UW Neurological Surgery Recent PubMed Publications

Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents.

Clin Cancer Res. 2017 Dec 01;23(23):7158-7164

Authors: Wages NA, Portell CA, Williams ME, Conaway MR, Petroni GR

Abstract
In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158-64. ©2017 AACR.

PMID: 28733439 [PubMed - indexed for MEDLINE]

Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations.

Mol Cancer Res. 2018 10;16(10):1491-1498

Authors: Wang AC, Jones DTW, Abecassis IJ, Cole BL, Leary SES, Lockwood CM, Chavez L, Capper D, Korshunov A, Fallah A, Wang S, Ene C, Olson JM, Geyer JR, Holland EC, Lee A, Ellenbogen RG, Ojemann JG

Abstract
Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (n = 8) diagnosed histologically as DIG/DIGA. Two of these cases clustered with other tumor entities, and were excluded from analysis. The remaining 16 cases were confirmed to be DIG/DIA by histology and by DNA methylation profiling. Somatic BRAF gene mutations were discovered in 7 instances (43.8%); 4 were BRAFV600E mutations, and 3 were BRAFV600D mutations. Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new TP53 mutation in one case, new ATRX deletion in one case, and in the third case, the original tumor harbored an EML4-ALK fusion, also present at recurrence. DIG/DIA are distinct pathologic entities that frequently harbor BRAFV600 mutations. Complete surgical resection is the ideal treatment, and overall prognosis is excellent. While, the small sample size and incomplete surgical records limit a definitive conclusion about the risk of tumor recurrence, the risk appears quite low. In rare cases with wild-type BRAF, malignant progression can be observed, frequently with the acquisition of other genetic alterations.Implications: DIG/DIA are a distinct molecular entity, with a subset frequently harboring either BRAF V600E or BRAF V600D mutations. Mol Cancer Res; 16(10); 1491-8. ©2018 AACR.

PMID: 30006355 [PubMed - indexed for MEDLINE]

The parathyroid hormone family member TIP39 interacts with sarco/endoplasmic reticulum Ca2+ - ATPase activity by influencing calcium homoeostasis.

Exp Dermatol. 2017 Sep;26(9):792-797

Authors: Sato E, Williams MR, Sanford JA, Sen GL, Nakama T, Imafuku S, Gallo RL

Abstract
Darier disease (DD) is a genetic skin disease that is associated with mutations in the ATP2A2 gene encoding the type 2 sarco/endoplasmic reticulum (ER) Ca2+ - ATPase (SERCA2). Mutations of this gene result in alterations of calcium homoeostasis, abnormal epidermal adhesion and dyskeratosis. Silencing of ATP2A2 in monolayer cell culture of keratinocytes reduces desmoplakin expression at the borders of cells and impacts cell adhesion. Here, we report establishment of a three-dimensional (3D) epidermal model of DD and use this model to evaluate peptide therapy with tuberoinfundibular peptide of 39 residues (TIP39) to normalize calcium transport. Gene silencing of ATP2A2 in keratinocytes grown in a 3D model resulted in dyskeratosis, partial parakeratosis and suprabasal clefts that resembled the histological changes seen in skin biopsies from patients with DD. TIP39, a peptide recently identified as a regulator of keratinocyte calcium transport, was then applied to this ATP2A2-silenced 3D epidermal model. In normal keratinocytes, TIP39 increased [Ca2+ ]i through the inositol trisphosphate (IP3) receptor pathway and stimulated differentiation. In monolayer ATP2A2-silenced keratinocytes, although TIP39 increased cytosolic calcium from the ER, the response was incomplete compared with its control. TIP39 was observed to reduce intercellular clefts of the gene-silenced epidermal model but did not significantly upregulate keratinocyte differentiation genes such as keratin 10 and filaggrin. These findings indicate that TIP39 is a modulator of ER calcium signalling and may be used as a potential strategy for improving aspects of DD.

PMID: 28094886 [PubMed - indexed for MEDLINE]

Prevalence of Abnormal Magnetic Resonance Imaging Findings in Children with Persistent Symptoms after Pediatric Sports-Related Concussion.

J Neurotrauma. 2017 Oct 01;34(19):2706-2712

Authors: Bonow RH, Friedman SD, Perez FA, Ellenbogen RG, Browd SR, Mac Donald CL, Vavilala MS, Rivara FP

Abstract
A subset of patients experience persistent symptoms after pediatric concussion, and magnetic resonance imaging (MRI) is commonly used to evaluate for pathology. The utility of this practice is unclear. We conducted a retrospective cohort study to describe the MRI findings in children with concussion. A registry of all patients seen at our institution from January 2010 through March 2016 with pediatric sports-related concussion was cross-referenced with a database of radiographical studies. Radiology reports were reviewed for abnormal findings. Patients with abnormal computed tomographies or MRI scans ordered for reasons other than concussion were excluded. Among 3338 children identified with concussion, 427 underwent MRI. Only 2 (0.5%) had findings compatible with traumatic injury, consisting in both of microhemorrhage. Sixty-one patients (14.3%) had abnormal findings unrelated to trauma, including 24 nonspecific T2 changes, 15 pineal cysts, eight Chiari I malformations, and five arachnoid cysts. One child underwent craniotomy for a cerebellar hemangioblastoma after presenting with ataxia; another had cortical dysplasia resected after seizure. The 2 patients with microhemorrhage each had three previous concussions, significantly more than patients whose scans were normal (median, 1) or abnormal without injury (median, 1.5; p = 0.048). MRI rarely revealed intracranial injuries in children post-concussion, and the clinical relevance of these uncommon findings remains unclear. Abnormalities unrelated to trauma are usually benign. However, MRI should be thoughtfully considered in children who present with concerning or atypical symptoms.

PMID: 28490224 [PubMed - indexed for MEDLINE]

Prevalence of Behavioral Health Conditions Across Frequency of Cannabis Use Among Adult Primary Care Patients in Washington State.

J Gen Intern Med. 2018 11;33(11):1833-1835

Authors: Lapham GT, Lee AK, Caldeiro RM, Glass JE, Carrell DS, Richards JE, Bradley KA

Abstract

PMID: 29992423 [PubMed - indexed for MEDLINE]

Virtual M-Mode for Echocardiography: A New Approach for the Segmentation of the Anterior Mitral Leaflet.

IEEE J Biomed Health Inform. 2019 01;23(1):305-313

Authors: Sultan MS, Martins N, Costa E, Veiga D, Ferreira MJ, Mattos S, Coimbra MT

Abstract
Rheumatic heart disease can result from repeated episodes of acute rheumatic fever, which damages the heart valves and reduces their functionality. Early manifestations of heart valve damage are visible in echocardiography in the form of valve thickening, shape changing and mobility reduction. The quantification of these features is important for a precise diagnosis and it is the main motivation for this work. The first step to make this quantification is to accurately identify and track the anterior mitral leaflet throughout the cardiac cycle. An accurate segmentation and tracking with minimum user interaction is still an open problem in literature due to low image quality, speckle noise, signal dropout and nonrigid deformations. In this work, we propose a novel approach for the identification of the anterior mitral valve leaflet in all frames. The method requires a single user-specified point on the posterior wall of the aorta as input, in the first frame. The echocardiography videos are converted into a new image space, the Virtual M-mode, which samples the original echocardiography image over automatically estimated scanning lines. This new image space not only provides the motion pattern of the posterior wall of the aorta, the anterior wall of the aorta and the posterior wall of the left atrium, but also provides the location of the structures in each frame. The location information is then used to initialize the localized active contours, followed by segmenting the anterior mitral leaflet. Results shown that the new image space has robustly identified the anterior mitral valve leaflet, without any failure. The median modified Hausdorff distance error of the proposed method was 2.3 mm, with a recall of 0.94.

PMID: 29994568 [PubMed - indexed for MEDLINE]

A Review of Recent Advances in Ultrasound, Placed in the Context of Pain Diagnosis and Treatment.

Curr Pain Headache Rep. 2018 Jul 10;22(9):60

Authors: Bobola MS, Chen L, Ezeokeke CK, Kuznetsova K, Lahti AC, Lou W, Myroniv AN, Schimek NW, Selby ML, Mourad PD

Abstract
Ultrasound plays a significant role in the diagnosis and treatment of pain, with significant literature reaching back many years, especially with regard to diagnostic ultrasound and its use for guiding needle-based delivery of drugs. Advances in ultrasound over at least the last decade have opened up new areas of inquiry and potential clinical efficacy in the context of pain diagnosis and treatment. Here we offer an overview of the recent literature associated with ultrasound and pain in order to highlight some promising frontiers at the intersection of these two subjects. We focus first on peripheral application of ultrasound, for which there is a relatively rich, though still young, literature. We then move to central application of ultrasound, for which there is little literature but much promise.

PMID: 29987680 [PubMed - indexed for MEDLINE]

Defining and Correcting Asymmetry in Isolated Unilateral Frontosphenoidal Synostosis: Differences in Orbital Shape, Facial Scoliosis, and Skullbase Twist Compared to Unilateral Coronal Synostosis.

J Craniofac Surg. 2018 Jan;29(1):29-35

Authors: Mundinger GS, Skladman R, Wenger T, Birgfeld CC, Gruss JS, Lee A, Ellenbogen R, Hopper RA

Abstract
INTRODUCTION: Isolated frontosphenoidal synostosis (FS) is a rare cause of fronto-orbital plagiocephaly that can be challenging to distinguish from isolated unicoronal synostosis (UC). The purpose of this paper is to analyze differences in fronto-orbital dysmorphology between the 2 conditions, to describe approaches for surgical correction, and to report surgical outcomes between FS and UC patients in a casecontrol fashion.
METHODS: Patients treated for craniosynostosis over a 12-year period at our institution were retrospectively evaluated under institutional review board approval. Frontosphenoidal synostosis patients who underwent bilateral fronto-orbital correction of anterior plagiocephaly with minimum 2-year follow-up, adequate pre-, and minimum 2-year postoperative computed tomography scans were included in the case-control portion of the study. These patients were randomly age-matched to UC patients meeting the same inclusion criteria. Preoperative and postoperative orbital shape and volumetric analysis was performed using Mimics software.
RESULTS: Twelve FS patients were treated during the study period. Seven of these patients met casecontrol inclusion criteria with average follow-up of 47.5 months. The characteristic FS orbit was a relatively wide, short, and shallow trapezoid, while the characteristic UC orbit was a relatively narrow, tall, and deep parallelogram. Frontosphenoidal synostosis orbits were significantly wider, shorter, shallower, and smaller than UC orbits. Surgical correction tailored to the differential dysmorphologies resulted in statistical equalization of these differences between affected and contralateral control orbits at follow-up, with the exception of UC orbital width, which remained significantly narrower than unaffected contralateral control. One patient in each group required cranioplasty for skull defects at follow-up, while no patient underwent surgical readvancement.
CONCLUSIONS: Frontosphenoidal synostosis and UC orbital shape differ significantly, and can be normalized using fronto-orbital advancement tailored to the distinct orbital dysmorphologies of these 2 groups.

PMID: 29065043 [PubMed - indexed for MEDLINE]

Giant Pediatric Rhabdoid Meningioma Associated with a Germline BAP1 Pathogenic variation: A Rare Clinical Case.

World Neurosurg. 2018 Jul 05;:

Authors: Ravanpay AC, Barkley A, White-Dzuro GA, Cimino PJ, Gonzalez-Cuyar LF, Lockwood C, Halasz LM, Hisama FM, Ferreira M

