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"Jon Collins"
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Fodor's Oregon
\"Fodor's correspondents highlight the best of Oregon, including Portland's quirky charm, the coast's beaches and bluffs, and outdoor activities in the Cascade Mountains. Our local experts vet every recommendation to ensure you make the most of your time, whether it's your first trip or your fifth.\" -- Back cover.
Book
Ube3a unsilencer for the potential treatment of Angelman syndrome
Deletion of the maternal
UBE3A
allele causes Angelman syndrome (AS)
;
because paternal
UBE3A
is epigenetically silenced by a long non-coding antisense (
UBE3A-ATS
) in neurons, this nearly eliminates UBE3A protein in the brain. Reactivating paternal
UBE3A
holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal
UBE3A
, but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (
S
)-PHA533533 acts through a novel mechanism to significantly increase paternal
Ube3a
mRNA and UBE3A protein levels while downregulating
Ube3a-ATS
in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (
S
)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (
S
)-PHA533533 unsilences paternal
UBE3A
in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal
UBE3A
.
Angelman syndrome is a neurodevelopmental disorder caused by the deletion of a single gene. Here, researchers discovered a small molecule that could be delivered peripherally to activate a dormant copy of the gene throughout the brain, providing a potential treatment opportunity.
Journal Article
Fodor's inside Portland
\"With its fascinating history, incomparable culinary landscape, and blossoming art scene, Portland has become one of the most sought-after destinations for the hip, curious traveler. Fodor's brand-new guidebook, Inside Portland, touches on the top tourist sights, from Powell's Bookstore to the International Rose Test Garden, but also delves into the under-the-radar places that only insiders from Portland know about.\"--Page 4 of cover.
Book
Recruitment of FBXO22 for targeted degradation of NSD2
Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCF
FBXO22
Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCF
FBXO22
. Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD.
Nie et al. describe a mechanism underlying the degradation of the histone methyltransferase NSD2 through the recruitment of FBXO22 E3 ligase, providing a chemical probe for NSD2 function study and targeted protein degradation.
Journal Article
The Hunger Games
Set in a future where the Capitol selects a boy and girl from the twelve districts to fight to the death on live television. Katniss Everdeen volunteers to take her younger sister's place for the latest match.
DVD
Synthetic LXR Ligand Inhibits the Development of Atherosclerosis in Mice
The nuclear receptors LXRα and LXRβ have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR-/-mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE-/-mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR-/-and apoE-/-mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.
Journal Article
Analysis of C4 Concentrations to Predict Impact of Patient‐Reported Diarrhea Associated With the Ileal Bile Acid Transporter Inhibitor Linerixibat
Linerixibat, an ileal bile acid transporter (IBAT) inhibitor, is being evaluated for the treatment of pruritus in primary biliary cholangitis (PBC). Diarrhea is commonly reported with this drug class as IBAT inhibition redirects bile acids (BA) to the colon. Serum 7‐alpha‐hydroxy‐4‐cholesten‐3‐one (C4) measurement is a validated method to identify BA diarrhea. To inform dose selection, we characterized the relationship between linerixibat dose, C4 levels, and patient‐reported bother on the gastrointestinal symptom rating scale (GSRS) diarrhea question. A kinetic‐pharmacodynamic model was developed using data from five Phase 1/2 trials, to describe the effect of linerixibat dose (1–180 mg) and regimen (once/twice daily) on C4 concentrations over time. GSRS data from patients with PBC and pruritus in the Phase 2b GLIMMER study (NCT02966834) were used to develop a proportional odds model to predict the probability of a score of 1–7 (no–very severe discomfort) to the question “Have you been bothered by diarrhea during the past week?” in relation to linerixibat dose. The two models were linked to describe the linerixibat dose‐C4‐diarrhea bother relationship. Models were validated using graphical and numerical assessment and visual predictive checks. Linerixibat caused dose‐dependent increases in C4 until saturation (~180 mg total daily dose). Increased C4 concentrations trended with increased GSRS diarrhea scores. Simulations demonstrated increases in moderate‐to‐very severe (≥ 4) diarrhea scores with increasing linerixibat dose. Increases in patient‐reported diarrhea scores were linerixibat dose‐dependent. Selecting an optimal dose that maximizes linerixibat's ability to improve pruritus while minimizing patient‐reported diarrhea bother is important to support treatment adherence.
