Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The standard pharmacokinetic model for the analysis of MRI contrast reagent (CR) bolus-tracking (B-T) data assumes that the mean intracellular water molecule lifetime (tau(i)) is effectively zero. This assertion is inconsistent with a considerable body of physiological measurements. Furthermore, theory and simulation show the B-T time-course shape to be very sensitive to the tau(i) magnitude in the physiological range (hundreds of milliseconds to several seconds). Consequently, this standard model aspect can cause significant underestimations (factors of 2 or 3) of the two parameters usually determined: K(trans), the vascular wall CR transfer rate constant, and v(e), the CR distribution volume (the extracellular, extravascular space fraction). Analyses of animal model data confirmed two predicted behaviors indicative of this standard model inadequacy: (1) a specific temporal pattern for the mismatch between the best-fitted curve and data; and (2) an inverse dependence of the curve's K(trans) and v(e) magnitudes on the CR dose. These parameters should be CR dose-independent. The most parsimonious analysis allowing for realistic tau(i) values is the 'shutter-speed' model. Its application to the experimental animal data essentially eliminated the two standard model signature inadequacies. This paper reports the first survey for the extent of this 'shutter-speed effect' in human data. Retrospective analyses are made of clinical data chosen from a range of pathology (the active multiple sclerosis lesion, the invasive ductal carcinoma breast tumor, and osteosarcoma in the leg) that provides a wide variation, particularly of K(trans). The signature temporal mismatch of the standard model is observed in all cases, and is essentially eliminated by use of the shutter-speed model. Pixel-by-pixel maps show that parameter values from the shutter-speed analysis are increased by more than a factor of 3 for some lesion regions. This endows the lesions with very high contrast, and reveals heterogeneities that are often not seen in the standard model maps. Normal muscle regions in the leg allow validation of the shutter-speed model K(trans), v(e), and tau(i) magnitudes, by comparison with results of previous careful rat leg studies not possible for human subjects.
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PMID:Evidence for shutter-speed variation in CR bolus-tracking studies of human pathology. 1557 8

Protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of arginine residues to form citrulline. This once obscure modification is now known to play a key role in the etiology of multiple autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, lupus, and ulcerative colitis) and in some forms of cancer. Among the five human PADs (PAD1, -2, -3, -4, and -6), it is unclear which isozyme contributes to disease pathogenesis. Toward the identification of potent, selective, and bioavailable PAD inhibitors that can be used to elucidate the specific roles of each isozyme, we describe tetrazole analogs as suitable backbone amide bond bioisosteres for the parent pan PAD inhibitor Cl-amidine. These tetrazole based analogs are highly potent and show selectivity toward particular isozymes. Importantly, one of the compounds, biphenyl tetrazole tert-butyl Cl-amidine (compound 13), exhibits enhanced cell killing in a PAD4 expressing osteosarcoma bone marrow (U2OS) cell line and can also block the formation of neutrophil extracellular traps. These bioisosteres represent an important step in our efforts to develop stable, bioavailable, and selective inhibitors for the PADs.
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PMID:Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors. 2555 47