Key Points A novel PI3Kδ inhibitor TGR-1202 synergizes with proteasome inhibitor carfilzomib by silencing c-Myc in preclinical models of lymphoma. The unique activity of TGR-1202 as a single agent and in combination with carfilzomib is driven by an unexpected activity targeting CK1ε.

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Purpose: To evaluate the pharmacologic activity of a novel inhibitor of IkB kinase b (IKK2), LY2409881, in preclinical models of B-and T-cell lymphoma, as a single agent and in combination with histone deacetylase (HDAC) inhibitors.Experimental Design: The in vitro activity of LY2409881 was determined using an ATP-based growth inhibition assay and flow cytometric assay of apoptosis in lymphoma cell lines. The in vivo activity of LY2409881 was determined using SCID-beige xenograft mouse model. The mechanism of action was determined using immunoblotting, immuofluorescence, and electrophoretic mobility shift assay. Synergy of LY2409881 with other drugs active in lymphoma was determined by calculating relative risk ratio (RRR) and combination index (CI).Results: LY2409881 inhibited constitutively activated NF-kB, and caused concentration-and time-dependent growth inhibition and apoptosis in lymphoma cells. In models of diffuse large B-cell lymphoma (DLBCL), the cytotoxicity of LY2409881 correlated with the overall activation status of NF-kB, but not simply in a pattern predicted by the cell-of-origin classification of these cell lines. LY2409881 was safe to mice at three dose levels, 50, 100, and 200 mg/kg, all of which caused significant inhibition of tumor growth. LY2409881 suppressed the activity of the NF-kB subunit p65 in lymphoma cells treated by the HDAC inhibitor romidepsin, underlying a potential mechanism of the marked synergy observed of these two drugs.Conclusion: Collectively, these data strongly suggest that targeting the NF-kB pathway in combination with romidepsin could represent a novel and potent regimen for the treatment of B-and T-cell lymphoma.

402 grew Pseudomonas(Ps.) cepacia. I n 208 c u l t u r e s , i t was t h e s i n g l e i s o l a t e . and i n 194 i t grew together with Staphylococcus aureus andlor Ps. aeruginos a , o r t o g e t h e r w i t h other gram-negative organisms. A t o t a l of 54 p a t i e n t s , (24 t o 22 y e a r s ) , 32 females and 22 males, with mild (2). moderate(l5) and advanced(37) degrees of CF has Ps. cepacia i s o l a t e d from b r o n c h i a l o r sputum c u l t u r e s . Ps. cepacia has been found i n p a t i e n t s who have never been h o s p i t a l i z e d and i n those who r a r e l y used a e r o s o l therapy. I t was recovered c o n s i s t e n t l y f o r 2 t o 3 years from 17 p a t i e n t s . Nine females and 5 males have died from r e s p i r a t o r y f a i l u r e . Premortem c u l t u r e s i n 12 p a t i e n t s grew Ps. cepacia alone o r together with Ps. aeruginosa. I n 10 autopsied c a s e s , the lung c u l t u r e grew Ps. cepacia alone i n 3 and Pa. aeruginosa i n 4. Pa. cepacia is r e s i s t a n t t o almost a l l a n t imicrobials including n a l i d i x i c a c i d and g a n t r i s i n b u t a few a r e s e n s i t i v e t o chloramphenicol. trimethoprim-sulfamethoxazole (TMP-SXT) and kanamycin. Good c l i n i c a l response has been observed i n those t r e a t e d w i t h TMP-SXT o r chloramphenicol. Transient d i sappearance of Ps. cepacia i n post-therapy c u l t u r e s has been achieved i n a few cases. The s i g n i f i c a n c e of t h i s f i n d i n g i s under study. The s u p e r i n f e c t i o n with Ps. cepacia of p a t i e n t s with CF with advanced d i s e a s e has made the a n t i m i c r o b i a l therapy more d i f f i c u l t . TEICHOIC ACID SEROLOGY I N VARIOUS STAPHYLO- COCCAL COAGULASE P O S I T I V E I N F E C T I O N S I N INFANTS AND CHILDREN.C h i n h T. Le a n d Edward B. Lewin ( S p o n . by M a r t i n R. K l e m p e r e r ) . U n i v . o f R o c h e s t e r S c h . o f Med. a n d D e n t . , S t r o n g M e m o r i a l H o s p i t a l , D e p a r t m e n t o f P e d i a t r i c s , R o c h e s t e r . N . Y .C o u n t e r i m m u n o e l e c t r o p h o r e s i s ( C I E ) a n d O u c h t e rl o n y g e l d i f f u s i o n w e r e u s e d f o r t h e d e t e c t i o n a n d t i t r a t i o n o f a n t i c o a g . p o s i t i v e (SC+) i n i n f a n t s a n d c h i l d r e n . Serum s a m p l e s w e r e o b t a i n e d o n a d m i s s i o n , a t 2 w e e k s , a n d up t o 1 2 w e e k s i n t o t h e i l l n e s s .TAA w e r e f o u n d by CIE i n 7 0 % ( 7 1 1 0 ) o f p a t i e n t s w i t h i n v a s i v e SC+ d is e a s e w i t h b a c t e r e m i a ( g r o u p A). 1 4 % ( 1 1 7 ) o f p at i e n t s w i t h SC+ i n f e c t i o n w i t h o u t b a c t e r e m i a ( g r o u p B ) , 0 % ( 0 1 1 9 ) o f p a t i e n t s w i t h b a c t e r e m i a a n d l o r i n v a s i v e i n f e c t i o n s n o t c a u s e d by SC+ ( g r o u p C ) a n d 0 % ( 0 1 1 3 ) o f n o n -i n f e c t e d , h o s p i t a l i z e d p a t i e n t s a n d h e a l t h y c h i l d r e...