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Purpose The aim of this study is to evaluate the safety and efficacy of ex vivo activated and expanded natural killer (NK) cell therapy (SNK01) plus pembrolizumab in a randomized phase I/IIa clinical trial.Materials and Methods Overall, 18 patients with advanced non–small cell lung cancer (NSCLC) and a programmed death ligand 1 tumor proportion score of 1% or greater who had a history of failed frontline platinum-based therapy were randomized (2:1) to receive pembrolizumab every 3 weeks +/– 6 weekly infusions of SNK01 at either 2×109 or 4×109 cells per infusion (pembrolizumab monotherapy vs. SNK01 combination). The primary endpoint was safety, whereas the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), overall survival, and quality of life.Results Since no dose-limiting toxicity was observed, the maximum tolerated dose was determined as SNK01 4×109 cells/dose. The safety data did not show any new safety signals when SNK01 was combined with pembrolizumab. The ORR and the 1-year survival rate in the NK combination group were higher than those in patients who underwent pembrolizumab monotherapy (ORR, 41.7% vs. 0%; 1-year survival rate, 66.7% vs. 50.0%). Furthermore, the median PFS was higher in the SNK01 combination group (6.2 months vs. 1.6 months, p=0.001).Conclusion Based on the findings of this study, the NK cell combination therapy may consider as a safe treatment method for stage IV NSCLC patients who had a history of failed platinum-based therapy without an increase in adverse events.

Immunotherapy with immune checkpoint inhibitors for non-small cell lung cancer (NSCLC) has emerged as an important treatment option. Although immunotherapy may significantly improve survival and quality of life, response rates are as low as 20% in NSCLC patients. The identification of reliable biomarkers predicting response to immunotherapy is required urgently to determine patient selection guidelines. Peripheral blood mononuclear cells (PBMCs) from nine NSCLC patients were collected pre- and post-treatment with immunotherapy. The immune cell composition of PBMCs was analyzed using CyTOF with an optimized 32-marker panel. The natural killer (NK) cell activity was assessed with the measurement of interferon (INF)-γ using an NK Vue™ kit. We found that the percentages of NK cell populations in the immune cells of PBMCs were prominently elevated in the immunotherapy responder group when compared with non-responders. While no meaningful differences were observed in other populations of immune cells, consistent with these results, the overall activity of NK cells in responders was highly elevated compared with that of non-responders. From the analysis of NK subsets, although differences in the population of early NK cells were not observed, the functionally differentiated late NK cells were prominently high in responders. The overall activity or number of NK cells may be a useful biomarker to predict immunotherapy response in patients with NSCLC.

Background Cancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. However, molecular mechanism to identify targets for controlling CSCs is poorly understood. Methods Gene Set Enrichment Analyses (GSEA) of Wnt/β-catenin and RAS signaling pathways in stem-like subtype of colorectal cancer (CRC) patients were performed using two gene expression data set. The therapeutic effects of destabilization of β-catenin and RAS were tested by treatment of small molecule KYA1797K using CRC patient derived cells. Results Treatment with KYA1797K, a small molecule that destabilizes both β-catenin and RAS via Axin binding, effectively suppresses the stemness of CSCs as shown in CRC spheroids and small intestinal tumors of ApcMin/+/K-RasG12DLA2 mice. Moreover, KYA1797K also suppresses the stemness of cells in CRC patient avatar model systems, such as patient-derived tumor organoids (PDTOs) and patient-derived tumor xenograft (PDTX). Conclusion Our results suggest that destabilization of both β-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells.

Background: Tumor-derived exosomal microRNAs are key elements of the cell-cell communications response to lots of stimuli. However, various functions of the exosome in tumor suppression by radiotherapy (RT) are not clearly understood. Our study showed a previously unknown interaction of p53 and histone deacetylase 5 (HDAC5) by radiation exposure in hepatocellular carcinoma (HCC). Methods: Using serial ultracentrifugation methods, radiation and non-radiation exosomes were purified to investigate the radioresistance of miRNA151a-3p. Radiation doses were treated in 2gy and 4gy using radiation equipment X-RAD 320 to observe the expression of HDAC5 and p53 in hepatic cancer cells. Exosomal miRNA bioinformatics analysis was conducted to find a variation in the miRNA configuration inside Exosome after radiation exposure.Results: HDAC5 and p53 interacted by exposure to radiation, which increased exosome release and altered microRNAs' composition within exosomes. Also, we have described the intercommunication occurring between irradiated and untreated cells via exosomal microRNAs that affect tumor proliferation. In particular, the expression of exosomal microR151a-3p was markedly reduced by radiation treatment. We confirmed that inhibition of exosomal microR151a-3p promotes suppression of non-irradiated cancer cells, thereby increasing RT sensitivity. Conclusion: our present findings demonstrated HDAC5 is a key component of the p53-mediated release of exosomes resulting in tumor suppression through exosomal microRNA-151a-3p in response to radiation. Finally, we highlight the important role of exosomal microRNA 151a-3p as a biomarker in enhancing RT sensitivity.

