Publications

Brief Report: Discordance Between Population Impact of Musculoskeletal Disorders and Scientific Representation: A Bibliometric Study.

5 hours 43 minutes ago
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Brief Report: Discordance Between Population Impact of Musculoskeletal Disorders and Scientific Representation: A Bibliometric Study.

Arthritis Care Res (Hoboken). 2019 01;71(1):56-60

Authors: Perruccio AV, Yip C, Power JD, Canizares M, Badley EM

Abstract
OBJECTIVE: Musculoskeletal disorders (MSDs) are a leading cause of healthy years lost due to premature mortality and disability. Our objective was to investigate whether MSDs were commensurably represented within the published health literature.
METHODS: MEDLINE bibliometric data were retrieved for 2011 and 2016. The 25 disease branches, including MSDs, were ranked according to published article counts, proportion of all publications, and increase in publications from 2011 to 2016. Rankings were also considered within 5 groupings of general health journals: geriatrics and gerontology, general and internal medicine, multidisciplinary sciences, primary health care, and public health.
RESULTS: There were 532,283 MEDLINE publications in 2016, a 16% increase over 2011. In 2016, MSDs ranked 13th in publication count, unchanged from 2011. The increase of 11% in MSD publications from 2011 was below the overall increase. Of 2016 publications, only 7% were MSD indexed, dropping from 7.3% in 2011. MSD-indexed publications had their highest ranking (8th) within geriatrics and gerontology, and lowest (19th) within public health.
CONCLUSION: MSDs appear underrepresented in the published health literature generally, and specifically within public health, despite their significant population impact. A broader focus on noncommunicable diseases associated with mortality omits noncommunicable diseases such as MSDs that are leading contributors to high morbidity and high costs, and such omission likely contributes to the neglect of recognizing MSDs as a health priority.

PMID: 29669396 [PubMed - indexed for MEDLINE]

Hippocampal tail volume as a predictive biomarker of antidepressant treatment outcomes in patients with major depressive disorder: a CAN-BIND report.

5 hours 43 minutes ago
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Hippocampal tail volume as a predictive biomarker of antidepressant treatment outcomes in patients with major depressive disorder: a CAN-BIND report.

Neuropsychopharmacology. 2019 Oct 14;:

Authors: Nogovitsyn N, Muller M, Souza R, Hassel S, Arnott SR, Davis AD, Hall GB, Harris JK, Zamyadi M, Metzak PD, Ismail Z, Downar J, Parikh SV, Soares CN, Addington JM, Milev R, Harkness KL, Frey BN, Lam RW, Strother SC, Rotzinger S, Kennedy SH, MacQueen GM

Abstract
Finding a clinically useful neuroimaging biomarker that can predict treatment response in patients with major depressive disorder (MDD) is challenging, in part because of poor reproducibility and generalizability of findings across studies. Previous work has suggested that posterior hippocampal volumes in depressed patients may be associated with antidepressant treatment outcomes. The primary purpose of this investigation was to examine further whether posterior hippocampal volumes predict remission following antidepressant treatment. Magnetic resonance imaging (MRI) scans from 196 patients with MDD and 110 healthy participants were obtained as part of the first study in the Canadian Biomarker Integration Network in Depression program (CAN-BIND 1) in which patients were treated for 16 weeks with open-label medication. Hippocampal volumes were measured using both a manual segmentation protocol and FreeSurfer 6.0. Baseline hippocampal tail (Ht) volumes were significantly smaller in patients with depression compared to healthy participants. Larger baseline Ht volumes were positively associated with remission status at weeks 8 and 16. Participants who achieved early sustained remission had significantly greater Ht volumes compared to those who did not achieve remission by week 16. Ht volume is a prognostic biomarker for antidepressant treatment outcomes in patients with MDD.

PMID: 31610545 [PubMed - as supplied by publisher]

White matter microstructure in women with acute and remitted anorexia nervosa: an exploratory neuroimaging study.

2 days 5 hours ago
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White matter microstructure in women with acute and remitted anorexia nervosa: an exploratory neuroimaging study.

