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Association Between Regional Adipose Tissue Distribution and Risk of Heart Failure Among Blacks.
Pandey A, Kondamudi N, Patel KV, Ayers C, Simek S, Hall ME, Musani SK, Blackshear C, Mentz RJ, Khan H, Terry JG, Correa A, Butler J, Neeland IJ, Berry JD
(2018) Circ Heart Fail 11: e005629
MeSH Terms: Adiposity, African Americans, Aged, Female, Heart Failure, Humans, Intra-Abdominal Fat, Male, Middle Aged, Obesity, Risk Assessment, Risk Factors, Tissue Distribution
Show Abstract · Added April 3, 2019
BACKGROUND - Obesity is highly prevalent among blacks and is associated with a greater risk of heart failure (HF). However, the contribution of regional adiposity depots such as visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue toward risk of HF in blacks is unknown.
METHODS AND RESULTS - We included 2602 participants (mean age: 59 years, 35% men) from the Jackson Heart Study without prevalent HF who underwent computed tomography quantification of VAT and subcutaneous adipose tissue during the second visit (2005-2009). The associations between different adiposity measures and HF were evaluated using adjusted Cox models. There were 122 incident HF events over a median follow-up of 7.1 years. Higher amounts of VAT were associated with greater risk of HF in age- and sex-adjusted analyses (hazard ratio [95% CI] per 1-SD higher VAT: 1.29 [1.09-1.52]). This association was attenuated and not significant after additional adjustment for traditional HF risk factors and body mass index. Overall obesity, represented by body mass index, was associated with higher risk of HF independent of risk factors and VAT (hazard ratio [95% CI] per 1-kg/m higher body mass index: 1.06 [1.02-1.11]). Subcutaneous adipose tissue was not associated with risk of HF in adjusted analyses.
CONCLUSIONS - In a community-dwelling black population, higher amounts of overall and visceral adiposity are associated with higher risk of HF. The association between VAT and HF risk in blacks may reflect differences in traditional HF risk factor burden. Future studies are needed to confirm this observation and clarify the independent role of different measures of adiposity on HF outcomes.
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13 MeSH Terms
Dual carrier-cargo hydrophobization and charge ratio optimization improve the systemic circulation and safety of zwitterionic nano-polyplexes.
Jackson MA, Bedingfield SK, Yu F, Stokan ME, Miles RE, Curvino EJ, Hoogenboezem EN, Bonami RH, Patel SS, Kendall PL, Giorgio TD, Duvall CL
(2019) Biomaterials 192: 245-259
MeSH Terms: Animals, Cations, Cell Line, Tumor, Female, Humans, Hydrophobic and Hydrophilic Interactions, Mice, Inbred BALB C, Mice, Nude, Nanostructures, Neoplasms, Polymers, RNA, Small Interfering, RNAi Therapeutics, Tissue Distribution
Show Abstract · Added April 10, 2019
While polymeric nano-formulations for RNAi therapeutics hold great promise for molecularly-targeted, personalized medicine, they possess significant systemic delivery challenges including rapid clearance from circulation and the potential for carrier-associated toxicity due to cationic polymer or lipid components. Herein, we evaluated the in vivo pharmacokinetic and safety impact of often-overlooked formulation parameters, including the ratio of carrier polymer to cargo siRNA and hydrophobic siRNA modification in combination with hydrophobic polymer components (dual hydrophobization). For these studies, we used nano-polyplexes (NPs) with well-shielded, zwitterionic coronas, resulting in various NP formulations of equivalent hydrodynamic size and neutral surface charge regardless of charge ratio. Doubling nano-polyplex charge ratio from 10 to 20 increased circulation half-life five-fold and pharmacokinetic area under the curve four-fold, but was also associated with increased liver enzymes, a marker of hepatic damage. Dual hydrophobization achieved by formulating NPs with palmitic acid-modified siRNA (siPA-NPs) both reduced the amount of carrier polymer required to achieve optimal pharmacokinetic profiles and abrogated liver toxicities. We also show that optimized zwitterionic siPA-NPs are well-tolerated upon long-term, repeated administration in mice and exhibit greater than two-fold increased uptake in orthotopic MDA-MB-231 xenografts compared to commercial transfection reagent, in vivo-jetPEI. These data suggest that charge ratio optimization has important in vivo implications and that dual hydrophobization strategies can be used to maximize both NP circulation time and safety.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
Mechanistic insight into the interaction of gastrointestinal mucus with oral diblock copolymers synthesized via ATRP method.
