Mechanisms of Acquired Resistance to AZD9291 A Mutation-Selective, Irreversible EGFR Inhibitor

IntroductionAZD9291, a third-generation and mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is active against patients with EGFRT790M-mutant non–small-cell lung cancer (NSCLC) who failed prior treatment with EGFR TKIs. However, acquired resistance to AZD9291 is inevitable. In this study, we identified the mechanisms of acquired resistance to AZD9291 in EGFRT790M-mutant NSCLC.MethodsFour NSCLC patients with both an EGFR exon 19 deletion and the EGFRT790M mutation after developing acquired resistance to first-generation EGFR TKIs received AZD9291 at doses of 20 to 80 mg/day in a phase I trial (NCT01802632). Paired tumor samples before and after treatment were obtained to evaluate EGFR modifications, alternative pathway activation, and histologic transformation. Genetic alterations were analyzed using Sanger sequencing, fluorescence in situ hybridization, real-time polymerase chain reaction, and targeted exome sequencing.ResultsAll four patients achieved a partial response (median duration of response, 9 months [range, 9–11 months]) and subsequently showed resistance to AZD9291. EGFRT790M-mutant clones depopulated AZD9291-resistant tumors to below 1% (baseline, 14%–36%) in three patients with progression: one with the loss of EGFRLREAT747del/T790M-double mutant clones and two accompanied by transformation to small-cell carcinoma and focal fibroblast growth factor receptor 1 (FGFR1) amplification, respectively. EGFRT790M-mutant clones remained and the EGFR ligand was overexpressed in one patient with focal progression to AZD9291.ConclusionAcquired resistance mechanisms of AZD9291 in patients with EGFRT790M-mutant NSCLC who failed treatment with first-generation EGFR TKIs include the loss of EGFRT790M-mutant clones plus alternative pathway activation or histologic transformation and EGFR ligand–dependent activation

P-TEFb Regulates Transcriptional Activation in Non-coding RNA Genes

Many non-coding RNAs (ncRNAs) serve as regulatory molecules in various physiological pathways, including gene expression in mammalian cells. Distinct from protein-coding RNA expression, ncRNA expression is regulated solely by transcription and RNA processing/stability. It is thus important to understand transcriptional regulation in ncRNA genes but is yet to be known completely. Previously, we identified that a subset of mammalian ncRNA genes is transcriptionally regulated by RNA polymerase II (Pol II) promoter-proximal pausing and in a tissue-specific manner. In this study, human ncRNA genes that are expressed in the early G1 phase, termed immediate early ncRNA genes, were monitored to assess the function of positive transcription elongation factor b (P-TEFb), a master Pol II pausing regulator for protein-coding genes, in ncRNA transcription. Our findings indicate that the expression of many ncRNA genes is induced in the G0–G1 transition and regulated by P-TEFb. Interestingly, a biphasic characteristic of P-TEFb-dependent transcription of serum responsive ncRNA genes was observed: Pol II carboxyl-terminal domain phosphorylated at serine 2 (S2) was largely increased in the transcription start site (TSS, -300 to +300) whereas overall, it was decreased in the gene body (GB, > +350) upon chemical inhibition of P-TEFb. In addition, the three representative, immediate early ncRNAs, whose expression is dependent on P-TEFb, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear enriched abundant transcript 1 (NEAT1), and X-inactive specific transcript (XIST), were further analyzed for determining P-TEFb association. Taken together, our data suggest that transcriptional activation of many human ncRNAs utilizes the pausing and releasing of Pol II, and that the regulatory mechanism of transcriptional elongation in these genes requires the function of P-TEFb. Furthermore, we propose that ncRNA and mRNA transcription are regulated by similar mechanisms while P-TEFb inhibition unexpectedly increases S2 Pol II phosphorylation in the TSSs in many ncRNA genes.One Sentence Summary: P-TEFb regulates Pol II phosphorylation for transcriptional activation in many stimulus-inducible ncRNA genes

