Publications by authors named "Christopher Lascola"

31 Publications

Neuroprotective Pentapeptide, CN-105, Improves Outcomes in Translational Models of Intracerebral Hemorrhage.

Neurocrit Care 2021 Jan 21. Epub 2021 Jan 21.

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

Background: Intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease for which there are no approved pharmacological interventions that improve outcomes. Apolipoprotein E (apoE) has emerged as a promising therapeutic target given its isoform-specific neuroprotective properties and ability to modify neuroinflammatory responses. We developed a 5-amino acid peptide, CN-105, that mimics the polar face of the apoE helical domain involved in receptor interactions, readily crosses the blood-brain barrier, and improves outcomes in well-established preclinical ICH models. In the current study, we investigated the therapeutic potential of CN-105 in translational ICH models that account for hypertensive comorbidity, sex, species, and age.

Methods: In three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2 J mice, spontaneously hypertensive female rats, or 11-month-old male mice within 24-h of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively.

Results: In spontaneously hypertensive male mice, there was a significant dose-dependent effect of CN-105 on vestibulomotor function at 0.05 and 0.20 mg/kg doses (p < 0.05; 95% CI: 0.91-153.70 and p < 0.001; 95% CI: 49.54-205.62), while 0.20 mg/kg also improved neuroseverity scores (p < 0.05; 95% CI: 0.27-11.00) and reduced ipsilateral brain edema (p < 0.05; 95% CI: - 0.037 to - 0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (p < 0.01; η  = 0.093) and neuroseverity scores (p < 0.05; η = 0.083), and reduced contralateral edema expansion (p < 0.01; 95% CI: - 1.41 to - 0.39). In 11-month-old male mice, CN-105 had a significant effect on vestibulomotor function (p < 0.001; η = 0.111) but not neuroseverity scores (p > 0.05; η = 0.034).

Conclusions: Acute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.
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http://dx.doi.org/10.1007/s12028-020-01184-yDOI Listing
January 2021

Author Correction: Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.

Sci Rep 2020 Apr 20;10(1):6898. Epub 2020 Apr 20.

Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-63178-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170870PMC
April 2020

Plasmonic gold nanostar-mediated photothermal immunotherapy for brain tumor ablation and immunologic memory.

Immunotherapy 2019 10 18;11(15):1293-1302. Epub 2019 Sep 18.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.

Brain tumors present unique therapeutic challenges and they include glioblastoma (GBM) and metastases from cancers of other organs. Current treatment options are limited and include surgical resection, radiation therapy, laser interstitial thermal therapy and chemotherapy. Although much research has been done on the development of immune-based treatment platforms, only limited success has been demonstrated. Herein, we demonstrate a novel treatment of GBM through the use of plasmonic gold nanostars (GNS) as photothermal inducers for synergistic imuno tothermal anotherap (SYMPHONY), which combines treatments using gold nanostar and laser-induced photothermal therapy with checkpoint blockade immunotherapy. In the treatment of a murine flank tumor model with the CT-2A glioma cell line, SYMPHONY demonstrated the capability of producing long-term survivors that rejects rechallenge with cancer cells, heralding the successful emergence of immunologic memory. This study is the first to investigate the use of this novel therapy for the treatment of GBM in a murine model.
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http://dx.doi.org/10.2217/imt-2019-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826862PMC
October 2019

Annexin A1 Bioactive Peptide Promotes Resolution of Neuroinflammation in a Rat Model of Exsanguinating Cardiac Arrest Treated by Emergency Preservation and Resuscitation.

Front Neurosci 2019 14;13:608. Epub 2019 Jun 14.

Systems Modeling of Perioperative Organ Injury Laboratory, Department of Anesthesiology, Duke University, Durham, NC, United States.

Neuroinflammation initiated by damage-associated molecular patterns, including high mobility group box 1 protein (HMGB1), has been implicated in adverse neurological outcomes following lethal hemorrhagic shock and polytrauma. Emergency preservation and resuscitation (EPR) is a novel method of resuscitation for victims of exsanguinating cardiac arrest, shown in preclinical studies to improve survival with acceptable neurological recovery. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has emerged as a key regulator of metabolic and energy stress response pathways in the brain and a pharmacological target to induce a neuronal pro-survival phenotype. This study aims to examine whether systemic administration of an Annexin-A1 bioactive peptide (ANXA1sp) could resolve neuroinflammation and induce sirtuin-3 regulated cytoprotective pathways in a novel rat model of exsanguinating cardiac arrest and EPR. Adult male rats underwent hemorrhagic shock and ventricular fibrillation, induction of profound hypothermia, followed by resuscitation and rewarming using cardiopulmonary bypass (EPR). Animals randomly received ANXA1sp (3 mg/kg, in divided doses) or vehicle. Neuroinflammation (HMGB1, TNFα, IL-6, and IL-10 levels), cerebral cell death (TUNEL, caspase-3, pro and antiapoptotic protein levels), and neurologic scores were assessed to evaluate the inflammation resolving effects of ANXA1sp following EPR. Furthermore, western blot analysis and immunohistochemistry were used to interrogate the mechanisms involved. Compared to vehicle controls, ANXA1sp effectively reduced expression of cerebral HMGB1, IL-6, and TNFα and increased IL-10 expression, which were associated with improved neurological scores. ANXA1sp reversed EPR-induced increases in expression of proapoptotic protein Bax and reduction in antiapoptotic protein Bcl-2, with a corresponding decrease in cerebral levels of cleaved caspase-3. Furthermore, ANXA1sp induced autophagic flux (increased LC3II and reduced p62 expression) in the brain. Mechanistically, these findings were accompanied by upregulation of the mitochondrial protein deacetylase Sirtuin-3, and its downstream targets FOXO3a and MnSOD in ANXA1sp-treated animals. Our data provide new evidence that engaging pro-resolving pharmacological strategies such as Annexin-A1 biomimetic peptides can effectively attenuate neuroinflammation and enhance the neuroprotective effects of EPR after exsanguinating cardiac arrest.
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http://dx.doi.org/10.3389/fnins.2019.00608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587399PMC
June 2019

