Biomarkers.

Background: The hippocampus, a region vital for memory and cognition, is prone to abnormal deposition of beta-amyloid (Aβ) during the early stages of the Alzheimer's disease. Aβ-associated pathophysiological mechanisms instigate dendritic deficit, neuronal loss, and neuroinflammation, leading to abnormal functional and behavioral changes. These factors directly impact tissue microstructures.

Alzheimer's Imaging Consortium.

Background: The hippocampus, a region vital for memory and cognition, is prone to abnormal deposition of beta-amyloid (Aß) during the early stages of the Alzheimer's disease. Aß-associated pathophysiological mechanisms instigate dendritic deficit, neuronal loss, and neuroinflammation, leading to abnormal functional and behavioral changes. These factors directly impact tissue microstructures.

The 'bIUreactor': An Open-Source 3D Tissue Research Platform.

We developed the open-source bIUreactor research platform for studying 3D structured tissues. The versatile and modular platform allows a researcher to generate 3D tissues, culture them with oxygenated perfusion, and provide cyclic loading, all in their own lab (in laboratorium) for an all in cost of $8,000 including 3D printer, printing resin, and electronics. We achieved this by applying a design philosophy that leverages 3D printing, open-source software and hardware, and practical techniques to produce the following: 1.

Estimating the synaptic density deficit in Alzheimer's disease using multi-contrast CEST imaging.

In vivo noninvasive imaging of neurometabolites is crucial to improve our understanding of the underlying pathophysiological mechanism in neurodegenerative diseases. Abnormal changes in synaptic organization leading to synaptic degradation and neuronal loss is considered as one of the primary factors driving Alzheimer's disease pathology. Magnetic resonance based molecular imaging techniques such as chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) can provide neurometabolite specific information which may relate to underlying pathological and compensatory mechanisms.

Use of multimodality imaging, histology, and treatment feasibility to characterize a transgenic -null rat model of glioblastoma.

Many drugs that show potential in animal models of glioblastoma (GBM) fail to translate to the clinic, contributing to a paucity of new therapeutic options. In addition, animal model development often includes histologic assessment, but multiparametric/multimodality imaging is rarely included despite increasing utilization in patient cancer management. This study developed an intracranial recurrent, drug-resistant, human-derived glioblastoma tumor in Sprague-Dawley - knockout rat and was characterized both histologically and using multiparametric/multimodality neuroimaging.

Biochemical testing for neuroblastoma using plasma free 3-O-methyldopa, 3-methoxytyramine, and normetanephrine.

Background: Neuroblastoma, the most common extracranial solid tumor of childhood, produces catecholamines that are metabolized within tumor cells. Homovanillic acid (HVA) and vanillylmandelic acid (VMA), the end products of catecholamine metabolism, have limited accuracy for testing of the tumors. This study assessed whether metabolites produced in earlier steps of catecholamine metabolism might offer improved diagnostic accuracy over urinary HVA and VMA.

Positron Emission Tomography Detects Expression of Disialoganglioside GD2 in Mouse Models of Primary and Metastatic Osteosarcoma.

The cell membrane glycolipid GD2 is expressed by multiple solid tumors, including 88% of osteosarcomas and 98% of neuroblastomas. However, osteosarcomas are highly heterogeneous, with many tumors exhibiting GD2 expression on <50% of the individual cells, while some tumors are essentially GD2-negative. Anti-GD2 immunotherapy is the current standard of care for high-risk neuroblastoma, but its application to recurrent osteosarcomas, for which no effective therapies exist, has been extremely limited.

Improved, one-pot synthesis of 6-[ F]fluorodopamine and quality control testing for use in patients with neuroblastoma.

6-[ F]Fluorodopamine ([ F]F-DA) is taken into cells via the norepinephrine transporter (NET). Recent [ F]F-DA positron emission tomography-computed tomography (PET-CT) imaging of adult neuroendocrine tumors shows a dramatic improvement in sensitivity over the standard-of-care, meta-iodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT)-CT. A new precursor (ALPdopamine™) allows no-carrier-added synthesis resulting in high-molar activity [ F]F-DA.

Molecular Detection and Analysis of Exosomes Using Surface-Enhanced Raman Scattering Gold Nanorods and a Miniaturized Device.

Exosomes are a potential source of cancer biomarkers. Probing tumor-derived exosomes can offer a potential non-invasive way to diagnose cancer, assess cancer progression, and monitor treatment responses. Novel molecular methods would facilitate exosome analysis and accelerate basic and clinical exosome research.

Developmental Venous Anomalies Mimicking Neoplasm on 11C-Methionine PET and DSC Perfusion MRI.

Elevated relative cerebral blood volume on perfusion MRI and increased uptake on C-methionine PET can be used to diagnose and guide biopsy of brain tumors but are not specific. We report increased uptake on C-methionine PET associated with 4 developmental venous anomalies (DVAs) in 3 children with brain tumors, which could potentially mimic tumor and misdirect biopsy. Because DVAs are not readily visible on CT, prevention of misdirected biopsy in patients with focally elevated C-methionine uptake and relative cerebral blood volume relies on close correlation with contrast-enhanced anatomic MRI to exclude DVA or other nonneoplastic etiology.

Enhancing both CT imaging and natural killer cell-mediated cancer cell killing by a GD2-targeting nanoconstruct.

Although nanomaterials have been widely investigated for drug delivery, imaging and immunotherapy, their potential roles in triggering innate cellular immune responses while simultaneously serving as imaging enhancer remain unexplored. In this work, gold nanoparticles (GNPs) conjugated to the tumor-targeting anti-GD2 antibody hu14.18K322A, namely HGNPs, were designed and synthesized to specifically enhance computerized tomography (CT) imaging contrast and to stimulate the attack of neuroblastoma and melanoma cells by natural killer (NK) cells.

