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Purpose NUT carcinoma (NC) is a solid tumor caused by the rearrangement of NUTM1 that usually develops in midline structures, such as the thorax. No standard treatment has been established despite high lethality. Thus, we investigated whether targeting the junction region of NUTM1 fusion breakpoints could serve as a potential treatment option for NC. Materials and Methods We designed and evaluated a series of small interfering RNAs (siRNAs) targeting the junction region of BRD4-NUTM1 fusion (B4N), the most common form of NUTM1 fusion. Droplet digital polymerase chain reaction using the blood of patients was also tested to evaluate the treatment responses by the junction sequence of the B4N fusion transcripts.Results As expected, the majority of NC fusion types were B4N (12 of 18, 67%). B4N fusion-specific siRNA treatment on NC cells showed specific inhibitory effects on the B4N fusion transcript and fusion protein without affecting the endogenous expression of the parent genes, resulting in decreased relative cell growth and attenuation of tumor size. In addition, the fusion transcript levels in platelet-rich-plasma samples of the NC patients with systemic metastasis showed a negative correlation with therapeutic effect, suggesting its potential as a measure of treatment responsiveness.Conclusion This study suggests that tumor-specific sequences could be used to treat patients with fusion genes as part of precision medicine for a rare but deadly disease.

Purpose The objective is to develop a real-time Mitochondrial ATP contents and Response Against Inhibiting and Stimulating Substrates (MitoRAISE) assay and assess its potential to evaluate the mitochondrial oxidative phosphorylation function. Methods MitoRAISE measures the total ATP contents, ATP synthesis capacity, and the response to inhibitory substrates. The measurements were all quantified with an ATP standard curve and validated with in vitro testing. MitoRAISE was then applied using peripheral blood mononuclear cells (PBMCs) from 35 healthy volunteers and 20 breast cancer patients. Result Results from isolated mitochondria, cells with different permeabilization percentages, and cells with damaged mitochondria demonstrated the ability of capturing ATP signals specifically from the mitochondria. Breast cancer PBMCs exhibited a significant increase in glutamic acid- and malic acid-induced mitochondrial ATP synthesis capacity yet a significant decrease in mitochondrial DNA copy number (mtDNA CN) compared to healthy PBMCs. Furthermore, breast cancer PBMCs mostly showed negative correlation between mtDNA CN and parameters from MitoRAISE but healthy individuals showed positive correlation. Conclusion We developed a quick and easy method to detect real-time mitochondrial activity in live cells. Monitoring mitochondrial ATP synthesis capacity and sensitivity to inhibitory substrates could aid in assessing the functional status of mitochondrial oxidative phosphorylation.

Supplementary Information

Combination therapy of ALK and β3 inhibitors shows promising results in vivo and in ALK-rearranged NSCLC

Treatment information of patients who received crizotinib

Purpose: Anaplastic lymphoma kinase (ALK)-positive cancers are sensitive to small-molecule ALK kinase inhibitors, but most cases experience failure following treatment. Hence, additional drug targets and combination therapeutic treatments are needed. We investigated gene expression that is regulated by the expression of ALK and explored its roles in cancer progression and therapeutic implication.Experimental Design: We screened ALK-rearranged non–small cell lung cancer (NSCLC) cases using immunohistochemistry and fluorescence in situ hybridization and then conducted multiplex gene expression analysis. We also performed a clinicopathologic analysis to validate the findings. Additional cellular experiments, including inhibition and migration assays, and in vivo lung cancer model studies were performed.Results: Among patients with ALK-rearranged NSCLC, integrin β3 (ITGB3) was one of the overexpressed genes in comparison with that in ALK-negative NSCLC (P = 0.0003). ALK and integrin β3 expression were positively correlated, and we discovered that high integrin β3 mRNA expression was associated with metastasis and more advanced tumor stages (P < 0.005; P < 0.05). Furthermore, we found that inhibition of both ALK and integrin β3 led to increased drug sensitivity in vitro and in vivo (both P < 0.05).Conclusions: We discovered a positive correlation between ALK and integrin β3 expression levels in ALK-rearranged NSCLC. Our findings suggest that high integrin β3 expression in ALK-rearranged NSCLC is associated with tumor progression and a worse prognosis. This finding demonstrates the prognostic value of integrin β3 and provides a rationale for combination treatment with ALK and integrin β3 inhibitors in patients with ALK-rearranged NSCLC. Clin Cancer Res; 24(17); 4162–74. ©2018 AACR.