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

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

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

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

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

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

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

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

Sex Differences in Gene and Protein Expression After Intracerebral Hemorrhage in Mice.

Transl Stroke Res 2019 04 13;10(2):231-239. Epub 2018 May 13.

Multidisciplinary Neuroprotection Laboratories, Duke University, Durham, NC, 22710, USA.

Sex dimorphism has been demonstrated after experimental intracerebral hemorrhage (ICH). Decreased mortality and improved neurobehavioral outcomes occur in female compared to male mice after intrastriatal autologous blood or collagenase injection. Sex-specific differences in post-ICH gene and protein expression may provide mechanistic insight into this phenomenon. Ten- to 12-week-old C57BL/6 male (M) and female in high estrous state (HE-F) underwent left intrastriatal collagenase injection. We assessed neurobehavioral outcomes over the first 30 days, hematoma volume and cerebral edema evolution over the first 24 h, and transcriptomic gene and protein expression at pre-selected time points during the acute phase of injury. Genome-wide expression profiling was performed with Affymetrix GeneChip Mouse Genome 2.0 Probes, and proteomics analyses were performed using mass spectroscopy. Sex does not affect hemorrhage evolution, but female sex is associated with improved neurobehavioral recovery after ICH. A total of 7037 probes qualified for our filtering criteria, representing 5382 mapped genes and 256 unmapped genes. Female-unique pathways involved cell development, growth, and proliferation, while male-unique pathways involved molecular degradation. At 6 and 24 h post-ICH, differential expression was observed in 850 proteins vs baseline in males, 608 proteins vs baseline in females, and 1 protein in females vs males. Female sex is associated with improved neurobehavioral recovery, and differential gene and protein expression after intrastriatal collagenase injection.
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http://dx.doi.org/10.1007/s12975-018-0633-zDOI Listing
April 2019

BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy.

Circulation 2017 Jul 25;136(3):281-296. Epub 2017 Apr 25.

From Department of Physiology and Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC (J.M.M., T.E.R., C.A.S., T.D.G., E.E.S); Department of Medicine, Division of Cardiology (T.J.M., J.L.R., S.B.M., C.D.K.), Department of Surgery, Division of General Surgery (K.W.S.), Department of Pharmacology and Cancer Biology (J.L.R., S.B.M., C.D.K.), Department of Radiology (T.N.V., C.D.L.), and Department of Molecular Genetics and Microbiology (S.K., D.A.M.), Duke University Medical Center, Durham, NC; and Department of Medicine, Division of Endocrinology (A.D., B.H.A.), Division of Cardiovascular Medicine (B.H.A.), and Robert M. Berne Cardiovascular Research Center (B.H.A.), University of Virginia School of Medicine, Charlottesville.

Background: Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered 2 overlapping quantitative trait loci in mice, and , that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a variant (Ile81Met) segregates with tissue protection from hind-limb ischemia.

Methods: We treated mice with either adeno-associated viruses encoding a control (green fluorescent protein) or 2 BAG3 (Bcl-2-associated athanogene-3) variants, namely Met81 or Ile81, and subjected the mice to hind-limb ischemia.

Results: We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of (C.B6-). BALB/c mice treated with adeno-associated virus encoding the BL6 BAG3 variant (Ile81; n=25) displayed reduced limb-tissue necrosis and increased limb tissue perfusion compared with Met81- (n=25) or green fluorescent protein- (n=29) expressing animals. BAG3, but not BAG3, improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of adeno-associated virus-BAG3 (n=9), but not BAG3 (n=10) or green fluorescent protein (n=5), improved ischemic limb blood flow and limb muscle histology and restored muscle function (force production). Compared with BAG3, BAG3 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux.

Conclusions: Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537727PMC
July 2017

The role of angiogenesis in Group 3 medulloblastoma pathogenesis and survival.

