Publications by authors named "Thomas A Kent"

86 Publications

Sonothrombolysis in Patients With Acute Ischemic Stroke With Large Vessel Occlusion: An Individual Patient Data Meta-Analysis.

Stroke 2021 Aug 25:STROKEAHA120030960. Epub 2021 Aug 25.

Department of Neurology, University of Tennessee Health Sciences Center, Memphis (G.T., A.W.A., A.V.A.).

Background And Purpose: Evidence about the utility of ultrasound-enhanced thrombolysis (sonothrombolysis) in patients with acute ischemic stroke (AIS) is conflicting. We aimed to evaluate the safety and efficacy of sonothrombolysis in patients with AIS with large vessel occlusion, by analyzing individual patient data of available randomized-controlled clinical trials.

Methods: We included all available randomized-controlled clinical trials comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in patients with AIS with large vessel occlusion. The primary outcome measure was the rate of complete recanalization at 1 to 36 hours following intravenous thrombolysis initiation. We present crude odds ratios (ORs) and ORs adjusted for the predefined variables of age, sex, baseline stroke severity, systolic blood pressure, and onset-to-treatment time.

Results: We included 7 randomized controlled clinical trials that enrolled 1102 patients with AIS. A total of 138 and 134 confirmed large vessel occlusion patients were randomized to treatment and control groups respectively. Patients randomized to sonothrombolysis had increased odds of complete recanalization compared with patients receiving intravenous thrombolysis alone (40.3% versus 22.4%; OR, 2.17 [95% CI, 1.03-4.54]; adjusted OR, 2.33 [95% CI, 1.02-5.34]). The likelihood of symptomatic intracranial hemorrhage was not significantly different between the 2 groups (7.3% versus 3.7%; OR, 2.03 [95% CI, 0.68-6.11]; adjusted OR, 2.55 [95% CI, 0.76-8.52]). No differences in the likelihood of asymptomatic intracranial hemorrhage, 3-month favorable functional and 3-month functional independence were documented.

Conclusions: Sonothrombolysis was associated with a nearly 2-fold increase in the odds of complete recanalization compared with intravenous thrombolysis alone in patients with AIS with large vessel occlusions. Further study of the safety and efficacy of sonothrombolysis is warranted.
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http://dx.doi.org/10.1161/STROKEAHA.120.030960DOI Listing
August 2021

The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke.

Transl Stroke Res 2021 Feb 24. Epub 2021 Feb 24.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, 199 Ren-Ai Road, Suzhou, 215123, Jiangsu, China.

Necroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar.
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http://dx.doi.org/10.1007/s12975-021-00888-3DOI Listing
February 2021

The Chemical Basis of Intracerebral Hemorrhage and Cell Toxicity With Contributions From Eryptosis and Ferroptosis.

Front Cell Neurosci 2020 8;14:603043. Epub 2020 Dec 8.

Center for Genomics and Precision Medicine, Department of Translational Medical Sciences, Institute of Biosciences and Technology, College of Medicine, Texas A&M Health Science Center, Houston, TX, United States.

Intracerebral hemorrhage (ICH) is a particularly devastating event both because of the direct injury from space-occupying blood to the sequelae of the brain exposed to free blood components from which it is normally protected. Not surprisingly, the usual metabolic and energy pathways are overwhelmed in this situation. In this review article, we detail the complexity of red blood cell degradation, the contribution of eryptosis leading to hemoglobin breakdown into its constituents, the participants in that process, and the points at which injury can be propagated such as elaboration of toxic radicals through the metabolism of the breakdown products. Two prominent products of this breakdown sequence, hemin, and iron, induce a variety of pathologies including free radical damage and DNA breakage, which appear to include events independent from typical oxidative DNA injury. As a result of this confluence of damaging elements, multiple pathways of injury, cell death, and survival are likely engaged including ferroptosis (which may be the same as oxytosis but viewed from a different perspective) and senescence, suggesting that targeting any single cause will likely not be a sufficient strategy to maximally improve outcome. Combination therapies in addition to safe methods to reduce blood burden should be pursued.
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http://dx.doi.org/10.3389/fncel.2020.603043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755086PMC
December 2020

Lone Star Stroke Consortium: A Collaborative State-Funded Model for Research.

Stroke 2020 12 29;51(12):3778-3786. Epub 2020 Oct 29.

Department of Neurology, Dell Medical School, The University of Texas at Austin (S.J.W.).

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http://dx.doi.org/10.1161/STROKEAHA.120.031547DOI Listing
December 2020

Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.

J Hypertens 2021 02;39(2):266-272

Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Objective: To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA).

Methods: We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER.

Results: The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53).

Conclusion: BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.
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http://dx.doi.org/10.1097/HJH.0000000000002628DOI Listing
February 2021

Manage Emotions to Reduce Aggression: A Pilot Study of a Brief Treatment to Help Veterans Reduce Impulsive Aggression.

J Nerv Ment Dis 2020 11;208(11):897-903

Hope and Healing Center & Institute, Houston.