In contrast to non-small cell lung cancer, there has been no significant progress in the development of therapies for the small cell lung cancer (SCLC) in recent decades. Although various targeted agents, including immunotherapies, have recently been developed for testing in clinical trials, novel therapeutic agents are still needed for SCLC. We developed a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated YPN-005, and sought to determine whether it showed any anticancer effects in SCLC cells, cisplatin or etoposide-resistant cells, or organoids derived from SCLC patients. In a panel of kinases assay, YPN-005 was highly selective for CDK7 and showed antiproliferative effects in SCLC and cells with acquired resistance to conventional anticancer drugs. Similar to other CDK7 inhibitors, YPN-005 treatment significantly decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Consistent with the in vitro results, YPN-005 treatment showed a significant inhibition of tumor growth through the suppression of RNA polymerase II phosphorylation. Finally, YPN-005 showed potent anticancer effects in organoids derived from SCLC patients compared to another CDK7 inhibitor, THZ1. Therapeutic targeting of CDK7 in SCLC might be suitable for clinical investigation, and YPN-005 may be a promising therapeutic option for primary SCLC and SCLC with acquired resistance to conventional therapy.

Differential chemo-sensitivity of cancer cells, which is attributed to the cellular heterogeneity and phenotypic variation of cancer cells, is considered to be the main reason for tumor recurrence after chemotherapy. Here, we generated small cell lung cancer patient-derived tumor organoids and subjected them to long-term expansion with the addition of WNT3A or R-spondin1. We confirmed that the organoids have similar genetic profiles, molecular characteristics, and morphological architectures to the corresponding patient tumor tissue during and after long-term expansion. Interestingly, the cellular heterogeneity of organoids is reflected in their differential response to cisplatin or etoposide. We propose to utilize the organoids as small cell lung cancer patient avatar models that would be ideal for investigating the mechanisms underlying tumor recurrence after chemotherapy, and would ultimately help to develop personalized medicine.

5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients., The relative enrichment of cancer stem cells after treatment results in tumour recurrence. Here, the authors show a mechanism where p53 induces WNT3, which increases the number of colorectal cancer stem cells following treatment of 5-fluorouracil.

Triple-negative breast cancer (TNBC) is a severe and heterogeneous disease that lacks an approved targeted therapy and has a poor clinical outcome to chemotherapy. Although the RAS-ERK signaling axis is rarely mutated in TNBC, ~50% of TNBCs show an increased copy number and overexpression of epidermal growth factor receptor (EGFR). However, EGFR-targeted therapies have offered no improvement in patient survival, underscoring the need to explore downstream targets, including RAS. We found that both β-catenin and RAS, as well as epidermal growth factor receptor (EGFR), are overexpressed and correlated with one another in tumor tissues of TNBC patients. KYA1797K, an Axin-binding small molecule reducing β-catenin and RAS expression via degradation and suppressing EGFR expression via transcriptional repression, inhibited the proliferation and the metastatic capability of stable cell lines as well as patient-derived cells (PDCs) established from TNBC patient tissues. KYA1797K also suppressed the stemness of 3D-cultured PDCs and xenografted tumors established by using residual tumors from TNBC patients and those established by the TNBC cell line. Targeting both the Wnt/β-catenin and RAS-ERK pathways via small molecules simultaneously reducing the levels of β-catenin, RAS, and EGFR could be a potential therapeutic approach for TNBC., Breast cancer: Dual pathway blockade shrinks aggressive tumors The triple-negative breast cancer (TNBC), a highly aggressive form of breast cancer may be susceptible to drug therapy that targets two critical signaling pathways, one that governs cell fate and the other that controls the cell cycle. Researchers from Yonsei University in Seoul, South Korea, had previously synthesized a small-molecule called KYA1797K and found that could lower levels of the proteins, β-catenin (a master regulator of cell fate decisions) and RAS (which controls cell division), in colorectal cancer cells. Now, Kang-Yell Choi, Soonmyung Paik, and colleagues have shown that KYA1797K has the same effects on β-catenin and RAS levels in cells taken from patients with TNBC. In cell lines and mouse models, KY1797K suppressed the proliferation and metastatic capability of TNBC, highlighting the therapeutic potential of this strategy degrading both β-catenin and RAS.

Although the development of drugs that control Ras is an emerging topic in cancer therapy, no clinically applicable drug is currently available. We have previously utilized knowledge of the Wnt/β-catenin signaling-dependent mechanism of Ras protein stability regulation to identify small molecules that inhibit the proliferation and transformation of various colorectal cancer (CRC) cells via degradation of both β-catenin and Ras. Due to the absence of Ras degradation in cells expressing a nondegradable mutant form of β-catenin and the need to determine an alternative mechanism of Ras degradation, we designed a cell-based system to screen compounds that degrade Ras independent of the Wnt/β-catenin signaling pathway. A cell-based high-content screening (HCS) system that monitors the levels of EGFP-K-RasG12V was established using HCT-116 cells harboring a nondegradable mutant CTNNB1 (ΔS45). Through HCS of a chemical library composed of 10,000 compounds and subsequent characterization of hits, we identified several compounds that degrade Ras without affecting the β-catenin levels. KY7749, one of the most effective compounds, inhibited the proliferation and transformation of CRC cells, especially KRAS-mutant cells that are resistant to the EGFR monoclonal antibody cetuximab. Small molecules that degrade Ras independent of β-catenin may able to be used in treatments for cancers caused by aberrant EGFR and Ras.