Journal Article
Ligand activation of LXRβ reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRα and apoE
Liver X receptors (LXRs) alpha and beta are transcriptional regulators of cholesterol homeostasis and potential targets for the development of antiatherosclerosis drugs. However, the specific roles of individual LXR isotypes in atherosclerosis and the pharmacological effects of synthetic agonists remain unclear. Previous work has shown that mice lacking LXRalpha accumulate cholesterol in the liver but not in peripheral tissues. In striking contrast, we demonstrate here that LXRalpha(-/-)apoE(-/-) mice exhibit extreme cholesterol accumulation in peripheral tissues, a dramatic increase in whole-body cholesterol burden, and accelerated atherosclerosis. The phenotype of these mice suggests that the level of LXR pathway activation in macrophages achieved by LXRbeta and endogenous ligand is unable to maintain homeostasis in the setting of hypercholesterolemia. Surprisingly, however, a highly efficacious synthetic agonist was able to compensate for the loss of LXRalpha. Treatment of LXRalpha(-/-)apoE(-/-) mice with synthetic LXR ligand ameliorates the cholesterol overload phenotype and reduces atherosclerosis. These observations indicate that LXRalpha has an essential role in maintaining peripheral cholesterol homeostasis in the context of hypercholesterolemia and provide in vivo support for drug development strategies targeting LXRbeta.
Journal Article
Activation of Liver X Receptor Improves Glucose Tolerance through Coordinate Regulation of Glucose Metabolism in Liver and Adipose Tissue
The control of lipid and glucose metabolism is closely linked. The nuclear receptors liver X receptor (LXR)α and LXRβ have been implicated in gene expression linked to lipid homeostasis; however, their role in glucose metabolism is not clear. We demonstrate here that the synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance. Analysis of gene expression in LXR agonist-treated mice reveals coordinate regulation of genes involved in glucose metabolism in liver and adipose tissue. In the liver, activation of LXR led to the suppression of the gluconeogenic program including down-regulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase expression. Inhibition of gluconeogenic genes was accompanied by an induction in expression of glucokinase, which promotes hepatic glucose utilization. In adipose tissue, activation of LXR led to the transcriptional induction of the insulin-sensitive glucose transporter, GLUT4. We show that the GLUT4 promoter is a direct transcriptional target for the LXR/retinoid X receptor heterodimer and that the ability of LXR ligands to induce GLUT4 expression is abolished in LXR null cells and animals. Consistent with their effects on GLUT4 expression, LXR agonists promote glucose uptake in 3T3-L1 adipocytes in vitro. Thus, activation of LXR alters the expression of genes in liver and adipose tissue that collectively would be expected to limit hepatic glucose output and improve peripheral glucose uptake. These results outline a role for LXRs in the coordination of lipid and glucose metabolism.
Journal Article
Population pharmacokinetics of belantamab mafodotin, a BCMA‐targeting agent in patients with relapsed/refractory multiple myeloma
Belantamab mafodotin (belamaf) is an antibody–drug conjugate (ADC) targeting B‐cell maturation antigen (BCMA). Nonlinear mixed‐effects models were developed to characterize the population pharmacokinetics (PopPK) of ADC, total monoclonal antibody (mAb), and cysteine‐maleimidocaproyl‐MMAF (cys‐mcMMAF) after 0.03–4.6 mg/kg dosing every 3 weeks in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM; DREAMM‐1, n = 73; DREAMM‐2, n = 218). Sequential modeling methodology was used. Individual post hoc parameter estimates from the final ADC model were used to develop total mAb and cys‐mcMMAF models. Formal covariate selection used a modified stepwise forward inclusion method with backward elimination. A linear, two‐compartment PopPK model with a time‐varying clearance (CL) described ADC PK. Initial ADC typical value for CL for a DREAMM‐2 patient was 0.936 L/day with a half‐life of 11.5 days, over time CL was reduced by 28% resulting in a half‐life of 14.3 days. Time to 50% maximal CL change was ~ 50 days. Baseline soluble BCMA (sBCMA), immunoglobulin (IgG), albumin, and bodyweight impacted ADC CL. Cys‐mcMMAF concentrations were described with a linear two‐compartment model linked to ADC; input rate was governed by deconjugation/intracellular proteolytic degradation of ADC represented by an exponentially decreasing MMAF:mAb (drug antibody ratio [DAR]) after each dose. Time to 50% DAR reduction was 10.3 days. Baseline sBCMA and IgG impacted cys‐mcMMAF central volume of distribution. In conclusion, ADC, total mAb, and cys‐mcMMAF concentration–time profiles in RRMM were well‐described by PopPK models, and exposure was most strongly impacted by disease‐related characteristics.
Journal Article