FKBP38 Regulates Self-Renewal and Survival of GBM Neurospheres.

Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway.

Chronic neuronal activation leads to elevated lactate dehydrogenase A through the AMP-activated protein kinase/hypoxia-inducible factor-1α hypoxia pathway.

Recent studies suggest that changes in neuronal metabolism are associated with epilepsy. High rates of ATP depletion, lactate dehydrogenase A and lactate production have all been found in epilepsy patients, animal and tissue culture models. As such, it can be hypothesized that chronic seizures lead to continuing elevations in neuronal energy demand which may lead to an adapted metabolic response and elevations of lactate dehydrogenase A.

Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib.

Background: The prognosis of glioblastoma (GBM) remains dismal because therapeutic approaches have limited effectiveness. A new targeted treatment using MEK inhibitors, including trametinib, has been proposed to improve GBM therapy. Trametinib had a promising preclinical effect against several cancers, but its adaptive treatment resistance precluded its clinical translation in GBM.

IDH-mutated gliomas promote epileptogenesis through d-2-hydroxyglutarate-dependent mTOR hyperactivation.

Background: Uncontrolled seizures in patients with gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Here, we hypothesize that the active metabolite d-2-hydroxyglutarate (d-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures.

Methods: We use a complementary study of in vitro neuron-glial cultures and electrographically sorted human cortical tissue from patients with IDH-mutant gliomas to test this hypothesis.

Adenosine A2A Receptor Activation Enhances Blood-Tumor Barrier Permeability in a Rodent Glioma Model.

The blood-tumor barrier (BTB) limits the entry of effective chemotherapeutic agents into the brain for treatment of malignant tumors like glioblastoma. Poor drug entry across the BTB allows infiltrative glioma stem cells to evade therapy and develop treatment resistance. Regadenoson, an FDA-approved adenosine A2A receptor (A2AR) agonist, has been shown to increase drug delivery across the blood-brain barrier in non-tumor-bearing rodents without a defined mechanism of enhancing BTB permeability.

Inhibition of protein phosphatase-2A with LB-100 enhances antitumor immunity against glioblastoma.

Purpose: Glioblastoma (GBM) carries a dismal prognosis despite standard multimodal treatment with surgery, chemotherapy and radiation. Immune checkpoint inhibitors, such as PD1 blockade, for treatment of GBM failed to show clinical benefit. Rational combination strategies to overcome resistance of GBM to checkpoint monotherapy are needed to extend the promise of immunotherapy to GBM management.

Convection-enhanced delivery of botulinum toxin serotype A into the nonhuman primate cisterna magna and hippocampus.

Objective: Botulinum toxin serotype A (BoNT/A) was reported to raise the seizure threshold when injected into the seizure focus of a kindled rodent model. Delivering BoNT/A to the nonhuman primate (NHP) central nervous system via convection-enhanced delivery (CED) has not been performed. The objective of this study was to determine the toxicity and distribution characteristics of CED of BoNT/A into the NHP hippocampus and cisterna magna.

Experimental upper bound and theoretical expectations for parity-violating neutron spin rotation in He.

Neutron spin rotation is expected from quark-quark weak interactions in the standard model, which induce weak interactions among nucleons that violate parity. We present the results from an experiment searching for the effect of parity violation via the spin rotation of polarized neutrons in a liquid He medium. The value for the neutron spin rotation angle per unit length in He, rad/m, is consistent with zero.

Convection-Enhanced Delivery of Muscimol Into the Bilateral Subthalamic Nuclei of Nonhuman Primates.

Background: Muscimol is a gamma-aminobutyric acid receptor agonist that selectively and temporarily inhibits neurons. Local bolus injection of muscimol has been used experimentally to inhibit neuronal populations within discrete anatomical structures and discern their physiological function.

Objective: To determine the safety and behavioral effects of convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei (STN) of nonhuman primate rhesus macaques (NHPs).

Transverse relaxation of cerebrospinal fluid depends on glucose concentration.

Purpose: To evaluate the biophysical processes that generate specific T values and their relationship to specific cerebrospinal fluid (CSF) content.

Materials And Methods: CSF T were measured ex vivo (14.1T) from isolated CSF collected from human, rat and non-human primate.

Histone Deacetylase Inhibitor SAHA Is a Promising Treatment of Cushing Disease.

Context: Remission failure following transsphenoidal surgery in Cushing disease (CD) from pituitary corticotroph tumors (CtTs) remains clinically challenging. Histone deacetylase inhibitors (HDACis) are antitumor drugs approved for clinical use, with the potential to affect adrenocorticotropin hormone (ACTH) hypersecretion by inhibiting pro-opiomelanocortin (POMC) transcription.

Objective: Testing the efficacy of suberoylanilide hydroxamic acid (SAHA) on human and murine ACTH-secreting tumor (AtT-20) cells.

Simulating vasogenic brain edema using chronic VEGF infusion.

OBJECTIVE To study peritumoral brain edema (PTBE), it is necessary to create a model that accurately simulates vasogenic brain edema (VBE) without introducing a complicated tumor environment. PTBE associated with brain tumors is predominantly a result of vascular endothelial growth factor (VEGF) secreted by brain tumors, and VEGF infusion alone can lead to histological blood-brain barrier (BBB) breakdown in the absence of tumor. VBE is intimately linked to BBB breakdown.

Spatial and temporal changes in cumulative human impacts on the world's ocean.

Human pressures on the ocean are thought to be increasing globally, yet we know little about their patterns of cumulative change, which pressures are most responsible for change, and which places are experiencing the greatest increases. Managers and policymakers require such information to make strategic decisions and monitor progress towards management objectives. Here we calculate and map recent change over 5 years in cumulative impacts to marine ecosystems globally from fishing, climate change, and ocean- and land-based stressors.

