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Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4 . Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).

Experimental E. coli endophthalmitis was produced in rabbits. The Limulus lysate test was applied to aqueous and vitreous samples at various intervals after the intravitreal injection of E. coli organisms. Results indicated that this test is feasible using vitreous and aqueous samples. The Limulus test was positive for E. coli endotoxin within hours after infection, requiring only 1 hr to determine the presence of endotoxin after sampling. This test may have some value in the rapid diagnosis of gram-negative endophthalmitis.

Experimental histoplasmic choroiditis was produced in primates by intracarotid injections of living H. capsulatum organisms. The severity of the choroiditis varied with inoculum size, as well as with site of injection (common carotid vs. internal carotid artery). A reproducible model of histoplasmic choroiditis in primates was produced with an internal carotid injection of 5,000 to 10,000 organisms/lb. The clinical and histopathological course of this acute choroiditis over the first 30 days is presented.