Abstract
Rhabdoid meningiomas are rare WHO grade 3 tumors that tend to follow an aggressive course. Pediatric rhabdoid meningioma is an exceedingly rare pathology commonly found on recurrent tumors in conjunction with lower grade meningioma pathology. Here, we present the case of a pediatric patient who came to us with a giant rhabdoid meningioma occurring in the right tentorium and invading the torcula and multiple venous structures, including the right jugular vein, down to the level of the right atrium. The patient underwent five separate surgeries for management of this tumor. Genetic analysis of the tumor revealed bi-allelic loss of BAP1 (BRCA1 associated protein-1) tumor suppressor gene. Peripheral blood testing showed that this patient was a germline carrier of a pathogenic BAP1 variant resulting in premature termination. Recently, BAP1 mutations have been described in adult rhabdoid meningiomas with aggressive features. This is the first case report of a pediatric rhabdoid meningioma associated with a germline BAP1 pathogenic variation. This case highlights the correlation between our evolving understanding of the role of BAP1 mutation and the aggressive course of rhabdoid meningiomas in an unprecedented context.
INTRODUCTION: Rhabdoid meningiomas are rare WHO grade 3 tumors that tend to follow an aggressive course, with an increased likelihood for local recurrence, remote metastasis, and CSF dissemination. Genetic testing has found certain genes associated with reduced time to tumor recurrence. BAP1 is a tumor suppressor gene that is associated with multiple tumors, including rhabdoid meningiomas.
CASE PRESENTATION: We present a case of a pediatric patient who presented with a rhabdoid meningioma occurring in the right tentorium and invading multiple venous structures, including the right jugular vein. The patient underwent five separate surgeries for management of this tumor. The first surgery was an intracranial tumor debulking with reconstruction of venous structures. Postoperatively, the patient was unable to have the ventricular catheter removed and underwent placement of a ventriculoperitoneal shunt. Significant recurrence of the intracranial portion of tumor was found during pre-operative imaging for her second stage procedure. She underwent a second craniotomy for resection of the tumor. Her postoperative MRI showed significant residual and the patient therefore underwent a third craniotomy for total tumor resection, which involved reconstruction of the superior sagittal sinus. She did well after this surgery with no new neurologic deficits. Her final operation involved resection of the residual tumor in the neck and chest by both otolaryngology and cardiothoracic surgery. This involved opening the jugular vein and resecting residual tumor from the intima. Pathology from all surgeries was consistent with rhabdoid meningioma, however the tissue from the biopsy and first craniotomy lacked the high-grade features that were found on subsequent resections. Genetic analysis found loss of both BAP1 tumor suppressor genes. Peripheral blood testing showed that this patient was a germline carrier of a pathogenic BAP1 variant.
DISCUSSION: Pediatric rhabdoid meningiomas represent a rare pathology, which are found on recurrent tumors in conjunction with lower grade meningioma pathology. Our patient presented with what was initially thought to be a low-grade meningioma with rhabdoid features that then transformed into a WHO grade III rhabdoid meningioma on recurrence. This tumor was discovered to have a bi-allelic loss of BAP-1 mutation and the patient was found to have a germline mutation in one of her BAP-1 alleles. Germline mutations in BAP-1 are associated with a cancer syndrome that involves uveal and cutaneous melanoma, malignant mesothelioma, atypical Spitz tumors, and clear cell renal cell carcinoma. Patients with this mutation are encouraged to undergo annual eye exams starting at the age of 11. The BAP-1 tumor predisposition syndrome (BAP1-TPDS) is most commonly an inherited mutation associated with incomplete penetrance and variation with non-overlapping tumor types.
CONCLUSION: Rhabdoid meningiomas are unlikely to be found in children and have a high rate of local recurrence. Gross total resection has to be balanced with risk of post-operative deficit. Genetic testing of this rare entity should be done to identify any hereditary germline mutations.

PMID: 29981911 [PubMed - as supplied by publisher]

Copy number profiling across glioblastoma populations has implications for clinical trial design.

Neuro Oncol. 2018 09 03;20(10):1368-1373

Authors: Cimino PJ, McFerrin L, Wirsching HG, Arora S, Bolouri H, Rabadan R, Weller M, Holland EC