Liu J, Cao J, Cao J, Han S, Liang Y, Bai M, Sun Y
(2018) Int J Nanomedicine 13: 2839-2856
MeSH Terms: Administration, Oral, Animals, Caco-2 Cells, Drug Carriers, Humans, Hydrophobic and Hydrophilic Interactions, Indoles, Intestinal Absorption, Intestinal Mucosa, Male, Methacrylates, Methylmethacrylates, Mice, Nanoparticles, Nylons, Particle Size, Polymers, Propionates, Tissue Distribution
Show Abstract · Added April 2, 2019
Introduction - Nanoparticles are increasingly used as drug carriers for oral administration. The delivery of drug molecules is largely dependent on the interaction of nanocarriers and gastrointestinal (GI) mucus, a critical barrier that regulates drug absorption. It is therefore important to understand the effects of physical and chemical properties of nanocarriers on the interaction with GI mucus. Unfortunately, most of the nanoparticles are unable to be prepared with satisfactory structural monodispersity to comprehensively investigate the interaction. With controlled size, shape, and surface chemistry, copolymers are ideal candidates for such purpose.
Materials and methods - We synthesized a series of diblock copolymers via the atom transfer radical polymerization method and investigated the GI mucus permeability in vitro and in vivo.
Results - Our results indicated that uncharged and hydrophobic copolymers exhibited enhanced GI absorption.
Conclusion - These results provide insights into developing optimal nanocarriers for oral administration.
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Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2-([F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide in a preclinical model of neuroinflammation.
Tang D, Fujinaga M, Hatori A, Zhang Y, Yamasaki T, Xie L, Mori W, Kumata K, Liu J, Manning HC, Huang G, Zhang MR
(2018) Eur J Med Chem 150: 1-8
MeSH Terms: Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Fluorine Radioisotopes, Humans, Inflammation, Ischemia, Male, Mice, Molecular Probes, Molecular Structure, Positron-Emission Tomography, Pyrazoles, Pyrimidines, Radioactive Tracers, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Receptors, GABA, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added March 22, 2018
Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2-[F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [F]DPA-714. We evaluated the performance of [F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BP), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging.
Copyright © 2018. Published by Elsevier Masson SAS.
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21 MeSH Terms
Pharmacokinetics, Tissue Localization, Toxicity, and Treatment Efficacy in the First Small Animal (Rabbit) Model of Intra-Arterial Chemotherapy for Retinoblastoma.
Daniels AB, Froehler MT, Pierce JM, Nunnally AH, Calcutt MW, Bridges TM, LaNeve DC, Williams PE, Boyd KL, Reyzer ML, Lindsley CW, Friedman DL, Richmond A
(2018) Invest Ophthalmol Vis Sci 59: 446-454
MeSH Terms: Animals, Antineoplastic Agents, Alkylating, Disease Models, Animal, Electroretinography, Fluorescein Angiography, Infusions, Intra-Arterial, Melphalan, Ophthalmic Artery, Rabbits, Retina, Retinal Neoplasms, Retinoblastoma, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tissue Distribution, Treatment Outcome, Vitreous Body
Show Abstract · Added April 5, 2018
Purpose - Current intra-arterial chemotherapy (IAC) drug regimens for retinoblastoma have ocular and vascular toxicities. No small-animal model of IAC exists to test drug efficacy and toxicity in vivo for IAC drug discovery. The purpose of this study was to develop a small-animal model of IAC and to analyze the ocular tissue penetration, distribution, pharmacokinetics, and treatment efficacy.
Methods - Following selective ophthalmic artery (OA) catheterization, melphalan (0.4 to 1.2 mg/kg) was injected. For pharmacokinetic studies, rabbits were euthanized at 0.5, 1, 2, 4, or 6 hours following intra-OA infusion. Drug levels were determined in vitreous, retina, and blood by liquid chromatography tandem mass spectrometry. To assess toxicity, angiograms, photography, fluorescein angiography, and histopathology were performed. For in situ tissue drug distribution, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) was performed. The tumor model was created by combined subretinal/intravitreal injection of human WERI-Rb1 retinoblastoma cells; the tumor was treated in vivo with intra-arterial melphalan or saline; and induction of tumor death was measured by cleaved caspase-3 activity.