Neuro Oncol 2017 Sep;19(9):1217-1227

Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Background: Of the 4 medulloblastoma subgroups, Group 3 is the most aggressive but the importance of angiogenesis is unknown. This study sought to determine the role of angiogenesis and identify clinically relevant biomarkers of tumor vascularity and survival in Group 3 medulloblastoma.

Methods: VEGFA mRNA expression and survival from several patient cohorts were analyzed. Group 3 xenografts were implanted intracranially in nude rats. Dynamic susceptibility weighted (DSC) MRI and susceptibility weighted imaging (SWI) were obtained. DSC MRI was used to calculate relative cerebral blood volume (rCBV) and flow (rCBF). Tumor vessel density and rat vascular endothelial growth factor alpha (VEGFA) expression were determined.

Results: Patient VEGFA mRNA levels were significantly elevated in Group 3 compared with the other subgroups (P < 0.001) and associated with survival. Xenografts D283, D341, and D425 were identified as Group 3 by RNA hierarchical clustering and MYC amplification. The D283 group had the lowest rCBV and rCBF, followed by D341 and D425 (P < 0.05). These values corresponded to histological vessel density (P < 0.05), rat VEGFA expression (P < 0.05), and survival (P = 0.002). Gene set enrichment analysis identified 5 putative genes with expression profiles corresponding with these findings: RNH1, SCG2, VEGFA, AGGF1, and PROK2. SWI identified 3 xenograft-independent categories of intratumoral vascular architecture with distinct survival (P = 0.004): organized, diffuse microvascular, and heterogeneous.

Conclusions: Angiogenesis plays an important role in Group 3 medulloblastoma pathogenesis and survival. DSC MRI and SWI are clinically relevant biomarkers for tumor vascularity and overall survival and can be used to direct the use of antivascular therapies for patients with Group 3 medulloblastoma.
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http://dx.doi.org/10.1093/neuonc/nox033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570262PMC
September 2017

Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.

Sci Rep 2016 10 7;6:34834. Epub 2016 Oct 7.

Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.

Presently, no pharmacological treatments have been demonstrated to improve long-term functional outcomes following intracerebral hemorrhage (ICH). Clinical evidence associates apolipoprotein E (apoE) genotype with ICH incidence and outcome. While apoE modifies neuroinflammatory responses through its adaptive role in glial downregulation, intact apoE holoprotein is too large to cross the blood-brain barrier (BBB). Therefore, we developed a 5-amino acid peptide - CN-105 - that mimics the polar face of the apoE helical domain involved in receptor interactions. In the current study, we investigated the therapeutic potential of CN-105 in a mouse model of ICH. Three doses of CN-105 (0.05 mg/kg) was administered by tail vein injection within 24 hours after ICH induction. Functional assessment showed durable improvement in vestibulomotor performance after CN-105 treatment, as quantified by increased Rotarod latencies on Days 1-5 post-ICH, and long-term improvement in neurocognitive performance, as quantified by reduced Morris water maze latencies on Days 29-32 post-ICH. Further, brain water content was significantly reduced, neuroinflammation was decreased and hippocampal CA3 neuronal survival was increased, although hemorrhage volume was not affected by CN-105. We concluded, therefore, that pentapeptide CN-105 improved short- and long-term neurobehavioral outcomes in a murine model of ICH, suggesting therapeutic potential for patients with acute ICH.
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http://dx.doi.org/10.1038/srep34834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054364PMC
October 2016

Anticancer therapeutic potential of Mn porphyrin/ascorbate system.

Free Radic Biol Med 2015 Dec 20;89:1231-47. Epub 2015 Oct 20.

Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, United States. Electronic address:

Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of Mn(III)P/Mn(II)P redox couple, ranged from -200 to +350 mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2>0 mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1mM) and MnPs (1 or 5 µM) alone did not trigger any alteration in cell viability, combined treatment suppressed cell viability up to 95%. No toxicity was observed with normal human breast epithelial HBL-100 cells. Bell-shape relationship, essentially identical to vo(Asc)oxvs E1/2, was also demonstrated between MnP/Asc-controlled cytotoxicity and E1/2-controlled vo(Asc)ox. Magnetic resonance imaging studies were conducted to explore the impact of ascorbate on T1-relaxivity. The impact of MnP/Asc on intracellular thiols and on GSH/GSSG and Cys/CySS ratios in 4T1 cells was assessed and cellular reduction potentials were calculated. The data indicate a significant increase in cellular oxidative stress induced by MnP/Asc. Based on vo(Asc)oxvs E1/2 relationships and cellular toxicity, MnTE-2-PyP(5+) was identified as the best catalyst among MnPs studied. Asc and MnTE-2-PyP(5+) were thus tested in a 4T1 mammary mouse flank tumor model. The combination of ascorbate (4 g/kg) and MnTE-2-PyP(5+) (0.2mg/kg) showed significant suppression of tumor growth relative to either MnTE-2-PyP(5+) or ascorbate alone. About 7-fold higher accumulation of MnTE-2-PyP(5+) in tumor vs normal tissue was found to contribute largely to the anticancer effect.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.10.416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684782PMC
December 2015

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage.

