12 research outputs found
MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A
Cell cycle exit is required for proper differentiation in most cells and is critical for normal development, tissue homeostasis, and tumor suppression. However, the mechanisms that link cell cycle exit with differentiation remain poorly understood. Here, we show that the master melanocyte differentiation factor, microphthalmia transcription factor (MITF), regulates cell cycle exit by activating the cell cycle inhibitor INK4A, a tumor suppressor that frequently is mutated in melanomas. MITF binds the INK4A promoter, activates p16Ink4a mRNA and protein expression, and induces retinoblastoma protein hypophosphorylation, thereby triggering cell cycle arrest. This activation of INK4A was required for efficient melanocyte differentiation. Interestingly, MITF was also required for maintaining INK4A expression in mature melanocytes, creating a selective pressure to escape growth inhibition by inactivating INK4A. These findings demonstrate that INK4A can be regulated by a differentiation factor, establish a mechanistic link between melanocyte differentiation and cell cycle exit, and potentially explain the tissue-specific tendency for INK4A mutations to occur in melanoma
First Administration of the Fc-Attenuated Anti-beta Amyloid Antibody GSK933776 to Patients with Mild Alzheimer's Disease: A Randomized, Placebo-Controlled Study
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Molecular genetics of uveal melanoma
In the past decade, there have been impressive advances in our understanding of chromosomal, genetic and molecular alterations that occur in uveal melanoma. Nevertheless, a coherent picture of the molecular pathogenesis of this eye cancer is yet to emerge. Herein, we review the findings to date, discuss the insights they provide, and suggest future directions for molecular research in uveal melanoma
GSK933776 plasma pharmacodynamics.
<p>A) Geometric mean plasma Aβ concentration–time plots over the three dosing intervals (semi-log plot). Plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased in dose-dependent manner. Peak:trough ratios for Aβ decreased with increasing dose of GSK933776. B) Week 12 ratio to baseline for CSF Aβ (Aβ1–42 and AβX–42) concentrations. Presented as individual values and mean (95%CI). There were no significant changes from baseline for Aβ1–42 or AβX–42.</p
Summary of most frequently reported adverse events.
<p>SD = single dose; RD = repeat dose.</p><p><sup>2</sup>Amyloid-related imaging abnormality-hemorrhage (ARIA-H)</p><p><sup>1</sup>Amyloid-related imaging abnormality-edema (ARIA-E);</p><p>Summary of most frequently reported adverse events.</p
Summary of patients’ baseline characteristics.
<p>SD = single dose; RD = repeat dose; SE = standard error.</p><p><sup>3</sup>Three patients participated in two dose levels of the single dose study and therefore the PGx sample was collected at the first dosing level in which they participated and not the second dosing level. <i>APOE</i> ε4 overall carriage frequency was calculated using the PGx population (n = 15), i.e., patients who participated in more than one dosing level were only taken into account once.</p><p><sup>2</sup>Six patients participated in part A and re-entered part B. Therefore the pharmacogenetic (PGx) sample was collected when the patients participated in part A and no PGx sample was collected during part B. <i>APOE</i> ε4 overall carriage frequency was calculated using the PGx population (n = 44), i.e., patients who participated in both parts were only taken into account once.</p><p><sup>1</sup>Values ranged from 20 to 26 for all patients except one, who scored 28.</p><p>Summary of patients’ baseline characteristics.</p
GSK933776 plasma pharmacokinetics.
<p>Time-course of plasma concentrations of GSK933776 by dose: medians (lines) and individual data (dots). LLQ is 100 ng/mL for the 0.1 mg/kg dose and 5 μg/mL for the 1, 3, and 6 mg/kg doses. SD = single dose; RD = repeat dose. Maximum plasma concentrations increased with dose.</p