6037 Background: Pembrolizumab (a humanized monoclonal antibody blocking programmed death receptor-1), and cetuximab (a chimeric monoclonal antibody inhibiting epidermal growth factor receptor) are both FDA-approved as single agents for second-line R/M HNSCC treatment. This is the first trial to combine pembrolizumab with cetuximab to evaluate anti-tumor synergy. As this specific drug combination has not been previously tested, an interim safety analysis was completed per protocol. Methods: Patients (pts) with R/M HNSCC were treated with pembrolizumab at a fixed dose of 200mg IV on day 1 with cetuximab 400mg/m2 loading dose followed by 250mg/m2 weekly (21-day cycle). The first 10 pts who enrolled and completed at least 1 cycle of therapy were included in the safety analysis. A mandatory study hold and Data Safety Monitoring Committee (DSMC) review were required if at least 4 of the 10 pts developed any grade (G) 3-4 non-hematologic toxicity. Results: Of the 10 patients included in the analysis, median age 58y (range 47-79y), M: F 5:5. 8 pts had mucosal (6 oral cavity, 1 oropharynx, 1 nasopharynx) and 2 had cutaneous HNSCC primaries. 65 adverse events (AEs) were reported in 9 pts; G1: 39, G2: 15, ≥G3: 11. Of the 11 ≥G3 AEs, only 1 was treatment-related (see Table). There were no treatment-related deaths or dose-limiting toxicities (DLTs). 3 pts discontinued treatment, none of which were due to toxicity (2 had disease progression, 1 withdrew from study). DSMC reviewed the safety data and permitted resumption of trial accrual. Of 7 evaluable pts, 4 partial responses were noted at first radiographic assessment. Clinical trial information: NCT03082534. Conclusions: Pembrolizumab combined with cetuximab has a very tolerable safety profile, with no DLTs. Efficacy analysis of this combination will be performed. Grade AE Frequency Description Related? Serious? 3 1 Acneiform rash Definite N 3 1 Hypotension Unlikely Y 3 1 Febrile neutropenia Unlikely Y 3 1 Fatigue Unlikely N 3 1 Dysphagia N Y 3 1 Aspiration N Y 3 1 Skin ulceration N Y 3 1 Lung infection N Y 4 1 Sepsis N Y 5 1 Death N Y 5 1 Death N Y
To analyze domestic potential market and characters of synthetic material industry in view of China great demand for synthetic materials. To indicate the potential products and countermeasures under the impact of world financial crisis environment.
An isoperimetric inequality for lower order nonzero Neumann eigenvalues of the Witten-Laplacian on bounded domains in a Euclidean space or a hyperbolic space has been proven in this paper. About this conclusion, we would like to point out two things: It strengthens the well-known Szeg\H{o}-Weinberger inequality for nonzero Neumann eigenvalues of the classical free membrane problem given in [J. Rational Mech. Anal. 3 (1954) 343--356] and [J. Rational Mech. Anal. 5 (1956) 633--636]; Recently, Xia-Wang [Math. Ann. 385 (2023) 863--879] gave a very important progress to the celebrated conjecture of M. S. Ashbaugh and R. D. Benguria proposed in [SIAM J. Math. Anal. 24 (1993) 557--570]. It is easy to see that our conclusion here covers Xia-Wang's this progress as a special case. In this paper, we have also proposed two open problems which can be seen as a generalization of Ashbaugh-Benguria's conjecture mentioned above.