Brain Imaging Behav. 2019 Oct 11;:

Authors: Miles AE, Kaplan AS, French L, Voineskos AN

Abstract
Anorexia nervosa (AN) is a highly heritable psychiatric disorder characterized by starvation and emaciation and associated with changes in brain structure. The precise nature of these changes remains unclear, as does their developmental time course and capacity for reversal with weight restoration. In this exploratory neuroimaging study, we sought to characterize changes in white matter microstructure in women with acute and remitted AN. Diffusion-weighted MRI data was collected from underweight women with a current diagnosis of AN (acAN: n = 23), weight-recovered women with a past diagnosis of AN (recAN: n = 23), and age-matched healthy control women (HC: n = 24). Image processing and analysis were performed with Tract-Based Spatial Statistics, part of FSL, and group differences in voxelwise, brain-wide fractional anisotropy (FA) and mean diffusivity (MD), indices of white matter microstructure, were tested with nonparametric permutation and threshold-free cluster enhancement. No significant main effect of group on FA was identified. A significant main effect of group on MD was observed in a large cluster covering 9.2% of white matter and including substantial portions of the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus, and post hoc analyses revealed similar effects of group on axial diffusivity (AD) and radial diffusivity (RD). Clusterwise MD was significantly higher in acAN participants (+3.8%) and recAN participants (+2.9%) than healthy controls, and the same was true for clusterwise AD and RD. Trait-based increases in diffusivity, changes in which have been associated with atypical myelination and impaired axon integrity, suggest a link between altered white matter microstructure and vulnerability to AN, and evidence of reduced oligodendrocyte density in AN provides further support for this hypothesis. Potential mechanisms of action include atypical neurodevelopment and systemic inflammation.

PMID: 31605281 [PubMed - as supplied by publisher]

MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2.

2 days 23 hours ago
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MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2.

Epigenetics Chromatin. 2019 Oct 10;12(1):63

Authors: Martínez de Paz A, Khajavi L, Martin H, Claveria-Gimeno R, Tom Dieck S, Cheema MS, Sanchez-Mut JV, Moksa MM, Carles A, Brodie NI, Sheikh TI, Freeman ME, Petrotchenko EV, Borchers CH, Schuman EM, Zytnicki M, Velazquez-Campoy A, Abian O, Hirst M, Esteller M, Vincent JB, Malnou CE, Ausió J

Abstract
BACKGROUND: MeCP2-a chromatin-binding protein associated with Rett syndrome-has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored.
RESULTS: Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes.
CONCLUSIONS: Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.

PMID: 31601272 [PubMed - in process]

A large data resource of genomic copy number variation across neurodevelopmental disorders.

2 days 23 hours ago
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A large data resource of genomic copy number variation across neurodevelopmental disorders.

NPJ Genom Med. 2019;4:26

Authors: Zarrei M, Burton CL, Engchuan W, Young EJ, Higginbotham EJ, MacDonald JR, Trost B, Chan AJS, Walker S, Lamoureux S, Heung T, Mojarad BA, Kellam B, Paton T, Faheem M, Miron K, Lu C, Wang T, Samler K, Wang X, Costain G, Hoang N, Pellecchia G, Wei J, Patel RV, Thiruvahindrapuram B, Roifman M, Merico D, Goodale T, Drmic I, Speevak M, Howe JL, Yuen RKC, Buchanan JA, Vorstman JAS, Marshall CR, Wintle RF, Rosenberg DR, Hanna GL, Woodbury-Smith M, Cytrynbaum C, Zwaigenbaum L, Elsabbagh M, Flanagan J, Fernandez BA, Carter MT, Szatmari P, Roberts W, Lerch J, Liu X, Nicolson R, Georgiades S, Weksberg R, Arnold PD, Bassett AS, Crosbie J, Schachar R, Stavropoulos DJ, Anagnostou E, Scherer SW

Abstract
Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

PMID: 31602316 [PubMed]

Protein-Protein Interaction Profiling in Candida albicans Revealed by Biochemical Purification-Mass Spectrometry (BP/MS).

2 days 23 hours ago
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Protein-Protein Interaction Profiling in Candida albicans Revealed by Biochemical Purification-Mass Spectrometry (BP/MS).

Methods Mol Biol. 2019;2049:203-211

Authors: Pourhaghighi R, O'Meara TR, Cowen LE, Emili A

Abstract
BP/MS is a new experimental proteomic platform for systematic study of native protein complexes and global protein-protein interaction networks based on deep biochemical purification of soluble protein extracts and mass spectrometry identification of coeluting proteins. Herein, we describe the application of this methodology to draft a high-confidence protein interaction network for Candida albicans.