The appropriate tongue reconstruction method is critical for better functional outcomes. The aim of this study was to determine the optimal reconstructive method for restoring postoperative function based on the extent of resection. We retrospectively reviewed 43 patients with lateral oral tongue cancer who underwent glossectomy between January 2010 and October 2014. Tongue mobility, articulation, verbal diadochokinesis, speech intelligibility and swallowing outcomes were assessed 2–3 years postoperative and were analyzed according to resected tongue volume and the method of reconstruction. In partial glossectomy cases, the secondary intention group had better function in tongue mobility, articulation, and speech intelligibility (p

Background Stabilization of RAS is a key event for the hyper-activation of Wnt/β-catenin signaling and activation of cancer stem cell (CSC) in colorectal cancer (CRC). WD Repeat protein 76 (WDR76) mediates the polyubiquitination-dependent degradation of RAS in hepatocellular carcinoma (HCC). We investigated whether WDR76 destabilizes RAS and acts as a tumor suppressor inhibiting CSC activation in CRC. Methods We generated mice with deletion of Wdr76 (Wdr76−/−) and crosses of Wdr76−/− with ApcMin/+ (Wdr76−/−; ApcMin/+) and compared them with wildtype mice (Wdr76+/+) and ApcMin/+ mice (Wdr76+/+; ApcMin/+), respectively. Intestinal crypt lengthening, tumorigenesis and CSC activation were analyzed by histology, immunohistochemistry, and immunoblotting. CRC cell line was engineered to stably express or knockdown WDR76 or control vector and was analyzed after spheroid culture. Results Wdr76−/− mice, with increased Ras level, displayed crypt elongation and hyper-proliferation. Wdr76−/−; ApcMin/+ mice developed more tumors with bigger sizes than ApcMin/+ mice and their tumors showed increased proliferation and CSC activation with elevated RAS and β-catenin levels. In CRC cells, overexpression or knockdown of WDR76 decreased or increased the numbers and sizes of CRC spheroids with inhibition or activation of CSC markers, respectively. In human CRC, lower level of WDR76 was associated with poor patient survival. Conclusions In analyses of mice with deletion of Wdr76 and CRC spheroids, we found that RAS stability plays important roles in tumorigenesis by affecting proliferation and CSC activation. Our results suggest that destabilization of RAS by WDR76 is a potential strategy for targeting malignant CRC involving CSC activation. Graphic abstract Electronic supplementary material The online version of this article (10.1186/s12964-019-0403-x) contains supplementary material, which is available to authorized users.

The epidermal growth factor receptor (EGFR) inhibitors such as erlotinib and gefitinib are widely used for treatment of non-small cell lung cancer (NSCLC), but they have shown limited efficacy in an unselected population of patients. The KRAS mutations, which are identified in approximately 20% of NSCLC patients, have shown to be associated with the resistance to the EGFR tyrosine kinase inhibitors (TKIs). Currently, there is no clinically available targeted therapy which can effectively inhibit NSCLC tumors harboring KRAS mutations. This study aims to show the effectiveness of KYA1797K, a small molecule which revealed anti-cancer effect in colorectal cancer by destabilizing Ras via inhibiting the Wnt/β-catenin pathway, for the treatment of KRAS-mutated NSCLC. While erlotinib fail to have anti-transforming effect in NSCLC cell lines harboring KRAS mutations, KYA1797K effectively inhibited the Ras-ERK pathway in KRAS-mutant NSCLC cell lines. As a result, KYA1797K treatment suppressed the growth and transformation of KRAS mutant NSCLC cells and also induced apoptosis. Furthermore, KYA1797K effectively inhibited Kras-driven tumorigenesis in the KrasLA2 mouse model by suppressing the Ras-ERK pathway. The destabilization of Ras via inhibition of the Wnt/β-catenin pathway is a potential therapeutic strategy for KRAS-mutated NSCLC that is resistant to EGFR TKI.

RAS proteins play critical roles in various cellular processes, including growth and transformation. RAS proteins are subjected to protein stability regulation via the Wnt/β-catenin pathway, and glycogen synthase kinase 3 beta (GSK3β) is a key player for the phosphorylation-dependent RAS degradation through proteasomes. GSK3β-mediated RAS degradation does not occur in cells that express a nondegradable mutant (MT) β-catenin. Here, we show that β-catenin directly interacts with RAS at the α-interface region that contains the GSK3β phosphorylation sites, threonine 144 and threonine 148 residues. Exposure of these sites by prior β-catenin degradation is required for RAS degradation. The introduction of a peptide that blocks the β-catenin-RAS interaction by binding to β-catenin rescues the GSK3β-mediated RAS degradation in colorectal cancer (CRC) cells that express MT β-catenin. The coregulation of β-catenin and RAS stabilities by the modulation of their interaction provides a mechanism for Wnt/β-catenin and RAS-ERK pathway cross-talk and the synergistic transformation of CRC by both APC and KRAS mutations.