Veterans with posttraumatic stress disorder (PTSD) report more aggression than civilians with PTSD. Because emotion regulation difficulties mediated the relationship between PTSD symptoms and impulsive aggression in veterans, we developed an intervention to increase emotion regulation skills. This pilot study tested the feasibility and acceptability of a three-session treatment, Manage Emotions to Reduce Aggression (MERA), and examined its effectiveness at reducing aggression and emotion dysregulation. Male combat veterans with PTSD and impulsive aggression completed assessments before and 4 weeks after MERA. Overt Aggression Scale measured frequency of aggression; Difficulties in Emotion Regulation Scale assessed emotion dysregulation. Most veterans (95%) who completed MERA and the posttreatment assessment (n = 20) reported MERA was helpful. Veterans in the intent-to-treat sample demonstrated a significant decrease in their frequency of aggression (Cohen's d = -0.55) and emotion dysregulation (Cohen's d = -0.55). MERA may be an innovative treatment that helps veterans reduce aggression.
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http://dx.doi.org/10.1097/NMD.0000000000001229DOI Listing
November 2020

Pervasive Genomic Damage in Experimental Intracerebral Hemorrhage: Therapeutic Potential of a Mechanistic-Based Carbon Nanoparticle.

ACS Nano 2020 03 21;14(3):2827-2846. Epub 2020 Feb 21.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States.

Therapy for intracerebral hemorrhage (ICH) remains elusive, in part dependent on the severity of the hemorrhage itself as well as multiple deleterious effects of blood and its breakdown products such as hemin and free iron. While oxidative injury and genomic damage have been seen following ICH, the details of this injury and implications remain unclear. Here, we discovered that, while free iron produced mostly reactive oxygen species (ROS)-related single-strand DNA breaks, hemin unexpectedly induced rapid and persistent nuclear and mitochondrial double-strand breaks (DSBs) in neuronal and endothelial cell genomes and in mouse brains following experimental ICH comparable to that seen with γ radiation and DNA-complexing chemotherapies. Potentially as a result of persistent DSBs and the DNA damage response, hemin also resulted in senescence phenotype in cultured neurons and endothelial cells. Subsequent resistance to ferroptosis reported in other senescent cell types was also observed here in neurons. While antioxidant therapy prevented senescence, cells became sensitized to ferroptosis. To address both senescence and resistance to ferroptosis, we synthesized a modified, catalytic, and rapidly internalized carbon nanomaterial, poly(ethylene glycol)-conjugated hydrophilic carbon clusters (PEG-HCC) by covalently bonding the iron chelator, deferoxamine (DEF). This multifunctional nanoparticle, DEF-HCC-PEG, protected cells from both senescence and ferroptosis and restored nuclear and mitochondrial genome integrity and . We thus describe a potential molecular mechanism of hemin/iron-induced toxicity in ICH that involves a rapid induction of DSBs, senescence, and the consequent resistance to ferroptosis and provide a mechanistic-based combinatorial therapeutic strategy.
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http://dx.doi.org/10.1021/acsnano.9b05821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850811PMC
March 2020

Use of a bioengineered antioxidant in mouse models of metabolic syndrome.

Expert Opin Investig Drugs 2020 Feb 20;29(2):209-219. Epub 2020 Jan 20.

Interdepartmental Program in Translation Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.

: Oxidative stress has been implicated in metabolic syndrome (MetS); however, antioxidants such as vitamin E have had limited success in the clinic. This prompts the question of what effects amore potent antioxidant might produce. A prime candidate is the recently developed bioengineered antioxidant, poly(ethylene glycol)-functionalizedhydrophilic carbon clusters (PEG-HCCs), which are capable of neutralizing the reactive oxygen species (ROS) superoxide anion and hydroxyl radical at10/molecule of PEG-HCC. In this project, we tested the potential of PEG-HCCs as a possible therapeutic for MetS.: PEG-HCC treatment lessened lipid peroxidation, aspartate aminotransferase levels, non-fastingblood glucose levels, and JNK phosphorylation inob/ob mice. PEG-HCC-treated WT mice had an increased response to insulin by insulin tolerance tests and adecrease in blood glucose by glucose tolerance tests. These effects were not observed in HFD-fed mice, regardless of treatment. PEG-HCCs were observed in the interstitial space of liver, spleen, skeletal muscle, and adipose tissue. No significant difference was shown in gluconeogenesis or inflammatory gene expression between treatment and dietary groups.: PEG-HCCs improved some parameters of disease possibly due to a resulting increase in peripheral insulin sensitivity. However, additional studies are needed to elucidate how PEG-HCCsare producing these effects.
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http://dx.doi.org/10.1080/13543784.2020.1716216DOI Listing
February 2020

Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer's disease from a ferroptosis perspective.

Prog Neurobiol 2020 01 8;184:101716. Epub 2019 Oct 8.