PMID: 31602613 [PubMed - in process]

Breath-Hold Blood Oxygen Level-Dependent MRI: A Tool for the Assessment of Cerebrovascular Reserve in Children with Moyamoya Disease.

4 days 8 hours ago
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Breath-Hold Blood Oxygen Level-Dependent MRI: A Tool for the Assessment of Cerebrovascular Reserve in Children with Moyamoya Disease.

AJNR Am J Neuroradiol. 2018 09;39(9):1717-1723

Authors: Dlamini N, Shah-Basak P, Leung J, Kirkham F, Shroff M, Kassner A, Robertson A, Dirks P, Westmacott R, deVeber G, Logan W

Abstract
BACKGROUND AND PURPOSE: There is a critical need for a reliable and clinically feasible imaging technique that can enable prognostication and selection for revascularization surgery in children with Moyamoya disease. Blood oxygen level-dependent MR imaging assessment of cerebrovascular reactivity, using voluntary breath-hold hypercapnic challenge, is one such simple technique. However, its repeatability and reliability in children with Moyamoya disease are unknown. The current study sought to address this limitation.
MATERIALS AND METHODS: Children with Moyamoya disease underwent dual breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging of cerebrovascular reactivity in the same MR imaging session. Within-day, within-subject repeatability of cerebrovascular reactivity estimates, derived from the blood oxygen level-dependent signal, was computed. Estimates were associated with demographics and intellectual function. Interrater reliability of a qualitative and clinically applicable scoring scheme was assessed.
RESULTS: Twenty children (11 males; 12.1 ± 3.3 years) with 30 MR imaging sessions (60 MR imaging scans) were included. Repeatability was "good" on the basis of the intraclass correlation coefficient (0.70 ± 0.19). Agreement of qualitative scores was "substantial" (κ = 0.711), and intrarater reliability of scores was "almost perfect" (κ = 0.83 and 1). Younger participants exhibited lower repeatability (P = .027). Repeatability was not associated with cognitive function (P > .05). However, abnormal cerebrovascular reactivity was associated with slower processing speed (P = .015).
CONCLUSIONS: Breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging is a repeatable technique for the assessment of cerebrovascular reactivity in children with Moyamoya disease and is reliably interpretable for use in clinical practice. Standardization of such protocols will allow further research into its application for the assessment of ischemic risk in childhood cerebrovascular disease.

PMID: 30139753 [PubMed - indexed for MEDLINE]

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma.

4 days 8 hours ago
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Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma.

Sci Signal. 2018 09 11;11(547):

Authors: Purzner T, Purzner J, Buckstaff T, Cozza G, Gholamin S, Rusert JM, Hartl TA, Sanders J, Conley N, Ge X, Langan M, Ramaswamy V, Ellis L, Litzenburger U, Bolin S, Theruvath J, Nitta R, Qi L, Li XN, Li G, Taylor MD, Wechsler-Reya RJ, Pinna LA, Cho YJ, Fuller MT, Elias JE, Scott MP

Abstract
A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.

PMID: 30206138 [PubMed - indexed for MEDLINE]

Recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma.

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Recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma.

Nature. 2019 Oct 09;:

Authors: Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P, Cavalli FMG, Juraschka K, Farooq H, Shibahara I, Vladoiu MC, Zhang J, Abeysundara N, Przelicki D, Skowron P, Gauer N, Luu B, Daniels C, Wu X, Forget A, Momin A, Wang J, Dong W, Kim SK, Grajkowska WA, Jouvet A, Fèvre-Montange M, Garrè ML, Rao AAN, Giannini C, Kros JM, French PJ, Jabado N, Ng HK, Poon WS, Eberhart CG, Pollack IF, Olson JM, Weiss WA, Kumabe T, López-Aguilar E, Lach B, Massimino M, Van Meir EG, Rubin JB, Vibhakar R, Chambless LB, Kijima N, Klekner A, Bognár L, Chan JA, Faria CC, Ragoussis J, Pfister SM, Goldenberg A, Wechsler-Reya RJ, Bailey SD, Garzia L, Morrissy AS, Marra MA, Huang X, Malkin D, Ayrault O, Ramaswamy V, Puente XS, Calarco JA, Stein L, Taylor MD