Tumor-derived exsosomes (TEXs) contain enriched miRNAs act as novel non-invasive biomarkers for cancer diagnosis, and they are involved in cancer progression. In this study, we aimed to investigate which and how exosomal miRNA affect cancer progression in non-small cell lung cancer (NSCLC). We found that the only of A549 cell-released exosomes promote an angiogenic phenotype in HUVEC cells compared to other lung cancer cell-released exosomes. Using a miRNA array and RNA sequencing approach, we identified that specific miRNAs can modulate angiogenesis in A549 cell-released exosomes. Among these miRNAs, miR-619-5p significantly induced angiogenesis in HUVEC cells. Subsequently, RCAN1.4 was identified as a target of miR-619-5p and the suppression of RCAN1.4 inhibited the angiogenesis of HUVEC cells. Furthermore, the suppression of RCAN1.4 by miR-619-5p promoted the cellular mobility and proliferation in in vitro, as well as in vivo, tumor growth and metastasis in non-small cell lung cancer (NSCLC) cells. In patients with non-small cell lung cancer (NSCLC), the level of RCAN1.4 expression was significantly lower in tumor tissues than normal lung tissues, whereas the level of miR-619-5p was a significant higher in tumor tissue than normal lung tissues. We also found that there was a significant inverse correlation between the expression of miR-619-5p and that of RCAN1.4. In addition, miR-619-5p expression was higher in exosomes isolated from plasma of patients with NSCLC than normal. Finally, hypoxia condition led to enhance the amount of miR-619-5p within NSCLC cells-derived exosomes. In conclusion, exosomal miR-619-5p promotes tumor growth and metastasis of NSCLC by regulating RCAN1.4 in endothelial and tumor cells, and it can serve as a diagnosis and prognostic indicator for NSCLC patients. Citation Format: Sang Yong Jung, Dong Ha Kim, Yong-Hee Cho, Yun Jung Choi, Seon Ye Kim, Ki Jung Sung, Chae Won Lee, Hyeon Jeong Lee, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho. Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2528.

e15559 Background: Despite the increased promise of checkpoint inhibitors in the treatment of non-small cell lung cancer, the majority of patients do not respond and the potential for severe toxicity is significant. Unfortunately, the predictive value of PD-L1 expression has not always proven to be definitive and the overall need to find better biomarkers that will optimize the selection of patients who will best respond to therapy remains. Recent evidence has pointed to Natural Killer (NK) cells as an essential mediator in overall response to checkpoint inhibitors. We explore whether NK cell populations and/or their activity have any correlation with response. Methods: Peripheral blood mononuclear cells (PBMCs) from nine patients with Stage IV non-small cell lung cancer (four adenocarcinoma, five squamous cell carcinoma) were collected pre and post six-weeks of checkpoint immunotherapy (six received pembrolizumab, and three received nivolumab). Overall, four of nine (44.5%) were diagnosed as SD or PR via RECIST 1.1. The immune cell composition of the PBMCs of all nine patients was analyzed using multi-variated single-cell analysis using mass cytometry (CyTOF) with an optimized 32-marker panel. Natural Killer (NK) cell activity was measured with the NKVue kit which detects NK-secreted IFN-γ levels using a quantitative sandwich ELISA from NK cells exposed to a specific recombinant cytokine. Results: The overall percentages of NK cell populations found in the immune cells of PBMCs were prominently elevated in patients who responded (SD or PR) to checkpoint therapy compared to those who had progressive disease (non-responders). While there were no significant differences in the population of other immune cells between these two groups, the overall NK cell activity in patients who responded was highly elevated compared to the NK cell activity in non-responders. From the analysis of NK subsets, there were no differences in the population of early NK cells between the two groups, but the functionally differentiated late NK cells were prominently high in the responder group. Conclusions: Natural Killer (NK) cells have been recently implicated to play a key role in anti-tumor response to checkpoint inhibitors and our results suggest that the overall number of NK cells and their activity could prove to be an independent and reliable predictive tool/biomarker in patients with NSCLC.

The effects of crystal orientation on the optical gain characteristics of blue AlInGaN/InGaN quantum-well (QW) structures with a reduced internal field were investigated by using the non-Markovian model with many-body effects. The AlInGaN/InGaN system has a larger matrix element than the conventional InGaN/GaN system because the former has a smaller internal field than the latter for relatively small crystal angles. As a result, for QW structures with a relatively small crystal angle (θ = 30°), the AlInGaN/InGaN system is shown to have a much larger optical gain than the conventional InGaN/GaN system. On the other hand, in the case of QW structures with a large crystal angle (θ = 90°), the AlInGaN/InGaN system is shown to have a smaller optical gain than the conventional InGaN/GaN system. Hence, we expect that we can obtain high-efficiency optoelectronic devices by using quaternary AlInGaN QW for relatively small crystal angles.