[Background] As the development of endocrine resistance and late recurrences are the major clinical concerns in hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC) patients, biomarkers to predict the occurrence of endocrine resistance or disease progression are crucial for improving patient outcomes. Aberrant HGF/c-MET signaling pathway has been reported to play a role in various cellular processes in cancer. Estrogen Receptor 1 (ESR1) mutations, encoding estrogen receptor α, are associated with endocrine resistance in HR+ breast cancer. PIK3CA hotspot mutations that induce hyperactivation of the PI3K are found in 30-40% of HR+ advanced breast cancers. In this context, we evaluated the prognostic values of c-MET-enriched CTC, ESR1 mutations, PIK3CA mutations, and cfDNA concentrations detected in the blood of HR+HER2- MBC patients. [Methods] MBC patients were prospectively enrolled during standard treatments at Samsung Medical Center (IRB No.2019-08-119). Circulating tumor cells (CTCs) were isolated using the GenoCTC® with c-MET-enriched or EpCAM-enriched CTC isolation kits (Genobio Corp., South Korea) from 4mL of blood each. PIK3CA and ESR1 hotspot mutations were analyzed by droplet digital PCR kits (Gencurix Inc., South Korea). cfDNA concentrations were calculated using ESR1 gene copy numbers from plasma. To compare the proportion of c-MET overexpression between primary breast tumors and metastatic sites in HR+HER2- breast cancer patients, primary breast (n=358) and metastatic sites (n=27) were independently collected. c-MET expression was evaluated by an immunohistochemistry assay using an anti-total c-MET (SP44) antibody with a Ventana Discovery XY automated system according to the manufacturer’s instruction. c-MET overexpression was defined if the staining was scored as 2+ or 3+. Progression-free survival (PFS) was defined as the time from blood draw to the first of either disease progression or death during standard therapy. [Results] Out of 93 patients with HR+ MBC, analysis was performed in 63 HR+HER2- MBC patients. Seventeen patients (27%) had one or more EpCAM-enriched CTCs, and fourteen patients (22%) had one or more c-MET-enriched CTCs detected in their blood. The median follow-up time and median time to censoring were 8.4 months and 18.7 months, respectively. According to the Kaplan-Meier survival analysis by log-rank test, c-MET-enriched CTCs, cfDNA concentrations, and ESR1 mutations were significantly associated with PFS (p=0.0026, 0.0064, and 0.011, respectively). However, PIK3CA mutations and EpCAM-enriched CTCs were not statistically significant with PFS (p=0.38 and 0.86, respectively). Multivariate analysis showed that both c-MET-enriched CTCs (HR=3.5, p=0.014) and cfDNA concentrations (HR=2.2, p=0.031) were independent predictors for PFS in HR+HER2- MBC. The proportion of c-MET overexpression was significantly higher in metastatic sites (22.2%) than in primary breast tumors (4.7%) in HR+HER2- breast cancer patients (p=0.00002). As c-MET-enriched CTCs and cfDNA concentrations were independent predictors of disease progression, patients were divided into two groups depending on the result of c-MET-enriched CTCs and cfDNA concentration. When patients with low c-MET-enriched CTC and cfDNA concentrations were classified as a low-risk group and other patients into a high-risk group, the high-risk group had a shorter PFS than the low-risk group (p=0.003). [Conclusion] This study provided c-MET-enriched CTCs and cfDNA concentrations calculated by ESR1 copy numbers in patient blood were significant independent predictors of disease progression in HR+HER2- MBC. The poor prognosis in the c-MET-enriched CTC-high group and the difference in the c-MET overexpression rate between the primary breast and metastatic sites suggested the importance of monitoring c-MET-enriched CTCs in the blood of HR+HER2- MBC patients. Citation Format: Jieun Park, Eun Sol Chang, Ji-Yeon Kim, Chaithanya Chelakkot, Minjung Sung, Ji-Young Song, Kyungsoo Jung, Na Young Kim, Hyegyeong Lee, Mi-Ran Kang, Yeon Hee Park, Young Kee Shin, Yoon-La Choi. The prognostic value of c-MET monitoring by using c-MET-enriched circulating tumor cells in HR-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-06-04.