Abstract
Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein-coding genes, and are rare in most paediatric cancers1-3. Here we report highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs (snRNAs) in ~50% of Sonic hedgehog medulloblastomas (Shh-MB), which were not present across other medulloblastoma subgroups. This U1-snRNA hotspot mutation (r.3a>g), was identified in <0.1% of 2,442 cancers across 36 other tumour types. Largely absent from infant Shh-MB, the mutation occurs in 97% of adults (Shhδ), and 25% of adolescents (Shhα). The U1-snRNA mutation occurs in the 5' splice site binding region, and snRNA mutant tumours have significantly disrupted RNA splicing with an excess of 5' cryptic splicing events. Mutant U1-snRNA-mediated alternative splicing inactivates tumour suppressor genes (PTCH1), and activates oncogenes (GLI2, CCND2), represents a novel target for therapy, and constitutes a highly recurrent and tissue-specific mutation of a non-protein coding gene in cancer.

PMID: 31597162 [PubMed - as supplied by publisher]

The U1 spliceosomal RNA is recurrently mutated in multiple cancers.

5 days 5 hours ago
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The U1 spliceosomal RNA is recurrently mutated in multiple cancers.

Nature. 2019 Oct 09;:

Authors: Shuai S, Suzuki H, Diaz-Navarro A, Nadeu F, Kumar SA, Gutierrez-Fernandez A, Delgado J, Pinyol M, López-Otín C, Puente XS, Taylor MD, Campo E, Stein LD

Abstract
Cancers are caused by genomic alterations known as drivers. While hundreds of drivers in coding genes are known, only a handful of non-coding drivers have been discovered to date despite intensive searching1,2. Attention has recently shifted to the role of altered RNA splicing in cancer; driver mutations that lead to transcriptome-wide aberrant splicing have been identified in multiple cancer types, although they have only been found in protein-coding splicing factors like SF3B1 (splicing factor 3b subunit 1)3-6. In contrast, cancer-related alterations in the non-coding component of the spliceosome, a series of small nuclear RNAs (snRNAs), have barely been studied due to the combined challenges of characterizing non-coding cancer drivers and the repetitive nature of snRNA genes1,7,8. Here we report a highly recurrent A>C somatic mutation at the third base of U1 snRNA in several tumour types. The primary function of U1 is to recognize the 5' splice site (5'SS) via base-pairing. This mutation changes the preferential A-U base-pairing between U1 and 5'SS to C-G base-pairing, thereby creating novel splice junctions and altering the splicing pattern of multiple genes, including known cancer drivers. Clinically, the A>C mutation is associated with alcohol abuse in hepatocellular carcinoma (HCC) and the aggressive IGHV unmutated subtype of chronic lymphocytic leukaemia (CLL). The U1 mutation also confers an adverse prognosis to CLL patients independently. Our study demonstrates one of the first non-coding drivers in spliceosomal RNAs, reveals a novel mechanism of aberrant splicing in cancer and may represent a new target for treatment. Our findings also suggest that driver discovery should be extended to a wider range of genomic regions.

PMID: 31597163 [PubMed - as supplied by publisher]

In planta proximity dependent biotin identification (BioID).

6 days 2 hours ago
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In planta proximity dependent biotin identification (BioID).

Sci Rep. 2018 06 15;8(1):9212

Authors: Khan M, Youn JY, Gingras AC, Subramaniam R, Desveaux D

Abstract
Proximity dependent biotin identification (BioID) has emerged as a powerful tool for studies of proteome architecture, including insoluble or membrane-associated proteins. The technique has been well established in mammalian cells but has yet to be applied to whole plant systems. Here we demonstrate the application of BioID on leaf tissues of the model plant Arabidopsis thaliana, thereby expanding the versatility of this important technique and providing a powerful proteomics tool for plant biologists.

