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A comparative assessment of preclinical chemotherapeutic response of tumors using quantitative non-Gaussian diffusion MRI.
Xu J, Li K, Smith RA, Waterton JC, Zhao P, Ding Z, Does MD, Manning HC, Gore JC
(2017) Magn Reson Imaging 37: 195-202
MeSH Terms: Animals, Bayes Theorem, Colonic Neoplasms, Diffusion Magnetic Resonance Imaging, Dimethyl Sulfoxide, Disease Models, Animal, Female, Humans, Mice, Mice, Nude, Models, Statistical, Organophosphates, Protein Kinase Inhibitors, Quinazolines
Show Abstract · Added April 6, 2017
BACKGROUND - Diffusion-weighted MRI (DWI) signal attenuation is often not mono-exponential (i.e. non-Gaussian diffusion) with stronger diffusion weighting. Several non-Gaussian diffusion models have been developed and may provide new information or higher sensitivity compared with the conventional apparent diffusion coefficient (ADC) method. However the relative merits of these models to detect tumor therapeutic response is not fully clear.
METHODS - Conventional ADC, and three widely-used non-Gaussian models, (bi-exponential, stretched exponential, and statistical model), were implemented and compared for assessing SW620 human colon cancer xenografts responding to barasertib, an agent known to induce apoptosis via polyploidy. Bayesian Information Criterion (BIC) was used for model selection among all three non-Gaussian models.
RESULTS - All of tumor volume, histology, conventional ADC, and three non-Gaussian DWI models could show significant differences between control and treatment groups after four days of treatment. However, only the non-Gaussian models detected significant changes after two days of treatment. For any treatment or control group, over 65.7% of tumor voxels indicate the bi-exponential model is strongly or very strongly preferred.
CONCLUSION - Non-Gaussian DWI model-derived biomarkers are capable of detecting tumor earlier chemotherapeutic response of tumors compared with conventional ADC and tumor volume. The bi-exponential model provides better fitting compared with statistical and stretched exponential models for the tumor and treatment models used in the current work.
Copyright © 2016 Elsevier Inc. All rights reserved.
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3 Members
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14 MeSH Terms
IQGAP1 makes PI(3)K signalling as easy as PIP, PIP, PIP.
Rameh LE, Mackey AM
(2016) Nat Cell Biol 18: 1263-1265
MeSH Terms: Animals, Humans, Models, Biological, Neoplasms, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Phosphorylation, Signal Transduction, ras GTPase-Activating Proteins
Show Abstract · Added November 26, 2018
Despite being one of the most studied signalling pathways, precisely how phospholipid synthesis is regulated in the phosphoinositide signalling cascade remains unclear. The scaffold protein IQGAP1 is now shown to orchestrate the assembly of a multi-enzyme complex that streamlines PtdIns(3,4,5)P synthesis to facilitate Akt activation in response to extracellular stimuli.
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MeSH Terms
Plasmin Prevents Dystrophic Calcification After Muscle Injury.
Mignemi NA, Yuasa M, Baker CE, Moore SN, Ihejirika RC, Oelsner WK, Wallace CS, Yoshii T, Okawa A, Revenko AS, MacLeod AR, Bhattacharjee G, Barnett JV, Schwartz HS, Degen JL, Flick MJ, Cates JM, Schoenecker JG
(2017) J Bone Miner Res 32: 294-308
MeSH Terms: Animals, Calcinosis, Cardiotoxins, Diphosphates, Fibrinolysin, Fibrinolysis, Genetic Predisposition to Disease, Mice, Inbred C57BL, Muscle, Skeletal, Ossification, Heterotopic, Regeneration
Show Abstract · Added October 3, 2016
Extensive or persistent calcium phosphate deposition within soft tissues after severe traumatic injury or major orthopedic surgery can result in pain and loss of joint function. The pathophysiology of soft tissue calcification, including dystrophic calcification and heterotopic ossification (HO), is poorly understood; consequently, current treatments are suboptimal. Here, we show that plasmin protease activity prevents dystrophic calcification within injured skeletal muscle independent of its canonical fibrinolytic function. After muscle injury, dystrophic calcifications either can be resorbed during the process of tissue healing, persist, or become organized into mature bone (HO). Without sufficient plasmin activity, dystrophic calcifications persist after muscle injury and are sufficient to induce HO. Downregulating the primary inhibitor of plasmin (α2-antiplasmin) or treating with pyrophosphate analogues prevents dystrophic calcification and subsequent HO in vivo. Because plasmin also supports bone homeostasis and fracture repair, increasing plasmin activity represents the first pharmacologic strategy to prevent soft tissue calcification without adversely affecting systemic bone physiology or concurrent muscle and bone regeneration. © 2016 American Society for Bone and Mineral Research.