Neuroendocrinology 2016 10;103(5):518-30. Epub 2015 Sep 10.

Background: Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats.

Methods: ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridial collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h after injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, proinflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury.

Results: Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and proinflammatory transcription factor phosphorylated nuclear factor-x03BA;B p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected.

Conclusions: Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.
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http://dx.doi.org/10.1159/000440883DOI Listing
May 2017

Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise.

J Natl Cancer Inst 2015 May 16;107(5). Epub 2015 Mar 16.

Duke Cancer Institute, Duke University Medical Center, Durham, NC (ASB, CDL, DW, CL, PMS, GRD, GP, MWD); Department of Internal Medicine, Massachusetts General Hospital, Boston, MA (ASB); Memorial Sloan Kettering Cancer Center, New York, NY (LWJ).

Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor-negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11-12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm(2), 95% CI = 1223 to 1865 vs 2168 cells/mm(2), 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.
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http://dx.doi.org/10.1093/jnci/djv040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822524PMC
May 2015

Intrastriatal injection of autologous blood or clostridial collagenase as murine models of intracerebral hemorrhage.

J Vis Exp 2014 Jul 3(89). Epub 2014 Jul 3.

Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University; Department of Neurology, Duke University;

Intracerebral hemorrhage (ICH) is a common form of cerebrovascular disease and is associated with significant morbidity and mortality. Lack of effective treatment and failure of large clinical trials aimed at hemostasis and clot removal demonstrate the need for further mechanism-driven investigation of ICH. This research may be performed through the framework provided by preclinical models. Two murine models in popular use include intrastriatal (basal ganglia) injection of either autologous whole blood or clostridial collagenase. Since, each model represents distinctly different pathophysiological features related to ICH, use of a particular model may be selected based on what aspect of the disease is to be studied. For example, autologous blood injection most accurately represents the brain's response to the presence of intraparenchymal blood, and may most closely replicate lobar hemorrhage. Clostridial collagenase injection most accurately represents the small vessel rupture and hematoma evolution characteristic of deep hemorrhages. Thus, each model results in different hematoma formation, neuroinflammatory response, cerebral edema development, and neurobehavioral outcomes. Robustness of a purported therapeutic intervention can be best assessed using both models. In this protocol, induction of ICH using both models, immediate post-operative demonstration of injury, and early post-operative care techniques are demonstrated. Both models result in reproducible injuries, hematoma volumes, and neurobehavioral deficits. Because of the heterogeneity of human ICH, multiple preclinical models are needed to thoroughly explore pathophysiologic mechanisms and test potential therapeutic strategies.
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http://dx.doi.org/10.3791/51439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211435PMC
July 2014

Effects of deep hypothermic circulatory arrest on the blood brain barrier in a cardiopulmonary bypass model--a pilot study.

Heart Lung Circ 2014 Oct 23;23(10):981-4. Epub 2014 May 23.

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. Electronic address:

Background: Neurologic injury is common after cardiac surgery and disruption of the blood brain barrier (BBB) has been proposed as a contributing factor. We sought to study BBB characteristics in a rodent model of cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA).

Methods: Adult rats were subjected to CPB/DHCA or to sham surgery. Analysis included Western blotting of relevant BBB proteins in addition to in vivo brain magnetic resonance imaging (MRI) with a clinically used low-molecular contrast agent.

Results: While quantitative analysis of BBB proteins revealed similar expression levels, MRI showed evidence of BBB disruption after CPB/DHCA compared to sham surgery.

Conclusions: Combining molecular BBB analysis and MRI technology in a rodent model is a highly translatable approach to study adverse neurologic outcomes following CPB/DHCA.
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http://dx.doi.org/10.1016/j.hlc.2014.04.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175088PMC
October 2014

pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH.

Neurocrit Care 2014 Feb;20(1):119-31

Multidisciplinary Neuroprotection Laboratories, Durham, NC, USA.

Background: Despite intensive research, neurological morbidity from delayed cerebral ischemia remains common after aneurysmal subarachnoid hemorrhage (SAH). In the current study, we evaluate the neuroprotective effects of a pH-dependent GluN2B subunit-selective NMDA receptor antagonist in a murine model of SAH.

Methods: Following induction of SAH, 12 ± 2 week old male C57-BL/6 mice received NP10075, a pH-dependent NMDA receptor antagonist, or vehicle. In a separate series of experiments, NP10075 and the non-pH sensitive NMDA antagonist, NP10191, were administered to normoglycemic and hyperglycemic mice. Both histological (right middle cerebral artery diameter, NeuN, and Fluoro-Jade B staining) and functional endpoints (rotarod latency and neuroseverity score) were evaluated to assess the therapeutic benefit of NP10075.