PMID: 29907827 [PubMed - indexed for MEDLINE]

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

6 days 2 hours ago
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Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

Acta Neuropathol. 2018 08;136(2):211-226

Authors: Pajtler KW, Wen J, Sill M, Lin T, Orisme W, Tang B, Hübner JM, Ramaswamy V, Jia S, Dalton JD, Haupfear K, Rogers HA, Punchihewa C, Lee R, Easton J, Wu G, Ritzmann TA, Chapman R, Chavez L, Boop FA, Klimo P, Sabin ND, Ogg R, Mack SC, Freibaum BD, Kim HJ, Witt H, Jones DTW, Vo B, Gajjar A, Pounds S, Onar-Thomas A, Roussel MF, Zhang J, Taylor JP, Merchant TE, Grundy R, Tatevossian RG, Taylor MD, Pfister SM, Korshunov A, Kool M, Ellison DW

Abstract
Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

PMID: 29909548 [PubMed - indexed for MEDLINE]

Heterogeneity within the PF-EPN-B ependymoma subgroup.

6 days 2 hours ago
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Heterogeneity within the PF-EPN-B ependymoma subgroup.

Acta Neuropathol. 2018 08;136(2):227-237

Authors: Cavalli FMG, Hübner JM, Sharma T, Luu B, Sill M, Zapotocky M, Mack SC, Witt H, Lin T, Shih DJH, Ho B, Santi M, Emery L, Hukin J, Dunham C, McLendon RE, Lipp ES, Gururangan S, Grossbach A, French P, Kros JM, van Veelen MC, Rao AAN, Giannini C, Leary S, Jung S, Faria CC, Mora J, Schüller U, Alonso MM, Chan JA, Klekner A, Chambless LB, Hwang EI, Massimino M, Eberhart CG, Karajannis MA, Lu B, Liau LM, Zollo M, Ferrucci V, Carlotti C, Tirapelli DPC, Tabori U, Bouffet E, Ryzhova M, Ellison DW, Merchant TE, Gilbert MR, Armstrong TS, Korshunov A, Pfister SM, Taylor MD, Aldape K, Pajtler KW, Kool M, Ramaswamy V

Abstract
Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

PMID: 30019219 [PubMed - indexed for MEDLINE]

CFH and ARMS2 Polymorphisms Interact with Zinc Supplements in Cognitive Impairment in the Women's Health Initiative Hormone Trial.

6 days 2 hours ago
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CFH and ARMS2 Polymorphisms Interact with Zinc Supplements in Cognitive Impairment in the Women's Health Initiative Hormone Trial.

J Alzheimers Dis. 2018;66(2):707-715

Authors: Kustra R, Awh CC, Rojas-Fernandez C, Zanke B

Abstract
BACKGROUND: An interaction between genetic variants in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) and high-dose zinc supplementation on progression to advanced age-related macular degeneration (AMD) exists. Because cognitive impairment (CI) is associated with AMD, we used data from the Women's Health Initiative (WHI) to search for a zinc/genetics interaction.
OBJECTIVE: To study the interaction of chronic zinc supplementation with genetic variants in CFH and ARMS2 on the development of CI.
BACKGROUND: Zinc dietary supplements, CFH and ARMS2 genotypes, and serial mental status was analyzed in participants with available genetic data (n = 7,483). Cognition was assessed using the Modified Mini-Mental State Examination. The development of CI over 5 years was analyzed by genotype and zinc intake using a repeated measures logistic regression model.
RESULTS: Zinc supplementation of approximately 15 mg/day was associated with decreased development of CI in women with 1 or 2 CFH and no ARMS2 risk alleles (OR = 0.46: 1 CFH risk allele; 0.20: 2 CFH risk alleles; p = 0.002).
CONCLUSION: Low-dose zinc (approximately 15 mg) is associated with reduced CI in women with 2 CFH and 0 ARMS2 AMD risk alleles. This interaction is opposite in direction to that observed in AMD, where patients with 2 CFH and 0 ARMS2 risk alleles had increased progression to neovascular AMD if treated with 80 mg/day of zinc. This may be due to a zinc dose-response or to a fundamental difference in the role of zinc in the progression of early CI versus advanced AMD.

PMID: 30320589 [PubMed - indexed for MEDLINE]

An Optimized Bistable Metabolic Switch To Decouple Phenotypic States during Anaerobic Fermentation.

6 days 2 hours ago
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An Optimized Bistable Metabolic Switch To Decouple Phenotypic States during Anaerobic Fermentation.