Small cell lung cancer (SCLC) is a fast-growing and malignant cancer that responds well to chemotherapy; however, the survival rate is less than 15% after 2 years of diagnosis. Therefore, novel therapeutic agents for treating SCLC patients need to be evaluated. This study aims to identify the therapeutic targets based on the comprehensive genomic profiling of SCLC patients. Among the molecular-profiled SCLC samples obtained using targeted sequencing, the array-based comparative genomic hybridization (array CGH) identified focal insulin receptor substrate 2 (IRS2) amplification in the SCLC patients. IRS2 amplification was confirmed in 5% of 73 SCLC patients. To determine whether IRS2 amplification could act as a therapeutic target, we generated a patient-derived xenograft (PDX) model and subsequently screened 43 targeted agents using the PDX-derived cells (PDCs). Ceritinib significantly inhibited the cell growth and impaired the tumor sphere formation in IRS2-expressing PDCs. Its effects were confirmed in various in vitro assays and were further validated in the mouse xenograft models. In this study, we present that IRS2 amplification and/or expression serve as preclinical implications for a novel therapeutic target in SCLC progression. Furthermore, we suggest that insulin-like growth factor-1 (IGF-1) receptor inhibitor-based therapy could be used for treating SCLC with IRS2 amplification. Keywords: IRS2, small cell lung cancer, SCLC, patient-derived xenograft, PDX, targeted therapy, Ceritinib

Purpose The purpose of this study was to investigate the concordance rate of PIK3CA mutations between primary and matched distant metastatic sites in patients with breast cancer and to verify whether there are differences in the frequency of PIK3CA hotspot mutations depending on the metastatic sites involved.Materials and Methods Archived formalin-fixed paraffin-embedded (FFPE) specimens of primary breast and matched distant metastatic tumors were retrospectively obtained for 49 patients. Additionally, 40 archived FFPE specimens were independently collected from different breast cancer metastatic sites, which were limited to three common sites: the liver, brain, and lung. PIK3CA mutations were analyzed using droplet digital PCR, including hotspots involving exons 9 and 20. Results After analysis of 49 breast tumors with matched metastasis sites, 87.8% showed concordance in PIK3CA mutation status. According to PIK3CA hotspot mutation testing in 89 cases of breast cancer metastatic sites, the proportion of PIK3CA mutations at sites of metastasis involving the liver, brain, and lung was 37.5%, 28.6%, and 42.9%, respectively, which did not result in statistical significance. Conclusion The high concordance of PIK3CA mutation status between primary and matched metastasis sites suggests that metastatic sites, regardless of the metastatic organ, could be considered sample sources for PIK3CA mutation testing for improved therapeutic strategies in patients with metastatic breast cancer.

This study examined the effects of perceptions of organizational justice on the quality of relationships between employees and organizations, employee job engagement, and subsequent effects on empl...

PurposeTo find biomarkers for disease, there have been constant attempts to investigate the genes that differ from those in the disease groups. However, the values that lie outside the overall pattern of a distribution, the outliers, are frequently excluded in traditional analytical methods as they are considered to be ‘some sort of problem.’ Such outliers may have a biologic role in the disease group. Thus, this study explored new biomarker using outlier analysis, and verified the suitability of therapeutic potential of two genes (TM4SF4 and LRRK2).Materials and MethodsModified Tukey’s fences outlier analysis was carried out to identify new biomarkers using the public gene expression datasets. And we verified the presence of the selected biomarkers in other clinical samples via customized gene expression panels and tissue microarrays. Moreover, a siRNA-based knockdown test was performed to evaluate the impact of the biomarkers on oncogenic phenotypes.ResultsTM4SF4 in lung cancer and LRRK2 in breast cancer were chosen as candidates among the genes derived from the analysis. TM4SF4 and LRRK2 were overexpressed in the small number of samples with lung cancer (4.20%) and breast cancer (2.42%), respectively. Knockdown of TM4SF4 and LRRK2 suppressed the growth of lung and breast cancer cell lines. The LRRK2 overexpressing cell lines were more sensitive to LRRK2-IN-1 than the LRRK2 under-expressing cell linesConclusionOur modified outlier-based analysis method has proved to rescue biomarkers previously missed or unnoticed by traditional analysis showing TM4SF4 and LRRK2 are novel target candidates for lung and breast cancer, respectively.