Abstract
Background: Copy number alterations form prognostic molecular subtypes of glioblastoma with clear differences in median overall survival. In this study, we leverage molecular data from several glioblastoma cohorts to define the distribution of copy number subtypes across random cohorts as well as cohorts with selection biases for patients with inherently better outcome.
Methods: Copy number subtype frequency was established for 4 glioblastoma patient cohorts. Two randomly selected cohorts include The Cancer Genome Atlas (TCGA) and the German Glioma Network (GGN). Two more selective cohorts include the phase II trial ARTE in elderly patients with newly diagnosed glioblastoma and a multi-institutional cohort focused on paired resected initial/recurrent glioblastoma. The paired initial/recurrent cohort also had exome data available, which allowed for evaluation of multidimensional scaling analysis.
Results: Smaller selective glioblastoma cohorts are enriched for copy number subtypes that are associated with better survival, reflecting the selection of patients who do well enough to enter a clinical trial or who are deemed well enough to undergo resection at recurrence. Adding exome data to copy number data provides additional data reflective of outcome.
Conclusions: The overall outcome for diffuse glioma patients is predicted by DNA structure at initial tumor resection. Molecular signature shifts across glioblastoma populations reflect the inherent bias of patient selection toward longer survival in clinical trials. Therefore it may be important to include molecular profiling, including copy number, when enrolling patients for clinical trials in order to balance arms and extrapolate relevance to the general glioblastoma population.

PMID: 29982740 [PubMed - indexed for MEDLINE]

Frequency of and factors associated with emergency department intracranial pressure monitor placement in severe paediatric traumatic brain injury.

Brain Inj. 2017;31(13-14):1745-1752

Authors: Kannan N, Quistberg A, Wang J, Groner JI, Mink RB, Wainwright MS, Bell MJ, Giza CC, Zatzick DF, Ellenbogen RG, Boyle LN, Mitchell PH, Vavilala MS

Abstract
OBJECTIVE: To examine the frequency of and factors associated with emergency department (ED) intracranial pressure (ICP) monitor placement in severe paediatric traumatic brain injury (TBI).
METHODS: Retrospective, multicentre cohort study of children <18 years admitted to the ED with severe TBI and intubated for >48 hours from 2007 to 2011.
RESULTS: Two hundred and twenty-four children had severe TBI and 75% underwent either ED, operating room (OR) or paediatric intensive care unit (PICU) ICP monitor placement. Four out of five centres placed ICP monitors in the ED, mostly (83%) fibreoptic. Nearly 40% of the patients who received ICP monitors get it placed in the ED (29% overall). Factors associated with ED ICP monitor placement were as follows: age 13 to <18 year olds compared to infants (aRR 2.02; 95% CI 1.37, 2.98), longer ED length of stay (LOS) (aRR 1.15; 95% CI 1.08, 1.21), trauma centre designation paediatric only I/II compared to adult/paediatric I/II (aRR 1.71; 95% CI 1.48, 1.98) and higher mean paediatric TBI patient volume (aRR 1.88;95% CI 1.68, 2.11). Adjusted for centre, higher bedside ED staff was associated with longer ED LOS (aRR 2.10; 95% CI 1.06, 4.14).
CONCLUSION: ICP monitors are frequently placed in the ED at paediatric trauma centres caring for children with severe TBI. Both patient and organizational level factors are associated with ED ICP monitor placement.

PMID: 28829632 [PubMed - indexed for MEDLINE]

An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12.

Sci Rep. 2018 07 02;8(1):9939

Authors: Keasar C, McGuffin LJ, Wallner B, Chopra G, Adhikari B, Bhattacharya D, Blake L, Bortot LO, Cao R, Dhanasekaran BK, Dimas I, Faccioli RA, Faraggi E, Ganzynkowicz R, Ghosh S, Ghosh S, Giełdoń A, Golon L, He Y, Heo L, Hou J, Khan M, Khatib F, Khoury GA, Kieslich C, Kim DE, Krupa P, Lee GR, Li H, Li J, Lipska A, Liwo A, Maghrabi AHA, Mirdita M, Mirzaei S, Mozolewska MA, Onel M, Ovchinnikov S, Shah A, Shah U, Sidi T, Sieradzan AK, Ślusarz M, Ślusarz R, Smadbeck J, Tamamis P, Trieber N, Wirecki T, Yin Y, Zhang Y, Bacardit J, Baranowski M, Chapman N, Cooper S, Defelicibus A, Flatten J, Koepnick B, Popović Z, Zaborowski B, Baker D, Cheng J, Czaplewski C, Delbem ACB, Floudas C, Kloczkowski A, Ołdziej S, Levitt M, Scheraga H, Seok C, Söding J, Vishveshwara S, Xu D, Foldit Players consortium, Crivelli SN