Evaluation of the biodistribution of 11C-methionine in children and young adults.

Unlabelled: The purpose of this study was to evaluate the biodistribution of (11)C-labeled methionine in non-tumor-involved organs in pediatric patients studied for malignant diseases.

Methods: Ninety-three children and young adults with known or suspected malignancies underwent (11)C-methionine PET and CT scans. Imaging began 5-15 min after injection of 740 MBq (20 mCi) per 1.

64Cu-p-NH2-Bn-DOTA-hu14.18K322A, a PET radiotracer targeting neuroblastoma and melanoma.

Unlabelled: The hu14.18K322A variant of the GD2-targeting antibody hu14.18 has been shown to elicit a level of antibody-dependent cell-mediated cytotoxicity toward human neuroblastoma cells similar to that of the parent antibody.

Leading neuroblastoma cells to die by multiple premeditated attacks from a multifunctionalized nanoconstruct.

To conquer complex and devastating diseases such as cancer, more coordinated and combined attack strategies are needed. We suggest that these can be beautifully achieved by using nanoconstruct design. We present an example showing that neuroblastoma cells are selectively killed by a nanoconstruct that specifically targets neuroblastoma cells, pushes cells to the vulnerable phase of the cell cycle, and greatly enhances radiation-induced cell death.

Steering carbon nanotubes to scavenger receptor recognition by nanotube surface chemistry modification partially alleviates NFκB activation and reduces its immunotoxicity.

Carbon nanotubes (CNTs) cause perturbations in immune systems and limit the application of CNTs in biomedicine. Here we demonstrate that a surface chemistry modification on multiwalled CNTs (MWCNTs) reduces their immune perturbations in mice and in macrophages. The modified MWCNTs change their preferred binding pattern from mannose receptor to scavenger receptor.

Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility.

Soluble carbon nanotubes show promise as materials for in vivo delivery and imaging applications. Several reports have described the in vivo toxicity of carbon nanotubes, but their effects on male reproduction have not been examined. Here, we show that repeated intravenous injections of water-soluble multiwalled carbon nanotubes into male mice can cause reversible testis damage without affecting fertility.

In vivo [11C]dihydrotetrabenazine binding in rat striatum: sensitivity to dopamine concentrations.

Introduction: The sensitivity of the in vivo binding of [(11)C]dihydrotetrabenazine ([(11)C]DTBZ) and [(11)C]methylphenidate ([(11)C]MPH) to their respective targets - vesicular monoamine transporter type 2 (VMAT2) and neuronal membrane dopamine transporter - after alterations in endogenous levels of dopamine was examined in the rat brain.

Methods: In vivo binding of [(11)C]DTBZ and [(11)C]MPH was determined using a bolus+infusion protocol. The in vitro number of VMAT2 binding sites was determined by autoradiography.

Anesthesia increases in vivo N-([18F]fluoroethyl)piperidinyl benzilate binding to the muscarinic cholinergic receptor.

The in vivo binding of N-[18F]fluoroethyl-piperidinyl benzilate ([18F]FEPB) to the muscarinic cholinergic receptor was measured in awake and anesthetized rats. Studies were done using an equilibrium infusion technique to provide estimates of specific binding as distribution volume ratios. Anesthesia with either isoflurane or sodium pentobarbital produced a significant (65-90%) increase of radiotracer binding in receptor-rich brain regions (striatum, cortex, hippocampus) relative to awake controls.

Evaluation of 18F-labeled acetylcholinesterase substrates as PET radiotracers.

Four 18F-labeled acetylcholinesterase (AChE) substrates, (S)-N-[18F]fluoroethyl-2-piperidinemethyl acetate (1), (R)-N-[18F]fluoroethyl-3-pyrrolidinyl acetate (2), N-[18F]fluoroethyl-4-piperidinyl acetate (3), and (R)-N-[18F]fluoroethyl-3-piperidinyl acetate (4), were evaluated for in vivo blood and brain metabolism in mice, brain pharmacokinetics in rats monkeys (M. nemistrina) using PET imaging. All 18F-labeled compounds were compared to N-[11C]methyl-4-piperidinyl propionate (PMP).

N-[(18)F]Fluoroethylpiperidinyl, N-[(18)F]fluoroethylpiperidinemethyl and N-[(18)F]fluoroethylpyrrolidinyl esters as radiotracers for acetylcholinesterase.

A series of N-fluoroethylpiperidinyl (1), N-fluoroethylpiperidinemethyl (2) and N-fluoroethylpyrrolidinyl (3) esters were synthesized and examined as new (18)F-labeled radiotracers for measuring brain cholinesterase activity. The fluoroethyl group, instead of methyl group, results in slower in vitro enzymatic cleavage rates and higher selectivity for AChE. Based on metabolism in mouse blood and PET time-activity curves in rats, two radiotracers were identified as potential candidates for further in vivo evaluation in higher species.

N-methylpiperidinemethyl, N-methylpyrrolidyl and N-methylpyrrolidinemethyl esters as PET radiotracers for acetylcholinesterase activity.

The N-[(11)C]methylpiperidinyl esters are used as radiopharmaceuticals for measuring brain cholinesterase activity. We have synthesized a series of N-methylpiperidinemethyl (1), N-methylpyrrolidinyl (2) and N-methylpyrrolidinemethyl (3) esters and examined the effects of sterric constraint and stereochemistry on cholinesterase-mediated cleavage. Acetylcholinesterase exhibited a preference for primary esters 1 and for the R-isomers of both 1 and 2.