Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy

Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid βâ glucosidase), with consequent cellular accumulation of glucosylceramide (GLâ 1). The disease is managed by intravenous administrations of recombinant glucocerebrosidase (imiglucerase), although symptomatic patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy (ERT) is not an option may also be treated by substrate reduction therapy (SRT) with miglustat. To determine whether the sequential use of both ERT and SRT may provide additional benefits, we compared the relative pharmacodynamic efficacies of separate and sequential therapies in a murine model of Gaucher disease (D409V/null). As expected, ERT with recombinant glucocerebrosidase was effective in reducing the burden of GLâ 1 storage in the liver, spleen, and lung of 3â monthâ old Gaucher mice. SRT using a novel inhibitor of glucosylceramide synthase (Genzâ 112638) was also effective, albeit to a lesser degree than ERT. Animals administered recombinant glucocerebrosidase and then Genzâ 112638 showed the lowest levels of GLâ 1 in all the visceral organs and a reduced number of Gaucher cells in the liver. This was likely because the additional deployment of SRT following enzyme therapy slowed the rate of reaccumulation of GLâ 1 in the affected organs. Hence, in patients whose disease has been stabilized by intravenously administered recombinant glucocerebrosidase, orally administered SRT with Genzâ 112638 could potentially be used as a convenient maintenance therapy. In patients naïve to treatment, ERT followed by SRT could potentially accelerate clearance of the offending substrate.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147062/1/jimd0281.pd

Resultats preliminaires de la campagne de forages du Joides Resolution sur le plateau de Kerguelen (ODP Leg 120)/ Preliminary results of ODP Leg 120 in the Central and Southern Kerguelen Plateau

Resume - Le Leg 120 du programme international de forages oceaniques (Ocean Drilling Project) a permis de determiner la nature et l\u27age du plateau de Kerguelen et de decrire son evolution depuis Ie Cretace. Le socle, fore aux sites 747, 749 ct 750, est compose de coulees basaltiqucs qui correspondent a des tholeiites transitionnelles saturees en silice. Ces basaltes se sont mis en place dans des conditions aeriennes ou sub-aeriennes avant Ie Cenomanien sur une surface quasiment horizontalc. Les premiers sediments, d\u27age Cenomanien, se sont deposes en milieu fluviatile. Au Campanien et a la fin du Maestrichtien Ie plateau a subside rapidement et a ete affecte par une phase tectonique extensive majeure entre 75 et 68 M.a. Ces deux evenernents marquent sans doute la separation du domaine sud du plateau de Kerguelen et de I\u27ensemble Broken Ridge-Diamantina Zone. Abstract - Leg 120 of the Ocean Drilling Program was devoted to studying the nature and evolution of the Central and Southern Kerguelen Plateau. The basement drilled at sites 747, 749 and 750 is composed of basaltic flows which are silica-saturated transitional tholeiites. These basalts were erupted prior to the Cenomanian under subaerial or shallow marine conditions and were emplaced on a near horizontal surface. The early sedimentation during the Cenomanian denotes fluvial conditions. During the Campanian and late Maestrichtian the plateau subsided rapidly and a major tectonic episode occurred between 75 and 68 M.a. These events are possibly related to the breakup between the Southern Kerguelen Plateau and Broken Ridge-Diamantina Zone

Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit inPatients WithRefractory Gastrointestinal Stromal Tumors A Phase 1b/2a Nonrandomized Clinical Trial

IMPORTANCE Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors. OBJECTIVE To assess whether combining a type II KIT inhibitor with a conformationcomplementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control. DESIGN, SETTING, AND PARTICIPANTS A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020. INTERVENTIONS Participants received 250, 350, 500, and 1000mg of PLX9486 alone (part 1) or 500 and 1000mg of PLX9486 together with 25 or 37.5mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal. MAIN OUTCOMES AND MEASURES Pharmacokinetics, safety, and tumor responseswere assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA. RESULTS A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14%(0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively. CONCLUSIONS AND RELEVANCE In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile