resolutions are the first full-length DERA structures revealing the presence of the C-terminal Tyr (Tyr224 in BH1352). Results from structure-based site-directed mutagenesis of BH1352 indicated a key role of the catalytic Lys155 and other active-site residues in the DRP cleavage and acetaldehyde condensation reactions. These experiments also revealed a 2.5-fold increase in acetaldehyde transformation to 1,3BDO (in combination with AKR) in the BH1352 F160Y and F160Y/M173I variants. The replacement of the wild type BH1352 by the F160Y or F160Y/M173I variants in E. coli cells expressing the DERA+AKR pathway increased the production of 1,3BDO from glucose five and six times, respectively. Our work provides detailed insights into the molecular mechanisms of substrate selectivity and activity of DERAs and identifies two DERA variants with enhanced activity for in vitro and in vivo 1,3BDO biosynthesis.

PMID: 31806708 [PubMed - as supplied by publisher]

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Nat Commun. 2019 Dec 05;10(1):5519

Authors: D'Abate L, Walker S, Yuen RKC, Tammimies K, Buchanan JA, Davies RW, Thiruvahindrapuram B, Wei J, Brian J, Bryson SE, Dobkins K, Howe J, Landa R, Leef J, Messinger D, Ozonoff S, Smith IM, Stone WL, Warren ZE, Young G, Zwaigenbaum L, Scherer SW

Abstract
Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

PMID: 31801954 [PubMed - in process]

The molecular landscape of ETMR at diagnosis and relapse.

Nature. 2019 Dec 04;:

Authors: Lambo S, Gröbner SN, Rausch T, Waszak SM, Schmidt C, Gorthi A, Romero JC, Mauermann M, Brabetz S, Krausert S, Buchhalter I, Koster J, Zwijnenburg DA, Sill M, Hübner JM, Mack N, Schwalm B, Ryzhova M, Hovestadt V, Papillon-Cavanagh S, Chan JA, Landgraf P, Ho B, Milde T, Witt O, Ecker J, Sahm F, Sumerauer D, Ellison DW, Orr BA, Darabi A, Haberler C, Figarella-Branger D, Wesseling P, Schittenhelm J, Remke M, Taylor MD, Gil-da-Costa MJ, Łastowska M, Grajkowska W, Hasselblatt M, Hauser P, Pietsch T, Uro-Coste E, Bourdeaut F, Masliah-Planchon J, Rigau V, Alexandrescu S, Wolf S, Li XN, Schüller U, Snuderl M, Karajannis MA, Giangaspero F, Jabado N, von Deimling A, Jones DTW, Korbel JO, von Hoff K, Lichter P, Huang A, Bishop AJR, Pfister SM, Korshunov A, Kool M

Abstract
Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

PMID: 31802000 [PubMed - as supplied by publisher]

Reactome and ORCID-fine-grained credit attribution for community curation.

Database (Oxford). 2019 Jan 01;2019:

Authors: Viteri G, Matthews L, Varusai T, Gillespie M, Milacic M, Cook J, Weiser J, Shorser S, Sidiropoulos K, Fabregat A, Haw R, Wu G, Stein L, D'Eustachio P, Hermjakob H

Abstract
Reactome is a manually curated, open-source, open-data knowledge base of biomolecular pathways. Reactome has always provided clear credit attribution for authors, curators and reviewers through fine-grained annotation of all three roles at the reaction and pathway level. These data are visible in the web interface and provided through the various data download formats. To enhance visibility and credit attribution for the work of authors, curators and reviewers, and to provide additional opportunities for Reactome community engagement, we have implemented key changes to Reactome: contributor names are now fully searchable in the web interface, and contributors can 'claim' their contributions to their ORCID profile with a few clicks. In addition, we are reaching out to domain experts to request their help in reviewing and editing Reactome pathways through a new 'Contribution' section, highlighting pathways which are awaiting community review. Database URL: https://reactome.org.

PMID: 31802127 [PubMed - in process]

Cost-Effectiveness of Reimbursing Infliximab for Moderate to Severe Crohn's Disease in China.

Adv Ther. 2019 Dec 03;:

