FIGURE 1 Relationship between pelabresib and platelet count values. A, Day 14 platelet count as a function of steady state AUC of pelabresib. B, Day 14 mean platelet count as a percent of baseline compared with pelabresib mean AUC. The coefficient of determination (R²) = 0.8122, obtained from a simple linear regression model with mean platelet count ratio as the dependent variable and pelabresib capsule dose as the independent variable (tablet doses were multiplied by 1.34 to convert to capsule doses). C, Mean platelet count over time. AUC, area under the curve; CPI-0610, pelabresib; CXDX, Cycle number Day number; X mg C, Capsule pelabresib dose; X mg T, Tablet pelabresib dose. More

FIGURE 2 Mean pelabresib plasma profiles and dose proportionality. A, Mean pelabresib plasma profile over time at Cycle 1 Day 1. B, Mean pelabresib plasma profile over time at Cycle 1 Day 14. C, Dose proportionality of mean steady-state AUC of patients treated with capsule and tablet doses o... More

FIGURE 3 Gene expression analysis of IL8 and CCR1 transcript levels after treatment with pelabresib. A, Relative expression of IL8 blood mRNA levels prior to and 2, 6, and 8 hours after pelabresib treatment. B, Relative expression of CCR1 blood mRNA levels prior to and 2, 6, and 8 hours after pelabresib treatment. Relative mRNA expression of IL8 and CCR1 after dosing is shown relative to the pretreatment values (y axis). C, Relative IL8 and CCR1 mRNA expression compared to the Cycle 1 Day 14 steady-state AUC. IL8 and CCR1 are represented as the average at the 2-hour time point following pelabresib administration over that of baseline in each dose group. The steady state (C1D14) AUC0–24 (hour/ng/mL, geometric mean of each dose level) is shown on the right y axis. T = tablet 125 mg and 225 mg were tablet formulations; all other doses were capsule formulation. More

FIGURE 1 ARID1A loss negatively correlates with the prognosis of 0.24–1.49OCCC. A, Top, representative images of ARID1A-negative or -positive OCCC clinical specimens and their respective Frequency distribution of the immunoreactivity scores for ARID1A; the dotted line represents the cutoff used to discriminate between ARID1A positive (+) and ARID1A negative (−) patients. C, Survival curves of ARID1A⁺vs. ARID1A⁻ patients expressed in years. From the left to the right: PFS [36 vs. 19; P = 0.046; HR = 0.43; 95% confidence interval (CI), 0.19–0.98], cancer-specific survival, CSS (36 vs. 18; P = 0.003; HR = 0.18; 95% CI, 0.06–0.55), overall survival (OS; 36 vs. 19; P = 0.004; HR = 0.23, 95% CI, 0.09–0.63). More

FIGURE 2 Stage I/II ARID1A negative patients have the same prognoses as stage III/IV ARID1A-positive patients. A, Survival curves of ARID1A⁺ (red) vs. ARID1A⁻ (blue) stage I/II patients expressed in years. From the left to the right: PFS (24 vs. 15; P = 0.034; HR = 0.29; 95% CI, 0.09–0.91), CSS (24 vs. 14; P = 0.0005; HR = 17.27; 95% CI, 2.538–117.6 – Mantel-Cox's logrank test), OS (24 vs. 15; P = 0.009; HR = 0.12; 95% CI, 0.02–0.59). B, Survival curves of stage III/IV ARID1A⁺ (red) vs. stage I/II ARID1A⁻ (blue) patients expressed in years. From the left to the right: PFS (12 vs. 15; P = 0.235; HR, 0.52; 95 CI, 0.18–1.52), CSS (12 vs. 14; P = 0.994; HR, 1.01; 95% CI, 0.29–3.49), OS (12 vs. 15; P = 0.899; HR, 1.08; 95% CI, 0.33–3.56). More

FIGURE 3 GLS1 expression is negatively correlated with ARID1A loss in OCCC. A, Top, representative images of GLS1 IHC staining in ARID1A-positive and ARID1A-negative OCCC specimens; bottom, respective ARID1A immunostainings. B, Frequency distribution of the GLS1 H-scores in ARID1A⁺ and ARID1A⁻ OCCC. C, Expression levels of GLS1 in ARID1A⁺ and ARID1A⁻ OCCC (ARID1A⁺ vs. ARID1A⁻: P = 0.0012). n = number of clinical specimens per group. The circled dots represent the cases for which an additional Western blot analysis has been performed. D, Representative images of GLS1 IHC staining in ARID1A wild-type (WT) and ARID1A-mutated (mut.) OCCC specimens. E, Expression levels of GLS1 in ARID1A wild-type (WT) and ARID1A-mutated (mut) OCCC. n = number of clinical specimens per group. More

