Faculty Bibliography

PURPOSE/OBJECTIVE:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. EXPERIMENTAL DESIGN/METHODS:To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples and xenograft models. RESULTS:We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. CONCLUSIONS:These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.

OBJECTIVE:To determine whether CSF biomarkers can be used as a predictor of freezing of gait (FOG) in Parkinson disease (PD) and to investigate the predictive value of clinical, dopamine transporter (DAT) imaging, and CSF parameters both separately and in combination. METHODS:to total tau at baseline. Demographic and clinical data and DAT imaging results were also investigated. Cox proportional-hazards regression analyses were performed to identify the factors predictive of FOG. From these results, we constructed a predictive model for the development of FOG. RESULTS:achieved a better discriminative ability (area under the curve 0.755, 95% CI 0.700-0.810) than any factor alone. CONCLUSION/CONCLUSIONS:to be a predictor of FOG in patients with early PD. Furthermore, the development of FOG within 4 years after diagnosis of PD can be predicted with acceptable accuracy with our risk model.

Background and Purpose/UNASSIGNED:Use of emergency medical services (EMS) is associated with decreased door-to-needle time in acute ischemic stroke (AIS). Whether patient language affects EMS utilization and prenotification in AIS has been understudied. We sought to characterize EMS use and prenotification by patient language among intravenous tissue plasminogen activator (IV-tPA) tissue plasminogen (IV-tPA) treated patients at a single center with a large Spanish-speaking patient population. Methods/UNASSIGNED:We performed a retrospective analysis of all patients who received IV-tPA in our emergency department between July 2011 and June 2016. Baseline characteristics, EMS use, and prenotification were compared between English- and Spanish-speaking patients. Logistic regression was used to measure the association between patient language and EMS use. Results/UNASSIGNED:= .8). In a multivariable model adjusted for age, sex, and NIHSS, Spanish speakers remained more likely to use EMS (odds ratio: 1.8, 95% confidence interval: 1.1-3.0). Conclusion/UNASSIGNED:Emergency medical services usage was higher in Spanish speakers compared to English speakers among AIS patients treated with IV-tPA; however, prenotification rates did not differ. Future studies should evaluate differences in EMS utilization according to primary language and ethnicity.

BACKGROUND AND PURPOSE/OBJECTIVE:Pediatric-onset multiple sclerosis (POMS) is a demyelinating disorder with unique clinical challenges. A brief computer-administered cognitive screening battery measuring processing speed (Cogstate) and the Brief International Cognitive Assessment in MS (BICAMS) detect cognitive impairment in POMS. The neuroanatomic correlates of these deficits are incompletely understood. The purpose of this study is to define the neuroanatomic underpinnings of deficits identified with cognitive screening batteries in POMS. METHODS:Participants with POMS and age-matched healthy controls (HCs) were screened with Cogstate and BICAMS. Diffusion tensor imaging assessed region-wise and tractography-based fractional anisotropy (FA). RESULTS:The POMS (n = 15) and HC (n = 21) groups were matched on age (mean ages 17.9 ± 3.2 vs. 17.8 ± 3.3 years, respectively) and on an estimate of general intellectual functioning. The Cogstate composite revealed significant slowing in POMS relative to HCs (P = .004), but the BICAMS composite did not significantly distinguish the groups (P = .10). The Cogstate composite showed moderate-to-strong correlations with regional FA (r = -.67 to -.82) and significantly associated with uncinate fasciculus FA following multiple comparisons correction (P = .002) in POMS. However, the BICAMS composite measure showed only weak-to-moderate correlations with FA in POMS (r = -.19 to -.57), with none surviving multiple comparisons correction. CONCLUSIONS:Computer-administered measures of cognitive processing are particularly sensitive in POMS and are closely linked to white matter FA.

Objective:Traditional neurology teaching states that when mean arterial pressure dips below a 60 mm Hg threshold, there is an increase in stroke risk due to cerebral hypoperfusion. The aim of this study was to determine whether intensive lowering of systolic blood pressure increases adverse cardiovascular outcomes by examining the association between achieved blood pressure values, specifically mean arterial pressure and pulse pressure, and risk of stroke. Methods:Data from participants in the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure (BP) trial were examined, using survival analysis to model minimal arterial pressure and average pulse pressure during the study period against risk of stroke, hypotension, and syncope, with death as a competing risk. Results:In both SPRINT and ACCORD participants, there was no increase in stroke risk with achieved mean arterial pressure values below 60 mm Hg. In SPRINT participants, achieved mean arterial pressure values greater than 90 mm Hg were associated with a 247% (HR: 3.47, 95% CI: 2.06-5.85) higher risk of stroke compared with participants in the 80-89 mmHg reference group. No association was found between low achieved pulse pressure values and greater stroke risk in either the SPRINT or ACCORD participants, as well as no association between mean arterial pressure and pulse pressure values and risk of syncope. Interpretation:Intensive lowering of systolic blood pressure does not increase risk of stroke in hypertensive patients, despite extremely low mean arterial pressure or pulse pressure values.

Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in Gba^L444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo. The link between heterozygous GBA mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous GBA mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with GBA heterozygous mutations. Abbreviations: AMBRA1: autophagy/beclin 1 regulator 1; BECN1: beclin 1, autophagy related; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chloroyphenylhydrazone; CYCS: cytochrome c, somatic; DNM1L/DRP1: dynamin 1-like; ER: endoplasmic reticulum; GBA: glucosylceramidase beta; GBA-PD: Parkinson disease with heterozygous GBA mutations; GD: Gaucher disease; GFP: green fluorescent protein; LC3B: microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated form of microtubule-associated protein 1 light chain 3 beta; MitoGreen: MitoTracker Green; MitoRed: MitoTracker Red; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH transcription factor; NBR1: NBR1, autophagy cargo receptor; Non-GBA-PD: Parkinson disease without GBA mutations; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; ROS: reactive oxygen species; SNCA: synuclein alpha; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1/Porin: voltage dependent anion channel 1; WT: wild type.

Introduction/UNASSIGNED:There is practice variability in the treatment of patients with minor ischemic stroke with thrombolysis. We sought to determine which clinical factors physicians prioritize in thrombolysis decision-making for minor stroke using adaptive conjoint analysis. Methods/UNASSIGNED:tests. Statistical significance was set at α = .05. Results/UNASSIGNED:Fifty-four participants completed the survey; 61% were vascular neurologists and 93% worked in academic centers. All neurological deficits were ranked higher than age, premorbid status, or potential contraindications to thrombolysis. Differences between each successive mean preference weight were significant: motor (31.7%, standard deviation [SD]: 9.5), language/speech (24.1%, SD: 9.6), other neurological deficits (16.6%, SD: 6.4), premorbid status (12.9%, SD: 6.6), age (10.1%, SD: 6.3), and potential thrombolysis contraindication (4.7%, SD: 4.4). Conclusion/UNASSIGNED:In a conjoint analysis, surveyed US physicians in academic practice assigned greater weight to motor and speech/language deficits than other neurological deficits, patient age, relative contraindications to thrombolysis, and premorbid disability when deciding to thrombolyse patients with minor stroke.