Authors: Chen H, Shi J, Pan Y, Zhang Z, Fang H, Chen Y, Chen W, Cao Q

Abstract
OBJECTIVES: To assess the cost-effectiveness of reimbursing infliximab for moderate-to-severe Crohn's disease (MS-CD) in China from the perspective of public insurance payers.
METHODS: A decision-analytic model with a lifetime time horizon was constructed to simulate the disease progression and direct medical costs in Chinese MS-CD patients under two scenarios: reimbursing infliximab vs. not reimbursing infliximab. A cross-sectional study and literature review were conducted to estimate model variables. The constructed decision-analytic model ran the base case, one-way sensitivity, and probabilistic sensitivity analyses (PSA) to assess the cost-effectiveness of reimbursing infliximab using reimbursed medical costs.
RESULTS: Base case analysis discounting health benefits and costs estimated that reimbursing infliximab could increase overall survival by 0.604 years, increase total quality-adjusted life years (QALY) by 0.697 QALY, reduce absolute lifetime surgery risk by 13.1%, and increase reimbursed costs by ¥29,409. The incremental cost-effectiveness ratio per gained additional QALY (ICER) based on discounted health benefits and reimbursed medical costs (3% per year) was ¥42,198. The one-way sensitivity analyses identified that the cost-effectiveness of reimbursing infliximab for MS-CD was mainly driven by the treatment efficacies of maintenance therapy, quality of life, and unit price of infliximab. PSA estimated that reimbursing infliximab was associated with a 63.8% chance to be cost-effective under the willingness-to-pay of the 2018 Chinese gross domestic product per capita (GDPPC).
CONCLUSION: Reimbursing infliximab for MS-CD in Chinese patients was highly attractive, costing Chinese public insurance payers less than the 2018 Chinese GDPPC to gain 1 QALY.

PMID: 31797196 [PubMed - as supplied by publisher]

Identifying Transitional High Cost Users from Unstructured Patient Profiles Written by Primary Care Physicians.

Pac Symp Biocomput. 2020;25:127-138

Authors: Zhang H, Candido E, Wilton AS, Duchen R, Jaakkimainen L, Wodchis W, Morris Q

Abstract
Identification and subsequent intervention of patients at risk of becoming High Cost Users (HCUs) presents the opportunity to improve outcomes while also providing significant savings for the healthcare system. In this paper, the 2016 HCU status of patients was predicted using free-form text data from the 2015 cumulative patient profiles within the electronic medical records of family care practices in Ontario. These unstructured notes make substantial use of domain-specific spellings and abbreviations; we show that word embeddings derived from the same context provide more informative features than pre-trained ones based on Wikipedia, MIMIC, and Pubmed. We further demonstrate that a model using features derived from aggregated word embeddings (EmbEncode) provides a significant performance improvement over the bag-of-words representation (82.48±0.35% versus 81.85±0.36% held-out AUROC, p = 3.2 × 10-4), using far fewer input features (5,492 versus 214,750) and fewer non-zero coefficients (1,177 versus 4,284). The future HCUs of greatest interest are the transitional ones who are not already HCUs, because they provide the greatest scope for interventions. Predicting these new HCU is challenging because most HCUs recur. We show that removing recurrent HCUs from the training set improves the ability of EmbEncode to predict new HCUs, while only slightly decreasing its ability to predict recurrent ones.

PMID: 31797592 [PubMed - in process]

TrackSigFreq: subclonal reconstructions based on mutation signatures and allele frequencies.

Pac Symp Biocomput. 2020;25:238-249

Authors: Harrigan CF, Rubanova Y, Morris Q, Selega A

Abstract
Mutational signatures are patterns of mutation types, many of which are linked to known mutagenic processes. Signature activity represents the proportion of mutations a signature generates. In cancer, cells may gain advantageous phenotypes through mutation accumulation, causing rapid growth of that subpopulation within the tumour. The presence of many subclones can make cancers harder to treat and have other clinical implications. Reconstructing changes in signature activities can give insight into the evolution of cells within a tumour. Recently, we introduced a new method, TrackSig, to detect changes in signature activities across time from single bulk tumour sample. By design, TrackSig is unable to identify mutation populations with different frequencies but little to no difference in signature activity. Here we present an extension of this method, TrackSigFreq, which enables trajectory reconstruction based on both observed density of mutation frequencies and changes in mutational signature activities. TrackSigFreq preserves the advantages of TrackSig, namely optimal and rapid mutation clustering through segmentation, while extending it so that it can identify distinct mutation populations that share similar signature activities.

PMID: 31797600 [PubMed - in process]

Genome Gerrymandering: optimal division of the genome into regions with cancer type specific differences in mutation rates.

Pac Symp Biocomput. 2020;25:274-285

Authors: Young A, Chmura J, Park Y, Morris Q, Atwal G

Abstract
The activity of mutational processes differs across the genome, and is influenced by chromatin state and spatial genome organization. At the scale of one megabase-pair (Mb), regional mutation density correlate strongly with chromatin features and mutation density at this scale can be used to accurately identify cancer type. Here, we explore the relationship between genomic region and mutation rate by developing an information theory driven, dynamic programming algorithm for dividing the genome into regions with differing relative mutation rates between cancer types. Our algorithm improves mutual information when compared to the naive approach, effectively reducing the average number of mutations required to identify cancer type. Our approach provides an efficient method for associating regional mutation density with mutation labels, and has future applications in exploring the role of somatic mutations in a number of diseases.

PMID: 31797603 [PubMed - in process]