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Purpose:Activating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking.Experimental Design:We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non–small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations.Results:In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both in vitro and in vivo. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared with other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X-mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with KRAS wild-type tumors.Conclusions:This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials.

Supplemental Figure 1

Supplementary Data from Comparative Analysis and Isoform-Specific Therapeutic Vulnerabilities of KRAS Mutations in Non–Small Cell Lung Cancer

Supplementary Data from A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non–Small Cell Lung Cancer

Purpose:The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood.Patients and Methods:We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP).Results:MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months.Conclusions:Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

Supplementary Methods

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non–small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08–178–01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08–178–01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08–178–01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08–178–01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08–178–01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification.Significance:This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non–small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08–178–01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08–178–01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08–178–01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08–178–01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08–178–01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification. Significance: This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.

Treatment trends for Parkinson’s disease are revolutionizing from conventional pharmaceutical treatment depending on the patient’s symptoms to closed-loop electroceutical treatment in order to minimize the crucial pharmacokinetic drawbacks. Over the decades, closed-loop neuromodulations have been achieved by electroceutical devices based on continuous electrical stimulation and sensing of electrophysiological biomarkers. However, critical drawbacks have been observed with vulnerable to artefacts from the nearby stimulation electrode and frequent adjustment of stimulation parameters. On the contrary, direct monitoring of neurochemicals allows high spatial resolution, signal specificity and interference-free detection compared to closed-loop DBS. Here, we propose an artificial homeostasis system with electrochemical sensing and pharmaceutical stimulation for impaired brain function. In order to implement the artificial homeostasis system by mimicking the brain system, we have reported an implantable multi-deformable double-sided DA-sensing probe with an all-in-one structure by integrating three-electrode system and drug refillable microfluidic probe with controllable injection for synchronized diagnosis and treatment. The experimental and computational analysis clearly indicate that the proposed probes could serve as potential tools for building artificial homeostasis by the bio-responsive closed-loop system with an electropharmaceutical approach.

Many research groups have been interested in the quartz crystal microbalance (QCM)-based gas sensors due to their superb sensitivity originated from direct mass sensing at the ng level. Despite such high sensitivities observed from QCM sensors, their ability to identify gas compounds still needs to be enhanced. Herein, we report a highly facile method that utilizes microcolumns integrated on a QCM gas-responsive system with enhanced chemical selectivity for sensing and ability to identify volatile organic compound single gases. Graphene oxide (GO) flakes are coated on the QCM electrode to substantially increase the adsorption of gas molecules, and periodic polydimethylsiloxane microcolumns with micrometer-scale width and height were installed on the GO-coated QCM electrode. The observed frequency shifts upon sensing of various single gas molecules (such as ethanol, acetone, hexane, etc.) can be analyzed accurately using a simple exponential model. The QCM sensor system with and without the microcolumn both exhibited high detection response values above 50 ng/cm2 for sensing of the gases. Notably, the QCM sensor equipped with the microcolumn features gas identification ability, which is observed as distinct diverging behavior of time constants upon detection of different gases caused by the difference in diffusional transfer of molecules through the microcolumns. For example, the difference in the calculated time constant between ethanol and acetone increased from 22.6 to 92.1 s after installation of the microcolumn. This approach provides an easy and efficient method for identification of single gases, and it may be applied in various advanced sensor systems to enhance their gas selectivity.