유기 반도체를 이용한 플로팅 게이트 메모리 트랜지스터 개발

Organic flash memories that employ solution-processed polymer semiconductors preferentially require internal stability of their active channel layers. In this paper, a series of new donor-acceptor copolymers based on cyclopentadithiophene (CDT) and diketopyrrolopyrrole (DPP) are synthesized to obtain high per-formance and operational stability of nonvolatile floating-gate memory transistors with various additional donor units including thiophene, thiophene-vinylene-thiophene (CDT-DPP-TVT), selenophene, and seleno-phene-vinylene-selenophene. Detailed analyses on the photophysical, two-dimensional grazing incident X-ray diffraction, and bias-stress stability are discussed, which reveal that the CDT-DPP-TVT exhibits excellent bi-as-stress stability over 105 s. To utilize the robust nature of CDT-DPP-TVT, floating-gate transistors are fabri-cated by embedding Au nanoparticles between CytopTM layers as a charge storage site. The resulting memory devices reveal bi-stable current states with high on/off current ratio larger than 104 and each state can be dis-tinguished for more than 1 year, indicating a long retention time. Moreover, a repetitive writing-reading-erasing-reading test clearly supports the reproducible memory operation with reversible and reliable electrical responses. All these results suggest that the internal stability of CDT-DPP-TVT makes this copolymer a prom-ising material for application in reliable organic flash memory.Y1. Introduction 1 2. Experimental Section 3 2.1 Materials 3 2.2 Fabrication of OFETs and Memory Devices 3 2.3 Thin Film and Device Characterization 3 3. Results and Discussions 4 4. Conclusion 16 5. References 17 국문요약 21본 논문은 유기 반도체를 이용한 플로팅 게이트 메모리 트랜지스터 개발 방법을 제시한다. 용액공정을 이용한 유기 플래쉬 메모리는 활성층의 내부 안정성이 중요하다. 높은 성능과 안정성의 비휘발성 플로팅 게이트 메모리 트랜지스터를 구현하기 위해 사이클로펜타디티오펜 (cyclopentadithiophene, CDT) 및 디케토피롤로피롤 (diketo-pyrrolopyrrole, DPP)에 기반하여 티오펜(thiophene), 티오펜-비닐렌-티오펜 (thiophene-vinylene-thiophene, TVT), 셀레노펜 (selenophene), 그리고 셀레노펜-비닐렌-셀레노펜(seleno-phene-vinylene-selenophene, SVS) 등 다양한 전자 주개-전자 받개 공중합체가 합성되었다. 위 4가지 전자 주개-전자 받개 공중합체를 바탕으로 광물리학적, 2차원 스침각 X-선 회절 분석법 및 바이어스 안정성에 대한 상세한 분석이 논의된다. 특히 바이어스 안정성 분석에서 CDT-DPP-TVT는 stress time이 105초를 넘는 우수한 안정성을 보여주었으며, 이러한 CDT-DPP-TVT의 특성을 활용하기 위해 전하 저장 장소로 금 나노 입자를 사용하여 플로팅 게이트 메모리 트랜지스터를 제조하였다. 결과적으로 메모리 트랜지스터는 104 보다 높은 on/off 전류 비율과 on과 off 상태에서 각각 1년 이상의 긴 보유시간을 나타냈다. 또한 반복적인 쓰기-읽기-지우기-읽기 평가를 통해 가역적이고 안정적인 메모리 트랜지스터 구동이 가능함을 보여주었다. 이러한 결과는 높은 내부 안정성을 지닌 CDT-DPP-TVT와 같은 공중합체가 신뢰성 있는 유기 플래쉬 메모리의 소재로써 유망한 재료임을 시사한다.MasterdCollectio

Hand gesture recognition with out-of-distribution gesture detection using a soft sensor embedded glove

Hand gesture recognition has been applied to many applications, such as sign language translation and virtual reality. Soft sensor embedded gloves have been widely used to collect gesture data for hand gesture recognition. Using a soft sensor embedded glove has an advantage compared to vision-based approaches, because it is less affected by the environment and is not restricted to the angle of camera sensors, especially when it is applied to virtual reality industry. One of the existing challenges in machine learning-based hand gesture recognition is that new gestures, which are not seen in the training stage, are often discovered in the testing stage. In order to overcome this challenge, in this work, a hand gesture recognition model is proposed based on one-dimensional convolutional neural networks (1D CNN) and long short-term memory (LSTM) as well as a clustering method. In particular, a clustering method is used to detect out-of-distribution gestures, which are not contained in the clusters that are consisted of hand gestures used in the training stage. The experiment results validate that the proposed hand gesture recognition model performs better than existing hand gesture recognition methods and a proposed clustering methods detects out-of-distribution gestures with high accuracy

