Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC

Recent and future situation of Japan’s T&D system

Japan suffered from the Great East Japan Earthquake followed by the nuclear disaster. As a result, we experienced rolling outages for a few months in the Tokyo and Tohoku area. Japan’s power transmission system consists of 50 Hz AC and 60 Hz AC in eastern and western Japan respectively. When the nuclear disaster occurred in Fukushima, enough electricity hasn’t been supplied in eastern area. Power interchange capacity between east and west was small because of small redundant T&D system design. Based on this rolling outage and some present electricity supplying issues in Japan, METI (Ministry of Economy, Trade and Industry) has set the electricity system reform committee to improve this situation and make a good T&D system for the future. This committee reported the discussed issue to the Japanese METI and METI proposed policy on Electricity System Reform to the Japanese Cabinet. As a result, the Japanese Electricity System Reform policy was adopted. This future T&D system deals with redundant T&D systems between east and west, how to handle large amounts of renewable electrical energy, and how to fully de-regulate the distribution market. HVDC (VSC system) will be introduced between Hokkaido and Honshu as a subsea cable transmission system and HVDC transmission system between eastern area and western area. This paper describes recent and future Japan’s T&D systems. This will be helpful to understand how to solve the issues of Japan’s T&D system

去勢雄性ラットにおける3H-Estramustine In vivo実験

Estradiol-3N-Bis-(2-chloroethyl) carbamate-17β-phosphate(estramustine phosphate，Estracyt(R))はホルモンを単体として制癌剤を高濃度に目的とする癌組織に運び、 そこで制癌効果を発揮させようという概念のもとに開発されたエストロゲン　–　制癌剤複合体であり、進行性前立腺癌の治療薬としてその有効性が報告されているが、今回、高比放射能活性をもつ3H-estramustine　を用いて去勢ラットにおける本薬剤の生体内動態について、特に前立腺に焦点を合わせて検討し、以下のような結果および結論が得られた。　1.去勢雄性ラットに3H-estramustineを腹腔内投与し、各臓器における放射活性を検討したところ、前立腺腹葉への3H-放射活性の選択的なとり込みが観察された。このような現象は3H-estramustine-17βおよび3H-estramustine acetate投与の際には観察されなかった。さらに3H-放射活性の前立腺腹葉における細胞内分布を経時的に追及したところ、精製核分画へのとり込みはサイトゾール分画の1.0-0.4%にすぎず、3H-放射活性のとり込みの大部分はサイトゾール分画にみられた。これらの結果より前立腺腹葉サイトゾール分画にはestramustineおよびその代謝物を長時間に保持する機構が存在することが示唆された。 2.前立腺腹葉サイトゾール分画に存在するestramustineまたはその代謝産物の結合蛋白に沈降常数は3-5sであり、これら結合蛋白はアンドロゲンリセプターとは異なる蛋白であることが推測された。Using estramustine of high specific radioactivity, we have investigated the uptake of estramustine in the different organs and some properties of binding proteins which bind estramustine and/or its metabolites in the ventral prostate of rat in in vivo experiments. The results and conclusions are as follows: 1. 3H-radioactivity was accumulated selectively in the ventral prostate of the castrated male rat after the administration of 3H-estramustine. Estramustine and its metabolites were retained in the ventral prostate for longer time, comparing with estradiol-17β or cyproterone acetate. The ammount　of radioactivity in purified nucleus of the ventral prostate was only 0.39% of that in the cytosol at 24 hours after the injection of 3H-estramustine. These results strongly suggested that there existed the mechanism of retention of est ramus tine and its metabolites in the cytosol of rat ventral prostate. 2. The sucrose density gradient analysis demonstrated that the ventral prostate cytosol binding proteins, which bind estramustine and/or its metabolites, have sedimentation coefficient of 3 to 5S and the pretreatment with injer:1-ion of estradiol-17βreducecd this 3-5S radioactive peak. Thin layer chromatographic analysis showed that 3H-compounds which bind 3-5S macromolecules were mainly estramustine and estrone-cytostatic complex (Leo 271 f) and that smaller amounts of estradiol-17β and estrone were detected. It is sure from these resuits that there exist in the cytosol of rat ventral prostate a macromolecule which bind hormone-cytostatic complexes and is different from androgen receptor