ACS Synth Biol. 2018 12 21;7(12):2854-2866

Authors: Venayak N, Raj K, Jaydeep R, Mahadevan R

Abstract
Metabolic engineers aim to genetically modify microorganisms to improve their ability to produce valuable compounds. Despite the prevalence of growth-coupled production processes, these strategies can significantly limit production rates. Instead, rates can be improved by decoupling and optimizing growth and production independently, and operating with a growth stage followed by a production stage. Here, we implement a bistable transcriptional controller to decouple and switch between these two states. We optimize the controller in anaerobic conditions, typical of industrial fermentations, to ensure stability and tight expression control, while improving switching dynamics. The stability of this controller can be maintained through a simulated seed train scale-up from 5 mL to 500 000 L, indicating industrial feasibility. Finally, we demonstrate a two-stage production process using our optimal construct to improve the instantaneous rate of lactate production by over 50%, motivating the use of these systems in broad metabolic engineering applications.

PMID: 30376634 [PubMed - indexed for MEDLINE]

Genome-wide germline correlates of the epigenetic landscape of prostate cancer.

6 days 2 hours ago
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Genome-wide germline correlates of the epigenetic landscape of prostate cancer.

Nat Med. 2019 Oct 07;:

Authors: Houlahan KE, Shiah YJ, Gusev A, Yuan J, Ahmed M, Shetty A, Ramanand SG, Yao CQ, Bell C, O'Connor E, Huang V, Fraser M, Heisler LE, Livingstone J, Yamaguchi TN, Rouette A, Foucal A, Espiritu SMG, Sinha A, Sam M, Timms L, Johns J, Wong A, Murison A, Orain M, Picard V, Hovington H, Bergeron A, Lacombe L, Lupien M, Fradet Y, Têtu B, McPherson JD, Pasaniuc B, Kislinger T, Chua MLK, Pomerantz MM, van der Kwast T, Freedman ML, Mani RS, He HH, Bristow RG, Boutros PC

Abstract
Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

PMID: 31591588 [PubMed - as supplied by publisher]

Isoform-specific requirement for GSK3α in sperm for male fertility.

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Isoform-specific requirement for GSK3α in sperm for male fertility.

Biol Reprod. 2018 08 01;99(2):384-394

Authors: Bhattacharjee R, Goswami S, Dey S, Gangoda M, Brothag C, Eisa A, Woodgett J, Phiel C, Kline D, Vijayaraghavan S

Abstract
Glycogen synthase kinase 3 (GSK3) is a highly conserved protein kinase regulating key cellular functions. Its two isoforms, GSK3α and GSK3β, are encoded by distinct genes. In most tissues the two isoforms are functionally interchangeable, except in the developing embryo where GSK3β is essential. One functional allele of either of the two isoforms is sufficient to maintain normal tissue functions. Both GSK3 isoforms, present in sperm from several species including human, are suggested to play a role in epididymal initiation of sperm motility. Using genetic approaches, we have tested requirement for each of the two GSK3 isoforms in testis and sperm. Both GSK3 isoforms are expressed at high levels during the onset of spermatogenesis. Conditional knockout of GSK3α, but not GSK3β, in developing testicular germ cells in mice results in male infertility. Mice lacking one allele each of GSK3α and GSK3β are fertile. Despite overlapping expression and localization in differentiating spermatids, GSK3β does not substitute for GSK3α. Loss of GSK3α impairs sperm hexokinase activity resulting in low ATP levels. Net adenine nucleotide levels in caudal sperm lacking GSK3α resemble immature caput epididymal sperm. Changes in the association of the protein phosphatase PP1γ2 with its protein interactors occurring during epididymal sperm maturation is impaired in sperm lacking GSK3α. The isoform-specific requirement for GSK3α is likely due to its specific binding partners in the sperm principal piece. Testis and sperm are unique in their specific requirement of GSK3α for normal function and male fertility.

PMID: 29385396 [PubMed - indexed for MEDLINE]

Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study.

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Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study.

J Neurol Neurosurg Psychiatry. 2018 08;89(8):851-858

Authors: Schneider R, McKeever P, Kim T, Graff C, van Swieten JC, Karydas A, Boxer A, Rosen H, Miller BL, Laforce R, Galimberti D, Masellis M, Borroni B, Zhang Z, Zinman L, Rohrer JD, Tartaglia MC, Robertson J, Genetic FTD Initiative (GENFI)

Abstract
OBJECTIVE: To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.
METHODS: GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer's disease (AD) and 10 healthy controls (HCs) of similar age.
RESULTS: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).
CONCLUSIONS: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

PMID: 29434051 [PubMed - indexed for MEDLINE]

Load matters: neural correlates of verbal working memory in children with autism spectrum disorder.

