Publications by authors named "Eric Thompson"

133 Publications

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

3D-Printed Capacitive Sensor Objects for Object Recognition Assays.

eNeuro 2021 Jan-Feb;8(1). Epub 2021 Jan 29.

Neurobehavioral Core Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC 27709

Object recognition tasks are widely used assays for studying learning and memory in rodents. Object recognition typically involves familiarizing mice with a set of objects and then presenting a novel object or displacing an object to a novel location or context. Learning and memory are inferred by a relative increase in time investigating the novel/displaced object. These tasks are in widespread use, but there are many inconsistencies in the way they are conducted across labs. Two major contributors to this are the lack of consistency in the method of measuring object investigation and the lack of standardization of the objects that are used. Current video-based automated algorithms can often be unreliable whereas manual scoring of object investigation is time consuming, tedious, and more subjective. To resolve these issues, we sought to design and implement 3D-printed objects that can be standardized across labs and use capacitive sensing to measure object investigation. Using a 3D printer, conductive filament, and low-cost off-the-shelf components, we demonstrate that employing 3D-printed capacitive touch objects is a reliable and precise way to perform object recognition tasks. Ultimately, this approach will lead to increased standardization and consistency across labs, which will greatly improve basic and translational research into learning and memory mechanisms.
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http://dx.doi.org/10.1523/ENEURO.0310-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877456PMC
January 2021

Image quality of EOS low-dose radiography in comparison with conventional radiography for assessment of ventriculoperitoneal shunt integrity.

J Neurosurg Pediatr 2021 Jan 8:1-7. Epub 2021 Jan 8.

4Neurosurgery, and.

Objective: Patients with shunted hydrocephalus often accumulate high levels of radiation over their lifetimes during evaluation of hardware integrity. Current practice involves the use of a series of conventional radiographs for this purpose. Newer low-dose EOS radiography is currently used to evaluate scoliosis but has not been explored to evaluate shunt integrity on a large scale. The goal of this study was to compare the quality of imaging using EOS low-dose radiography to conventional radiography to evaluate shunt tubing.

Methods: A retrospective chart review was performed on 57 patients who previously had both conventional radiographs and low-dose EOS images of their cerebral shunt tubing from 2000 to 2018. Patient demographics (age, sex, type of shunt tubing, primary diagnosis) were collected. Conventional radiographic images and low-dose EOS images were independently analyzed by a neurosurgeon and neuroradiologist in three categories: image quality, delineation of shunt, and distinction of shunt compared to adjacent anatomy.

Results: All patients had shunted hydrocephalus due to spina bifida and Chiari type II malformation. Ratings of EOS and conventional radiographic images by both raters did not differ significantly in terms of image quality (rater 1, p = 0.499; rater 2, p = 0.578) or delineation of shunt (p = 0.107 and p = 0.256). Conventional radiographic images received significantly higher ratings than EOS on the ability to distinguish the shunt versus adjacent anatomy by rater 1 (p = 0.039), but not by rater 2 (p = 0.149). The overall score of the three categories combined was not significantly different between EOS and conventional radiography (rater 1, p = 0.818; rater 2, p = 0.186). In terms of cost, an EOS image was less costly than a conventional radiography shunt series ($236-$366 and $1300-$1547, respectively). The radiation dose was also lower for EOS images, with an effective dose of 0.086-0.140 mSv compared to approximately 1.6 mSv for a similar field of view with conventional radiography.

Conclusions: The image quality of low-dose EOS radiography does not significantly differ from conventional radiography for the evaluation of cerebral shunts. In addition, EOS affords a much lower radiation dose and a lower cost.
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http://dx.doi.org/10.3171/2020.8.PEDS20428DOI Listing
January 2021

Comparative Animal Mucomics: Inspiration for Functional Materials from Ubiquitous and Understudied Biopolymers.

ACS Biomater Sci Eng 2020 10 14;6(10):5377-5398. Epub 2020 Sep 14.

The PhD Program in Biochemistry, Graduate Center of the City University of New York, 365 Fifth Avenue, New York, New York 10016, United States.

The functions of secreted animal mucuses are remarkably diverse and include lubricants, wet adhesives, protective barriers, and mineralizing agents. Although present in all animals, many open questions related to the hierarchical architectures, material properties, and genetics of mucus remain. Here, we summarize what is known about secreted mucus structure, describe the work of research groups throughout the world who are investigating various animal mucuses, and relate how these studies are revealing new mucus properties and the relationships between mucus hierarchical structure and hydrogel function. Finally, we call for a more systematic approach to studying animal mucuses so that data sets can be compared, omics-style, to address unanswered questions in the emerging field of mucomics. One major result that we anticipate from these efforts is design rules for creating new materials that are inspired by the structures and functions of animal mucuses.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00713DOI Listing
October 2020

Perioperative Assessment of Cerebellar Masses and the Potential for Cerebellar Cognitive Affective Syndrome.

World Neurosurg 2020 12 16;144:222-230. Epub 2020 Sep 16.

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.

