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PurposeThis first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase.Patients and methodsPatients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy.ResultsForty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission >4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD.ConclusionCC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment.Clinical trial registrationNCT01353625.

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

Target recognition and anti-interference technology have become key technologies that determine the performance of precision guided weapons. Aiming at the combat characteristics of infrared air-to-air missiles in complex confrontation scene, this paper analyzes its target recognition and anti-interference development needs, and proposes a hybrid intelligent anti-interference algorithm that combines traditional algorithms and deep learning. This algorithm makes full use of the high reliability advantages of traditional algorithms in certain scene and the high-dimensional feature extraction capabilities of deep learning algorithms in complex scene, maximizing the mining of missile detection scene information, which is of great significance for improving the system’s anti-interference capability. On this basis, an air combat data set for algorithm testing and training is constructed, covering typical air combat scene. The experimental results show that under the same feature fusion conditions, the full anti-interference probability of the hybrid intelligent anti-jamming algorithm in typical scene reaches 71.56%, which is 15.77% higher than the traditional algorithm, which verifies the effectiveness of the algorithm.

The elastic wave propagation and vibration attenuation zones for periodically scattering piles in unsaturated ground were investigated using Finite-Element Method (FEM) and Bloch periodic theory. The unsaturated ground was modelled by unsaturated poroviscoelastic medium with the weak form governing equations derived from the mass and momentum conservative equations using Galerkin method and Fourier transform. The quadratic polynomial eigenvalue equations for the unsaturated medium were obtained using the Bloch periodic theory, and solved by FEM for the complex eigenvalues to evaluate the band gaps of the pile-soil system. The eigenvalue bands combined with the frequency response function were used to analyse the mitigation effects of piles in unsaturated ground with different soil properties and piles parameters. This research found that the pile-soil system has three propagational waves, in which the shear wave and the slow longitudinal wave carry low-frequency vibrations that undermine the attenuation effects of the piles barrier. The increasing soil saturation degree affects the attenuation effects by reducing the soil modulus and increasing the fluid content. And both of those two mechanisms reduce the frequency of the attenuation zones (AZ), which improves the low-frequency vibration attenuation, and reduces the width of AZ that could reduce the vibration mitigation effects. [ABSTRACT FROM AUTHOR]