Center for Genomics and Precision Medicine, Institute of Biosciences and Technology, College of Medicine, Texas A&M Health Science Center, Houston, TX, United States; Department of Chemistry, Rice University, Houston, TX, United States; Stanley H. Appel Department of Neurology, Houston Methodist Hospital, Houston, TX, United States. Electronic address:

The complexity of Alzheimer's disease (AD) complicates the search for effective treatments. While the key roles of pathologically modified proteins has occupied a central role in hypotheses of the pathophysiology, less attention has been paid to the potential role for transition metals overload, subsequent oxidative stress, and tissue injury. The association of transition metals, the major focus heretofore iron and amyloid, the same can now be said for the likely pathogenic microtubular associated tau (MAPT). This review discusses the interplay between iron, pathologically modified tau and oxidative stress, and connects many related discoveries. Basic principles of the transition to pathological MAPT are discussed. Iron, its homeostatic mechanisms, the recently described phenomenon of ferroptosis and purported, although still controversial roles in AD are reviewed as well as considerations to overcome existing hurdles of iron-targeted therapeutic avenues that have been attempted in AD. We summarize the involvement of multiple pathological pathways at different disease stages of disease progression that supports the potential for a combinatorial treatment strategy targeting multiple factors.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850812PMC
January 2020

Critical Comparison of the Superoxide Dismutase-like Activity of Carbon Antioxidant Nanozymes by Direct Superoxide Consumption Kinetic Measurements.

ACS Nano 2019 10 17;13(10):11203-11213. Epub 2019 Sep 17.

Division of Hematology, Department of Internal Medicine , University of Texas-McGovern Medical School , 6431 Fannin Street , Houston , Texas 77030 , United States.

The superoxide dismutase-like activity of poly(ethylene glycolated) hydrophilic carbon clusters (PEG-HCCs), anthracite and bituminous graphene quantum dots (PEG-aGQDs and PEG-bGQDs, respectively), and two fullerene carbon nanozymes, tris malonyl-C fullerene (C3) and polyhydroxylated-C fullerene (C-OH), were compared using direct optical stopped-flow kinetic measurements, together with three native superoxide dismutases (SODs), CuZnSOD, MnSOD, and FeSOD, at both pH 12.7 and 8.5. Computer modeling including both SOD catalytic steps and superoxide self-dismutation enabled the best choice of catalyst concentration with minimal contribution to the observed kinetic change from the substrate self-dismutation. Biexponential fitting to the kinetic data ranks the rate constant (M s) in the order of PEG-HCCs > CuZnSOD ≈ MnSOD ≈ PEG-aGQDs ≈ PEG-bGQDs > FeSOD ≫ C3 > C-OH at pH 12.7 and MnSOD > CuZnSOD ≈ PEG-HCCs > FeSOD > PEG-aGQDs ≈ PEG-bGQDs ≫ C3 ≈ C-OH at pH 8.5. Nonlinear regression of the kinetic model above yielded the same ranking as the biexponential fit, but provided better mechanistic insight. The data obtained by freeze-quench EPR direct assay at pH 12.7 also yield the same ranking as stopped-flow data. This is a necessary assessment of a panel of proclaimed carbon nano SOD mimetics using the same two direct methods, revealing a dramatic, 3-4 orders of magnitude difference in SOD activity between PEG-HCCs/PEG-GQDs from soluble fullerenes.
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http://dx.doi.org/10.1021/acsnano.9b04229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832779PMC
October 2019

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke.

Ther Adv Neurol Disord 2019 12;12:1756286419860652. Epub 2019 Jul 12.

Departments of Neurology and Neurogeriatry, John Wesling Medical Center Minden, Ruhr University Bochum, Minden, Germany.

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers.

Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials.

Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06-0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89-1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0-2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01-2.31; p = 0.04).

Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.
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http://dx.doi.org/10.1177/1756286419860652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628520PMC
July 2019

Catalytic oxidation and reduction reactions of hydrophilic carbon clusters with NADH and cytochrome C: features of an electron transport nanozyme.

Nanoscale 2019 Jun;11(22):10791-10807

Texas A&M Health Science Center Institute of Biosciences and Technology, Houston, Texas 77030, USA.

Previously, our group reported on the promising efficacy of poly(ethylene glycol)-hydrophilic carbon clusters (PEG-HCCs) to work as broadly active and high capacity antioxidants in brain ischemia and injury models including stroke and traumatic brain injury coupled with hemorrhagic shock. PEG-HCCs are a carbon nanomaterial derived from harsh oxidation of single wall carbon nanotubes and covalently modified with poly(ethylene glycol). They retain no tubular remnants and are composed of a highly oxidized carbon core functionalized with epoxy, peroxyl, quinone, ketone, carboxylate, and hydroxyl groups. HCCs are the redox active carbon core of PEG-HCCs, which have a broad reduction potential range starting at +200 mV and extending to -2 V. Here we describe a new property of these materials: the ability to catalytically transfer electrons between key surrogates and proteins of the mitochondrial electron transport complex in a catalytic fashion consistent with the concept of a nanozyme. The estimated reduction potential of PEG-HCCs is similar to that of ubiquinone and they enabled the catalytic transfer of electrons from low reduction potential species to higher reduction electron transport complex constituents. PEG-HCCs accelerated the reduction of resazurin (a test indicator of mitochondrial viability) and cytochrome c by NADH and ascorbic acid in solution. Kinetic experiments suggested a transient tertiary complex. Electron paramagnetic resonance demonstrated NADH increased the magnitude of PEG-HCCs' intrinsic radical, which then reduced upon subsequent addition of cytochrome c or resazurin. Deconvolution microscopy identified PEG-HCCs in close proximity to mitochondria after brief incubation with cultured SHSY-5Y human neuroblastoma cells. Compared to methylene blue (MB), considered a prototypical small molecule electron transport shuttle, PEG-HCCs were more protective against toxic effects of hydrogen peroxide in vitro and did not demonstrate impaired cell viability as did MB. PEG-HCCs were protective in vitro when cells were exposed to sodium cyanide, a mitochondrial complex IV poison. Because mitochondria are a major source of free radicals in pathology, we suggest that this newly described nanozyme action helps explain their in vivo efficacy in a range of injury models. These findings may also extend their use to mitochondrial disorders.
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http://dx.doi.org/10.1039/c9nr00807aDOI Listing
June 2019