Abstract
Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort called WeFold, was initiated to promote collaboration within the CASP community and attract researchers from other fields to contribute new ideas to CASP. Members of the WeFold coopetition (cooperation and competition) participated in CASP as individual teams, but also shared components of their methods to create hybrid pipelines and actively contributed to this effort. We assert that the scale and diversity of integrative prediction pipelines could not have been achieved by any individual lab or even by any collaboration among a few partners. The models contributed by the participating groups and generated by the pipelines are publicly available at the WeFold website providing a wealth of data that remains to be tapped. Here, we analyze the results of the 2014 and 2016 pipelines showing improvements according to the CASP assessment as well as areas that require further adjustments and research.

PMID: 29967418 [PubMed - indexed for MEDLINE]

Examining Emergency Department Treatment Processes in Severe Pediatric Traumatic Brain Injury.

J Healthc Qual. 2017 Nov/Dec;39(6):334-344

Authors: Ajdari A, Boyle LN, Kannan N, Rowhani-Rahbar A, Wang J, Mink R, Ries B, Wainwright M, Groner JI, Bell MJ, Giza C, Zatzick DF, Ellenbogen RG, Mitchell PH, Rivara FP, Vavilala MS

Abstract
BACKGROUND: In the treatment of pediatric traumatic brain injury (TBI), timely treatment of patients can affect the outcome. Our objectives were to examine the treatment process of acute pediatric TBI and the impact of non-value-added time (NVAT) on patient outcomes.
METHODS: Data for 136 pediatric trauma patients (age < 18 years) with severe TBI from 2 trauma centers in the United States were collected. A process flow and value stream map identified NVATs and their sources in the treatment process. Cluster and regression analysis were used to examine the relationship between NVAT, as a percentage of the patient's length of stay (LOS), and the patient outcome, measured by their corresponding Glasgow outcome scale.
RESULTS: There were 14 distinct sources of NVAT identified. A regression analysis showed that increased NVAT was associated with less favorable outcomes (relative ratio = 1.015, confidence interval = [1.002-1.029]). Specifically, 1% increase in the NVAT-to-LOS ratio was associated with a 1.5% increase in the chance of a less favorable outcome (i.e., death or vegetative state).
CONCLUSION: The NVAT has a significant impact on the outcome of pediatric TBI, and every minute spent on performing non-value-added processes can lead to an increase in the likelihood of less favorable outcomes.

PMID: 28166114 [PubMed - indexed for MEDLINE]

Pd-Catalyzed Suzuki-Miyaura and Hiyama-Denmark Couplings of Aryl Sulfamates.

Org Lett. 2016 11 18;18(22):5784-5787

Authors: Melvin PR, Hazari N, Beromi MM, Shah HP, Williams MJ

Abstract
Using a recently discovered precatalyst, the first Pd-catalyzed Suzuki-Miyaura reactions using aryl sulfamates that occur at room temperature are reported. In complementary work, it is demonstrated that a related precatalyst can facilitate the coupling of aryl silanolates, which are less toxic and reactive nucleophiles than boronic acids with aryl chlorides. By combining our results using modern electrophiles and nucleophiles, the first Hiyama-Denmark reactions using aryl sulfamates are reported.

PMID: 27808517 [PubMed - indexed for MEDLINE]

Corticospinal tract atrophy and motor fMRI predict motor preservation after functional cerebral hemispherectomy.

J Neurosurg Pediatr. 2018 01;21(1):81-89

Authors: Wang AC, Ibrahim GM, Poliakov AV, Wang PI, Fallah A, Mathern GW, Buckley RT, Collins K, Weil AG, Shurtleff HA, Warner MH, Perez FA, Shaw DW, Wright JN, Saneto RP, Novotny EJ, Lee A, Browd SR, Ojemann JG