Purpose: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%–2% of non–small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. Patients and Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). Results: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion–positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion–positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

Assembly of RAS molecules into complexes at the cell membrane is critical for RAS signaling. We previously showed that oncogenic KRAS codon 61 mutations increase its affinity for RAF, raising the possibility that KRASQ61H, the most common KRAS mutation at codon 61, upregulates RAS signaling through mechanisms at the level of RAS assemblies. We show here that KRASQ61H exhibits preferential binding to RAF relative to PI3K in cells, leading to enhanced MAPK signaling in in vitro models and human NSCLC tumors. X-ray crystallography of KRASQ61H:GTP revealed that a hyperdynamic switch 2 allows for a more stable interaction with switch 1, suggesting that enhanced RAF activity arises from a combination of absent intrinsic GTP hydrolysis activity and increased affinity for RAF. Disruption of KRASQ61H assemblies by the RAS oligomer–disrupting D154Q mutation impaired RAF dimerization and altered MAPK signaling but had little effect on PI3K signaling. However, KRASQ61H oligomers but not KRASG12D oligomers were disrupted by RAF mutations that disrupt RAF–RAF interactions. KRASQ61H cells show enhanced sensitivity to RAF and MEK inhibitors individually, whereas combined treatment elicited synergistic growth inhibition. Furthermore, KRASQ61H tumors in mice exhibited high vulnerability to MEK inhibitor, consistent with cooperativity between KRASQ61H and RAF oligomerization and dependence on MAPK signaling. These findings support the notion that KRASQ61H and functionally similar mutations may serve as predictive biomarkers for targeted therapies against the MAPK pathway. Significance: These findings show that oncogenic KRASQ61H forms a cooperative RAS–RAF ternary complex, which renders RAS-driven tumors vulnerable to MEKi and RAFi, thus establishing a framework for evaluating RAS biomarker-driven targeted therapies.

What is the role of organizational factors in fostering regulatory reform in response to new technological development? Existing studies provide useful frameworks to understand regulatory reform in rapidly changing circumstances but still lack a systematic analysis of how organizational factors affect regulatory reform in the public sector. To fill this gap, we examine the impact of several institutional elements that are central to defining organizational characteristics, such as job tasks, bureaucratic autonomy, and organizational culture. We theorize that regulatory reform is more likely when public sector organizations are more receptive to external changes, which are determined by these characteristics. We leverage original surveys from over 1,000 civil servants in Korea, one of the front runners in new technological development, and find support for our prediction. We find that the implementation of regulatory reforms is more likely when 1) organizational tasks are relevant to scientific and technological development, 2) higher levels of bureaucratic autonomy are granted, 3) agency heads demonstrate stronger leadership, and 4) organizational culture is less authoritarian. Our study makes clear contributions to the literature on public management and regulation theory, and has important implications for regulatory reform in the face of new technological development.

Gold electroless plating for surface finishing of electronic circuits, named electroless nickel immersion gold (ENIG), is widely practiced in the electronics packaging industry. Noncyanide substitu...

Purpose:Activating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking.Experimental Design:We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non–small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations.Results:In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both in vitro and in vivo. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared with other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X-mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with KRAS wild-type tumors.Conclusions:This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials.

The clinical efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in EGFR-mutant non–small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor–resistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.

A subset of drug-resistant EGFR -mutant MET -amplified lung cancer switches oncogenic dependence to MET and is treatable with MET inhibitor monotherapy.

We examine performance impact on management by investigating whether information on past organizational performance (‘performance feedback’) influences future managerial quality. We employ a regres...

RAF protein kinases are effectors of the GTP-bound form of the small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

Assembly of RAS molecules into complexes at the cell membrane is critical for RAS signaling. We previously showed that oncogenic KRAS codon 61 mutations increase its affinity for RAF, raising the possibility that KRAS

Exon 20 insertion (Ex20Ins) mutations are the third most prevalent epidermal growth factor receptor (EGFR) activating mutation and the most prevalent HER2 mutation in non-small cell lung cancer (NSCLC). Novel therapeutics for the patients with Ex20Ins mutations are urgently needed, due to their poor responses to the currently approved EGFR and HER2 inhibitors. Here we report the discovery of highly potent and broadly effective EGFR and HER2 Ex20Ins mutant inhibitors. The co-crystal structure of compound 1 b in complex with wild type EGFR clearly revealed an additional hydrophobic interaction of 4-fluorobenzene ring within a deep hydrophobic pocket, which has not been widely exploited in the development of EGFR and HER2 inhibitors. As compared with afatinib, compound 1 a exhibited superior inhibition of proliferation and signaling pathways in Ba/F3 cells harboring either EGFR or HER2 Ex20Ins mutations, and in the EGFR P772_H773insPNP patient-derived lung cancer cell line DFCI127. Our study identifies promising strategies for development of EGFR and HER2 Ex20Ins mutant inhibitors.

Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E2 ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E2 mainly functions through oestrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not in the stroma. We found that E2 induced cervical epithelial cell proliferation in epithelial ERα-deficient mice. We also found that E2 promoted the development of CIN and CxCa in epithelial ERα-deficient K14E7 mice and that all neoplastic epithelial cells were negative for ERα. In addition, proliferation indices were similar between ERα- and ERα+ CxCa. These results indicate that epithelial ERα is not necessary for E2 -induced CIN and CxCa. Taking these findings together, we conclude that stromal ERα rather than epithelial ERα mediates oncogenic E2 signalling in CxCa. Our results support stromal ERα signalling as a therapeutic target for the disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Researchers typically need to filter several academic papers to find those relevant to their research. This filtering is cumbersome and time-consuming because the number of published academic papers is growing exponentially. Some researchers have focused on developing better recommender systems for academic papers by using citation analysis and content analysis. Most traditional content analysis is implemented using a keyword matching process, and thus it cannot consider the semantic contexts of items. Further, citation analysis-based techniques rely on the number of links directly citing or being cited in a single-level network. Consequently, it may be difficult to recommend the appropriate papers when the paper of interest does not have enough citation information. To address these problems, we propose a recommendation system for academic papers that combines citation analysis and network analysis. The proposed method is based on multilevel citation networks that compare all the indirectly linked papers to the paper of interest to inspect the structural and semantic relationships among them. Thus, the proposed method tends to recommend informative and useful papers related to both the research topic and the academic theory. The comparison results based on real data showed that the proposed method outperformed the Google Scholar and SCOPUS algorithms.

We propose a content-based filtering algorithm based on a multiattribute network.Network analysis can consider similarities among indirectly-connected items.The proposed method addresses the data sparsity and over-specialization problems.The experiment with MovieLens demonstrates the robustness of the proposed method. Content-based filtering (CBF), one of the most successful recommendation techniques, is based on correlations between contents. CBF uses item information, represented as attributes, to calculate the similarities between items. In this study, we propose a novel CBF method that uses a multiattribute network to effectively reflect several attributes when calculating correlations to recommend items to users. In the network analysis, we measure the similarities between directly and indirectly linked items. Moreover, our proposed method employs centrality and clustering techniques to consider the mutual relationships among items, as well as determine the structural patterns of these interactions. This mechanism ensures that a variety of items are recommended to the user, which improves the performance. We compared the proposed approach with existing approaches using MovieLens data, and found that our approach outperformed existing methods in terms of accuracy and robustness. Our proposed method can address the sparsity problem and over-specialization problem that frequently affect recommender systems. Furthermore, the proposed method depends only on ratings data obtained from a user's own past information, and so it is not affected by the cold start problem.

TiO2 nanotubes (TNTs) were successfully synthesized from different alkaline media (i.e., NaOH and KOH) by using a microwave hydrothermal process. The effects of different alkaline media on the formation of TiO2 nanotubes and their physicochemical properties were investigated. The phases of different TiO2 nanostructures were studied by using X-ray diffraction patterns. Morphologies of the nanostructures were observed with a transmission electron microscope. The optical properties of the nanostructures were evaluated through the absorption behavior using UV–Vis diffuse reflectance spectroscopy. The photocatalytic activities of the TiO2 nanostructures were evaluated by the degradation of methylene blue aqueous dye solution under the simulated solar light irradiation. Similarly, the photovoltaic efficiencies of the prepared samples were investigated by making photo-anode layers in the Dye Sensitized Solar Cells (DSSCs). The results revealed that in comparison to the single layered TiO2 nanostructures in the DSSC, creation of a double layer structure significantly enhanced the efficiency of DSSC.

