Targeting the Mevalonate Pathway Suppresses ARID1A-Inactivated Cancers by Promoting Pyroptosis

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation and in a humanized immunocompetent ARID1A mutant patient-derived OCCC mouse model. Our data indicate that inhibition of the mevalonate pathway simultaneously suppresses tumor cell growth and boosts antitumor immunity by promoting pyroptosis, which synergizes with ICB in suppressing ARID1A-mutated cancers

Video_1_A time-dependent offset field approach to simulating realistic interactions between beating hearts and surgical devices in virtual interventional radiology.MP4

Endovascular interventional radiology (IR) is a minimally invasive procedure for the treatment of vascular diseases. This procedure requires physicians to be highly skilled at manipulating interventional devices under the guidance of two-dimensional X-ray imaging. By offering a non-error-sensitive and radiation-free environment, a virtual reality-based simulator provides a promising alternative for surgical skills training and surgery planning. Building a realistic and interactive simulator is a challenging task. To achieve better realism, this paper proposes a novel method of simulating the heartbeat for both standard and patient-specific anatomical data. A time-dependent offset field approach is proposed to efficiently and stably simulate the interactive behavior between the dynamic heart mesh and surgical devices. For medical imaging simulation, we propose a GPU-based linear depth subtraction method to approximate fluoroscopic images based on the attenuation of the X-ray. On this basis, a topology-based flow map method is proposed to simulate the propagation of the contrast medium in angiography. Experimental results show that the proposed algorithm can simulate heartbeat stably for meshes with varying geometrical shapes and complexities. In efficiency, the dynamic heart mesh can interact with surgical devices stably at 60 frames/s. Under the simulated fluoroscopic imaging effect, the injected contrast medium can realistically visualize both dynamic and static vessels. In a face validity by medical students and clinicians, the category of effectiveness score 8.35 out of 10 on average, demonstrating that our simulator is useful in surgical skills training and surgery planning.</p