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Load matters: neural correlates of verbal working memory in children with autism spectrum disorder.

J Neurodev Disord. 2018 06 01;10(1):19

Authors: Vogan VM, Francis KE, Morgan BR, Smith ML, Taylor MJ

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterised by diminished social reciprocity and communication skills and the presence of stereotyped and restricted behaviours. Executive functioning deficits, such as working memory, are associated with core ASD symptoms. Working memory allows for temporary storage and manipulation of information and relies heavily on frontal-parietal networks of the brain. There are few reports on the neural correlates of working memory in youth with ASD. The current study identified the neural systems underlying verbal working memory capacity in youth with and without ASD using functional magnetic resonance imaging (fMRI).
METHODS: Fifty-seven youth, 27 with ASD and 30 sex- and age-matched typically developing (TD) controls (9-16 years), completed a one-back letter matching task (LMT) with four levels of difficulty (i.e. cognitive load) while fMRI data were recorded. Linear trend analyses were conducted to examine brain regions that were recruited as a function of increasing cognitive load.
RESULTS: We found similar behavioural performance on the LMT in terms of reaction times, but in the two higher load conditions, the ASD youth had lower accuracy than the TD group. Neural patterns of activations differed significantly between TD and ASD groups. In TD youth, areas classically used for working memory, including the lateral and medial frontal, as well as superior parietal brain regions, increased in activation with increasing task difficulty, while areas related to the default mode network (DMN) showed decreasing activation (i.e., deactivation). The youth with ASD did not appear to use this opposing cognitive processing system; they showed little recruitment of frontal and parietal regions across the load but did show similar modulation of the DMN.
CONCLUSIONS: In a working memory task, where the load was manipulated without changing executive demands, TD youth showed increasing recruitment with increasing load of the classic fronto-parietal brain areas and decreasing involvement in default mode regions. In contrast, although they modulated the default mode network, youth with ASD did not show the modulation of increasing brain activation with increasing load, suggesting that they may be unable to manage increasing verbal information. Impaired verbal working memory in ASD would interfere with the youths' success academically and socially. Thus, determining the nature of atypical neural processing could help establish or monitor working memory interventions for ASD.

PMID: 29859034 [PubMed - indexed for MEDLINE]

Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma.

1 week ago
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Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma.

J Neuropathol Exp Neurol. 2018 08 01;77(8):696-702

Authors: Thompson EM, Brown M, Dobrikova E, Ramaswamy V, Taylor MD, McLendon R, Sanks J, Chandramohan V, Bigner D, Gromeier M

Abstract
Poliovirus oncolytic immunotherapy is a putatively novel approach to treat pediatric brain tumors. This work sought to determine expression of the poliovirus receptor (PVR), CD155, in low-grade and malignant pediatric brain tumors and its ability to infect, propagate, and inhibit cell proliferation. CD155 expression in pleomorphic xanthoastrocytoma (PXA), medulloblastoma, atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, and anaplastic ependymoma specimens was assessed. The ability of the polio: rhinovirus recombinant, PVSRIPO, to infect PXA (645 [BRAF V600E mutation], 2363) and medulloblastoma (D283, D341) cells were determined by viral propagation measurement and cell proliferation. PVR mRNA expression was evaluated in 763 medulloblastoma and 1231 normal brain samples. CD155 was expressed in all 12 patient specimens and in PXA and medulloblastoma cell lines. One-step growth curves at a multiplicity of infection of 10 demonstrated productive infection and peak plaque formation units at 5-10 hours. PVSRIPO infection significantly decreased cellular proliferation in 2363, 645, and D341 cell lines at 48 hours (p < 0.05) and resulted in cell death. PVR expression was highest in medulloblastoma subtypes Group 3γ, WNTα, and WNTβ (p < 0.001). This proof-of-concept in vitro study demonstrates that PVSRIPO is capable of infecting, propagating, prohibiting cell proliferation, and killing PXA and Group 3 medulloblastoma.

PMID: 29878245 [PubMed - indexed for MEDLINE]

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