• Book : 282()
• Pub. Date : 2025
• Page : pp.120501
• Keyword :

• Book : 302(1)
• Pub. Date : 2025
• Page : pp.120786
• Keyword :

• Book : 603()
• Pub. Date : 2025
• Page : pp.155419
• Keyword :

• Book : 1053()
• Pub. Date : 2025
• Page : pp.122961
• Keyword :

• Book : 211()
• Pub. Date : 2025
• Page : pp.110927
• Keyword :

• Book : 211()
• Pub. Date : 2025
• Page : pp.110918
• Keyword :

• Book : 211()
• Pub. Date : 2025
• Page : pp.110933
• Keyword :

Abstract

We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.

• Book : 74(1)
• Pub. Date : 2025
• Page : pp.8
• Keyword :

Abstract

Burning plasma performance, transport, and the effect of hydrogen isotope (H, D, D-T fuel mix) on confinement has been predicted for ITER baseline scenario (IBS) conditions using nonlinear gyrokinetic profile predictions. Accelerated by surrogate modeling (Rodriguez-Fernandez et al 2022 Nucl. Fusion62 076036), high fidelity, nonlinear gyrokinetic simulations performed with the CGYRO code (Candy et al 2016 J. Comput. Phys.324 73), were used to predict profiles of Ti, Te, and ne while including the effects of alpha heating, auxiliary power (NBI + ECH), collisional energy exchange, and radiation losses inside of $ r / a $ = 0.9. Predicted profiles and resulting energy confinement are found to produce fusion power and gain that are approximately consistent with mission goals ($ P_{\text{fusion}} = 500 $ MW at Q = 10) for the baseline scenario and exhibit energy confinement that is within 1σ of the H-mode energy confinement scaling. The power of the surrogate modeling technique is demonstrated through the prediction of alternative ITER scenarios with reduced computational cost. These scenarios include conditions with maximized fusion gain and an investigation of potential resonant magnetic perturbation (RMP) effects on performance with a minimal number of gyrokinetic profile iterations required (3-6). These predictions highlight the stiff ITG nature of the core turbulence predicted in the ITER baseline and demonstrate that $ Q @@\symbol{'3E} @@ $ 17 conditions may be accessible by reducing auxiliary input power while operating in IBS conditions. Prediction of full kinetic profiles allowed for the projection of hydrogen isotope effects around ITER baseline conditions. The gyrokinetic fuel ion species was varied from H, D, and 50/50 D-T and kinetic profiles were predicted. Results indicate that a weak or negligible isotope effect will be observed to arise from core turbulence in IBS conditions. The resulting energy confinement, turbulence, and density peaking, and the implications for ITER operations will be discussed.

• Book : 65(1)
• Pub. Date : 2025
• Page : pp.016002
• Keyword :

• Book : 227()
• Pub. Date : 2025
• Page : pp.112351
• Keyword :