Results - OA was selectively catheterized for 79 of 79 (100%) eyes in 47 of 47 (100%) rabbits, and melphalan was delivered successfully in 31 of 31 (100%) eyes, without evidence of vascular occlusion or retinal damage. For treated eyes, maximum concentration (Cmax) in the retina was 4.95 μM and area under the curve (AUC0→∞) was 5.26 μM·h. Treated eye vitreous Cmax was 2.24 μM and AUC0→∞ was 4.19 μM·h. Vitreous Cmax for the treated eye was >100-fold higher than for the untreated eye (P = 0.01), and AUC0→∞ was ∼50-fold higher (P = 0.01). Histology-directed MALDI-IMS revealed highest drug localization within the retina. Peripheral blood Cmax was 1.04 μM and AUC0→∞ was 2.07 μM·h. Combined subretinal/intravitreal injection of human retinoblastoma cells led to intra-retinal tumors and subretinal/vitreous seeds, which could be effectively killed in vivo with intra-arterial melphalan.
Conclusions - This first small-animal model of IAC has excellent vitreous and retinal tissue drug penetration, achieving levels sufficient to kill human retinoblastoma cells, facilitating future IAC drug discovery.
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16 MeSH Terms
Identifying -mediators for -eQTLs across many human tissues using genomic mediation analysis.
Yang F, Wang J, GTEx Consortium, Pierce BL, Chen LS
(2017) Genome Res 27: 1859-1871
MeSH Terms: Databases, Genetic, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Selection, Genetic, Tissue Distribution
Show Abstract · Added November 29, 2017
The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (-eQTLs). More research is needed to identify effects of genetic variation on distant genes (-eQTLs) and understand their biological mechanisms. One common -eQTLs mechanism is "mediation" by a local () transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are "-mediators" of -eQTLs, including those "-hubs" involved in regulation of many -genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying -eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study -mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of -hubs and -eQTL regulation across tissue types.
© 2017 Yang et al.; Published by Cold Spring Harbor Laboratory Press.
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12 MeSH Terms
Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation.
Felts AS, Rodriguez AL, Blobaum AL, Morrison RD, Bates BS, Thompson Gray A, Rook JM, Tantawy MN, Byers FW, Chang S, Venable DF, Luscombe VB, Tamagnan GD, Niswender CM, Daniels JS, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2017) J Med Chem 60: 5072-5085
MeSH Terms: Allosteric Regulation, Aminopyridines, Animals, Chemistry Techniques, Synthetic, Drug Evaluation, Preclinical, HEK293 Cells, High-Throughput Screening Assays, Humans, Macaca fascicularis, Male, Mice, Inbred Strains, Picolinic Acids, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added March 21, 2018
Preclinical evidence in support of the potential utility of mGlu NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu versus the other mGlu receptors, and binding studies established a K value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.
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4 Members
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16 MeSH Terms
High-Resolution Image Stitching as a Tool to Assess Tissue-Level Protein Distribution and Localization.
Millis BA, Tyska MJ
(2017) Methods Mol Biol 1606: 281-296
MeSH Terms: Humans, Image Processing, Computer-Assisted, Microscopy, Confocal, Proteins, Software, Tissue Distribution
Show Abstract · Added April 10, 2018
High-resolution microscopy has traditionally come at the expense of field of view, resulting in suboptimal interpretation of protein distribution throughout large or complex samples. Likewise, a low-resolution microscopic approach inhibits the ability of researchers to precisely localize proteins of interest at the subcellular level. Until recently, the ability to combine the strengths of these approaches was limited and technically impractical for most laboratories to implement. Continued advances in microscope automation, sophisticated software applications, and modern workstations have enabled expansion of such combinatorial approaches to researchers outside computationally focused fields. Through image stitching, researchers can acquire large field-of-view, multidimensional datasets, at the diffraction limit of high-numerical aperture objectives to effectively map protein distribution in large samples with high precision. Here, we outline a protocol for acquisition of such datasets with the purpose of introducing inexperienced researchers to the methodology of large image stitching using the widely available technology of laser point-scanning confocal microscopy in combination with basic microscope automation and freely available software for post-acquisition processing.
