Peter van Mourik

148 Chapter 7 a. F508del/S1251N Forskolin stimulation t = 60 min t = 0 min Gen + VX-770 DMSO g. h. 0 1000 2000 3000 4000 -125 -100 -75 -50 -25 0 25 r = - 0.708 P= <0.001 Organoids vs. SCC (n=33) Organoid swelling (AUCat 0.128 M fsk) μ Absolute change in SCC (mmol/L) Absolutechange in FEV1 (%predicted) Organoids vs. FEV1 (n=35) Organoid swelling (AUCat 0.128 M fsk) μ 0 1000 2000 3000 4000 -10 0 10 20 30 r = 0.575 P= <0.001 Absolutechange in FEV1 (%predicted) -125 -100 -75 -50 -25 0 25 -10 0 10 20 30 SCC vs. FEV1 (n=31) r = -0.198 P = 0.29 Absolute change in SCC (mmol/L) Genistein+Curcumin inS1251N/F508del VX-770 inS1251N/R117H VX-809+VX-770 inR347P/F508del Genistein+Curcumin inS1251N/R117H VX-770 inG1249R/F508del VX-770 inS1251N/A455E VX-770 inS1251N/1717-1G>A VX-770 inS1251N/F508del VX-770 inS945L/F508del VX-770 inG461R/F508del VX-770 inR334W/R764X VX-770 inR553X/4375-3T>A VX-809+VX-770 inW1282X/F508del Organoids vs. FEV1 (n=21) c. Absolutechange in FEV1 (%predicted) Organoid swelling (AUCat 0.128M fsk) μ r = 0.610 P = 0.003 0 1000 2000 3000 4000 -10 0 10 20 30 SCC vs. FEV1 (n=18) e. -125 -100 -75 -50 -25 0 25 -10 0 10 20 30 r = - 0.366 P = 0.14 Absolutechange in FEV1 (%predicted) Absolute change in SCC (mmol/L) Organoids vs. SCC (n=18) Absolute change in SCC (mmol/L) Organoid swelling (AUCat 0.128M fsk) μ d. r = - 0.762 P = <0.001 0 1000 2000 3000 4000 -125 -100 -75 -50 -25 0 25 k. i. j. SCC vs. FEV1 (n=13) -125 -100 -75 -50 -25 0 25 -10 0 10 20 30 r = - 0.157 P = 0.61 Absolutechange in FEV1 (%predicted) Absolute change in SCC (mmol/L) Organoids vs. FEV1 (n=14) r = 0.480 P = 0.08 Organoid swelling (AUCat 0.128M fsk) μ Absolutechange in FEV1 (%predicted) 0 1000 2000 3000 4000 -10 0 10 20 30 Organoid swelling (AUCat 0.128M fsk) μ Absolute change in SCC (mmol/L) 0 1000 2000 3000 4000 -125 -100 -75 -50 -25 0 25 r = - 0.695 P = 0.008 Organoids vs. SCC (n=13) b. S1251N/F508del (n=3) 0.008 0.02 0.05 0.128 0.32 0.8 2 5 0 750 1500 2250 3000 3750 4500 5250 6000 Forskolin ( μ M) Organoid swelling (AUC) kc - 100uM <40% or >90% Total f. ≥40% and ≤90% DMSO VX-7703 M μ Genistein10 M+ Curcumin50 M μ μ Curc