A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response ...to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.
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.
Artisanal and small-scale gold mining (ASGM) utilizes mercury (Hg) for the extraction of gold (Au) and is responsible for the largest anthropogenic source of emissions and releases of Hg to the ...environment. Previous estimates of Hg use in ASGM have varied widely. In this effort, Hg losses in ASGM were derived from the difference between estimates of total Au production and the production reported by conventional gold mining. On the basis of this result, the average ratio of Hg lost to Au produced in ASGM was estimated to be 1.96 in Africa, 4.63 in Latin America, and 1.23 in Asia. The difference among regions can be attributed to the amalgamation procedure used by the miners, in which whole-ore amalgamation is predominant in Latin America and Asia. The obtained estimated ratio of Hg
lost
:Au
produced
suggested the possibility to detect either Au or Hg smuggling from one country to another. On the other hand, the importance of considering cyanidation in ASGM was also suggested.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Indium is a rare metal that is an essential raw material for indium tin oxide (ITO) essential for transparent electrodes for displays. However, its supply is unstable as it is a by-product of zinc. ...In this research, we investigated the domestic substance flow of indium used for liquid crystal applications in Japan. Accordingly, we quantitatively evaluated the amount of indium contained in the process loss and the content of indium in end-of-life products. Through this quantification, we examined the visualization of loss in the entire flow and the usability of end-of-life products as secondary production. Consequently, it was found that the amount of indium used in the production of end-use-products in Japan has increased significantly due to the growth of liquid crystal display TVs, particularly in preparation for the transition to terrestrial digital broadcasting in 2011, and has drastically decreased after 2012. Meanwhile, some manufacturing bases have been relocated from Japan to other countries, and a certain proportion of end-use-products are imported, by which we infer the domestic input amount of end-use-products in recent years is estimated to have remained at approximately 4 t. Based on the result, after having continued to increase to the maximum value of approximately 70 t in 2014, the in-use stock has exhibited a gradually decreasing trend. Moreover, the indium content in end-of-life products has continued to increase, and in 2015, it exceeded the amount of the end-use-products input into society. Furthermore, compared with the process loss at the time of processing from ITO to a display, the gap has been narrowed from 100 times or more, and the indium content in end-of-life products in 2008 to about 15 times in 2017. These results suggest that the recycling potential of end-of-life products has increased with the spread of indium-based products.
In this research, a recycling process for palladium using “dry aqua regia,” which consists of iron(III) chloride–potassium chloride, was proposed. Palladium was dissolved in “dry aqua regia,” and the ...dissolved palladium was recovered by leaching with potassium chloride solution with added ammonium chloride and nitric acid. Palladium was almost completely dissolved in 3 h at 600 K, and the recovery ratio of dissolved palladium was up to 80%. In addition, the dissolution of palladium in coexistence with platinum and the dissolution of platinum-palladium alloy by “dry aqua regia” were also tested. The dissolved palladium and platinum were separated and recovered by solid–liquid separation technique using the difference in solubility of their compounds in potassium chloride and sodium chloride solutions. As a result, pure compounds of each element were recovered. This result suggested the possibility of using “dry aqua regia” for the separation of platinum-group metals.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objectives
To investigate the efficacy of selective upper tract urinary cytology using extracorporeal 5‐aminolevulinic acid for the diagnosis of upper urinary tract urothelial carcinoma.
Methods
We ...evaluated 104 patients who underwent radical nephroureterectomy and were diagnosed pathologically as having upper urinary tract urothelial carcinoma between March 2013 and May 2019 in Osaka Rosai Hospital. Preoperatively, we collected upper tract urinary cytology from both sides, and compared the sensitivity and specificity between conventional urine cytology and 5‐aminolevulinic acid‐induced fluorescent urine cytology.
Results
The sensitivity of 5‐aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology was significantly higher than conventional cytology (90.4% vs 66.3%, P < 0.001), whereas the specificity was equally high (100% vs 98.2%, P = 1.0). In more detailed analysis, the sensitivity of 5‐aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology was significantly higher than that of conventional cytology unrelated to patients’ age (<76 years: 90.2% vs 68.6%, P = 0.013; ≥76 years: 90.6% vs 64.2%, P = 0.021), sex (male: 89.2% vs 67.5%, P = 0.001; female: 95.2% vs 61.9%, P = 0.02) or pT stage (pT1 or less: 91.4% vs 69.0%, P = 0.005; pT2 or more: 89.1% vs 63.0%, P = 0.006), tumor grade (high grade: 91.0% vs 70.5%, P = 0.002; low grade: 88.5% vs 53.8%, P = 0.013), and tended to be more efficacious for tumors that could not be detected by imaging techniques (83.3% vs 50.0%, P = 0.075).
Conclusions
5‐Aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology is more sensitive than conventional cytology for the diagnosis of upper urinary tract urothelial carcinoma, regardless of pT stage and tumor grade.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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