The cerebellum was long perceived to be a region of limited importance with primary functions in the regulation of motor control. A degree of its functional topography in motor modulation has been traditionally appreciated. However, an evolving body of evidence supports its role in a range of cognitive processes, including executive decision making, language, emotional processing, and working memory. To this end, numerous studies of cerebellar stroke syndromes as well as investigations with functional magnetic resonance imaging and diffusion tensor imaging have given clinicians a better model of the functional topography within the cerebellum and the essential lanes of communication with the cerebrum. With this deeper understanding, neurosurgeons should integrate these domains into the perioperative evaluation and postoperative rehabilitation of patients with cerebellar tumors. This review aims to discuss these understandings and identify valuable tools for implementation into clinical practice.
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http://dx.doi.org/10.1016/j.wneu.2020.09.048DOI Listing
December 2020

Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer.

Mol Cancer Ther 2020 09 30;19(9):1763-1769. Epub 2020 Jun 30.

Department of Neurosurgery, Duke University, Durham, North Carolina.

Tyrosine kinase inhibitors have revolutionized the world of cancer treatment in recent years, profoundly improving survival of patients with chronic myeloid leukemia (CML) and beyond. However, off-target toxicities of these inhibitors are well-described, and resistance has become a paramount concern. Novel allosteric inhibitors of the Abelson (ABL) family of tyrosine kinases, including GNF-2, GNF-5, and ABL-001, are equipped to overcome these issues. Several contemporary studies have demonstrated their potential efficacy in three key areas: primary hematologic and solid malignancies, metastasis, and combination with other small molecules. Further, ongoing clinical trials are investigating the efficacy of ABL-001 for the treatment of CML and recurrent solid tumors. This work reviews the current literature of the preclinical testing of GNF-2 and GNF-5 and the preclinical and clinical testing of ABL-001. Future research will continue to evaluate these promising inhibitors as both first-line therapy for solid tumors and salvage therapy when more traditional drugs such as imatinib fail.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484003PMC
September 2020

Current medulloblastoma subgroup specific clinical trials.

Transl Pediatr 2020 Apr;9(2):157-162

Department of Neurosurgery, Duke University, Durham, NC, USA.

Medulloblastoma is a heterogeneous disease with at least four distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Recently there has been considerable progress defining the molecular drivers and prognostic factors of each subgroup. However, this information has only rarely been used to stratify risk or impact treatment. The purpose of this work is to provide an update on current clinical trials that provide molecularly stratified treatment paradigms. A search was conducted on ClinicalTrials.gov using the following search terms: "medulloblastoma and subgroup", "medulloblastoma and SHH", "medulloblastoma and WNT", and "medulloblastoma and Non-WNT/Non-SHH". This search resulted in nine distinct clinical trials, five for newly diagnosed medulloblastoma and four for recurrent medulloblastoma. Four trials for newly diagnosed medulloblastoma had a component of craniospinal irradiation reduction for patients with WNT medulloblastoma. Molecularly stratified trials for recurrent medulloblastoma largely focus on SHH. As these trials are ongoing, there are limited data available. A trial in which newly-diagnosed WNT patients received modest chemotherapy without radiation has been closed to accrual due to several early failures. Phase II trials evaluating vismodegib for SHH medulloblastoma in children and adults have been disappointing. In conclusion, although there is an expanding array of clinical trials which incorporate molecular data in prescribing treatment for newly-diagnosed and recurrent medulloblastoma, treatments for these diseases are fairly uniform, with craniospinal radiation dose being the main variable. As the drivers of the distinct subgroups and their associated prognoses are better elucidated, future clinical trials and novel targeted agents are needed to improve outcomes and reduce toxicity where feasible.
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http://dx.doi.org/10.21037/tp.2020.03.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237968PMC
April 2020

Evaluation of a eukaryote phylogenetic microarray for environmental monitoring of marine sediments.

Mar Pollut Bull 2020 May 2;154:111102. Epub 2020 Apr 2.

Department of Biology, University of Bergen, Bergen, Norway; NORCE, Bergen, Norway; Ocean Bergen AS, Bergen, Norway.

Increased exploitation of resources in sensitive marine ecosystems emphasizes the importance of knowledge regarding ecological impacts. However, current bio-monitoring practices are limited in terms of target-organisms and temporal resolution. Hence, developing new technologies is vital for enhanced ecosystem understanding. In this study, we have applied a prototype version of a phylogenetic microarray to assess the eukaryote community structures of marine sediments from an area with ongoing oil and gas drilling activity. The results were compared with data from both sequencing (metabarcoding) and morphology-based monitoring to evaluate whether microarrays were capable of detecting ecosystem disturbances. A significant correlation between microarray data and chemical pollution indicators, as well as sequencing-based results, was demonstrated, and several potential indicator organisms for pollution-associated parameters were identified, among them a large fraction of microorganisms not covered by traditional morphology-based monitoring. This suggests that microarrays have a potential in future environmental monitoring.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111102DOI Listing
May 2020

Magnetic resonance-guided stereotactic laser ablation therapy for the treatment of pediatric brain tumors: a multiinstitutional retrospective study.

J Neurosurg Pediatr 2020 Mar 27:1-9. Epub 2020 Mar 27.

Departments of7Neurosurgery and.

Objective: This study aimed to assess the safety and efficacy of MR-guided stereotactic laser ablation (SLA) therapy in the treatment of pediatric brain tumors.

