Rethinking Closed-loop Training for Autonomous Driving

Recent advances in high-fidelity simulators have enabled closed-loop training of autonomous driving agents, potentially solving the distribution shift in training v.s. deployment and allowing training to be scaled both safely and cheaply. However, there is a lack of understanding of how to build effective training benchmarks for closed-loop training. In this work, we present the first empirical study which analyzes the effects of different training benchmark designs on the success of learning agents, such as how to design traffic scenarios and scale training environments. Furthermore, we show that many popular RL algorithms cannot achieve satisfactory performance in the context of autonomous driving, as they lack long-term planning and take an extremely long time to train. To address these issues, we propose trajectory value learning (TRAVL), an RL-based driving agent that performs planning with multistep look-ahead and exploits cheaply generated imagined data for efficient learning. Our experiments show that TRAVL can learn much faster and produce safer maneuvers compared to all the baselines. For more information, visit the project website: https://waabi.ai/research/travlComment: ECCV 202

First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors.

PurposeTepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and methodsPatients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsOne hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.ConclusionsTepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials

Visualization balloon occlusion-assisted technique in the treatment of large or giant paraclinoid aneurysms: A study of 17 cases series

ObjectiveAlthough balloon-assisted techniques are valuable in aneurysm clipping, repeated angiography and fluoroscopy are required to understand the location and shape of the balloon. This study investigated the value of visualization balloon occlusion-assisted techniques in aneurysm hybridization procedures.MethodsWe propose a visualization balloon technique that injects methylene blue into the balloon, allowing it to be well visualized under a microscope without repeated angiography. This study retrospects the medical records of 17 large or giant paraclinoid aneurysms treated by a visualization balloon occlusion-assisted technique in a hybrid operating room. Intraoperative surgical techniques, postoperative complications, and immediate and long-term angiographic findings are highlighted.ResultsAll 17 patients had safe and successful aneurysm clipping surgery with complete angiographic occlusion. Under the microscope, the balloon injected with methylene blue is visible through the arterial wall. The position and shape of the balloon can be monitored in real time without repeated angiography and fluoroscopic guidance. Two cases of intraoperative visualization balloon shift and slip into the aneurysm cavity were detected in time, and there were no cases of balloon misclipping or difficult removal. Of 17 patients, four patients (23.5%) experienced short-term complications, including pulmonary infection (11.8%), abducens nerve paralysis (5.9%), and thalamus hemorrhage (5.9%). The rate of vision recovery among patients with previous visual deficits was 70% (7 of 10 patients). The mean follow-up duration was 32.76 months. No aneurysms or neurological deficits recurred among all patients who completed the follow-up.ConclusionOur study indicates that microsurgical clipping with the visualization balloon occlusion-assisted technique seems to be a safe and effective method for patients with large or giant paraclinoid aneurysms to reduce the surgical difficulty and simplify the operation process of microsurgical treatment alone

Model-informed dose selection in early oncology drug development

Drug developers in oncology indication has been struggling with a low probability of success for decades. In my thesis, we studied how to improve the clinical proof-of-concept success rate with quantitative dosing rationale. We reviewed the classical dose selection strategies and the emerging transition of mathematical model-informed optimization strategies in anti-cancer drug development. Then we presented two case studies: first-in-human dose selection of avelumab, a monoclonal antibody, and the recommended phase II dose determination of tepotinib, a small-molecule kinase inhibitor. It showed how quantitative tools informed the dose selection with precision, and streamlined the early drug development path by avoiding unnecessary dose steps. The accumulating clinical data also proved, in both cases, successful dose strategies. By integrating preclinical in-vitro/in-vivo and clinical data across multiple development stages, the quantitative frameworks interpret the accumulating knowledge with great synergy, showing a high potential of model-informed optimization strategy to improve efficiency in drug development

Immobilization of <i>Pseudomonas fluorescens</i> Lipase on Hollow Poly(o-phenylenediamine) Microspheres and Its Application in the Preparation of Citronellyl Acetate

In order to address the challenges associated with free lipase in organic solvents, including aggregation, poor stability, and low catalytic efficiency, this study developed two types of poly(o-phenylenediamine) microspheres (solid and hollow) as supports for immobilizing lipase. The immobilization process utilized an adsorption method, with the poly(o-phenylenediamine) hollow microspheres being identified as the optimal support in a 2:5 enzyme-to-support ratio. On this basis, the lipase was immobilized by the covalent binding method. The immobilization conditions consisted of treating the support with 2% glutaraldehyde and immobilization at 40 °C for 2 h in pH 7.0 buffer. The specific activity of the immobilized enzyme was 5.3 times higher than that of the free enzyme. Covalent-binding immobilized lipase was also used for the preparation of citronellyl acetate by transesterification reaction, and, in optimized reaction conditions where the amount of immobilized enzyme was 0.1 g/mL, the reaction temperature was 50 °C and the shaking speed was 200 r/min during the reaction. Under these conditions, the citronellyl acetate yields can exceed 99% after 2 h. Furthermore, the stability of the immobilized lipase was investigated, and the residual activity of the immobilized enzyme was 95% after seven repetitions, while that of the free enzyme was only 70%. After 56 days of storage at room temperature, the immobilized enzyme retained 60% of its original viability, while the free enzyme retained only 31%