Results: Administration of NP10075 was well tolerated and had minimal hemodynamic effects following SAH. Administration of the pH-sensitive NMDA antagonist NP10075, but not NP10191, was associated with a durable improvement in the functional performance of both normoglycemic and hyperglycemic animals. NP10075 was also associated with a reduction in vasospasm in the middle cerebral artery associated with hemorrhage. There was no significant difference between treatment with nimodipine + NP10075, as compared to NP10075 alone.

Conclusions: These data demonstrate that use of a pH-dependent NMDA antagonist has the potential to work selectively in areas of ischemia known to undergo acidic pH shifts, and thus may be associated with selective regional efficacy and fewer behavioral side effects than non-selective NMDA antagonists.
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http://dx.doi.org/10.1007/s12028-013-9944-9DOI Listing
February 2014

ApolipoproteinE mimetic peptides improve outcome after focal ischemia.

Exp Neurol 2013 Mar 6;241:67-74. Epub 2012 Dec 6.

Department of Medicine (Neurology), Duke University School of Medicine, Durham, NC 27710, USA.

Growing clinical evidence implicates isoform-specific effects of apolipoprotein E (apoE) in reducing neuroinflammation and mediating adaptive responses following ischemic and traumatic brain injury. However, the intact apoE holoprotein does not cross the blood-brain barrier and thus has limited therapeutic potential. We have created a small peptide, COG1410 (acetyl-AS-Aib-LRKL-Aib-KRLL-amide), derived from the apoE receptor-binding region. COG1410 retains the anti-inflammatory and neuroprotective biological properties of the intact holoprotein and penetrates the blood-brain barrier. In the current study, we utilized a murine model of transient focal cerebral ischemia and reperfusion to demonstrate that intravenous (IV) administration of COG1410 reduces infarct volume and radiographic progression of infarct, and improves functional outcome as assessed by rotarod when delivered up to 4h after ischemia onset.
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http://dx.doi.org/10.1016/j.expneurol.2012.11.027DOI Listing
March 2013

Xenon neuroprotection in experimental stroke: interactions with hypothermia and intracerebral hemorrhage.

Anesthesiology 2012 Dec;117(6):1262-75

University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Xenon has been proven to be neuroprotective in experimental brain injury. The authors hypothesized that xenon would improve outcome from focal cerebral ischemia with a delayed treatment onset and prolonged recovery interval.

Methods: Rats were subjected to 70 min temporary focal ischemia. Ninety minutes later, rats were treated with 0, 15, 30, or 45% Xe for 20 h or 0 or 30% Xe for 8, 20, or 44 h. Outcome was measured after 7 days. In another experiment, after ischemia, rats were maintained at 37.5° or 36.0°C for 20 h with or without 30% Xe. Outcome was assessed 28 days later. Finally, mice were subjected to intracerebral hemorrhage with or without 30% Xe for 20 h. Brain water content, hematoma volume, rotarod function, and microglial activation were measured.

Results: Cerebral infarct sizes (mean±SD) for 0, 15, 30, and 45% Xe were 212±27, 176±55, 160±32, and 198±54 mm, respectively (P=0.023). Neurologic scores (median±interquartile range) followed a similar pattern (P=0.002). Infarct size did not vary with treatment duration, but neurologic score improved (P=0.002) at all xenon exposure durations (8, 20, and 44 h). Postischemic treatment with either 30% Xe or subtherapeutic hypothermia (36°C) had no effect on 28-day outcome. Combination of these interventions provided long-term benefit. Xenon improved intracerebral hemorrhage outcome measures.

Conclusion: Xenon improved focal ischemic outcome at 7, but not 28 days postischemia. Xenon combined with subtherapeutic hypothermia produced sustained recovery benefit. Xenon improved intracerebral hemorrhage outcome. Xenon may have potential for clinical stroke therapy under carefully defined conditions.
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http://dx.doi.org/10.1097/ALN.0b013e3182746b81DOI Listing
December 2012

Mn porphyrins as novel molecular magnetic resonance imaging contrast agents.

J Endourol 2012 Nov 4;26(11):1420-4. Epub 2012 Oct 4.

Department of Urology/Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.

Background And Purpose: In this study, we investigated the potential of a new class of therapeutic Mn porphyrins as molecular MRI probes for prostate cancer imaging. Two compounds of different bioavailibility were investigated: Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) and Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTnHex-2-PyP(5+)). These compounds have previously been shown to have adjunctive antineoplastic activity through their actions as powerful superoxide dismutase mimics, peroxynitrite scavengers, and modulators of cellular redox-based signaling pathways. Strong paramagnetic MRI contrast properties and affinity for cancer cells suggest their potential application as novel diagnostic imaging agents.

Materials And Methods: MRI experiments were performed at 7.0T on a Bruker Biospec horizontal bore scanner. All in-vivo experiments were performed on 12 C57 black mice implanted with RM-9 prostate cancer cells on the hind limb. Two mg/kg of MnTnHex-2-PyP(5+) (n=6) and 8 mg/kg MnTE-2-PyP(5+) (n=6) were administered intraperitoneally 90 minutes before imaging. All the images were collected using a volume coil and processed using Paravision 4.0.