Highly Oxidized Graphene Quantum Dots from Coal as Efficient Antioxidants.

ACS Appl Mater Interfaces 2019 May 26;11(18):16815-16821. Epub 2019 Apr 26.

Hematology, Internal Medicine . University of Texas McGovern Medical School-Houston , Houston , Texas 77030 , United States.

Graphene quantum dots (GQDs) have recently been employed in various fields including medicine as antioxidants, primarily because of favorable biocompatibility in comparison to common inorganic quantum dots, although the structural features that lead to the biological activities of GQDs are poorly understood. Here, we report that coal-derived GQDs and their poly(ethylene glycol)-functionalized derivatives serve as efficient antioxidants, and we evaluate their electrochemical, chemical, and in vitro biological activities.
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http://dx.doi.org/10.1021/acsami.9b01082DOI Listing
May 2019

Pooled analysis suggests benefit of catheter-based hematoma removal for intracerebral hemorrhage.

Neurology 2019 04 20;92(15):e1688-e1697. Epub 2019 Mar 20.

From the Michael E. DeBakey VA Medical Center Stroke Program (P.M., N.S.) and Analytical Software and Engineering Research Laboratory, Department of Neurology (P.M., N.S., T.A.K.), Baylor College of Medicine, Houston, TX; Department of Neurology (S.B.M.) and Clinical and Translational Neuroscience Unit (S.B.M.), Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY; APHP (Y.S.), Urgences Cerebro-Vasculaire, Pitié-Salpêtrière, and UPMC Paris Sorbonne Universités (Y.S.), Paris, France; Departments of Statistics and Bioengineering (M.K.) and Chemistry (T.A.K.), Rice University, Houston; Institute of Biosciences and Technology (IBT) (T.A.K.), Texas A&M Health Science Center-Houston Campus; and Department of Neurology (T.A.K.), Houston Methodist Hospital and Research Institute, TX.

Objective: To develop models of outcome for intracerebral hemorrhage (ICH) to identify promising and futile interventions based on their early phase results without need for correction for baseline imbalances.

Methods: We developed a pooled outcome model from the control arms of randomized control trials and tested different interventions against the model at comparable baseline conditions. Eligible clinical trials and large case series were identified from multiple library databases. Models based on baseline factors reported in the control arms were tested for the ability to predict functional outcome (modified Rankin Scale score) and mortality. Interventions were grouped into blood pressure control, fibrinolytic-assisted hematoma evacuation, hemostatic medications, and neuroprotective agents. Statistical intervals around the model were generated at the = 0.1 level to screen how each trial's outcome compared to expected outcome.

Results: Fourteen control arms with 3,386 patients were used to develop 7 alternate models for functional outcome. The model incorporating baseline NIH Stroke Scale, age, and hematoma volume yielded the best fit (adjusted = 0.89). All early phase treatments that eventually resulted in negative late phase trials were identified as negative by this method. Early phase fibrinolytic-assisted hematoma evacuation studies showed the most promise trending toward improved functional outcome with no suggestion of an increase in mortality, supporting its further study.

Conclusions: We successfully developed an outcome model for ICH that identified interventions destined to be negative while identifying a promising one. Such an approach may assist in prioritizing resources prior to multicenter trial.
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http://dx.doi.org/10.1212/WNL.0000000000007269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511084PMC
April 2019

Telemedicine in Prehospital Acute Stroke Care: An Expanding Infrastructure for Treatment and Research.

J Am Heart Assoc 2019 03;8(6):e012259

1 Institute of Biosciences and Technology Texas A&M Health Science Center Houston TX.

See Article by Geisler et al.
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http://dx.doi.org/10.1161/JAHA.119.012259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475042PMC
March 2019

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial.

Lancet Neurol 2019 04;18(4):338-347

Departments of Neurology and Neurogeriatry, John Wesling Medical Center Minden, Ruhr University Bochum, Minden, Germany.

Background: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke.

Methods: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility.

Findings: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53).

Interpretation: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care.

Funding: Cerevast Therapeutics.
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http://dx.doi.org/10.1016/S1474-4422(19)30026-2DOI Listing
April 2019

Functional and Structural Improvement with a Catalytic Carbon Nano-Antioxidant in Experimental Traumatic Brain Injury Complicated by Hypotension and Resuscitation.