Methods: Data from 17 North American centers were retrospectively reviewed. Clinical, technical, and radiographic data for pediatric patients treated with SLA for a diagnosis of brain tumor from 2008 to 2016 were collected and analyzed.

Results: A total of 86 patients (mean age 12.2 ± 4.5 years) with 76 low-grade (I or II) and 10 high-grade (III or IV) tumors were included. Tumor location included lobar (38.4%), deep (45.3%), and cerebellar (16.3%) compartments. The mean follow-up time was 24 months (median 18 months, range 3-72 months). At the last follow-up, the volume of SLA-treated tumors had decreased in 80.6% of patients with follow-up data. Patients with high-grade tumors were more likely to have an unchanged or larger tumor size after SLA treatment than those with low-grade tumors (OR 7.49, p = 0.0364). Subsequent surgery and adjuvant treatment were not required after SLA treatment in 90.4% and 86.7% of patients, respectively. Patients with high-grade tumors were more likely to receive subsequent surgery (OR 2.25, p = 0.4957) and adjuvant treatment (OR 3.77, p = 0.1711) after SLA therapy, without reaching significance. A total of 29 acute complications in 23 patients were reported and included malpositioned catheters (n = 3), intracranial hemorrhages (n = 2), transient neurological deficits (n = 11), permanent neurological deficits (n = 5), symptomatic perilesional edema (n = 2), hydrocephalus (n = 4), and death (n = 2). On long-term follow-up, 3 patients were reported to have worsened neuropsychological test results. Pre-SLA tumor volume, tumor location, number of laser trajectories, and number of lesions created did not result in a significantly increased risk of complications; however, the odds of complications increased by 14% (OR 1.14, p = 0.0159) with every 1-cm3 increase in the volume of the lesion created.

Conclusions: SLA is an effective, minimally invasive treatment option for pediatric brain tumors, although it is not without risks. Limiting the volume of the generated thermal lesion may help decrease the incidence of complications.
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http://dx.doi.org/10.3171/2020.1.PEDS19496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885863PMC
March 2020

Auditory detection learning is accompanied by plasticity in the auditory evoked potential.

Neurosci Lett 2020 03 28;721:134781. Epub 2020 Jan 28.

U.S. Air Force Research Laboratory, United States.

Auditory detection can improve with practice. These improvements are often assumed to arise from selective attention processes, but longer-term plasticity as a result of training may also play a role. Here, listeners were trained to detect either an 861-Hz or 1058-Hz tone (counterbalanced across participants) presented in noise at SNRs varying from -10 to -24 dB. On the following day, they were tasked with detecting 861-Hz and 1058-Hz tones at an SNR of -21 dB. In between blocks of this active task, EEG was recorded during passive presentation of trained and untrained frequency tones in quiet. Detection accuracy and confidence ratings were higher for trials at listeners' trained, than untrained-frequency (i.e., learning occurred). During passive exposure to sounds, the P2 component of the auditory evoked potential (∼150 - 200 ms post tone onset) was larger in amplitude for the trained compared to the untrained frequency. An analysis of global field power similarly yielded a stronger response for trained tones in the P2 time window. These effects were obtained during passive exposure, suggesting that training induced improvements in detection are not solely related to changes in selective attention. Rather, there may be an important role for changes in the long-term neural representations of sounds.
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http://dx.doi.org/10.1016/j.neulet.2020.134781DOI Listing
March 2020

Trans-splicing of mRNAs links gene transcription to translational control regulated by mTOR.

BMC Genomics 2019 Nov 29;20(1):908. Epub 2019 Nov 29.

Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, Norway.

Background: In phylogenetically diverse organisms, the 5' ends of a subset of mRNAs are trans-spliced with a spliced leader (SL) RNA. The functions of SL trans-splicing, however, remain largely enigmatic.

Results: We quantified translation genome-wide in the marine chordate, Oikopleura dioica, under inhibition of mTOR, a central growth regulator. Translation of trans-spliced TOP mRNAs was suppressed, consistent with a role of the SL sequence in nutrient-dependent translational control of growth-related mRNAs. Under crowded, nutrient-limiting conditions, O. dioica continued to filter-feed, but arrested growth until favorable conditions returned. Upon release from unfavorable conditions, initial recovery was independent of nutrient-responsive, trans-spliced genes, suggesting animal density sensing as a first trigger for resumption of development.

Conclusion: Our results are consistent with a proposed role of trans-splicing in the coordinated translational down-regulation of nutrient-responsive genes under growth-limiting conditions.
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http://dx.doi.org/10.1186/s12864-019-6277-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883708PMC
November 2019

Crystal structures of two solvated 2-aryl-3-phenyl-2,3-di-hydro-4-pyrido[3,2-][1,3]thia-zin-4-ones.

Acta Crystallogr E Crystallogr Commun 2019 Nov 22;75(Pt 11):1689-1693. Epub 2019 Oct 22.

Pennsylvania State University, Schuylkill Campus, 200 University Drive, Schuylkill Haven, PA 17972, USA.

