Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of EGFR and HER2.

In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.

Monitoring Recessions: A Bayesian Sequential Quickest Detection Method.

Monitoring business cycles faces two potentially conflicting objectives: accuracy and timeliness. To strike a balance between the dual objectives, we develop a Bayesian sequential quickest detection method to identify turning points in real time and propose a sequential stopping time as a solution. Using four monthly indexes of real economic activity in the US, we evaluate the method's real-time ability to date the past five recessions. The proposed method identifies similar turning point dates as the National Bureau of Economic Research (NBER), with no false alarms, but on average dates peaks 4 months faster and troughs 10 months faster relative to the NBER announcement. The timeliness of our method is also notable compared to the dynamic factor Markov-switching model - the average lead time is about 5 months in dating peaks and 2 months in dating troughs.

Results of Laboratory Testing of 15 Cookstove Designs in Accordance with the ISO/IWA Tiers of Performance.

The widespread adoption and sustained use of modern cookstoves has the potential to reduce harmful effects to climate, health, and the well-being of approximately one-third of the world's population that currently rely on biomass fuel for cooking and heating. In an effort to understand and develop cleaner burning and more efficient cookstoves, 15 stove design and fuel/loading combinations were evaluated in the laboratory using the International Workshop Agreement's five-tiered (0-4) rating system for fuel use and emissions. The designs evaluated include rocket-type combustion chamber models including reduced firepower, sunken pots, and chimneys (three stoves); gasifier-type combustion chambers using prepared fuels in the form of wood pellets (four stoves); forced draft stoves with a small electric fan (five stoves); and a single insulated charcoal stove with preheated secondary air. It was found that a charcoal burning stove was the only stove to meet all the Tier 4 levels of performance. Achieving over 40% thermal efficiency at high power was made possible by reducing firepower and gaps around the pot, although batch-fed stoves generally do not "turn down" for optimal low power performance. While all stoves met Tier 4 for carbon monoxide, only stoves equipped with electrical fans reduced respirable particulate matter to Tier 4 levels. Finally, stoves with chimneys and integrated pots were fuel efficient and virtually eliminated indoor emissions. It is hoped that these design techniques will be useful in further development and evolution of high-performance cookstove designs.

[Study on composing prescription laws of treating aplastic anemia by Chinese medicine using applying data mining technique].

OBJECTIVE: To explore composing prescription laws of treating aplastic anemia (AA) by Chinese medicine (CM). METHODS: The literatures on treating AA by CM were recruited from various medical periodicals at home from 1979 to 2009 including China National Knowledge Infrastructure (CNKI), VIP information network, and Wangfang data knowledge service platform. The database correlated to CM features was established using the technique of computer data bank. The data mining (DM) technique was applied to analyze drugs sorts, frequency of drug application, and association degree. RESULTS: Three hundred and eleven pertinent literatures including 677 prescriptions and 254 Chinese herbs (CHs) were screened. There were 69 CHs for invigorating deficiency, 42 for heat clearing, 20 for promoting blood circulation and removing blood stasis, 16 for arresting bleeding, and 16 for relieving exterior syndrome, which occupied the top 5. The frequency of drug application of 254 CHs amounted to 7 547, in which the frequency of drug application of Mongolian milkvetch root, Rehmannia root, Suberect spatholobus stem, Hairyvein agrimonia herb, and Chinese thorowax root were 379, 248, 167, 85, and 13 respectively, and they occupied the first place of CHs for invigorating deficiency, heat clearing, promoting blood circulation and removing blood stasis, arresting bleeding, and relieving exterior syndrome, respectively. The number of the prescriptions containing 12, 10, and 11 CHs was occupied the top 3. The coverage rate of the prescription including Mongolian milkvetch root and Chinese angelica was 60%, and thus 4 core drugs groups were established covering invigorating qi and enriching the blood, reinforcing Shen and supporting yang, replenishing yin to tonify Shen, tonifying Shen to replenish essence, and invigorating qi and enriching blood respectively. Summarized were six potential composing prescription laws covering invigorating qi and enriching blood, reinforcing Shen and supporting yang, replenishing yin to tonify Shen, strengthening Pi and harmonizing Wei, tonifying the blood and promoting blood circulation, clearing away heat and toxic materials, and removing heat from the blood to stop bleeding. CONCLUSIONS: Applying DM technique, the fundamental core drugs groups consisting of Mongolian milkvetch root and Chinese angelica were discovered. The 4 core drugs groups established were in accordance with the realization of modern CM for the pathomechanism of AA. The 6 composing prescription laws summarized revealed the rules of drug application.

A fully integrated continuous-time 50-Hz notch filter with center frequency tunability.

A novel continuous-time notch filter based on current steering technique was described in this paper. The second-order notch filter consisted of two integrators, one unity-gain inverter and two alpha blocks that were fully integrated onto a silicon chip. The circuit was implemented in SMIC mixed-signal 0.18 nm 1P6M process with the die area of 0.06 mm(2). Post-annotated simulation indicated the continuous-time notch filter was capable of providing 55.4 dB attenuation for the 50 Hz power line interference and its center frequency was tunable against process variations.