Single particle Mie calculations of near micron-sized TiO2 particles predict strong light scattering dominating the visible range that would give rise to a white appearance. We demonstrate that a polydisperse collection of these “white” particles can result in the generation of visible colors through ensemble scattering. The weighted averaging of the scattering over the particle size distribution modifies the sharp, multiple, high order scattering modes from individual particles into broad variations in the collective extinction. These extinction variations are apparent as visible colors for particles suspended in organic solvent at low concentration, or for a monolayer of particles supported on a transparent substrate viewed in front of a white light source. We further exploit the color variations on optical sensitivity to the surrounding environment to promote micron-sized TiO2 particles as stable and robust agents for detecting the optical index of homogeneous media with high contrast sensitivities. Su...

Semitransparent colorful organic solar cells (OSC) provide exciting opportunities for harnessing sunlight as colored windows. Previously, color filter (CF) electrodes on (OSC) were demonstrated via vacuum-deposition techniques, resulting in deposition-induced damage. Thus, we present CF integrated organic photovoltaics (CF-OPVs) using solution-processed TiO2-AcAc as the dielectric component. The noninvasive processing substantially expands the range of usable active materials, allowing the device to display pure and vibrant colors that are independent of the inherent color of the active material and show superior optical and photovoltaic characteristics. These results provide practical pathways to realizing colored semitransparent solar cells.

// Fabiola F. Mehta 1 , Jieun Son 1 , Sylvia C. Hewitt 2 , Eunjung Jang 1 , John P. Lydon 3 , Kenneth S. Korach 2 and Sang-Hyuk Chung 1 1 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA 2 Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA Correspondence to: Sang-Hyuk Chung, email: // Keywords : progesterone receptor, estrogen receptor α, epithelium, female reproductive tract, mouse model, Pathology Section Received : August 04, 2015 Accepted : March 02, 2016 Published : March 17, 2016 Abstract While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P 4 ) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P 4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock−in mouse models expressing ERα mutants, we determined that the DNA−binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus.

Electronic wastes containing precious metals have great potential as a sustainable source of such metals. Separation and refining, however, remain complicated, and none of the existing technologies have yet experienced commercialization. A novel porphyrin-based porous polymer, named COP-180, was recently introduced as a powerful adsorbent option, especially for gold, and in this study, aspects of desorption and recovery of adsorbed gold and regeneration of the polymer were investigated. A hydrometallurgical method using non-cyanide leaching agents was developed, and an acid thiourea-based solution was found to be particularly suited for the method based on COP-180 with gold desorption efficiency of 97%. Fourier-transform infrared spectroscopy spectra demonstrated the unaffected structure of COP-180 after desorption, implying the potential of its reuse. This high desorption efficiency was achieved even without typical aiding agents by means of a formamidine disulfide-mediated route that prevented thiourea consumption, which is considered a major drawback of the otherwise promising reagent. Using this method, the polymer was able to maintain more than 94% desorption efficiency after five times of regeneration. The results suggest that acid thiourea can offer a workable means of recovering gold particularly from the excellent gold-adsorbent of COP-180, and that repeated regeneration is also possible.

The explosive growth of the world-wide-web and the emergence of e-commerce has led to the development of recommender systems. Recommender systems are personalized information filtering used to identify a set of items that will be of interest to a certain user. This paper reviews recommender systems and presents their pros and cons. †

Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa). Estradiol (E(2)) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin 14 (K14) promoter. E(2) mainly works through estrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not stroma. We found that E(2) induced cervical epithelial cell proliferation in epithelial ERα-deficient mice. We also found that E(2) promoted the development of CIN and CxCa in epithelial ERα-deficient K14E7 mice, and all neoplastic epithelial cells were negative for ERα. In addition, proliferation indices were similar between ERα(−) and ERα(+) CxCa. These results indicate that epithelial ERα is not necessary for E(2)-induced CIN and CxCa. Taken together, we conclude that stromal ERα, rather than epithelial ERα, mediates oncogenic E(2) signaling in CxCa. Our results support stromal ERα signaling as a therapeutic target for the disease.