The synthesis and crystal structures of 2-(4-fluoro-phen-yl)-3-phenyl-2,3-di-hydro-4-pyrido[3,2-][1,3]thia-zin-4-one toluene hemisolvate (), CHFNOS·0.5CH, and 2-(4-nitro-phen-yl)-3-phenyl-2,3-di-hydro-4-pyrido[3,2-][1,3]thia-zin-4-one iso-propanol 0.25-solvate 0.0625-hydrate (), CHNOS·0.25CHO·0.0625HO, are reported. Both are racemic mixtures (centrosymmetric crystal structures) of the individual com-pounds and incorporate solvent mol-ecules in their structures. Compound has four thia-zine mol-ecules in the asymmetric unit. All the thia-zine rings in this study show an envelope pucker, with the C atom bearing the substituted phenyl ring displaced from the other atoms. The phenyl and aryl rings in each of the mol-ecules are roughly orthogonal to each other, with dihedral angles of about 75°. The extended structures of and are consolidated by C-H⋯O and C-H⋯N(π), as well as T-type (C-H⋯π) inter-actions. Parallel aromatic ring inter-actions (π-π stacking) are observed only in .
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http://dx.doi.org/10.1107/S2056989019013781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829726PMC
November 2019

Switching of INCENP paralogs controls transitions in mitotic chromosomal passenger complex functions.

Cell Cycle 2019 09 15;18(17):2006-2025. Epub 2019 Jul 15.

a Sars International Centre for Marine Molecular Biology, University of Bergen , Bergen , Norway.

A single inner centromere protein (INCENP) found throughout eukaryotes modulates Aurora B kinase activity and chromosomal passenger complex (CPC) localization, which is essential for timely mitotic progression. It has been proposed that INCENP might act as a rheostat to regulate Aurora B activity through mitosis, with successively higher activity threshold levels for chromosome alignment, the spindle checkpoint, anaphase spindle transfer and finally spindle elongation and cytokinesis. It remains mechanistically unclear how this would be achieved. Here, we reveal that the urochordate, , possesses two INCENP paralogs, which display distinct localizations and subfunctionalization in order to complete M-phase. INCENPa was localized on chromosome arms and centromeres by prometaphase, and modulated Aurora B activity to mediate H3S10/S28 phosphorylation, chromosome condensation, spindle assembly and transfer of the CPC to the central spindle. Polo-like kinase (Plk1) recruitment to CDK1 phosphorylated INCENPa was crucial for INCENPa-Aurora B enrichment on centromeres. The second paralog, INCENPb was enriched on centromeres from prometaphase, and relocated to the central spindle at anaphase onset. In the absence of INCENPa, meiotic spindles failed to form, and homologous chromosomes did not segregate. INCENPb was not required for early to mid M-phase events but became essential for the activity and localization of Aurora B on the central spindle and midbody during cytokinesis in order to allow abscission to occur. Together, our results demonstrate that INCENP paralog switching on centromeres modulates Aurora B kinase localization, thus chronologically regulating CPC functions during fast embryonic divisions in the urochordate . CCAN: constitutive centromere-associated network; CENPs: centromere proteins; cmRNA: capped messenger RNA; CPC: chromosomal passenger complex; INCENP: inner centromere protein; Plk1: polo-like kinase 1; PP1: protein phosphatase 1; PP2A: protein phosphatase 2A; SAC: spindle assembly checkpoint; SAH: single α-helix domain.
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http://dx.doi.org/10.1080/15384101.2019.1634954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681789PMC
September 2019

Evidence-Based Medicine in the Clinical Learning Environment of Pediatric Hospital Medicine.

Pediatr Clin North Am 2019 08;66(4):713-724

Section of Hospital Medicine, St Christopher's Hospital for Children, 160 East Erie Avenue, Philadelphia, PA 19134, USA.

The article begins with an overview of evidence-based medicine (EBM), including its history and core principles. Next, the article discusses how the current clinical learning environment has shaped EBM, including the accessibility and portability of technology; the access to electronic search engines and libraries; and the movement toward applying the best evidence through order sets, clinical guidelines, and pathways to work toward standardizing care. The article ends with a focus on how educators can influence a trainee's knowledge, skills, attitudes, and behaviors regarding EBM.
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http://dx.doi.org/10.1016/j.pcl.2019.03.001DOI Listing
August 2019

ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma.

Neurosurgery 2020 05;86(5):742-751

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Background: An impermeable blood-brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG).

Objective: To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG.

Methods: The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed.

Results: Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305).

Conclusion: ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.
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http://dx.doi.org/10.1093/neuros/nyz212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443593PMC
May 2020

Pediatrics.

Oper Neurosurg (Hagerstown) 2019 Aug;17(Suppl 2):S182-S208

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

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http://dx.doi.org/10.1093/ons/opz078DOI Listing
August 2019

Childhood cerebellar tumours mirror conserved fetal transcriptional programs.

Nature 2019 08 1;572(7767):67-73. Epub 2019 May 1.

Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.
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http://dx.doi.org/10.1038/s41586-019-1158-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675628PMC
August 2019

Transmyocardial revascularization (TMR): current status and future directions.

Indian J Thorac Cardiovasc Surg 2018 Dec 8;34(Suppl 3):330-339. Epub 2018 Oct 8.

Saint Luke's Mid America Heart Institute, 4320 Wornall Rd, Medical Plaza II, Suite 50, Kansas City, MO 64111 USA.