To identify predictors of becoming a daily cigarette smoker over the course of 4 years.We identified 12- to 24-year-olds at wave 1 of the US Population Assessment of Tobacco and Health Study and determined ever use, age at first use, and daily use through wave 4 for 12 tobacco products.Sixty-two percent of 12- to 24-year-olds (95% confidence interval [CI]: 60.1% to 63.2%) tried tobacco, and 30.2% (95% CI: 28.7% to 31.6%) tried ≥5 tobacco products by wave 4. At wave 4, 12% were daily tobacco users, of whom 70% were daily cigarette smokers (95% CI: 67.4% to 73.0%); daily cigarette smoking was 20.8% in 25- to 28-year-olds (95% CI: 18.9% to 22.9%), whereas daily electronic cigarette (e-cigarette) vaping was 3.3% (95% CI: 2.4% to 4.4%). Compared with single product triers, the risk of progressing to daily cigarette smoking was 15 percentage points higher (adjusted risk difference [aRD] 15%; 95% CI: 12% to 18%) among those who tried ≥5 products. In particular, e-cigarette use increased the risk of later daily cigarette smoking by threefold (3% vs 10%; aRD 7%; 95% CI: 6% to 9%). Daily smoking was 6 percentage points lower (aRD -6%; 95% CI: -8% to -4%) for those who experimented after age 18 years.Trying e-cigarettes and multiple other tobacco products before age 18 years is strongly associated with later daily cigarette smoking. The recent large increase in e-cigarette use will likely reverse the decline in cigarette smoking among US young adults.
L-Phenylalanin(L-Phe) and L-Tyrosine(L-Tyr) were separated from the beer yeast extract using their selective adsorption on active carbon followed by elution with aqueous ammonia and ethanol.The obtained substances are in accordance with their corresponding product standards.The adsorption of L-Tyr and L-Phe on commercial activated carbon at different pH values in the solution has been investigated.An optimal separation technology is proposed with the adsorption carried out at the pH value of 5.8 followed by elution with 1mol/L aqueous ammonia and 60% ethanol,respectively.The method gives an effective separation of amino acids from the beer yeast extract.
In this paper, by mainly using the rearrangement technique and suitably constructing trial functions, under the constraint of fixed weighted volume, we can successfully obtain several isoperimetric inequalities for the first and the second Dirichlet eigenvalues, the first nonzero Neumann eigenvalue of the Witten-Laplacian on bounded domains in space forms. These spectral isoperimetric inequalities extend those classical ones (i.e. the Faber-Krahn inequality, the Hong-Krahn-Szeg\H{o} inequality and the Szeg\H{o}-Weinberger inequality) of the Laplacian.
The Mann-Whitney-Wilcoxon rank sum test (MWWRST) is a widely used method for comparing two treatment groups in randomized control trials, particularly when dealing with highly skewed data. However, when applied to observational study data, the MWWRST often yields invalid results for causal inference. To address this limitation, Wu et al. (2014) introduced an approach that incorporates inverse probability weighting (IPW) into this rank-based statistics to mitigate confounding effects. Subsequently, Mao (2018), Zhang et al. (2019), and Ai et al. (2020) extended this IPW estimator to develop doubly robust estimators. Nevertheless, each of these approaches has notable limitations. Mao's method imposes stringent assumptions that may not align with real-world study data. Zhang et al.'s (2019) estimators rely on bootstrap inference, which suffers from computational inefficiency and lacks known asymptotic properties. Meanwhile, Ai et al. (2020) primarily focus on testing the null hypothesis of equal distributions between two groups, which is a more stringent assumption that may not be well-suited to the primary practical application of MWWRST. In this paper, we aim to address these limitations by leveraging functional response models (FRM) to develop doubly robust estimators. We demonstrate the performance of our proposed approach using both simulated and real study data.
Presents a direct online parameter optimization method using a quasi-Newton approach to find compensators, which can minimize the measured track mis-registration (TMR) for hard disk drive (HDD) servo systems, without prior knowledge of disturbance/noise models. An optimal controller for a plant with uncertainty can be obtained within a pre-found robust stable region by using the gradient information of TMR with respect to controller parameters based on nominal plant model. The searching time is shorter compared with other non-gradient optimization methods such as random neighborhood search and genetic algorithms. Both simulation and implementation results show the effectiveness of the proposed method. In addition, it is also proved that if the measurement noise is white noise, an optimal controller that minimizes the measured TMR also minimizes the true TMR.