Abstract
OBJECTIVE The potential loss of motor function after cerebral hemispherectomy is a common cause of anguish for patients, their families, and their physicians. The deficits these patients face are individually unique, but as a whole they provide a framework to understand the mechanisms underlying cortical reorganization of motor function. This study investigated whether preoperative functional MRI (fMRI) and diffusion tensor imaging (DTI) could predict the postoperative preservation of hand motor function. METHODS Thirteen independent reviewers analyzed sensorimotor fMRI and colored fractional anisotropy (CoFA)-DTI maps in 25 patients undergoing functional hemispherectomy for treatment of intractable seizures. Pre- and postoperative gross hand motor function were categorized and correlated with fMRI and DTI findings, specifically, abnormally located motor activation on fMRI and corticospinal tract atrophy on DTI. RESULTS Normal sensorimotor cortical activation on preoperative fMRI was significantly associated with severe decline in postoperative motor function, demonstrating 92.9% sensitivity (95% CI 0.661-0.998) and 100% specificity (95% CI 0.715-1.00). Bilaterally robust, symmetric corticospinal tracts on CoFA-DTI maps were significantly associated with severe postoperative motor decline, demonstrating 85.7% sensitivity (95% CI 0.572-0.982) and 100% specificity (95% CI 0.715-1.00). Interpreting the fMR images, the reviewers achieved a Fleiss' kappa coefficient (κ) for interrater agreement of κ = 0.69, indicating good agreement (p < 0.01). When interpreting the CoFA-DTI maps, the reviewers achieved κ = 0.64, again indicating good agreement (p < 0.01). CONCLUSIONS Functional hemispherectomy offers a high potential for seizure freedom without debilitating functional deficits in certain instances. Patients likely to retain preoperative motor function can be identified prior to hemispherectomy, where fMRI or DTI suggests that cortical reorganization of motor function has occurred prior to the operation.

PMID: 29099351 [PubMed - indexed for MEDLINE]

Skill not athleticism predicts individual variation in match performance of soccer players.

Proc Biol Sci. 2017 Dec 13;284(1868):

Authors: Wilson RS, David GK, Murphy SC, Angilletta MJ, Niehaus AC, Hunter AH, Smith MD

Abstract
Just as evolutionary biologists endeavour to link phenotypes to fitness, sport scientists try to identify traits that determine athlete success. Both disciplines would benefit from collaboration, and to illustrate this, we used an analytical approach common to evolutionary biology to isolate the phenotypes that promote success in soccer, a complex activity of humans played in nearly every modern society. Using path analysis, we quantified the relationships among morphology, balance, skill, athleticism and performance of soccer players. We focused on performance in two complex motor activities: a simple game of soccer tennis (1 on 1), and a standard soccer match (11 on 11). In both contests, players with greater skill and balance were more likely to perform better. However, maximal athletic ability was not associated with success in a game. A social network analysis revealed that skill also predicted movement. The relationships between phenotypes and success during individual and team sports have potential implications for how selection acts on these phenotypes, in humans and other species, and thus should ultimately interest evolutionary biologists. Hence, we propose a field of evolutionary sports science that lies at the nexus of evolutionary biology and sports science. This would allow biologists to take advantage of the staggering quantity of data on performance in sporting events to answer evolutionary questions that are more difficult to answer for other species. In return, sports scientists could benefit from the theoretical framework developed to study natural selection in non-human species.

PMID: 29187623 [PubMed - indexed for MEDLINE]

von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury.

Blood. 2018 09 06;132(10):1075-1084

Authors: Wu Y, Liu W, Zhou Y, Hilton T, Zhao Z, Liu W, Wang M, Yeon J, Houck K, Thiagarajan P, Zhang F, Shi FD, Wu X, Li M, Dong JF, Zhang J

Abstract
von Willebrand factor (VWF) is an adhesive ligand, and its activity is proteolytically regulated by the metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat 13). An elevated level of plasma VWF has been widely considered a marker for endothelial cell activation in trauma and inflammation, but its causal role in these pathological conditions remains poorly defined. Using a fluid percussion injury mouse model, we demonstrated that VWF released during acute traumatic brain injury (TBI) was activated and became microvesicle-bound. The VWF-bound microvesicles promoted vascular leakage and systemic coagulation. Recombinant ADAMTS-13 given either before or after TBI reduced the VWF reactivity with minimal influence on VWF secretion. rADAMTS-13 protected the integrity of endothelial cell barriers and prevented TBI-induced coagulopathy by enhancing VWF cleavage without impairing basal hemostasis. Promoting microvesicle clearance by lactadherin had efficacy similar to that of rADAMTS-13. This study uncovers a novel synergistic action between VWF and cellular microvesicles in TBI-induced vascular leakage and coagulopathy and demonstrates protective effects of rADAMTS-13.