The global market for drones is growing fastthanks to their efficiency, flexibility, and new valuesembedded in various fields. They, however, have somelimitations of operation due to battery issues. This articlesuggests how to resolve the battery issue, how to define theWPT drone, and how to find the most optical spectrumallocation for WPT drones through literature reviews andfield specialist interviews. After considering 4 majorconstraints, this paper proposes that 2.45GHz or 5.8GHzallows more flexible and efficient use of spectrum in thefuture. These important changes are expected to createfurther opportunities for drones to support a variety ofapplications, ranging from real-time monitoring fordisaster, public safety, dynamic outside broadcasting and networking.

Treatment of advanced gastric cancer patients with current standard chemotherapeutic agents frequently results in resistance, leading to poor overall survival. However, there has been no success in developing strategies to overcome it. We showed the expression levels of both &beta, catenin and RAS were significantly increased and correlated in tissues of 756 gastric cancer (GC) patients and tissues of primary- and acquired-resistance patient-derived xenograft tumors treated with 5-fluorouracil and oxaliplatin modulated with leucovorin (FOLFOX). On the basis of our previous studies, where small molecules to suppress colorectal cancer (CRC) via degrading both &beta, catenin and RAS were developed, we tested the effectiveness of KYA1797K, a representative compound functioning by binding axin, in the growth of GC cells. The efficacy test of the drugs using gastric tumor organoids of Apc1638N mice showed that the CD44 and ALDH1A3 cancer stem cell markers were induced by FOLFOX, but not by KYA1797K. KYA1797K also efficiently suppressed tumors generated by re-engrafting the FOLFOX-resistant patient-derived xenograft (PDX) tumors, which also showed resistance to paclitaxel. Overall, the small-molecule approach degrading both &beta, catenin and RAS has potential as a therapeutic strategy for treating GC patients resistant to current standard chemotherapies.

Objectives: Activation of the Wnt/β-catenin signaling pathway inhibits adipogenesis by maintaining preadipocytes in an undifferentiated state. We investigated the effect of indirubin-3′-oxime (I3O), which was screened as an activator of the Wnt/β-catenin signaling, on inhibiting the preadipocyte differentiation in vitro and in vivo. Methods: 3T3L1 preadipocytes were differentiated with 0, 4 or 20 μM of I3O. The I3O effect on adipocyte differentiation was observed by Oil-red-O staining. Activation of Wnt/β-catenin signaling in I3O-treated 3T3L1 cells was shown using immunocytochemical and immunoblotting analyses for β-catenin. The regulation of adipogenic markers was analyzed via real-time reverse transcription-PCR (RT-PCR) and immunoblotting analyses. For the in vivo study, mice were divided into five different dietary groups: chow diet, high-fat diet (HFD), HFD supplemented with I3O at 5, 25 and 100 mg kg−1. After 8 weeks, adipose and liver tissues were excised from the mice and subject to morphometry, real-time RT-PCR, immunoblotting and histological or immunohistochemical analyses. In addition, adipokine and insulin concentrations in serum of the mice were accessed by enzyme-linked immunosorbent assay. Results: Using a cell-based approach to screen a library of pharmacologically active small molecules, we identified I3O as a Wnt/β-catenin pathway activator. I3O inhibited the differentiation of 3T3-L1 cells into mature adipocytes and decreased the expression of adipocyte markers, CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ, at both mRNA and protein levels. In vivo, I3O inhibited the development of obesity in HFD-fed mice by attenuating HFD-induced body weight gain and visceral fat accumulation without showing any significant toxicity. Factors associated with metabolic disorders such as hyperlipidemia and hyperglycemia were also improved by treatment of I3O. Conclusion: Activation of the Wnt/β-catenin signaling pathway can be used as a therapeutic strategy for the treatment of obesity and metabolic syndrome and implicates I3O as a candidate anti-obesity agent.

New approaches to robotic thyroidectomy help to prevent neck scarring and improve surgical ergonomics. The purpose of this study was to compare the efficacy and advantages of a gasless unilateral axillary (GUA) approach and an axillo-breast (GUAB) approach in robotic thyroidectomy. We retrospectively reviewed the data of 131 patients who underwent robotic thyroidectomy with or without central neck dissection using a GUAB (90 cases) or GUA (41 cases) approach between September 2009 and December 2011. We excluded patients who underwent simultaneous lateral neck dissection and cases within the learning curve. We compared patient and tumor characteristics, surgical outcomes, perioperative complications, and cosmetic satisfaction between the two approaches. Robotic thyroidectomy was successful in all patients. There were no differences in terms of patient and tumor characteristics, extent of thyroidectomy and central neck dissection, operative time, and postoperative complications between the two approaches. Cosmetic satisfaction was excellent in both groups. There was no difference in satisfaction with the cosmetic result in the neck area, but the GUA patients expressed higher satisfaction with the appearance of the breast. The surgical outcomes of GUA and GUAB approaches are similar in robotic thyroidectomy. Both are safe, effective, and yield cosmetically excellent results when performed by an experienced robotic thyroid surgeon. However, a GUA approach is associated with superior cosmetic satisfaction with the appearance of the breast.