© 2016 American Society for Bone and Mineral Research.
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2 Members
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11 MeSH Terms
Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus.
Freedman BI, Divers J, Russell GB, Palmer ND, Bowden DW, Carr JJ, Wagenknecht LE, Hightower RC, Xu J, Smith SC, Langefeld CD, Hruska KA, Register TC
(2015) Am J Nephrol 42: 391-401
MeSH Terms: Adult, African Americans, Aged, Albuminuria, Blood Pressure, Bone Density, Carotid Arteries, Coronary Vessels, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Fibroblast Growth Factors, Follow-Up Studies, Glomerular Filtration Rate, Glycated Hemoglobin A, Humans, Iliac Artery, Kidney Function Tests, Male, Middle Aged, Phosphates, Plaque, Atherosclerotic, Renin-Angiotensin System, Risk Factors, Tomography, X-Ray Computed, Vitamin D
Show Abstract · Added September 29, 2016
BACKGROUND - Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial.
METHODS - Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate.
RESULTS - The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m2, urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up.
CONCLUSIONS - Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy.
© 2016 S. Karger AG, Basel.
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1 Members
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26 MeSH Terms
VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.
Nickols HH, Yuh JP, Gregory KJ, Morrison RD, Bates BS, Stauffer SR, Emmitte KA, Bubser M, Peng W, Nedelcovych MT, Thompson A, Lv X, Xiang Z, Daniels JS, Niswender CM, Lindsley CW, Jones CK, Conn PJ
(2016) J Pharmacol Exp Ther 356: 123-36
MeSH Terms: Allosteric Regulation, Animals, Anti-Anxiety Agents, Astrocytes, Behavior, Animal, Brain, Dose-Response Relationship, Drug, Drug Discovery, GABA Agonists, HEK293 Cells, Humans, Inositol Phosphates, MAP Kinase Signaling System, Membrane Potentials, Mice, Mice, Inbred C57BL, Picolinic Acids, Pyridines, Radioligand Assay, Rats, Receptor, Metabotropic Glutamate 5, Synaptic Transmission
Show Abstract · Added February 18, 2016
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [(3)H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
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3 Members
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22 MeSH Terms
PI(3,5)P2 controls endosomal branched actin dynamics by regulating cortactin-actin interactions.
Hong NH, Qi A, Weaver AM
(2015) J Cell Biol 210: 753-69
MeSH Terms: Actin-Related Protein 2-3 Complex, Actins, Binding Sites, Cell Line, Tumor, Cortactin, Endosomes, Enzyme Activation, HeLa Cells, Humans, Phosphatidylinositol Phosphates, Protein Binding, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Wiskott-Aldrich Syndrome Protein, Neuronal, rab GTP-Binding Proteins
Show Abstract · Added February 15, 2016
Branched actin critically contributes to membrane trafficking by regulating membrane curvature, dynamics, fission, and transport. However, how actin dynamics are controlled at membranes is poorly understood. Here, we identify the branched actin regulator cortactin as a direct binding partner of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and demonstrate that their interaction promotes turnover of late endosomal actin. In vitro biochemical studies indicated that cortactin binds PI(3,5)P2 via its actin filament-binding region. Furthermore, PI(3,5)P2 competed with actin filaments for binding to cortactin, thereby antagonizing cortactin activity. These findings suggest that PI(3,5)P2 formation on endosomes may remove cortactin from endosome-associated branched actin. Indeed, inhibition of PI(3,5)P2 production led to cortactin accumulation and actin stabilization on Rab7(+) endosomes. Conversely, inhibition of Arp2/3 complex activity greatly reduced cortactin localization to late endosomes. Knockdown of cortactin reversed PI(3,5)P2-inhibitor-induced actin accumulation and stabilization on endosomes. These data suggest a model in which PI(3,5)P2 binding removes cortactin from late endosomal branched actin networks and thereby promotes net actin turnover.