Purpose: Cardiac surgeons are increasingly faced with a more complex patient who has developed a pattern of diffuse coronary artery disease (CAD), which is refractory to medical, percutaneous, and surgical interventions. This paper will review the clinical science surrounding transmyocardial revascularization (TMR) with an emphasis on the results from randomized controlled trials.

Methods: Randomized controlled trials which evaluated TMR used as sole therapy and when combined with coronary artery bypass grafting were reviewed. Pertinent basic science papers exploring TMR's possible mechanism of action along with future directions, including the synergism between TMR and cell-based therapies were reviewed.

Results: Two laser-based systems have been approved by the United States Food and Drug Administration (FDA) to deliver laser therapy to targeted areas of the left ventricle (LV) that cannot be revascularized using conventional methods: the holmium:yttrium-aluminum-garnet (Ho:YAG) laser system (CryoLife, Inc., Kennesaw, GA) and the carbon dioxide (CO) Heart Laser System (Novadaq Technologies Inc., (Mississauga, Canada). TMR can be performed either as a stand-alone procedure (sole therapy) or in conjunction with coronary artery bypass graft (CABG) surgery in patients who would be incompletely revascularized by CABG alone. Societal practice guidelines have been established and are supportive of using TMR in the difficult population of patients with diffuse CAD.

Conclusions: Patients with diffuse CAD have increased operative and long-term cardiac risks predicted by incomplete revascularization. The documented operative and long-term benefits associated with sole therapy and adjunctive TMR in randomized trials supports TMR's increased use in this difficult patient population.
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http://dx.doi.org/10.1007/s12055-018-0702-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525905PMC
December 2018

Development and testing of an 18S rRNA phylogenetic microarray for marine sediments.

J Microbiol Methods 2018 11 15;154:95-106. Epub 2018 Oct 15.

Department of Biology, University of Bergen, Bergen, Norway; Uni Research AS, Uni Research Environment, Bergen, Norway. Electronic address:

There is increasing interest in finding new, more efficient methods for routine monitoring of anthropogenic effects on benthic biodiversity and ecosystems. A range of molecular methods have been developed for assessing biodiversity the last decades. Particularly interesting are microarrays targeting phylogenetic marker genes, such as the small subunit of ribosomal RNA in eukaryotes (18S rRNA). This method can detect a large number of taxonomic groups in several samples simultaneously within a relatively short time and has the potential for incorporation in automated remote sensing pipelines. In this study we developed and tested a microarray for eukaryotes in marine sediments. The probes were designed to target 18S rRNA OTUs obtained through metabarcoding of marine sediments. The resulting microarray was tested using both a spiked sample consisting of 50 plasmid-clones and further, samples of genomic DNA extracted from marine sediments. We developed a filtration pipeline to eliminate noise and reduce the number of false positives, making it possible to detect and quantify most of the OTUs with ≥ 0.1% abundance in the spiked sample. Our data indicated that the microarray was specific at higher taxonomic levels. However, the specificity decreased with increasing sequence similarity suggesting cross-hybridization between closely related OTUs. When using genomic DNA isolated from marine sediment there was a positive correlation between hybridization intensity signals and abundance of sequencing reads, suggesting a quantitative behavior of the microarray. Overall, the data suggest a potential for microarrays as a tool for high throughput sediment monitoring.
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http://dx.doi.org/10.1016/j.mimet.2018.10.007DOI Listing
November 2018

Development of the house secreting epithelium, a major innovation of tunicate larvaceans, involves multiple homeodomain transcription factors.

Dev Biol 2018 11 11;443(2):117-126. Epub 2018 Sep 11.

Sars International Centre for Marine Molecular Biology, University of Bergen, Thormøhlensgt, 55, N-5008 Bergen, Norway; Key Laboratory of Marine Genetics and Breeding, Ocean University of China, Ministry of Education, Qingdao 266003, China. Electronic address:

The mechanisms driving innovations that distinguish large taxons are poorly known and essentially accessible via a candidate gene approach. A spectacular acquisition by tunicate larvaceans is the house, a complex extracellular filtration device. Its components are secreted by the oikoplastic epithelium which covers the animal trunk. Here we describe the development of this epithelium in larvae through the formation of specific cellular territories known to produce distinct sets of house proteins (Oikosins). It involves cell divisions and morphological differentiation but very limited cell migration. A diverse set of homeobox genes, most often duplicated in the genome, are transiently and site-specifically expressed in the trunk epithelium at early larval stages. Using RNA interference, we show that two prop duplicates are involved in the differentiation of a region on and around the dorsal midline, regulating morphology and the production of a specific oikosin. Our observations favor a scenario in which multiple homeobox genes and most likely other developmental transcription factors were recruited for this innovation. Their frequent duplications probably predated, but were not required for the emergence of the house.
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http://dx.doi.org/10.1016/j.ydbio.2018.09.006DOI Listing
November 2018

Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status.

J Neurooncol 2018 Nov 17;140(2):261-268. Epub 2018 Aug 17.

Department of Neurosurgery, Duke University, Durham, NC, USA.