Results: Phantom studies reveal remarkably high T1 relaxivity changes for both metalloporphyrins, which are twofold to threefold higher than commercially available gadolinium chelates. Observable detection limits using conventional T1-weighted MRI are in the low micromolar range for both compounds. In vivo, MR relaxation changes in prostate tumor xenografts were readily observed after a single injection of either MnTE-2-PyP(5+)or MnTnHex-2-PyP(5+), with tumor contrast to background ratio greatest after MnTE-2-PyP(5+) administration.

Conclusion: After a single dose of MnTE-2-PyP(5+), contrast changes in prostate tumors are up to sixfold greater than in surrounding, noncancerous tissues, suggesting the potential use of this metalloporphyrin as a novel diagnostic probe for detecting prostate malignancy using MRI.
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http://dx.doi.org/10.1089/end.2012.0171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495112PMC
November 2012

Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer.

J Appl Physiol (1985) 2012 Jul 17;113(2):263-72. Epub 2012 May 17.

Duke University Medical Center, Durham, NC 27710, USA.

The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with "productive" tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.
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http://dx.doi.org/10.1152/japplphysiol.01575.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404704PMC
July 2012

Mn-porphyrins as novel molecular magnetic resonance imaging contrast agents.

J Endourol 2011 Nov 3:1420-4. Epub 2011 Nov 3.

Department of Urology/Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.

Background And Purpose: In this study, we investigated the potential of a new class of therapeutic Mn porphyrins as molecular MRI probes for prostate cancer imaging. Two compounds of different bioavailibility were investigated: Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5 +)) and Mn(III) mesotetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTnHex-2-PyP(5 +)). These compounds have previously been shown to have adjunctive antineoplastic activity through their actions as powerful superoxide dismutase mimics, peroxynitrite scavengers, and modulators of cellular redox-based signaling pathways. Strong paramagnetic MRI contrast properties and affinity for cancer cells suggest their potential application as novel diagnostic imaging agents.

Materials And Methods: MRI experiments were performed at 7.0T on a Bruker Biospec horizontal bore scanner. All in-vivo experiments were performed on 12 C57 black mice implanted with RM-9 prostate cancer cells on the hind limb. Two mg/kg of MnTnHex-2-PyP(5 +) (n = 6) and 8 mg/kg MnTE-2-PyP(5 +) (n = 6) were administered intraperitoneally 90 minutes before imaging. All the images were collected using a volume coil and processed using Paravision 4.0.

Results: Phantom studies reveal remarkably high T1 relaxivity changes for both metalloporphyrins, which are twofold to threefold higher than commercially available gadolinium chelates. Observable detection limits using conventional T1-weighted MRI are in the low micromolar range for both compounds. In vivo, MR relaxation changes in prostate tumor xenografts were readily observed after a single injection of either MnTE-2-PyP(5 +) or MnTnHex-2-PyP(5 +), with tumor contrast to background ratio greatest after MnTE-2-PyP(5 +) administration.

Conclusion: After a single dose of MnTE-2-PyP(5 +), contrast changes in prostate tumors are up to sixfold greater than in surrounding, noncancerous tissues, suggesting the potential use of this metalloporphyrin as a novel diagnostic probe for detecting prostate malignancy using MRI.
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http://dx.doi.org/10.1089/end.2011.0133DOI Listing
November 2011

Radiation dose exposure for lumbar spine epidural steroid injections: a comparison of conventional fluoroscopy data and CT fluoroscopy techniques.

AJR Am J Roentgenol 2011 Oct;197(4):778-82

Department of Radiology, Duke University Medical Center, Box 3808, Erwin Rd, Durham, NC 27710, USA.

Objective: The purpose of this article is to compare the radiation dose of conventional fluoroscopy-guided lumbar epidural steroid injections (ESIs) and CT fluoroscopy (CTF)-guided lumbar ESI using both clinical data and anthropomorphic phantoms.

Materials And Methods: We performed a retrospective review of dose parameters for 14 conventional fluoroscopy ESI procedures performed by one proceduralist and 42 CTF-guided ESIs performed by three proceduralists (14 each). By use of imaging techniques similar to those for our clinical cohorts, a commercially available anthropomorphic male phantom with metal oxide semiconductor field effect transistor detectors was scanned to obtain absorbed organ doses for conventional fluoroscopy-guided and CTF-guided ESIs. Effective dose (ED) was calculated from measured organ doses.

Results: The mean conventional fluoroscopy time for ESI was 37 seconds, and the mean procedural CTF time was 4.7 seconds. Calculated ED for conventional fluoroscopy was 0.85 mSv compared with 0.45 mSv for CTF. The greatest contribution to the radiation dose from CTF-guided ESI came from the planning lumbar spine CT scan, which had an ED of 2.90 mSv when z-axis ranged from L2 to S1. This resulted in a total ED for CTF-guided ESI (lumbar spine CT scan plus CTF) of 3.35 mSv.

