Germline USP36 Mutation Confers Resistance to EGFR-TKIs by Upregulating MLLT3 Expression in Patients with Non-Small Cell Lung Cancer.

PURPOSE: Although somatic mutations were explored in depth, limited biomarkers were found to predict the resistance of EGFR tyrosine kinase inhibitors (EGFR-TKI). Previous studies reported N6-methyladenosine (m6A) levels regulated response of EGFR-TKIs; whether the germline variants located in m6A sites affected resistance of EGFR-TKIs is still unknown. EXPERIMENTAL DESIGN: Patients with non-small cell lung cancer (NSCLC) with EGFR-activating mutation were enrolled to investigate predictors for response of EGFR-TKIs using a genome-wide-variant-m6A analysis. Bioinformatics analysis and series of molecular biology assays were used to uncover the underlying mechanism. RESULTS: We identified the germline mutation USP36 rs3744797 (C > A, K814N) was associated with survival of patients with NSCLC treated with gefitinib [median progression-free survival (PFS): CC vs. CA, 16.30 vs. 10.50 months, P < 0.0001, HR = 2.45] and erlotinib (median PFS: CC vs. CA, 14.13 vs. 9.47 months, P = 0.041, HR = 2.63). Functionally, the C > A change significantly upregulated USP36 expression by reducing its m6A level. Meanwhile, rs3744797_A (USP36 MUT) was found to facilitate proliferation, migration, and resistance to EGFR-TKIs via upregulating MLLT3 expression in vitro and in vivo. More importantly, MLLT3 and USP36 levels are tightly correlated in patients with NSCLC, which were associated with prognosis of patients. Mechanistically, USP36 MUT stabilized MLLT3 by deubiquitinating MLLT3 in nucleoli and consequently activating its downstream signaling (HIF1α and Snai). Furthermore, inhibition of MLLT3 alleviated USP36 variant-induced EGFR-TKIs resistance in EGFR-mutant NSCLC. CONCLUSIONS: These findings characterized rs3744797 as an oncogenic variant in mediating EGFR-TKI resistance and tumor aggressiveness through deubiquitinating MLLT3, highlighting the variant as a predictive biomarker for EGFR-TKI response in NSCLC.

Microbial mechanisms to transform the super-trace element tellurium: a systematic review and discussion of nanoparticulate phases.

Tellurium is a super-trace metalloid on Earth. Owing to its excellent physical and chemical properties, it is used in industries such as metallurgy and manufacturing, particularly of semiconductors and - more recently - solar panels. As the global demand for tellurium rises, environmental issues surrounding tellurium have recently aroused concern due to its high toxicity. The amount of tellurium released to the environment is increasing, and microorganisms play an important role in the biogeochemical cycling of environmental tellurium. This review focuses on novel developments on tellurium transformations driven by microbes and includes the following sections: (1) history and applications of tellurium; (2) toxicity of tellurium; (3) microbial detoxification mechanisms against soluble tellurium anions including uptake, efflux and methods of reduction, and reduced ability to cope with oxidation stress or repair damaged DNA; and (4) the characteristics and applications of tellurium nanoparticles (TeNPs) produced by microbes. This review raises the awareness of microorganisms in tellurium biogeochemical cycling and the growing applications for microbial tellurium nanoparticles.

Ultrasound to guided epicutaneo-caval catheter insertion in newborn infants.

Objective: Recently, ultrasound (US) has been increasingly used for epicutaneo-caval catheter (ECC) tip positioning; however, the selection of blood vessels for ECC still depends on the operator's subjective judgment. This study aimed to explore the value of US in decision-making regarding the great saphenous vein (GSV), tip navigation, and tip location of ECC. Methods: Catheterization through the GSV of the lower extremity was selected. The running condition of the GSV was assessed by using US, and the angle between the GSV and the femoral vein was observed and measured. We selected the GSV with a smaller angle to the femoral vein for ECC catheterization. Results: ECC catheterization under ultrasound guidance increased the success rate at the time of catheterization from 82.5% to 100% (increased by 17.5%) and shortened the catheterization time from 56.1 ± 5.30 min to 31.5 ± 2.58 min on average (shortened by 44%). The incidence rate of catheter-related complications decreased by 58.2% catheter days from 6.80/1,000 to 2.84/1,000. Conclusion: ECC insertion under the guidance of US has numerous advantages, including significantly improving the success rate of one-time catheterization, shortening the time of catheterization, and reducing catheter-related complications.

[Screening, identification and activity evaluation of pancreatic lipase inhibition in Prunella vulgaris].

Pancreatic lipase (PL) inhibitors were firstly screened from Prunella vulgaris with PL immobilized on carboxylic acid-terminated magnetic nanoparticles, then these possible inhibitors were identified by LC-MS/MS and mixed standards. Finally, their inhibitory effects and types on PL were tested by p-nitrophenol method. The results showed that four PL inhibitors were screened out from P. vulgaris and confirmed by LC-MS/MS and mixed standards. The IC58 and inhibition types were as follows: caffeic acid [(252.3±3.6) mg·L⁻¹, anti-competitive inhibition], rutin [(91.2±1.6)mg·L⁻¹, competitive inhibition], hesperidin [(31.5±4.4) mg·L⁻¹, competitive inhibition] and ursolic acid [(41.3±2.2) mg·L⁻¹, competitive inhibition]. Their inhibitive types and abilities on PL were related to their molecular size, hydrophobicity and the number of hydrogen bond with PL triplet.