© 2015 Hong et al.
1 Communities
1 Members
0 Resources
16 MeSH Terms
A Spectrum: Nephrocalcinosis-Nephrolithiasis.
Hsi RS, Stoller ML
(2015) J Urol 194: 1188-9
MeSH Terms: Calcium Oxalate, Calcium Phosphates, Humans, Kidney Calculi, Nephrocalcinosis, Nephrostomy, Percutaneous, Tomography, X-Ray Computed
Added January 16, 2018
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1 Members
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7 MeSH Terms
Ferric pyrophosphate citrate administered via dialysate reduces erythropoiesis-stimulating agent use and maintains hemoglobin in hemodialysis patients.
Gupta A, Lin V, Guss C, Pratt R, Ikizler TA, Besarab A
(2015) Kidney Int 88: 1187-94
MeSH Terms: Adult, Aged, Dialysis Solutions, Diphosphates, Double-Blind Method, Female, Hematinics, Hemoglobins, Humans, Iron, Male, Middle Aged, Renal Dialysis, Trace Elements
Show Abstract · Added August 5, 2015
Ferric pyrophosphate citrate (FPC) is a water-soluble iron salt administered via dialysate to supply iron directly to transferrin. The PRIME study tested whether treatment with FPC could reduce prescribed erythropoiesis-stimulating agent (ESA) use and maintain hemoglobin in hemodialysis patients. This 9-month, randomized, placebo-controlled, double-blind, multicenter clinical study included 103 patients undergoing hemodialysis 3-4 times weekly. The FPC group received dialysate containing 2 μmol/l of iron. The placebo group received standard dialysate. A blinded central anemia management group facilitated ESA dose adjustments. Intravenous iron was administered according to the approved indication when ferritin levels fell below 200 μg/l. The primary end point was the percentage change from baseline in prescribed ESA dose at end of treatment. Secondary end points included intravenous iron use and safety. At the end of treatment, there was a significant 35% reduction in prescribed ESA dose in FPC-treated patients compared with placebo. The FPC patients used 51% less intravenous iron than placebo. Adverse and serious adverse events were similar in both groups. Thus, FPC delivered via dialysate significantly reduces the prescribed ESA dose and the amount of intravenous iron needed to maintain hemoglobin in chronic hemodialysis patients.
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14 MeSH Terms
Aromatic hydroxylation of salicylic acid and aspirin by human cytochromes P450.