J Neurotrauma 2019 07 13;36(13):2139-2146. Epub 2019 Mar 13.

2 Department of Chemistry, Rice University, Houston, Texas.

Hypotension worsens outcome after all severities of traumatic brain injury (TBI), with loss of cerebral autoregulation being a potential contributor. Previously, we demonstrated that intravenous injection of a high capacity catalytic antioxidant, poly(ethylene)glycol conjugated hydrophilic carbon clusters (PEG-HCCs) rapidly restored cerebral perfusion and acutely restored brain oxidative balance in a TBI model complicated by hemorrhagic hypotension without evidence of toxicity. Here, we tested whether these acute effects translated into behavioral and structural benefit. TBI was generated by a cortical contusion impactor in 38 Long Evans rats, followed by blood withdrawal to a target mean arterial pressure of 40 mm Hg. PEG-HCC (2 mg/kg) or diluent was injected intravenously 80 min later at the onset of blood resuscitation followed by another injection 2 h later (doses determined in prior studies). Performance on beam walking (performed on days 1-5) and Morris water maze (MWM) (performed on days 11-15) was tested, and lesion size was determined at the termination. PEG-HCC treatment nearly completely prevented motor dysfunction ( < 0.001 vs. diluent), improved MWM performance ( < 0.001; treatment vs. time interaction) and reduced lesion size by 61% ( = 0.054). Here we show that treatment with PEG-HCCs at a clinically realistic time point (onset of resuscitation) prevented a major portion of the neurological dysfunction induced in this TBI model, and that PEG-HCCs are candidates for additional study as a potential therapeutic agent.
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http://dx.doi.org/10.1089/neu.2018.6027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602099PMC
July 2019

Rho Guanine Nucleotide Exchange Factor Is a Risk Gene for Intracranial Aneurysms.

Circ Genom Precis Med 2018 07;11(7):e002099

Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, China (X.Y., Z.Z., Y.Z., M.L., L.H., R.J., S.Y., J.Z., F.Y.).

Background: Intracranial aneurysm (IA) is usually a late-onset disease, affecting 1% to 3% of the general population and leading to life-threatening subarachnoid hemorrhage. Genetic susceptibility has been implicated in IAs, but the causative genes remain elusive.

Methods: We performed next-generation sequencing in a discovery cohort of 20 Chinese IA patients. Bioinformatics filters were exploited to search for candidate deleterious variants with rare and low allele frequency. We further examined the candidate variants in a multiethnic sample collection of 86 whole exome sequenced unsolved familial IA cases from 3 previously published studies.

Results: We identified that the low-frequency variant c.4394C>A_p.Ala1465Asp (rs2298808) of was significantly associated with IA in our Chinese discovery cohort (=7.3×10; odds ratio=7.34). It was subsequently replicated in Japanese familial IA patients (=0.039; odds ratio=4.00; 95% confidence interval=0.832-14.8) and was associated with IA in the large Chinese sample collection comprising 832 sporadic IA-affected and 599 control individuals (=0.041; odds ratio=1.51; 95% confidence interval=1.02-Inf). When combining the sequencing data of all familial IA patients from 4 different ethnicities (ie, Chinese, Japanese, European American, and French-Canadian), we identified a significantly increased mutation burden for (21/106 versus 11/306; =8.1×10; odds ratio=6.6; 95% confidence interval=2.9-15.8) in cases as compared with controls. In zebrafish, was highly expressed in the brain blood vessel. knockdown caused blood extravasation in the brain region. Endothelial lesions were identified exclusively on cerebral blood vessels in the -deficient zebrafish.

Conclusions: Our results provide compelling evidence that is a risk gene for IA.
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http://dx.doi.org/10.1161/CIRCGEN.117.002099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141028PMC
July 2018

Efficacy of Novel Carbon Nanoparticle Antioxidant Therapy in a Severe Model of Reversible Middle Cerebral Artery Stroke in Acutely Hyperglycemic Rats.

Front Neurol 2018 9;9:199. Epub 2018 Apr 9.

Department of Neurology and Center for Translational Research on Inflammatory Diseases, Baylor College of Medicine, Michael E. DeBakey VA Medical Center, Houston, TX, United States.

Introduction: While oxidative stress can be measured during transient cerebral ischemia, antioxidant therapies for ischemic stroke have been clinically unsuccessful. Many antioxidants are limited in their range and/or capacity for quenching radicals and can generate toxic intermediates overwhelming depleted endogenous protection. We developed a new antioxidant class, 40 nm × 2 nm carbon nanoparticles, hydrophilic carbon clusters, conjugated to poly(ethylene glycol) termed PEG-HCCs. These particles are high-capacity superoxide dismutase mimics, are effective against hydroxyl radical, and restore the balance between nitric oxide and superoxide in the vasculature. Here, we report the effects of PEG-HCCs administered during reperfusion after transient middle cerebral artery occlusion (tMCAO) by suture in the rat under hyperglycemic conditions. Hyperglycemia occurs in one-third of stroke patients and worsens clinical outcome. In animal models, this worsening occurs largely by accelerating elaboration of reactive oxygen species (ROS) during reperfusion.