// Yong-Hee Cho 1, 2 , Pu-Hyeon Cha 1, 2 , Saluja Kaduwal 1, 2 , Jong-Chan Park 1, 2 , Sang-Kyu Lee 1, 2 , Jeong-Soo Yoon 1, 2 , Wookjin Shin 1, 2 , Hyuntae Kim 1, 2 , Eun Ji Ro 1, 2 , Kyung-Hwa Koo 1, 2 , Ki-Sook Park 3 , Gyoonhee Han 1, 2 , Kang-Yell Choi 1, 2 1 Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea 2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea 3 College of Medicine, East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Korea Correspondence to: Kang-Yell Choi, email: kychoi@yonsei.ac.kr Keywords: Apc mutation, K-Ras mutation, tumor budding, metastatic colorectal cancer, Ras destabilizer Received: August 20, 2016 Accepted: October 19, 2016 Published: November 07, 2016 ABSTRACT APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APC Min /+ /K-Ras G12D LA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.

The emergence of metallic conduction in layered dichalcogenide semiconductor materials by chemical doping is one of key issues for two-dimensional (2D) materials engineering. At present, doping methods for layered dichalcogenide materials have been limited to an ion intercalation between layer units or electrostatic carrier doping by electrical bias owing to the absence of appropriate substitutional dopant for increasing the carrier concentration. Here, we report the occurrence of metallic conduction in the layered dichalcogenide of SnSe2 by the direct Se-site doping with Cl as a shallow electron donor. The total carrier concentration up to ~1020 cm−3 is achieved by Cl substitutional doping, resulting in the improved conductivity value of ~170 S·cm−1 from ~1.7 S·cm−1 for non-doped SnSe2. When the carrier concentration exceeds ~1019 cm−3, the conduction mechanism is changed from hopping to degenerate conduction, exhibiting metal-insulator transition behavior. Detailed band structure calculation reveals that the hybridized s-p orbital from Sn 5s and Se 4p states is responsible for the degenerate metallic conduction in electron-doped SnSe2.

APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both B-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Targeting these signaling pathways may therefore be an ideal strategy for treating mCRC; however, therapeutics targeting both of these pathways have not been developed because the mechanisms regulating these pathways are not well understood. Based on our recent identification of the B-catenin destruction complex-mediated Ras protein stability mechanism, we screened a small-molecule library to identify compounds that destabilize both B-catenin and Ras proteins via inhibition of the Wnt/B-catenin pathway. Among the effective small molecules destabilizing both B-catenin and Ras proteins via inhibition of the Wnt/β-catenin pathway, we characterized KY1022, a small molecule that most effectively inhibits EMT, an initial process of metastasis. As shown by in vitro and in vivo studies using APCMin/+/K-RasG12DLA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. Our results suggest that a small molecular approach degrading both B-catenin and Ras via inhibition of the Wnt/B-catenin signaling would be an ideal strategy for treatment of CRC including mCRC. Citation Format: Eun Ji Ro, Jeong-Ha Hwang, Yong-Hee Cho, Kang-Yell Choi. Simultaneous inhibition of the Wnt/B-catenin and Ras pathways by KY1022 effectively suppresses tumor initiation and progression of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4181.

Both the Wnt/β-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. Inhibition of these signaling may therefore be an ideal strategy for treating CRC. We identified KY1220, a compound that destabilizes both β-catenin and Ras, via targeting the Wnt/β-catenin pathway, and synthesized its derivative KYA1797K. KYA1797K bound directly to the regulators of G-protein signaling domain of axin, initiating β-catenin and Ras degradation through enhancement of the β-catenin destruction complex activating GSK3β. KYA1797K effectively suppressed the growth of CRCs harboring APC and KRAS mutations, as shown by various in vitro studies and by in vivo studies using xenograft and transgenic mouse models of tumors induced by APC and KRAS mutations. Destabilization of both β-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other type cancers activated Wnt/β-catenin and Ras pathways.

// Kyoung-Hwa Koo 1,2 , Woo-Jeong Jeong 1,2 , Yong-Hee Cho 1,2 , Jong-Chan Park 1,2 , Do Sik Min 1,3 and Kang-Yell Choi 1,2 1 Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea 2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea 3 Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea Correspondence to: Kang-Yell Choi, email: // Keywords : endometrial cancer, estrogen, tumorigenesis, K-Ras, PKCδ Received : February 27, 2015 Accepted : April 30, 2015 Published : May 08, 2015 Abstract Estrogens are considered as a major risk factor of endometrial cancer. In this study, we identified a mechanism of tumorigenesis in which K-Ras protein is stabilized via estrogen signaling through the ER-α36 receptor. PKCδ was shown to stabilize K-Ras specifically via estrogen signaling. Estrogens stabilize K-Ras via inhibition of polyubiquitylation-dependent proteasomal degradation. Estrogen-induced cellular transformation was abolished by either K-Ras or PKCδ knockdown. The role of PKCδ in estrogen-induced tumorigenesis was confirmed in a mouse xenograft model by reduction of tumors after treatment with rottlerin, a PKCδ inhibitor. Finally, levels of PKCδ correlated with that of Ras in human endometrial tumor tissues. Stabilization of K-Ras by estrogen signaling involving PKCδ up-regulation provides a potential therapeutic approach for treatment of endometrial cancer.