Introduction: Pleomorphic xanthoastrocytoma (PXA) is a rare Grade II and III glioma. Surgical resection is the mainstay of treatment, however, adjuvant therapy is sometimes necessary. Given the rarity of PXA, chemotherapeutic efficacy data is limited. The importance of the BRAF V600E mutation in the context of MAP kinase pathway inhibition is unknown. The purpose of this study was to perform an in vivo screen of a variety to agents to determine efficacy against both V600E mutant and non-mutant PXA.

Methods: The efficacy of bevacizumab, temozolomide, lomustine (CCNU), irinotecan (CPT 11), a tyrosine kinase inhibitor (sorafenib), a selective MEK1/2 inhibitor (cobimetinib), and a BRAF inhibitor (vemurafenib) were assessed in two subcutaneous xenografts: D645 PXA (V600E-mutant) and D2363 PXA (V600E-non-mutant) (n = 5-10 mice). Select agents were also assessed in an intracranial model of D2363 PXA (n = 6-9). Subcutaneous tumor growth and survival were the endpoints.

Results: Temozolomide, bevacizumab, CPT 11, and sorafenib significantly inhibited subcutaneous tumor growth in both V600E-mutant and V600E-non-mutant models (P < 0.05). MEK inhibition (cobimetinib) but not BRAF inhibition (vemurafenib) also inhibited tumor growth regardless of V600E mutation (P < 0.05). Temozolomide, CPT 11, and bevacizumab also prolonged survival in a V600E-non-mutant intracranial model (median overall survival (OS) 68.5, 62.5, and 42.5 days, respectively) in contrast to controls (31.5 days, P < 0.001).

Conclusions: These findings suggest that when adjuvant treatment is clinically indicated for PXA, temozolomide, CPT 11, or bevacizumab may be considered. Additionally, a trial of a MEK inhibitor or tyrosine kinase inhibitor could be considered for PXA regardless of V600E mutation status.
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http://dx.doi.org/10.1007/s11060-018-2975-5DOI Listing
November 2018

Sulfonylurea receptor 1 expression is variable in adult and pediatric brain tumors.

Clin Neuropathol 2018 Sep/Oct;37(5):221-227

Introduction: Edema is a significant cause of neuromorbidity in children and adults with brain tumors. Agents used to control this effect, such as corticosteroids, have their own associated morbidities. Sulfonylurea receptor 1 (SUR1) is a transmembrane protein that regulates the activity of ion channels in neurons, glia, and endothelial cells. SUR1 expression is upregulated in neuroinflammatory conditions. Inhibition of SUR1 with glyburide decreases edema and neuroinflammation by countering cytotoxic edema and apoptosis in rodent models of subarachnoid hemorrhage, stroke, trauma, and cerebral metastases. However, the expression of SUR1 in human brain tumors has not been elucidated. The purpose of this study was to determine SUR1 expression and cellular colocalization in a variety of human brain tumor specimens.

Materials And Methods: Six glioblastoma, 12 cerebral metastases, 11 medulloblastoma, 9 supratentorial ependymoma, and 8 posterior fossa ependymoma specimens were analyzed using immunofluorescence. SUR1 expression and colocalization with blood vessels, neurons, and glial cells was analyzed and compared using ANOVA.

Results: SUR1 expression was found in all specimens examined as a percentage of the total tissue area (mean ± SD): glioblastoma 3.9 ± 4, cerebral metastases 4.1 ± 3.1, medulloblastoma 8.2 ± 7.2, supratentorial ependymoma 9.1 ± 7, and posterior fossa ependymoma 8.1 ± 5.9. SUR1 expression was greater in supratentorial ependymoma compared to glioblastoma and metastases (p < 0.05) and greater in medulloblastoma compared to glioblastoma (p < 0.05). SUR1 colocalized most reliably with the neuronal marker, NeuN, in glioblastoma, metastases, and posterior fossa ependymoma samples (p < 0.05). SUR1 colocalized most reliably with the endothelial cell marker, CD31, in medulloblastoma samples (p < 0.05).

Conclusion: SUR1 is a putative therapeutic target to reduce neuroinflammation in adult and pediatric brain tumors. Inhibition of SUR1 may result in neuronal stabilization in glioblastoma, cerebral metastases, and posterior fossa ependymoma and reduced edema in medulloblastoma.
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http://dx.doi.org/10.5414/NP301102DOI Listing
January 2019

Socioeconomic Factors, Perioperative Complications, and 30-Day Readmission Rates Associated With Delayed Cranial Vault Reconstruction for Craniosynostosis.

J Craniofac Surg 2018 Oct;29(7):1767-1771

Department of Neurosurgery, Duke University Medical Center, Durham, NC.

Background: Premature fusion of the cranial sutures can lead to significant neurocognitive, developmental, and esthetic consequences, especially if not corrected within the first year of life. This study aimed to identify the drivers of delayed cranial vault reconstruction (CVR) and its impact on complication and 30-day readmission rates among craniosynostosis patients.

Methods: The medical records of all children who underwent CVR for craniosynostosis between 2005 and 2017 at an academic institution were retrospectively reviewed. A delay in operation was defined by surgery performed >12 months of age. Patient demographics, comorbidities, perioperative complication rates, and 30-day readmission rates were collected.