Methods: PEG-HCCs were studied for their protective ability against hydrogen peroxide in b.End3 brain endothelial cell line and E17 primary cortical neuron cultures. , hyperglycemia was induced by streptozotocin injection 2 days before tMCAO. 58 Male Sprague-Dawley rats were analyzed. They were injected IV with PBS or PEG-HCCs (4 mg/kg 2×) at the time of recanalization after either 90- or 120-min occlusion. Rats were survived for up to 3 days, and infarct volume characteristics and neurological functional outcome (modified Bederson Score) were assessed.

Results: PEG-HCCs were protective against hydrogen peroxide in both culture models. improvement was found after PEG-HCCs with 90-min ischemia with reduction in infarct size (42%), hemisphere swelling (46%), hemorrhage score (53%), and improvement in Bederson score (70%) ( = 0.068-0.001). Early high mortality in the 2-h in the PBS control group precluded detailed analysis, but a trend was found in improvement in all factors, e.g., reduction in infarct volume (48%;  = 0.034) and a 56% improvement in Bederson score ( = 0.055) with PEG-HCCs.

Conclusion: This nano-antioxidant showed some improvement in several outcome measures in a severe model of tMCAO when administered at a clinically relevant time point. Long-term studies and additional models are required to assess potential for clinical use, especially for patients hyperglycemic at the time of their stroke, as these patients have the worst outcomes.
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http://dx.doi.org/10.3389/fneur.2018.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900022PMC
April 2018

RIP1K Contributes to Neuronal and Astrocytic Cell Death in Ischemic Stroke via Activating Autophagic-lysosomal Pathway.

Neuroscience 2018 02 8;371:60-74. Epub 2017 Nov 8.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China. Electronic address:

Although the receptor-interacting protein 1 kinase (RIP1K)-regulated necroptosis can be evoked by cerebral ischemia, the effects of RIP1K in mediating neuronal and astrocytic cell death and the underlying mechanisms remain poorly understood. This study evaluates the contribution of RIP1K to ischemic stroke-induced neuronal and astrocytic cell death, and the activation of autophagic-lysosomal pathway. Using an in vitro oxygen and glucose deprivation (OGD) in primary cultured neurons or astrocytes and a permanent middle cerebral artery occlusion (pMCAO) model in rats or mice, we observed the role of RIP1K in the ischemic neuronal and astrocytic cell death and the underlying mechanisms by pharmacological or genetic inhibition of RIP1K. pMCAO or OGD condition led to an increase in RIP1K, RIP3K and RIP1K-RIP3K complex. RIP1K knockdown or necrostatin-1 (Nec-1, a specific inhibitor of RIP1K) treatment reduced infarct volume, improved neurological deficits, increased microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP) levels, and attenuated neuronal or astrocytic necrotic cell death in the ischemic cortex. RIP1K knockdown decreased RIP1K-RIP3K complex formation, light chain 3 II (LC3II) and active cathepsin B levels and lysosomal membrane permeability (LMP). Furthermore, a combination of Nec-1 and an inhibitor of autophagy or cathepsin B produced an enhancement of protective effect on neuronal or astrocytic cell death. RIP1K-mediated necroptosis may play important roles in ischemia-induced neuronal and astrocytic cell death through the activation of autophagic-lysosomal pathway.
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http://dx.doi.org/10.1016/j.neuroscience.2017.10.038DOI Listing
February 2018

Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma.

Neuro Oncol 2018 01;20(1):113-122

The University of Texas MD Anderson Cancer Center, Department of Neuro-Oncology, Houston, Texas, USA.

Background: Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials.

Methods: A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative.

Results: Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care.

Conclusion: The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.
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http://dx.doi.org/10.1093/neuonc/nox144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761583PMC
January 2018

Correlating quantitative susceptibility mapping with cognitive decline in Alzheimer's disease.

Brain 2017 08;140(8):2069-2072

Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.

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http://dx.doi.org/10.1093/brain/awx167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669403PMC
August 2017

Sevoflurane postconditioning attenuates reactive astrogliosis and glial scar formation after ischemia-reperfusion brain injury.

Neuroscience 2017 07 10;356:125-141. Epub 2017 May 10.

Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China. Electronic address:

Cerebral ischemia leads to astrocyte's activation and glial scar formation. Glial scar can inhibit axonal regeneration during the recovery phase. It has demonstrated that sevoflurane has neuroprotective effects against ischemic stroke, but its effects on ischemia-induced formation of astrogliosis and glial scar are unknown. This study was designed to investigate the effect of sevoflurane postconditioning on astrogliosis and glial scar formation in ischemic stroke model both in vivo and in vitro. The results showed that 2.5% of sevoflurane postconditioning could significantly reduce infarction volume and improve neurologic deficits. And it could also decrease the expression of the glial scar marker glial fibrillary acidic protein (GFAP), neurocan and phosphacan in the peri-infarct region and markedly reduce the thickness of glial scar after ischemia/reperfusion (I/R). Consistent with the in vivo data, in the oxygen and glucose deprivation/reoxygenation (OGD/Re) model, sevoflurane postconditioning could protect astrocyte against OGD/Re-induced injury, decrease the expression of GFAP, neurocan and phosphacan. Further studies demonstrated that sevoflurane postconditioning could down-regulate the expression of Lamp1 and active cathepsin B, and block I/R or OGD/Re-induced release of cathepsin B from the lysosomes into cytoplasm. In order to confirm whether inhibition of cathepsin B could attenuate the formation of glial scar, we used cathepsin B inhibitor CA-074Me as a positive control. The results showed that inhibition of cathepsin B could decrease the expression of GFAP, neurocan and phosphacan. Taken together, sevoflurane postconditioning can attenuate astrogliosis and glial scar formation after ischemic stroke, associating with inhibition of the activation and release of lysosomal cathepsin B.
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http://dx.doi.org/10.1016/j.neuroscience.2017.05.004DOI Listing
July 2017

Inhibition of autophagy blocks cathepsins-tBid-mitochondrial apoptotic signaling pathway via stabilization of lysosomal membrane in ischemic astrocytes.

Cell Death Dis 2017 02 16;8(2):e2618. Epub 2017 Feb 16.

Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science; Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China.

Our previous study and others have demonstrated that autophagy is activated in ischemic astrocytes and contributes to astrocytic cell death. However, the mechanisms of ischemia-induced autophagy remain largely unknown. In this study, we established a rat's model of permanent middle cerebral artery occlusion (pMCAO) and an in vitro oxygen and glucose deprivation (OGD) model. Autophagy was inhibited by either pharmacological treatment with 3-methyladenine (3-MA) and wortmannin (Wort) or genetic treatment with knockdown of Atg5 in primary cultured astrocytes and knockout of Atg5 in mouse embryonic fibroblast (MEF) cells, respectively. We found that pharmacological or genetic inhibition of autophagy reversed pMCAO or OGD-induced increase in LC3-II, active cathepsin B and L, tBid, active caspase-3 and cytoplastic cytochrome c (Cyt-c), and suppressed the injury-induced reduction in mitochondrial Cyt-c in ischemic cortex, in injured astrocytes and MEF cells. Immunofluorescence analysis showed that 3-MA or Wort treatment reversed OGD-induced release of cathepsin B and L from the lysosome to the cytoplasm and activation of caspase-3 in the astrocytes. Furthermore, treatment of 3-MA or Wort decreased OGD-induced increase in lysosomal membrane permeability and enhanced OGD-induced upregulation of lysosomal heat shock protein 70.1B (Hsp70.1B) in astrocytes. Inhibition of autophagy by 3-MA or Wort reduced infarction volume in rats and protected OGD-induced astrocytic cell injury. A non-selective caspase inhibitor z-VAD-fmk or a specific caspase-3 inhibitor Q-DEVD-OPh also rescued OGD-induced astrocytic cell injury. In conclusion, our presenting data suggest that inhibition of autophagy blocks cathepsins-tBid-mitochondrial apoptotic signaling pathway via stabilization of lysosomal membranes, possibly due to upregulation of the lysosomal Hsp70.1B in ischemic astrocytes.
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http://dx.doi.org/10.1038/cddis.2017.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386481PMC
February 2017

Perylene Diimide as a Precise Graphene-like Superoxide Dismutase Mimetic.

ACS Nano 2017 02 31;11(2):2024-2032. Epub 2017 Jan 31.

Hematology, Internal Medicine, University of Texas Houston Medical School , Houston, Texas 77030, United States.

Here we show that the active portion of a graphitic nanoparticle can be mimicked by a perylene diimide (PDI) to explain the otherwise elusive biological and electrocatalytic activity of the nanoparticle construct. Development of molecular analogues that mimic the antioxidant properties of oxidized graphenes, in this case the poly(ethylene glycolated) hydrophilic carbon clusters (PEG-HCCs), will afford important insights into the highly efficient activity of PEG-HCCs and their graphitic analogues. PEGylated perylene diimides (PEG-PDI) serve as well-defined molecular analogues of PEG-HCCs and oxidized graphenes in general, and their antioxidant and superoxide dismutase-like (SOD-like) properties were studied. PEG-PDIs have two reversible reduction peaks, which are more positive than the oxidation peak of superoxide (O). This is similar to the reduction peak of the HCCs. Thus, as with PEG-HCCs, PEG-PDIs are also strong single-electron oxidants of O. Furthermore, reduced PEG-PDI, PEG-PDI, in the presence of protons, was shown to reduce O to HO to complete the catalytic cycle in this SOD analogue. The kinetics of the conversion of O to O and HO by PEG-PDI was measured using freeze-trap EPR experiments to provide a turnover number of 133 s; the similarity in kinetics further supports that PEG-PDI is a true SOD mimetic. Finally, PDIs can be used as catalysts in the electrochemical oxygen reduction reaction in water, which proceeds by a two-electron process with the production of HO, mimicking graphene oxide nanoparticles that are otherwise difficult to study spectroscopically.
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http://dx.doi.org/10.1021/acsnano.6b08211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333640PMC
February 2017

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

Mech Ageing Dev 2017 01 20;161(Pt A):163-176. Epub 2016 Sep 20.