In this study, we developed an automatic veneer sorting system controlled by nonlinear friction and nonlinear stiffness. With these nonlinear characteristics, it was difficult to analysis and to control the system in the fast. However it is necessary to consider nonlinear characteristics to satisfy accurate and rapid control demand in these days. We used not only nonlinear friction but also nonlinear stiffness and combined both to control the system. An experimental device was designed with 4 AC servo-motors and 2 Sensors. Through a series of experiment, we found nonlinear friction characteristics among roller versus veneer and veneer versus veneer and nonlinear stiffness characteristics with stacked veneers. Finally, we showed that the proposed control algorithm was very effective for veneer sorting system with nonlinear friction and stiffness.

INTRODUCTION Aberrant activations of Wnt/β-catenin and Ras signaling pathways by APC (90%) and K-Ras (40-50%) mutations are closely interacted and accelerate CRC tumorigenesis. Protein level of β-catenin as well as Ras is increased by APC loss via inhibiting GSK3B-mediated poly-ubiquitination dependent Ras degradation through recruitment of β-TrCP E3 linker. Moreover, additional K-Ras mutation results in the liver metastasis by secondary activation of the Wnt/β-catenin signaling pathways via Ras-ERK and -AKT pathways in addition to the initial activation by APC loss. Consequently, both β-catenin and Ras were highly increased in human CRC patient tissues, especially in metastatic tumor. EXPERIMENT PROCEDURES To investigate the synergistic effects of aberrant Wnt/β-catenin and Ras signaling pathways on tumor development to metastasis, we established the APCMin/+/K-RasG12DLA2 compound mouse that harbor APC and K-Ras mutations in animal model. We also analyzed Ras protein level using human CRC patient tissues of normal mucosa and adenocarcinoma (N=24) and metastatic adenocarcinoma (N=26) and tumor budding (N=10). To recapitulate the metastatic tumor environment which have enriched receptor tyrosine kinases (RTKs), we maintained and experimented with EGF (20ng/ml) in every in vitro studies. RESULTS We observed that both β-catenin and Ras were increased in adenocarcinoma and metastatic adenocarcinoma of human CRC compared with normal mucosa. Interestingly, both β-catenin and Ras were most significantly increased in tumor budding regions which histopathologically represent epithelial mesenchymal transition (EMT). In murine model, the EMT phenomenon was effectively induced and invasion of small intestinal tumors were occurred in APCMin/+/K-RasG12DLA2 with increased level of β-catenin and Ras compared with APCMin/+. However, EMT phenomenon and its following events such as migration and invasion of CRC cells induced by APC and K-Ras mutations were abolished by destabilization of β-catenin and Ras. CONCLUSION Our results show that destabilizing β-catenin and Ras could be effective therapeutic targets for inhibiting metastasis in the early stage of CRC development Citation Format: Yong-Hee Cho, Jeong-Soo Yoon, Kang-Yell Choi. Destabilizing β-catenin and Ras could be an ideal therapy for treating metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 911. doi:10.1158/1538-7445.AM2017-911

Mitochondrial respiration is required for hypoxia-inducible factor (HIF)-1α stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Herein, small molecules that inhibit HIF-1α protein stability by targeting mitochondrial energy production were screened using the Library of Pharmacologically Active Compounds and cell growth assay in galactose or glucose medium. NNC 55-0396, a T-type Ca(2+) channel inhibitor, was selected as a hit from among 1,280 small molecules. NNC 55-0396 suppressed mitochondrial reactive oxygen species-mediated HIF-1α expression as well as stabilization by inhibiting protein synthesis in a dose-dependent manner. NNC 55-0396 inhibited tumor-induced angiogenesis in vitro and in vivo by suppressing HIF-1α stability. Moreover, NNC 55-0396 significantly suppressed glioblastoma tumor growth in a xenograft model. Thus, NNC 55-0396, a small molecule targeting T-type Ca(2+) channel, was identified by the systemic cell-based assay and was shown to have antiangiogenic activity via the suppression of HIF-1α signal transduction. These results provide new insights into the biological network between ion channel and HIF-1α signal transduction.HIF-1α overexpression has been demonstrated in hypoxic cancer cells. NNC 55-0396, a T-type Ca(2+) channel inhibitor, inhibited HIF-1α expression via both proteasomal degradation and protein synthesis pathways. T-type Ca(2+) channel inhibitors block angiogenesis by suppressing HIF-1α stability and synthesis. NNC 55-0396 could be a potential therapeutic drug candidate for cancer treatment.

House dust mites (HDMs) are a common cause of allergic asthma. The group 2 allergen from Dermatophagoides farinae, Der f 2, is one of the major HDM allergens. Elevated Der f 2 immunoglobulin E (IgE) levels are observed in most of the allergic patients. Interleukin-13 (IL-13), a gene associated with asthma pathology, was induced by Der f 2 in BEAS-2B human airway epithelial cells; however, the signaling pathways associated with Der f 2 are not fully understood. In this study, we identified a role of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, a well-known potential target for anti-asthma drugs, in the IL-13 induction by Der f 2. First, Der f 2 activated the PI3K/Akt pathway, which subsequently activated the nuclear factor-kappa B (NF-κB) pathway and induced IL-13 expression in BEAS-2B cells. Treatment with the PI3K inhibitor LY294002 abolished Der f 2-induced activation of Akt and NF-κB and the expression of IL-13. Furthermore, Der f 2-induced activation of the PI3K/Akt and NF-κB pathways, expression of IL-13, and the blockade of these effects with a PI3K inhibitor were confirmed in the lungs of mice that were intranasally exposed to Der f 2. Taken together, these results indicate that the PI3K/Akt pathway regulates Der f 2-induced IL-13 expression via activation of the NF-κB pathway.