Bojić M, Sedgeman CA, Nagy LD, Guengerich FP
(2015) Eur J Pharm Sci 73: 49-56
MeSH Terms: Aspirin, Benzaldehydes, Biotransformation, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Deferoxamine, Enzyme Inhibitors, Humans, Hydroxylation, Isoenzymes, Microsomes, Liver, NADP, Organophosphates, Oxidation-Reduction, Reactive Oxygen Species, Recombinant Proteins, Salicylic Acid
Show Abstract · Added March 14, 2018
Aspirin (acetylsalicylic acid) is a well-known and widely-used analgesic. It is rapidly deacetylated to salicylic acid, which forms two hippuric acids-salicyluric acid and gentisuric acid-and two glucuronides. The oxidation of aspirin and salicylic acid has been reported with human liver microsomes, but data on individual cytochromes P450 involved in oxidation is lacking. In this study we monitored oxidation of these compounds by human liver microsomes and cytochrome P450 (P450) using UPLC with fluorescence detection. Microsomal oxidation of salicylic acid was much faster than aspirin. The two oxidation products were 2,5-dihydroxybenzoic acid (gentisic acid, documented by its UV and mass spectrum) and 2,3-dihydroxybenzoic acid. Formation of neither product was inhibited by desferrioxamine, suggesting a lack of contribution of oxygen radicals under these conditions. Although more liphophilic, aspirin was oxidized less efficiently, primarily to the 2,5-dihydroxy product. Recombinant human P450s 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 all catalyzed the 5-hydroxylation of salicylic acid. Inhibitor studies with human liver microsomes indicated that all six of the previously mentioned P450s could contribute to both the 5- and 3-hydroxylation of salicylic acid and that P450s 2A6 and 2B6 have contributions to 5-hydroxylation. Inhibitor studies indicated that the major human P450 involved in both 3- and 5-hydroxylation of salicylic acid is P450 2E1.
Copyright © 2015 Elsevier B.V. All rights reserved.
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17 MeSH Terms
Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling.
de Seigneux S, Courbebaisse M, Rutkowski JM, Wilhelm-Bals A, Metzger M, Khodo SN, Hasler U, Chehade H, Dizin E, Daryadel A, Stengel B, NephroTest Study Group, Girardin E, Prié D, Wagner CA, Scherer PE, Martin PY, Houillier P, Feraille E
(2015) J Am Soc Nephrol 26: 1608-18
MeSH Terms: Adult, Albuminuria, Analysis of Variance, Animals, Benzimidazoles, Blotting, Western, Child, Disease Models, Animal, Fibroblast Growth Factors, Humans, Kidney Tubules, Proximal, Male, Mice, Mice, Transgenic, Nephrotic Syndrome, Parathyroid Hormone, Phosphates, Prospective Studies, Proteinuria, Rats, Rats, Wistar, Sensitivity and Specificity, Sodium-Phosphate Cotransporter Proteins, Type IIa, Tetrazoles, Urinalysis
Show Abstract · Added December 26, 2018
Proteinuria and hyperphosphatemia are cardiovascular risk factors independent of GFR. We hypothesized that proteinuria induces relative phosphate retention via increased proximal tubule phosphate reabsorption. To test the clinical relevance of this hypothesis, we studied phosphate handling in nephrotic children and patients with CKD. Plasma fibroblast growth factor 23 (FGF-23) concentration, plasma phosphate concentration, and tubular reabsorption of phosphate increased during the proteinuric phase compared with the remission phase in nephrotic children. Cross-sectional analysis of a cohort of 1738 patients with CKD showed that albuminuria≥300 mg/24 hours is predictive of higher phosphate levels, independent of GFR and other confounding factors. Albuminuric patients also displayed higher plasma FGF-23 and parathyroid hormone levels. To understand the molecular mechanisms underlying these observations, we induced glomerular proteinuria in two animal models. Rats with puromycin-aminonucleoside-induced nephrotic proteinuria displayed higher renal protein expression of the sodium-phosphate co-transporter NaPi-IIa, lower renal Klotho protein expression, and decreased phosphorylation of FGF receptor substrate 2α, a major FGF-23 receptor substrate. These findings were confirmed in transgenic mice that develop nephrotic-range proteinuria resulting from podocyte depletion. In vitro, albumin did not directly alter phosphate uptake in cultured proximal tubule OK cells. In conclusion, we show that proteinuria increases plasma phosphate concentration independent of GFR. This effect relies on increased proximal tubule NaPi-IIa expression secondary to decreased FGF-23 biologic activity. Proteinuria induces elevation of both plasma phosphate and FGF-23 concentrations, potentially contributing to cardiovascular disease.
Copyright © 2015 by the American Society of Nephrology.
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