Conclusion: The ED for the CTF-guided ESI was almost half that of conventional fluoroscopy because of the shorter fluoroscopy time. However, the overall radiation dose for CTF-guided ESIs can be up to four times higher when a full diagnostic lumbar CT scan is performed as part of the procedure. Radiation dose reduction for CTF-guided ESI is best achieved by minimizing the dose from the preliminary planning lumbar spine CT scan.
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http://dx.doi.org/10.2214/AJR.10.6102DOI Listing
October 2011

Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.

PLoS One 2011 2;6(9):e23943. Epub 2011 Sep 2.

Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.

Objective: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC.

Methods: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging.

Results: Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality.

Conclusions: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023943PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166282PMC
December 2011

Synthesis and preliminary evaluation of n.c.a. iodoquine: a novel radiotracer with high uptake in cells with high ALDH1 expression.

Curr Radiopharm 2012 Jan;5(1):47-58

Duke University Medical Center, DUMC, Durham, NC 27710, USA.

Purpose: Chloroquine has demonstrated high affinity for aldehyde dehydrogenase 1A1 (ALDH1), an enzyme expressed in the highly tumorigenic CD133+ brain tumor initiating subpopulation. The purpose of this study is to report the novel synthesis of a chloroquine analogue, n.c.a. iodoquine, and the in vitro and in vivo uptake in cells with high ALDH1 content.

Methods And Materials: Iodoquine was synthesized in novel no-carrier-added forms (n.c.a.) for both 125I and 123I. I25I IQ and 18F FDG cell uptake assays were performed in the L1210 and L1210cpa (cyclophosphamide resistant), A549, and MG456 glioblastoma cell lines. Uptake was expressed as a percent of the administered activity. 125I IQ biodistribution studies assessed organ uptake at 1, 4, and 24 hours after IV administration (n= 15 total; 5 mice/timepoint). Radiation dosimetry estimates were calculated using standard OLINDA/EXM software. In vivo imaging of 123I IQ uptake in MG456 glioblastoma mouse model (n=10) was performed with small animal high resolution micro-SPECT. Autoradiography and histology co-localized radiotracer and tumor biodistribution. Uptake in MG456 glioblastoma tumors was quantified with gamma counting.

Results: L1210 cpa (high ALDH1) showed significantly higher 125I IQ uptake compared to the parental L1210 (low ALDH1) for all time points through 4 hours (20.7% ± 1.4% versus 11.0% ± 0.5%; 21.3% ± 0.9% versus 11.0% ± 0.4%; 20.6% ± 0.7% versus 9.4% ± 0.3%; and 15.7% ± 0.7% versus 7.5% + 0.4% at 30 minutes, and 1, 2 and 4 hours, respectively; p < 0.001 for all time points). In the CD133+ fraction of MG456 glioblastoma cell line, IQ uptake was significantly higher compared to FDG at all time points through 4 hours (81.5% ± 0.9% versus 1.3% ± 0.1%; 88.8% ± 0.4% versus 1.3% ± 0.1%; 87.8% ± 2.1% versus 1.7% ± 0.2%; and 87.0% ± 2.4% versus 1.8% ± 0.1 at 30 minutes, and 1, 2 and 4 hours, respectively; p > 0.001 for all time points). The A549 lung cancer cell line also showed high IQ uptake through 4 hours. IQ normal biodistribution studies showed rapid renal excretion and very low normal background brain activity after IV administration. In vivo micro-SPECT images showed mild uptake in larger MG456 glioblastomas (n=6) as verified with autoradiography and histology. Gamma well counter uptake in large tumors was 2.3% ± 0.48% ID/g (n=5).

Conclusion: Iodoquine localizes to cells with high ALDH1 content. Cell assays show high 125I IQ uptake in the MG456 cell line, and in vivo micro-SPECT imaging showed mild 123I IQ uptake in MG456 glioblastomas. Further studies are necessary to investigate 131I IQ as a potential therapeutic agent targeting the highly tumorigenic CD133+ brain tumor stem cell subpopulation.
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http://dx.doi.org/10.2174/1874471011205010047DOI Listing
January 2012

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.

Nature 2011 Apr 20;472(7344):437-42. Epub 2011 Mar 20.

Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.
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http://dx.doi.org/10.1038/nature09965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090611PMC
April 2011

CT fluoroscopy-assisted cervical transforaminal steroid injection: tips, traps, and use of contrast material.

AJR Am J Roentgenol 2010 Oct;195(4):888-94

Department of Radiology, Division of Neuroradiology, Duke University Medical Center, Durham, NC 27710, USA.

Objective: CT fluoroscopy-assisted cervical transforaminal steroid injection is an effective therapeutic option for cervical radiculopathy, yet it is approached with trepidation by some interventionalists. CT fluoroscopy is superior to conventional fluoroscopy for delineating complex anatomic relations in the neck but must be combined with careful technique to avoid rare but serious complications. We describe the anatomy of the neural foramen, our technique of CT fluoroscopy-assisted cervical transforaminal steroid injection, and the CT appearance of appropriate and inappropriate needle positions.