Results: A total of 96 patients underwent primary CVR, with 79 (82.3%) patients undergoing nondelayed surgery and 17 (17.7%) patients undergoing surgery >12 months of age. Children undergoing delayed surgery were significantly more likely to be non-White (P < 0.0001), have Medicaid insurance (P = 0.023), and have a non-English primary language (P < 0.005). There was increased incidence of developmental disability identified at first consult (no-delay: 3.9% vs delay: 41.2%, P < 0.0001) and increased intracranial pressure (no-delay: 6.3% vs delay: 29.4%, P < 0.005) among children undergoing delayed surgery. The delayed cohort had a significantly higher unplanned 30-day readmission rate (no-delay: 0.0% vs delay: 5.9%, P = 0.03).

Conclusion: Our study suggests that craniosynostosis patients who are non-White, have a non-English primary language, and have Medicaid insurance are at risk for delayed primary surgery, which may lead to increased 30-day readmission. Interventions are necessary to reduce craniosynostosis patients' barriers to care to minimize the sequelae associated with delayed surgery.
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http://dx.doi.org/10.1097/SCS.0000000000004787DOI Listing
October 2018

Specialization of CDK1 and cyclin B paralog functions in a coenocystic mode of oogenic meiosis.

Cell Cycle 2018 23;17(12):1425-1444. Epub 2018 Jul 23.

a Department of Biological Sciences , University of Bergen , Bergen , Norway.

Oogenesis in the urochordate, Oikopleura dioica, occurs in a large coenocyst in which vitellogenesis precedes oocyte selection in order to adapt oocyte production to nutrient conditions. The animal has expanded Cyclin-Dependant Kinase 1 (CDK1) and Cyclin B paralog complements, with several expressed during oogenesis. Here, we addressed functional redundancy and specialization of CDK1 and cyclin B paralogs during oogenesis and early embryogenesis through spatiotemporal analyses and knockdown assays. CDK1a translocated from organizing centres (OCs) to selected meiotic nuclei at the beginning of the P4 phase of oogenesis, and its knockdown impaired vitellogenesis, nurse nuclear dumping, and entry of nurse nuclei into apoptosis. CDK1d-Cyclin Ba translocated from OCs to selected meiotic nuclei in P4, drove meiosis resumption and promoted nuclear envelope breakdown (NEBD). CDK1d-Cyclin Ba was also involved in histone H3S28 phosphorylation on centromeres and meiotic spindle assembly through regulating Aurora B localization to centromeres during prometaphase I. In other studied species, Cyclin B3 commonly promotes anaphase entry, but we found O. dioica Cyclin B3a to be non-essential for anaphase entry during oogenic meiosis. Instead, Cyclin B3a contributed to meiotic spindle assembly though its loss could be compensated by Cyclin Ba.
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http://dx.doi.org/10.1080/15384101.2018.1486167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986761PMC
November 2019

Complications following pediatric cranioplasty after decompressive craniectomy: a multicenter retrospective study.

J Neurosurg Pediatr 2018 09 8;22(3):225-232. Epub 2018 Jun 8.

17Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.

OBJECTIVE In children, the repair of skull defects arising from decompressive craniectomy presents a unique set of challenges. Single-center studies have identified different risk factors for the common complications of cranioplasty resorption and infection. The goal of the present study was to determine the risk factors for bone resorption and infection after pediatric cranioplasty. METHODS The authors conducted a multicenter retrospective case study that included all patients who underwent cranioplasty to correct a skull defect arising from a decompressive craniectomy at 13 centers between 2000 and 2011 and were less than 19 years old at the time of cranioplasty. Prior systematic review of the literature along with expert opinion guided the selection of variables to be collected. These included: indication for craniectomy; history of abusive head trauma; method of bone storage; method of bone fixation; use of drains; size of bone graft; presence of other implants, including ventriculoperitoneal (VP) shunt; presence of fluid collections; age at craniectomy; and time between craniectomy and cranioplasty. RESULTS A total of 359 patients met the inclusion criteria. The patients' mean age was 8.4 years, and 51.5% were female. Thirty-eight cases (10.5%) were complicated by infection. In multivariate analysis, presence of a cranial implant (primarily VP shunt) (OR 2.41, 95% CI 1.17-4.98), presence of gastrostomy (OR 2.44, 95% CI 1.03-5.79), and ventilator dependence (OR 8.45, 95% CI 1.10-65.08) were significant risk factors for cranioplasty infection. No other variable was associated with infection. Of the 240 patients who underwent a cranioplasty with bone graft, 21.7% showed bone resorption significant enough to warrant repeat surgical intervention. The most important predictor of cranioplasty bone resorption was age at the time of cranioplasty. For every month of increased age the risk of bone flap resorption decreased by 1% (OR 0.99, 95% CI 0.98-0.99, p < 0.001). Other risk factors for resorption in multivariate models were the use of external ventricular drains and lumbar shunts. CONCLUSIONS This is the largest study of pediatric cranioplasty outcomes performed to date. Analysis included variables found to be significant in previous retrospective reports. Presence of a cranial implant such as VP shunt is the most significant risk factor for cranioplasty infection, whereas younger age at cranioplasty is the dominant risk factor for bone resorption.
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http://dx.doi.org/10.3171/2018.3.PEDS17234DOI Listing
September 2018

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

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

Department of Neurosurgery, Duke University, Durham, North Carolina.