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Combinatorial optimization of PEG architecture and hydrophobic content improves ternary siRNA polyplex stability, pharmacokinetics, and potency in vivo.
Werfel TA, Jackson MA, Kavanaugh TE, Kirkbride KC, Miteva M, Giorgio TD, Duvall C
(2017) J Control Release 255: 12-26
MeSH Terms: Animals, Cell Line, Cell Line, Tumor, Female, Humans, Hydrophobic and Hydrophilic Interactions, Luciferases, Methacrylates, Mice, Mice, Nude, Polyethylene Glycols, RNA, Small Interfering, Tissue Distribution
Show Abstract · Added March 14, 2018
A rationally-designed library of ternary siRNA polyplexes was developed and screened for gene silencing efficacy in vitro and in vivo with the goal of overcoming both cell-level and systemic delivery barriers. [2-(dimethylamino)ethyl methacrylate] (DMAEMA) was homopolymerized or copolymerized (50mol% each) with butyl methacrylate (BMA) from a reversible addition - fragmentation chain transfer (RAFT) chain transfer agent, with and without pre-conjugation to polyethylene glycol (PEG). Both single block polymers were tested as core-forming units, and both PEGylated, diblock polymers were screened as corona-forming units. Ternary siRNA polyplexes were assembled with varied amounts and ratios of core-forming polymers to PEGylated corona-forming polymers. The impact of polymer composition/ratio, hydrophobe (BMA) placement, and surface PEGylation density was correlated to important outcomes such as polyplex size, stability, pH-dependent membrane disruptive activity, biocompatibility, and gene silencing efficiency. The lead formulation, DB4-PDB12, was optimally PEGylated not only to ensure colloidal stability (no change in size by DLS between 0 and 24h) and neutral surface charge (0.139mV) but also to maintain higher cell uptake (>90% positive cells) than the most densely PEGylated particles. The DB4-PDB12 polyplexes also incorporated BMA in both the polyplex core- and corona-forming polymers, resulting in robust endosomolysis and in vitro siRNA silencing (~85% protein level knockdown) of the model gene luciferase across multiple cell types. Further, the DB4-PDB12 polyplexes exhibited greater stability, increased blood circulation time, reduced renal clearance, increased tumor biodistribution, and greater silencing of luciferase compared to our previously-optimized, binary parent formulation following intravenous (i.v.) delivery. This polyplex library approach enabled concomitant optimization of the composition and ratio of core- and corona-forming polymers (indirectly tuning PEGylation density) and identification of a ternary nanomedicine optimized to overcome important siRNA delivery barriers in vitro and in vivo.
Copyright © 2017 Elsevier B.V. All rights reserved.
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13 MeSH Terms
Evaluation of TSPO PET Ligands [F]VUIIS1009A and [F]VUIIS1009B: Tracers for Cancer Imaging.
Tang D, Li J, Buck JR, Tantawy MN, Xia Y, Harp JM, Nickels ML, Meiler J, Manning HC
(2017) Mol Imaging Biol 19: 578-588
MeSH Terms: Animals, Binding Sites, Blood Proteins, Carrier Proteins, Cell Line, Tumor, Diagnostic Imaging, Fluorine Radioisotopes, Glioma, Ligands, Male, Mice, Inbred C57BL, Positron-Emission Tomography, Rats, Tissue Distribution, Whole Body Imaging
Show Abstract · Added April 6, 2017
PURPOSE - Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [F]VUIIS1009A ([F]3A) and [F]VUIIS1009B ([F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.
PROCEDURES - VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D H-N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [F]VUIIS1009A and [F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.
RESULTS - Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [F]VUIIS1009A ([F]3A) and [F]VUIIS1009B ([F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [F]VUIIS1009A and [F]VUIIS1009B exhibited greater binding potential (k /k )in tumor tissue compared to [F]DPA-714. Interestingly, [F]VUIIS1009B exhibited significantly greater tumor uptake (V ) than [F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.
CONCLUSIONS - The novel PET ligand [F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.
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15 MeSH Terms