Single particle Mie calculations of near micron-sized TiO

In this study, electrically-facilitated forward osmosis (FO) employing proton exchange membrane (PEM) was established for the purpose of microalgae dewatering. An increase in water flux was observed when an external voltage was applied to the FO equipped with the PEM; as expected, the trend became more dramatic with both concentration of draw solution and applied voltage raised. With this FO used for microalgae dewatering, 247% of increase in flux and 86% in final biomass concentration were observed. In addition to the effect on flux improvement, the electrically-facilitated FO exhibited the ability to remove chlorophyll from the dewatered biomass, down to 0.021±0015mg/g cell. All these suggest that the newly suggested electrically-facilitated FO, one particularly employed PEM, can indeed offer a workable way of dewatering of microalgae; it appeared to be so because it can also remove the ever-problematic chlorophyll from extracted lipids in a simultaneous fashion.

Effective, stable, and economical anode catalysts are prerequisite for the practical use of a promising sulfide-based fuel cell platform, named direct alkaline sulfide fuel cell (DASFC). In this study, metal sulfides (MeS, Me = Mo, Fe, Co) were investigated as potential candidates suited for such a purpose. Physical and electrochemical properties of MeS catalysts were measured using X-ray diffraction (XRD), cyclic voltammetry (CV), I–V analysis, and electrochemical impedance spectrophotometry (EIS). All MeS catalysts exhibited strong catalytic activity toward sulfide oxidation at alkaline conditions, with the highest performance observed with CoS, recording maximum power density of 29.18 mW cm−2 at 70 °C. MeS catalysts, with superb sulfur tolerance, appear to be potent anode catalysts for the DASFC application.

Ag and γ-MnO2 binary catalyst was tested as a cathode catalyst candidate for carbon dioxide reduction reaction in electrolytic cell. Prepared γ-MnO2 was characterized by X-ray diffraction (XRD) and a field-emission scanning electron microscope (SEM). The electrocatalytic activity of Ag/γ-MnO2 binary catalyst toward CO2 reduction was investigated by cyclic voltammetry (CV). The results of CV measurement indicated that Ag/γ-MnO2 containing 10 wt% of silver was found to have a higher catalytic activity than carbon-supported 10 wt% Ag and improve catalytic performance as much as that of 50 wt% of carbon-supported Ag. The suggested binary catalyst with low content of Ag had a substantial improvement in catalytic activity. It is anticipated manganese dioxide plays a crucial role in electron transport and stabilization of intermediate enhancing multiple electron participation in reduction process. This result, along with its exceedingly low cost, thus suggests that γ-MnO2 is indeed a promising co-catalyst toward CO2 reduction.