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.
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http://dx.doi.org/10.1093/jnen/nly045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044395PMC
August 2018

The clinical importance of medulloblastoma extent of resection: a systematic review.

J Neurooncol 2018 Sep 23;139(3):523-539. Epub 2018 May 23.

Division of Haematology/Oncology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Programme in Neuroscience and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.

Background: Although the majority of current medulloblastoma adjuvant therapy protocols treat patients with ≥ 1.5 cm residual tumor as high risk with increased craniospinal irradiation, the true prognostic significance of extent of resection (EOR) in medulloblastoma is unknown.

Objectives: We sought to synthesize the body of literature on EOR and survival to determine if a definitive association exists.

Data Sources/eligibility Criteria: A PubMed search was conducted for the terms "medulloblastoma" combined with "extent of resection," "overall survival," "progression free survival," "gross total resection," "near total resection," "partial resection," or "subtotal resection." Studies that performed a statistical analysis of EOR and survival were included.

Results: Sixteen articles including 1489 patients found a statistically significant association between EOR and survival, 20 articles including 2335 patients did not find a significant association between EOR and survival, and 14 articles including 2950 patients had mixed results. The three articles that accounted for molecular subgroup found varying associations between EOR and progression free survival, while no association was found between EOR and overall survival.

Limitations: This review is limited by inconsistent definitions of EOR, the retrospective nature of the articles analyzed, and infrequent use of multivariate statistical analyses.

Conclusions: The prognostic importance of EOR for medulloblastoma is unclear and warrants re-evaluation, particularly in the context of molecular subgrouping.
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http://dx.doi.org/10.1007/s11060-018-2906-5DOI Listing
September 2018

Performance of next-generation sequencing on small tumor specimens and/or low tumor content samples using a commercially available platform.

PLoS One 2018 27;13(4):e0196556. Epub 2018 Apr 27.

University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States of America.

Background: Next generation sequencing tests (NGS) are usually performed on relatively small core biopsy or fine needle aspiration (FNA) samples. Data is limited on what amount of tumor by volume or minimum number of FNA passes are needed to yield sufficient material for running NGS. We sought to identify the amount of tumor for running the PCDx NGS platform.

Methods: 2,723 consecutive tumor tissues of all cancer types were queried and reviewed for inclusion. Information on tumor volume, success of performing NGS, and results of NGS were compiled. Assessment of sequence analysis, mutation calling and sensitivity, quality control, drug associations, and data aggregation and analysis were performed.

Results: 6.4% of samples were rejected from all testing due to insufficient tumor quantity. The number of genes with insufficient sensitivity make definitive mutation calls increased as the percentage of tumor decreased, reaching statistical significance below 5% tumor content. The number of drug associations also decreased with a lower percentage of tumor, but this difference only became significant between 1-3%. The number of drug associations did decrease with smaller tissue size as expected. Neither specimen size or percentage of tumor affected the ability to pass mRNA quality control. A tumor area of 10 mm2 provides a good margin of error for specimens to yield adequate drug association results.

Conclusions: Specimen suitability remains a major obstacle to clinical NGS testing. We determined that PCR-based library creation methods allow the use of smaller specimens, and those with a lower percentage of tumor cells to be run on the PCDx NGS platform.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196556PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922576PMC
July 2018

Distinct core promoter codes drive transcription initiation at key developmental transitions in a marine chordate.

BMC Genomics 2018 02 26;19(1):164. Epub 2018 Feb 26.

Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, N-5006, Norway.

Background: Development is largely driven by transitions between transcriptional programs. The initiation of transcription at appropriate sites in the genome is a key component of this and yet few rules governing selection are known. Here, we used cap analysis of gene expression (CAGE) to generate bp-resolution maps of transcription start sites (TSSs) across the genome of Oikopleura dioica, a member of the closest living relatives to vertebrates.

Results: Our TSS maps revealed promoter features in common with vertebrates, as well as striking differences, and uncovered key roles for core promoter elements in the regulation of development. During spermatogenesis there is a genome-wide shift in mode of transcription initiation characterized by a novel core promoter element. This element was associated with > 70% of male-specific transcription, including the use of cryptic internal promoters within operons. In many cases this led to the exclusion of trans-splice sites, revealing a novel mechanism for regulating which mRNAs receive the spliced leader. Binding of the cell cycle regulator, E2F1, is enriched at the TSS of maternal genes in endocycling nurse nuclei. In addition, maternal promoters lack the TATA-like element found in zebrafish and have broad, rather than sharp, architectures with ordered nucleosomes. Promoters of ribosomal protein genes lack the highly conserved TCT initiator. We also report an association between DNA methylation on transcribed gene bodies and the TATA-box.

Conclusions: Our results reveal that distinct functional promoter classes and overlapping promoter codes are present in protochordates like in vertebrates, but show extraordinary lineage-specific innovations. Furthermore, we uncover a genome-wide, developmental stage-specific shift in the mode of TSS selection. Our results provide a rich resource for the study of promoter structure and evolution in Metazoa.
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http://dx.doi.org/10.1186/s12864-018-4504-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389100PMC
February 2018