FIGURE 4 GLS1 expression in ARID1A-negative OCCC is similar to the one of normal tissues. A, Bottom left and its inset, representative image of GLS1 staining in normal ovary. Bottom center and its inset, representative image of GLS1 staining in normal Fallopian tube. Bottom right, representative image of GLS1 staining in ARID1A-negative (−) OCCC. B, Expression levels of GLS1 in ARID1A-negative OCCC and in normal tissues. (ARID1A- vs. normal: P = 0.8285). n = number of clinical specimens per group. More

FIGURE 5 GLS1 overexpression may be a protective factor in OCCC. A, Kaplan-Meier curves of OCCC patients, divided by high (≥200, blue), intermediate (<200, ≥100, red) and low (<100, black) GLS1 expression levels. From left to right: PFS (12 vs. 19 vs. 22; P = 0.013; HR by 10 points increase = 0.93; 95% CI, 0.88–0.99), CSS (12 vs. 19 vs. 21; P = 0.014; HR by 10 points increase = 0.91; 95% CI, 0.85–0.98). OS (12 vs. 19 vs. 22; P = 0.021; HR by 10 points increase = 0.93; 95% CI, 0.87–0.99). Survival times are expressed in years. B, Kaplan–Meier curves of ARID1A⁺ patients, divided by high (≥200, blue), intermediate (<200, ≥100, red) and low (<100, black) GLS1 expression levels. From left to right: PFS (11 vs. 14 vs. 10, P = 0.023, HR by 10 points increase = 0.91; 95% CI, 0.84–0.99), CSS (11 vs. 14 vs. 10, P = 0.036, HR by 10 points increase = 0.88; 95% CI, 0.79–0.99), OS (11 vs. 14 vs. 10, P = 0.093; HR by 10 points increase = 0.93; 95% CI, 0.85–1.01). Survival times are expressed in years. C, Kaplan–Meier curves of ARID1A⁻ patients, divided by high (≥200, blue), intermediate (<200, ≥100, red) and low (<100, black) GLS1 expression levels. From left to right: PFS (1 vs. 4 vs. 12, P = 0.487; HR by 10 points increase = 0.96; 95% CI, 0.86–1.07), CSS (1 vs. 4 vs. 11; P = 0.647; HR by 10 points increase = 0.97; 95% CI, 0.87–1.09), OS (1 vs. 4 vs. 12; P = 0.511; HR = 0.97; 95% CI, 0.87–1.07). Survival times are expressed in years. More

FIGURE 1 Aged gastric organoids exhibit increased cellular proliferation and enhanced Wnt/β-catenin signaling. A, Representative images of young and aged gastric organoids on days 0 and 4. Scale bar: 500 μm. B, The numbers of young and aged gastric organoids larger than 50 μm in diameter on days 0, 2, and 4 (n = 3). C, Cell viability assay of young and aged gastric organoids performed on day 4. D, Survival of the young and aged gastric organoids (n = 3). E, Representative images of young and aged gastric organoids cultured in the presence (WRC+) and the absence (WRC−) of Wnt3a, R-Spondin1, and Chir99021. Scale bar: 500 μm. F, Cell viability assay of young and aged gastric organoids cultured in WRC+ and WRC− medium performed on day 4 (n = 3). G, TCF reporter activity of young and aged gastric organoids (n = 3). n.s., not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001. More

FIGURE 2 Cellular senescence is suppressed in aged gastric organoids. A, GSEA for (left) G₂–M checkpoint-related genes and (right) senescence-related genes. B, The expression of genes related to cellular proliferation and cell cycle in young and aged gastric organoids (n = 3). C, The expression of senescence-inducing genes in young and aged gastric organoids (n = 3). D, Immunofluorescence for genes related to cellular proliferation and senescence in young and aged gastric organoids (n = 5). E-cad: E-cadherin. E, Representative images of SABG assay for young and aged gastric organoids. Scale bar: 50 μm. F, The ratio of senescent cells in young and aged gastric organoids assessed by SABG assay (n = 3). G, The expression of SASP-related genes in young and aged gastric organoids (n = 3). n.s., not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001. More