Introduction: Non-small cell lung cancers harboring sensitizing gain-of-function mutations in the epidermal growth factor receptor (EGFR) are treated with small molecule EGFR kinase inhibitors including erlotinib and osimertinib. Unfortunately, the clinical efficacy of these inhibitors is limited by progression to drug resistance. Genomic amplification of the hepatocyte growth factor receptor (MET) is a prevalent mechanism of resistance to clinical EGFR inhibitors. EGFR mutant lung cancers with MET amplification are co-dependent on signaling through EGFR and MET kinases, whereby either oncogene can phosphorylate the EGFR family receptor ERBB3, activating downstream signaling and promoting survival. These EGFR/MET co-dependent cancers are characteristically resistant to treatment with individual drugs, but retain sensitivity to combination treatment with EGFR and MET inhibitors. Here, we describe three patient-derived EGFR mutant, MET amplified lung cancer models that exhibit a switch away from EGFR, to MET oncogene dependence. Methods: We established and characterized patient-derived lung cancer cell lines and xenograft models harboring concurrent EGFR activating mutations (EGFR L858R or EGFR Del19) and genomic MET copy number gain. Three patient-derived models—DFCI81, DFCI161, and DFCI307—were developed from pleural effusion and core biopsy specimens of patients whose tumors progressed on erlotinib. Clinical samples were immediately sorted and stably cultured in vitro or engrafted into immunodeficient mice. Results: DFCI81, DFCI161, and DFCI307 cell lines and xenograft models retained mutant EGFR expression, but exhibited resistance to clinical EGFR inhibitors and sensitivity to single-agent c-MET inhibitors, including crizotinib and savolitinib. Comparing our EGFR-mutant and MET-dependent cell lines to EGFR/MET-codependent models, we observed that EGFR expression was significantly reduced in our models compared to controls. Ectopic overexpression of EGFR Del19 and EGFR L858R in DFCI81 and DFCI161 cell lines, respectively, was sufficient to confer crizotinib resistance and induce EGFR/MET co-dependency. We demonstrated that MET-mediated ERBB3 phosphorylation drives downstream PI3K activation to promote cell proliferation and survival in DFCI81 and DFCI161 cells. In these contexts, ERBB3 reactivation by recombinant ligand treatment was sufficient to induce EGFR-mediated ERBB3 activation, conferring resistance to single-agent crizotinib treatment. Conclusions: We have identified and characterized three patient-derived models of treatment refractory EGFR mutant lung cancer that exhibit a switch to MET oncogene dependency. Clinically, we predict a subset of EGFR mutant, MET-dependent tumors exists, and can be identified de novo by a reduced EGFR to MET expression ratio: a potential biomarker predictive of sensitivity to single-agent MET inhibition. Citation Format: Pinar Ö. Eser, Raymond M. Paranal, Michael J. Poitras, Man Xu, Stephen Wang, Atsuko Ogino, Jihyun Choi, Pavlos Missios, Heidi M. Haikala, Jieun Son, Mika Lin, Masahiko Yanagita, Prafulla C. Gokhale, George Q. Daley, Pasi A. Jänne. Switch to MET oncogene dependence as a novel mechanism of drug resistance in EGFR-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1732.

cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cells and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-beta. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.

Estradiol (E2) and human papillomavirus (HPV) cooperate to cause cervical cancer. The role of estrogen receptor α (ERα) in cervical cancer has been underappreciated. Chronic treatment with E2 promotes the development of cervical cancer in K14E7 transgenic mice expressing HPV16 E7 oncoprotein. In the present study, we bred K14E7 to mice with conditional ablation of Esr1 (ERα-coding gene) in the cervical epithelial cells (Wnt7aCre/Esr1f/f; Esr1ed/ed). We found that E2 promoted the development of ERα cervical cancer in K14E7/Esr1ed/ed mice. In addition, proliferation and apoptotic indices of ERα cancer in K14E7/Esr1ed/ed mice were similar to those of ERα+ cancer in K14E7/Esr1f/f mice. We also found that E2 increased the epithelium thickness and epithelial cell proliferation in the cervix of Esr1ed/ed mice. Our published results have demonstrated that deletion of Esr1 in the cervical stroma promotes the regression of cervical precancer lesions in K14E7 mice. In patients, ERα is expressed in the cancer stroma but not cancer epithelial cells. These observations support that stromal ERα, rather than epithelial ERα, mainly mediates oncogenic E2 signaling for cervical cancer. They also suggest that stromal ERα might be an effective therapeutic target for cervical cancer. Note: This abstract was not presented at the conference. Citation Format: Jieun Son, Sang-Hyuk Chung. Development of estrogen-dependent and estrogen receptor-negative cervical cancer in HPV transgenic mice [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B28.