PMID: 29941674 [PubMed - indexed for MEDLINE]

A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma Identifies Driver Functions in Addition to NF-κB.

Cell Rep. 2018 06 26;23(13):3787-3797

Authors: Ozawa T, Arora S, Szulzewsky F, Juric-Sekhar G, Miyajima Y, Bolouri H, Yasui Y, Barber J, Kupp R, Dalton J, Jones TS, Nakada M, Kumabe T, Ellison DW, Gilbertson RJ, Holland EC

Abstract
The majority of supratentorial ependymomas (ST-ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between C11orf95 and RELA (RELAFUS). Neural stem cells transduced with RELAFUSex vivo form ependymomas when implanted in the brain. These tumors display enhanced NF-κB signaling, suggesting that this aberrant signal is the principal mechanism of oncogenesis. However, it is not known whether RELAFUS is sufficient to drive de novo ependymoma tumorigenesis in the brain and, if so, whether these tumors also arise from neural stem cells. We show that RELAFUS drives ST-ependymoma formation from periventricular neural stem cells in mice and that RELAFUS-induced tumorigenesis is likely dependent on a series of cell signaling pathways in addition to NF-κB.

PMID: 29949764 [PubMed - indexed for MEDLINE]

Identification and characterization of two novel alternatively spliced E2F1 transcripts in the rat CNS.

Mol Cell Neurosci. 2018 10;92:1-11

Authors: Jackson DP, Ting JH, Pozniak PD, Meurice C, Schleidt SS, Dao A, Lee AH, Klinman E, Jordan-Sciutto KL

Abstract
E2F1 is a transcription factor classically known to regulate G0/G1 to S phase progression in the cell cycle. In addition, E2F1 also regulates a wide range of apoptotic genes and thus has been well studied in the context of neuronal death and neurodegenerative diseases. However, its function and regulation in the mature central nervous system are not well understood. Alternative splicing is a well-conserved post-transcriptional mechanism common in cells of the CNS and is necessary to generate diverse functional modifications to RNA or protein products from genes. Heretofore, physiologically significant alternatively spliced E2F1 transcripts have not been reported. In the present study, we report the identification of two novel alternatively spliced E2F1 transcripts: E2F1b, an E2F1 transcript retaining intron 5, and E2F1c, an E2F1 transcript excluding exon 6. These alternatively spliced transcripts are observed in the brain and neural cell types including neurons, astrocytes, and undifferentiated oligodendrocytes. The expression of these E2F1 transcripts is distinct during maturation of primary hippocampal neuroglial cells. Pharmacologically-induced global translation inhibition with cycloheximide, anisomycin or thapsigargin lead to significantly reduced expression of E2F1a, E2F1b and E2F1c. Conversely, increasing neuronal activity by elevating the concentration of potassium chloride selectively increased the expression of E2F1b. Furthermore, experiments expressing these variants in vitro show the transcripts can be translated to generate a protein product. Taken together, our data suggest that the alternatively spliced E2F1 transcript behave differently than the E2F1a transcript, and our results provide a foundation for future investigation of the function of E2F1 splice variants in the CNS.

PMID: 29936143 [PubMed - indexed for MEDLINE]

Angiographic perfusion imaging of intracranial stenting.

J Clin Neurosci. 2018 Feb;48:100-102

Authors: Ene CI, Morton RP, Kelly CM, Levitt MR, Ghodke B

Abstract
Two-dimensional angiographic perfusion imaging (2DAP) is a new technique permitting perfusion imaging during angiography, and has been used to study cerebral vasospasm. Here we report our experience with this technique following angioplasty and stent placement in a patient with symptomatic and medically refractory stenosis of the right supraclinoid internal carotid artery. We found that intraprocedural angiographic perfusion imaging provided real-time and objective evidence of improved cerebral perfusion during intervention. Following treatment, the patient remains symptom-free at last follow-up.

PMID: 29183679 [PubMed - indexed for MEDLINE]