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA; Houston Methodist Neurological Institute, Houston, TX 77030, USA; Weill Medical College of Cornell University, New York, USA. Electronic address:

A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated aging and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.mad.2016.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316312PMC
January 2017

Biocompatibility of reduced graphene oxide nanoscaffolds following acute spinal cord injury in rats.

Surg Neurol Int 2016 23;7:75. Epub 2016 Aug 23.

Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA; Division of Pediatric Neurosurgery, Texas Children's Hospital, Houston, Texas, USA.

Background: Graphene has unique electrical, physical, and chemical properties that may have great potential as a bioscaffold for neuronal regeneration after spinal cord injury. These nanoscaffolds have previously been shown to be biocompatible in vitro; in the present study, we wished to evaluate its biocompatibility in an in vivo spinal cord injury model.

Methods: Graphene nanoscaffolds were prepared by the mild chemical reduction of graphene oxide. Twenty Wistar rats (19 male and 1 female) underwent hemispinal cord transection at approximately the T2 level. To bridge the lesion, graphene nanoscaffolds with a hydrogel were implanted immediately after spinal cord transection. Control animals were treated with hydrogel matrix alone. Histologic evaluation was performed 3 months after the spinal cord transection to assess in vivo biocompatibility of graphene and to measure the ingrowth of tissue elements adjacent to the graphene nanoscaffold.

Results: The graphene nanoscaffolds adhered well to the spinal cord tissue. There was no area of pseudocyst around the scaffolds suggestive of cytotoxicity. Instead, histological evaluation showed an ingrowth of connective tissue elements, blood vessels, neurofilaments, and Schwann cells around the graphene nanoscaffolds.

Conclusions: Graphene is a nanomaterial that is biocompatible with neurons and may have significant biomedical application. It may provide a scaffold for the ingrowth of regenerating axons after spinal cord injury.
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http://dx.doi.org/10.4103/2152-7806.188905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009578PMC
September 2016

Mechanistic Study of the Conversion of Superoxide to Oxygen and Hydrogen Peroxide in Carbon Nanoparticles.

ACS Appl Mater Interfaces 2016 Jun 10;8(24):15086-92. Epub 2016 Jun 10.

Hematology, Department of Internal Medicine, University of Texas Houston Medical School , Houston, Texas 77030, United States.

Hydrophilic carbon clusters (HCCs) are oxidized carbon nanoparticles with a high affinity for electrons. The electron accepting strength of HCCs, employing the efficient conversion of superoxide (O2(•-)) to molecular oxygen (O2) via single-electron oxidation, was monitored using cyclic voltammetry and electron paramagnetic resonance spectroscopy. We found that HCCs possess O2 reduction reaction (ORR) capabilities through a two-electron process with the formation of H2O2. By comparing results from aprotic solvents to those obtained from ORR activity in aqueous media, we propose a mechanism for the origin of the antioxidant and superoxide dismutase mimetic properties of poly(ethylene glycolated) hydrophilic carbon clusters (PEG-HCCs).
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http://dx.doi.org/10.1021/acsami.6b03502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920082PMC
June 2016

Insulin Resistance Intervention After Stroke Trial of Pioglitazone: Is This Perhaps the End of the Beginning?

Stroke 2016 07 24;47(7):1962-4. Epub 2016 May 24.

From the Department of Medicine, University of Thessaly, Larissa, Greece (G.N.); Stroke Outcomes Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX (T.A.K.); and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (T.A.K.).

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http://dx.doi.org/10.1161/STROKEAHA.116.013230DOI Listing
July 2016

Single-session emotion regulation skills training to reduce aggression in combat veterans: A clinical innovation case study.

Psychol Serv 2016 05;13(2):170-7

Michael E. DeBakey Veterans Affairs Medical Center.

Posttraumatic stress disorder (PTSD) is common among returning veterans, and aggression frequently co-occurs with PTSD. Veterans with PTSD most commonly engage in impulsive aggression, or aggression that is emotionally charged, unplanned, and uncontrolled, rather than premeditated aggression, which is planned and controlled. Previous research demonstrated a variety of emotions can result in aggression, rather than the traditional conceptualization that only anger leads to aggression. In a veteran sample, deficiencies in the ability to regulate emotions (emotion dysregulation) mediated the relationship between PTSD and impulsive aggression. These results suggest that teaching veterans with PTSD and impulsive aggression how to regulate emotions may decrease aggression. The cases presented illustrate the use of an innovative, single-session emotion regulation treatment for combat veterans with PTSD. Two cases are presented to generate hypotheses on who might benefit from this treatment in the future. The two male veterans treated with this protocol differed in how frequently they used the emotion regulation skills after the treatment and in their treatment outcomes. Teaching veterans how to regulate their emotions in a condensed time frame may be beneficial for certain veterans, and further research on this brief treatment is warranted. (PsycINFO Database Record
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http://dx.doi.org/10.1037/ser0000071DOI Listing
May 2016
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