A slow neutron polarimeter for the measurement of parity-odd neutron rotary power.

We present the design, description, calibration procedure, and an analysis of systematic effects for an apparatus designed to measure the rotation of the plane of polarization of a transversely polarized slow neutron beam as it passes through unpolarized matter. This device is the neutron optical equivalent of a crossed polarizer/analyzer pair familiar from light optics. This apparatus has been used to search for parity violation in the interaction of polarized slow neutrons in matter.

Cumulative human impacts on Mediterranean and Black Sea marine ecosystems: assessing current pressures and opportunities.

Management of marine ecosystems requires spatial information on current impacts. In several marine regions, including the Mediterranean and Black Sea, legal mandates and agreements to implement ecosystem-based management and spatial plans provide new opportunities to balance uses and protection of marine ecosystems. Analyses of the intensity and distribution of cumulative impacts of human activities directly connected to the ecological goals of these policy efforts are critically needed.

Model for concomitant microdialysis sampling of the pons and cerebral cortex in rhesus macaques (Macaca mulatta).

Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that fail to respond to treatment. We hypothesize that the protective features of the pons may hinder chemotherapeutic agents from entering pontine tissue compared with cortical brain tissue. To test this hypothesis, we developed a unique nonhuman primate model using microdialysis, a continuous in vivo extracellular sampling technique, to compare drug exposure concurrently in pontine tissue, cortical tissue, CSF, and plasma after intravenous administration of chemotherapeutic agents.

Comparison of pulsed versus continuous convective flow for central nervous system tissue perfusion: laboratory investigation.

Object: Although pulsatile and continuous infusion paradigms have been described for convective delivery of drugs, the effectiveness and properties of each flow paradigm are unknown. To determine the effectiveness and properties of pulsatile and continuous convective infusion paradigms, the authors compared these convective flow methods in the gray and white matter of primates.

Methods: Six primates (Macaca mulatta) underwent convective infusion of Gd-DPTA (5 mM) into the cerebral gray matter (thalamus) or white matter (frontal lobe) using pulsed (intermittent pulses of 15 μl/min) or continuous (1 μl/min) convective flow.

Convection-enhanced delivery of M13 bacteriophage to the brain.

Object: Recent studies indicate that M13 bacteriophage, a very large nanoparticle, binds to β-amyloid and α-synuclein proteins, leading to plaque disaggregation in models of Alzheimer and Parkinson disease. To determine the feasibility, safety, and characteristics of convection-enhanced delivery (CED) of M13 bacteriophage to the brain, the authors perfused primate brains with bacteriophage.

Methods: Four nonhuman primates underwent CED of M13 bacteriophage (900 nm) to thalamic gray matter (4 infusions) and frontal white matter (3 infusions).

Tracking accuracy of T2- and diffusion-weighted magnetic resonance imaging for infusate distribution by convection-enhanced delivery.

Object: Because convection-enhanced delivery relies on bulk flow of fluid in the interstitial spaces, MR imaging techniques that detect extracellular fluid and fluid movement may be useful for tracking convective drug distribution. To determine the tracking accuracy of T2-weighted and diffusion-weighted MR imaging sequences, the authors followed convective distribution of radiolabeled compounds using these imaging sequences in nonhuman primates.

Methods: Three nonhuman primates underwent thalamic convective infusions (5 infusions) with (14)C-sucrose (MW 342 D) or (14)C-dextran (MW 70,000 D) during serial MR imaging (T2- and diffusion-weighted imaging).

Effect of concentration on the accuracy of convective imaging distribution of a gadolinium-based surrogate tracer.

Object: Accurate real-time imaging of coinfused surrogate tracers can be used to determine the convective distribution of therapeutic agents. To assess the effect that a concentration of a Gd-based surrogate tracer has on the accuracy of determining the convective distribution, the authors infused different concentrations of Gd-diethylenetriamine pentaacetic acid (DTPA) in primates during MR imaging.

Methods: Five nonhuman primates underwent convective infusion (1 or 5 mM, 21-65 μl) of Gd-DTPA alone, Gd-DTPA and (14)C-sucrose, or Gd-DTPA and (14)C-dextran into the bilateral striata.

Differential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebral C6 gliomas.

Nitric oxide (NO) signaling in tumors and endothelial cells regulates vascular permeability and blood flow and therefore influences tumor uptake and response to therapeutic compounds. As delivery and efficacy of chemotherapy is impaired in CNS neoplasms due to a partially intact blood-brain barrier (BBB), we studied the effects of NO released by the short-acting NO donor disodium 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate methanolate (PROLI/NO) on BBB integrity and blood flow in C6 gliomas using [¹⁴C]-aminoisobutyric acid (AIB) and [¹⁴C]-iodoantipyrine quantitative autoradiography. PROLI/NO selectively increased intratumoral uptake of [¹⁴C]AIB and [¹⁴C]sucrose when given as a 3-minute intracarotid infusion or a 15-minute i.

Cholera toxin regulates a signaling pathway critical for the expansion of neural stem cell cultures from the fetal and adult rodent brains.

Background: New mechanisms that regulate neural stem cell (NSC) expansion will contribute to improved assay systems and the emerging regenerative approach that targets endogenous stem cells. Expanding knowledge on the control of stem cell self renewal will also lead to new approaches for targeting the stem cell population of cancers.

Methodology/principal Findings: Here we show that Cholera toxin regulates two recently characterized NSC markers, the Tie2 receptor and the transcription factor Hes3, and promotes the expansion of NSCs in culture.