Clinical efficacy and identification of factors confer resistance to afatinib(tyrosine kinase inhibitor)in EGFR-overexpressing esophageal squamous cell carcinoma

Epidermal growth factor receptor(EGFR)is reportedly overexpressed in most esophageal squamous cell carcinoma(ESCC)patients,but anti-EGFR treatments offer limited survival benefits.Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC.This proof-of-concept,phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients(n=41)with EGFR overexpression(NCT03940976).The study met its primary endpoint,with a confirmed objective response rate(ORR)of 39%in 38 efficacy-evaluable patients and a median overall survival of 7.8 months,with a manageable toxicity profile.Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2(NTRK2)was negatively associated with afatinib sensitivity and might serve as a predictive biomarker,irrespective of EGFR expression.Notably,knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment.Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

Proactive planning of bandwidth resource using simulation-based what-if predictions for Web services in the cloud

Resource planning is becoming an increasingly important and timely problem for cloud users.As more Web services are moved to the cloud,minimizing network usage is often a key driver of cost control.Most existing approaches focus on resources such as CPU,memory,and disk I/O.In particular,CPU receives the most attention from researchers,but the bandwidth is somehow neglected.It is challenging to predict the network throughput of modem Web services,due to the factors of diverse and complex response,evolving Web services,and complex network transportation.In this paper,we propose a methodology of what-if analysis,named Log2Sim,to plan the bandwidth resource of Web services.Log2Sim uses a lightweight workload model to describe user behavior,an automated mining approach to obtain characteristics of workloads and responses from massive Web logs,and traffic-aware simulations to predict the impact on the bandwidth consumption and the response time in changing contexts.We use a real-life Web system and a classic benchmark to evaluate Log2Sim in multiple scenarios.The evaluation result shows that Log2Sim has good performance in the prediction of bandwidth consumption.The average relative error is 2%for the benchmark and 8% for the real-life system.As for the response time,Log2Sim cannot produce accurate predictions for every single service request,but the simulation results always show similar trends on average response time with the increase of workloads in different changing contexts.It can provide sufficient information for the system administrator in proactive bandwidth planning.

Climate evolution of southwest Australia in the Miocene and its main controlling factors

At present, the seasonal melting and expansion of the Antarctic ice sheet affect the location and intensification of the westerlies, as well as the precipitation and continental weathering and erosion in southwest Australia. The Miocene was an important period when the Earth's climate state transitioned from a warmhouse to an icehouse and the East Antarctic Ice Sheet underwent large-scale melting and expansion. At that time, Australia was closer to the Antarctic region than it is now. This makes Australia an ideal target area for studying the coupling relationship among the atmosphere, hydrosphere, lithosphere, and cryosphere. Based on the comprehensive analysis of the siliciclastic mass accumulation rate, grain size, clay minerals, and elemental composition of the sediments at Site U1516 of the International Ocean Discovery Program Expedition 369, we reconstructed the Miocene climate evolution and the continental weathering and erosion history of southwest Australia on a tectonic time scale. Our indicators show that the climate was dry and that continental weathering and erosion were weak, with a small amount of terrestrial material transported to the ocean during the Early to Middle Miocene(22–12.7 Ma). However, as mentioned in previous studies of nearby sites, precipitation and river runoff increased prominently with enhanced continental weathering at 12.7–8 Ma, which was related to the northward migration or intensification of the westerlies, possibly due to increased sea ice in the Southern Ocean. In addition, we found that the evolution of the South Asian monsoon and the westerly belt were synchronized in the Miocene, which indicates that the South Asian monsoon system at that time may also have been affected by the high-latitude signals of the Southern Hemisphere. We speculate that the significant decrease in deep-sea temperature and the expansion of the surface sea temperature gradient in latitude and longitude until the permanent East Antarctic Ice Sheet formed(~12.8 Ma) played an important role in the transmission of Antarctic signals to low latitudes.