Zinc oxide nanoparticles trigger autophagy-mediated cell death through activating lysosomal TRPML1 in normal kidney cells

Zinc oxide nanoparticles (ZnO NPs) have been widely used in various materials including sunscreens, cosmetics, over-the-counter topical skin products, and pigments. As traces of the used ZnO NPs have been found in the kidney, it is crucial to uncover their potential risks. The aim of this study is to elucidate detrimental effects of ZnO NPs and the molecular mechanism behind their renal toxicity. Cytotoxic effects were measured by MTT assay after HK2 cells were exposed to ZnO NPs for 24 h and IC50 value was determined. ROS and intracellular Zn2+ levels were detected by flow cytometry, and localization of Zn2+ and lysosome was determined by confocal microscopy. Occurrence of autophagy and detection of autophagic flux were determined by Western blot and confocal microscopy, respectively. We performed unpaired student t test for two groups, and one-way ANOVA with Tukey’s post hoc for over three groups. ZnO NPs induced cell death in human renal proximal tubule epithelial cells, HK2. Cytosolic Zn2+ caused autophagy-mediated cell death rather than apoptosis. Cytosolic Zn2+ processed in lysosome was released by TRPML1, and inhibition of TRPML1 significantly decreased autophagic flux and cell death. The findings of this study suggest that ZnO NPs strongly induce autophagy-mediated cell death in human kidney cells. Controlling TRPML1 can be potentially used to prevent the kidney from ZnO NPs-induced toxicity

A framework to predict the quality of answers with non-textual features

New types of document collections are being developed by various web services. The service providers keep track of non-textual features such as click counts. In this paper, we present a framework to use non-textual features to predict the quality of documents. We also show our quality measure can be successfully incorporated into the language modeling-based retrieval model. We test our approach on a collection of question and answer pairs gathered from a community based question answering service where people ask and answer questions. Experimental results using our quality measure show a significant improvement over our baseline

Structure-Based virtual screening and de novo design of PIM1 inhibitors with anticancer activity from natural products

© 2021 by the authors. Background: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis. Methods: to identify effective PIM1 kinase inhibitors, structurebased virtual screening of natural products of plant origin and de novo design were carried out using the protein-ligand binding free energy function improved by introducing an adequate dehydration energy term. Results: as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels. The results of extensive docking simulations showed that the inhibitory activity stemmed from the formation of multiple hydrogen bonds in combination with hydrophobic interactions in the ATP-binding site. Optimization of the biochemical potency by chemical modifications of the 2-benzylidenebenzofuran-3(2H)-one scaffold led to the discovery of several nanomolar inhibitors with antiproliferative activities against human breast cancer cell lines. Conclusions: these new PIM1 kinase inhibitors are anticipated to serve as a new starting point for the development of anticancer medicine.11Nsciescopu

1.1-µm Band Extended Wide-Bandwidth Wavelength-Swept Laser Based on Polygonal Scanning Wavelength Filter

We demonstrated a 1.1-µm band extended wideband wavelength-swept laser (WSL) that combined two semiconductor optical amplifiers (SOAs) based on a polygonal scanning wavelength filter. The center wavelengths of the two SOAs were 1020 nm and 1140 nm, respectively. Two SOAs were connected in parallel in the form of a Mach-Zehnder interferometer. At a scanning speed of 1.8 kHz, the 10-dB bandwidth of the spectral output and the average power were approximately 228 nm and 16.88 mW, respectively. Owing to the nonlinear effect of the SOA, a decrease was observed in the bandwidth according to the scanning speed. Moreover, the intensity of the WSL decreased because the oscillation time was smaller than the buildup time. In addition, a cholesteric liquid crystal (CLC) cell was fabricated as an application of WSL, and the dynamic change of the first-order reflection of the CLC cell in the 1-µm band was observed using the WSL. The pitch jumps of the reflection band occurred according to the electric field applied to the CLC cell, and instantaneous changes were observed