Conclusion: Understanding anatomy will help to avoid complications and optimize the therapeutic potential of cervical transforaminal steroid injection. Use of contrast material for CT fluoroscopic guidance facilitates appropriate needle positioning and reduces the risk of complications.
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http://dx.doi.org/10.2214/AJR.10.4369DOI Listing
October 2010

Brain natriuretic peptide improves long-term functional recovery after acute CNS injury in mice.

J Neurotrauma 2010 Jan;27(1):217-28

Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.

There is emerging evidence to suggest that brain natriuretic peptide (BNP) is elevated after acute brain injury, and that it may play an adaptive role in recovery through augmentation of cerebral blood flow (CBF). Through a series of experiments, we tested the hypothesis that the administration of BNP after different acute mechanisms of central nervous system (CNS) injury could improve functional recovery by improving CBF. C57 wild-type mice were exposed to either pneumatic-induced closed traumatic brain injury (TBI) or collagenase-induced intracerebral hemorrhage (ICH). After injury, either nesiritide (hBNP) (8 microg/kg) or normal saline were administered via tail vein injection at 30 min and 4 h. The mice then underwent functional neurological testing via rotorod latency over the following 5 days and neurocognitive testing via Morris water maze testing on days 24-28. Cerebral blood flow (CBF) was assessed by laser Doppler from 25 to 90 min after injury. After ICH, mRNA polymerase chain reaction (PCR) and histochemical staining were performed during the acute injury phase (<24 h) to determine the effects on inflammation. Following TBI and ICH, administration of hBNP was associated with improved functional performance as assessed by rotorod and Morris water maze latencies (p < 0.01). CBF was increased (p < 0.05), and inflammatory markers (TNF-alpha and IL-6; p < 0.05), activated microglial (F4/80; p < 0.05), and neuronal degeneration (Fluoro-Jade B; p < 0.05) were reduced in mice receiving hBNP. hBNP improves neurological function in murine models of TBI and ICH, and was associated with enhanced CBF and downregulation of neuroinflammatory responses. hBNP may represent a novel therapeutic strategy after acute CNS injury.
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http://dx.doi.org/10.1089/neu.2009.1022DOI Listing
January 2010

Pharmacogenomic effects of apolipoprotein e on intracerebral hemorrhage.

Stroke 2009 Feb 24;40(2):632-9. Epub 2008 Dec 24.

Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.

Background And Purpose: The purpose of the study was to evaluate the effect of APOE genotype and the feasibility of administering an apolipoprotein E-mimetic therapeutic to modify outcomes in a murine model of intracerebral hemorrhage.

Methods: Intracerebral hemorrhage was induced via stereotactic injection of 0.1 U Clostridial collagenase into the left basal ganglia of wild-type and apolipoprotein-E targeted-replacement mice, consisting of either homozygous 3/3 or 4/4 genotypes. Animals were randomized to receive either vehicle or apolipoprotein E-mimetic peptide. Outcomes included functional neurological tests (21-point neuroseverity score and Rotorod latency) over the initial 7 days after injury, radiographic and histological hemorrhage size at 3 and 7 days, brain water content for cerebral edema at 24 hours, and quantitative polymerase chain reaction for inflammatory markers at 6, 24, and 48 hours.

Results: Apolipoprotein-E targeted-replacement mice consisting of homozygous 3/3 demonstrated superior neuroseverity scores and Rotorod latencies over the first 3 days after intracerebral hemorrhage, decreased cerebral edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase at 6 hours when compared to their apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 counterparts. After intravenous administration of 1 mg/kg apolipoprotein E-mimetic peptide, both wild-type and apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 exhibited improved functional outcomes over 7 days after intracerebral hemorrhage, less edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase when compared to mice that did not receive the peptide.

Conclusions: Our data indicate that APOE genotype influences neurological outcome after intracerebral hemorrhage in a murine model. In particular APOE4 is associated with poor functional outcome and increased cerebral edema. Additionally, this outcome can be modified by the addition of an apolipoprotein E mimetic-peptide, COG1410.
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http://dx.doi.org/10.1161/STROKEAHA.108.530402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699752PMC
February 2009

Molecular imaging in Alzheimer's disease.

Neuroimaging Clin N Am 2005 Nov;15(4):827-35, x-xi

Department of Radiology and Neurobiology, Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC 27710, USA.

Molecular imaging represents a new term for a long-standing quest to image cellular and molecular processes in vivo. The development of a successful molecular imaging approach starts with a well-defined diagnostic question best answered using in vivo imaging. A selective target for a particular disease state is then identified and a biocompatible probe selective for that target is developed. Many of the challenges of finding selective disease targets and probes that bind selectively to those targets in vivo are evident in the 25-year history of molecular imaging in Alzheimer's disease. This article provides a brief overview of molecular imaging in Alzheimer's disease and its potential for early diagnosis and treatment development.
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http://dx.doi.org/10.1016/j.nic.2005.09.006DOI Listing
November 2005
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