In current photoacoustic tomography (PAT) systems, ultrasound transducer arrays and multi-channel data acquisition (DAQ) electronics are used to receive the PA signals. To achieve real-time PA imaging, massive 1D or even 2D transducer arrays and large number of DAQ channels are necessary. As a result, the ultrasound receiver becomes very complex, bulky and also costly. In this paper, we report the development of novel micromachined silicon acoustic delay line systems, which are expected to provide a new approach to address the above issue. First, fundamental building block structures of the acoustic delay line systems were designed and fabricated. Their acoustic properties were characterized with ultrasound and photoacoustic measurements. Second, two different acoustic delay line systems (parallel and serial) were designed and fabricated using advanced micromachining processes to ensure compact size, high accuracy, and good repeatability. The transmission of multiple acoustic signals in the acoustic delay line systems were studied with ultrasound experiment. Experimental results show that the silicon acoustic delay line systems can guide multiple channels of acoustic signals with low loss and distortion. With the addition of a set of suitable time delays, the time-delay acoustic signals arrived at a single-element transducer at different times and were unambiguously received and processed by the following DAQ electronics. Therefore, the micromachined silicon acoustic delay line systems could be used to combine multiple signal channels into a single one (without the involvement of electronic multiplexing), thereby reducing the complexity and cost of the ultrasound receiver for real-time PAT application.

Objective: Tinnitus is a common disorder, but the etiology of this disorder remains unknown. The objective of this study was to assess the correlation between anatomic type and the thickness of the anterior inferior cerebellar artery (AICA) loop with tinnitus, using 3D-fast imaging employing steady state acquisition magnetic resonance image (MRI).Method: Seventy-four patients with tinnitus and 82 asymptomatic controls were included in this study. Otologic symptoms, which were measured based on the results of a pure tone audiometry, were reviewed. We evaluated the position and thickness of the AICA vascular loop in 3D-FIESTA MRI using 2 scoring systems. The first system was Chavda classification based on the anatomic location of the AICA loop. The second scoring system was used to measure the thickness of the AICA loop. The AICA loops were classified into 2 groups based on thickness, thinner than adjacent facial nerve and thicker than the facial nerve.Results: Ears with type I, II AICA loops showed signifi...

We theoretically discuss a possible design of a terahertz intersubband Raman laser. Simulation results show that terahertz Raman gain above 30 cm−1 at 4.2 THz can be produced in these devices using mid-infrared pump intensities below 2 MW/cm2.

We performed a systematic magneto-optical Kerr spectroscopy study of Ga${}_{1\ensuremath{-}x}$Mn${}_{x}$As with varying Mn densities as a function of temperature, magnetic field, and photon energy. Unlike previous studies, the magnetization easy axis was perpendicular to the sample surface, allowing us to take remanent polar Kerr spectra in the absence of an external magnetic field. The remanent Kerr angle strongly depended on the photon energy, exhibiting a large positive peak at $~1.7$ eV. This peak increased in intensity and blueshifted with Mn doping and further blueshifted with annealing. Using a 30-band $\mathbf{k}\ifmmode\cdot\else\textperiodcentered\fi{}\mathbf{p}$ model with antiferromagnetic $s,p$-$d$ exchange interaction, we calculated the dielectric tensor of Ga${}_{1\ensuremath{-}x}$Mn${}_{x}$As in the interband transition region, assuming that our samples are in the metallic regime and the impurity band has merged with the valence band. Our modeling successfully reproduces the observed spectra.

There is currently considerable interest in terahertz (THz) difference frequency generation (DFG) utilizing near-resonant intersubband nonlinearity in quantum cascade lasers and other quantum well heterostructures. Such devices were shown to operate at room temperature, but their power demonstrated so far has been rather low. In all previous works the intracavity configuration was studied, in which the nonlinear mixing region was placed inside a pump laser cavity. Here we obtain the upper limits on the THz DFG power that can be achieved in intersubband quantum well systems under external optical pumping. We consider strong optical fields and include all resonant absorption or pump depletion, and nonlinear saturation effects by self-consistently solving three coupled wave equations, the Poisson equation, and density matrix equations. Although we use a GaInAs/AlInAs double quantum well heterostructure as an example, our analysis is applicable to any material system possessing resonant second-order optical nonlinearity. The maximal THz DFG power is reached for intermediate pump intensities of the order of the saturation intensity. Further increase of the pump intensity results in the decrease of the maximum THz DFG power. We analyze the dependence of THz power on the length and doping of the nonlinear mixing region, and present the design of the optimal structures.