Purpose: Anaplastic lymphoma kinase (ALK)-positive cancers are sensitive to small-molecule ALK kinase inhibitors, but most cases experience failure following treatment. Hence, additional drug targets and combination therapeutic treatments are needed. We investigated gene expression that is regulated by the expression of ALK and explored its roles in cancer progression and therapeutic implication. Experimental Design: We screened ALK-rearranged non–small cell lung cancer (NSCLC) cases using immunohistochemistry and fluorescence in situ hybridization and then conducted multiplex gene expression analysis. We also performed a clinicopathologic analysis to validate the findings. Additional cellular experiments, including inhibition and migration assays, and in vivo lung cancer model studies were performed. Results: Among patients with ALK-rearranged NSCLC, integrin β3 (ITGB3) was one of the overexpressed genes in comparison with that in ALK-negative NSCLC (P = 0.0003). ALK and integrin β3 expression were positively correlated, and we discovered that high integrin β3 mRNA expression was associated with metastasis and more advanced tumor stages (P < 0.005; P < 0.05). Furthermore, we found that inhibition of both ALK and integrin β3 led to increased drug sensitivity in vitro and in vivo (both P < 0.05). Conclusions: We discovered a positive correlation between ALK and integrin β3 expression levels in ALK-rearranged NSCLC. Our findings suggest that high integrin β3 expression in ALK-rearranged NSCLC is associated with tumor progression and a worse prognosis. This finding demonstrates the prognostic value of integrin β3 and provides a rationale for combination treatment with ALK and integrin β3 inhibitors in patients with ALK-rearranged NSCLC. Clin Cancer Res; 24(17); 4162–74. ©2018 AACR.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by poor patient prognosis and for which no targeted therapies are currently available. TNBC can be further categorized as either basal-like (BLBC) or quintuple-negative breast cancer (QNBC). In the present study, we aimed to identify novel molecular therapeutic targets for TNBC by analyzing the mRNA expression of TNBC-related genes in publicly available microarray data sets. We found that Engrailed 1 (EN1) was significantly overexpressed in TNBC. Using breast cancer cell lines, we found that EN1 was more highly expressed in TNBC than in other breast cancer subtypes. EN1 expression was analyzed in 199 TNBC paraffin-embedded tissue samples by immunohistochemistry. EN1 protein expression was positively associated with reduced overall survival (OS) rate in patients with QNBC, but not those with BLBC. The importance of EN1 expression in QNBC cell viability and tumorigenicity was evaluated using the QNBC cell lines, HCC38 and HCC1395. Based on our data, EN1 may promote the proliferation, migration, and multinucleation of QNBC cells, likely via the transcriptional activation of HDAC8, UTP11L, and ZIC3. We also demonstrated that actinomycin D effectively inhibits EN1 activity in QNBC cells. The results of the present study suggest that EN1 activity is highly clinically relevant to the survival prognosis of patients with QNBC and EN1 is a promising potential therapeutic target for future QNBC treatment.

As the number of older adults living with chronic conditions continues to rise, they will require assistance with activities of daily living (ADL) and healthcare tasks to continue living independently in their homes. One proposed solution to assist with the care needs of an aging population and a shrinking healthcare workforce is robotic technology. Using a cross-sectional survey design, we purposively sampled adults (≥18 years old) to assess generational acceptance and perceived usefulness of robots to assist with ADLs, healthcare tasks, and evaluate acceptance of robotic healthcare assistance across different settings. A total of 499 adults (age range [years] 18-98, Mean = 38.7, SD = 22.7) responded to the survey. Significant differences were found among young, middle-aged, and older adults on perceived usefulness of robots for cleaning, escorting them around town, acting as companionship, delivering meals, assessing sadness and calling for help, providing medical advice, taking vital sign assessments, and assisting with personal care (p < 0.05). The majority of younger adults reported that they would like a robot to provide healthcare assistance in the hospital, compared to middle-aged and older adults (p < 0.001). Results of this study can guide the design of robots to assist adults of all ages with useful tasks.

Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLCs) show good clinical response to ALK inhibitors. However, some ALK-rearranged NSCLC patients show various primary responses with unknown reasons. Previous studies focused on the clinical aspects of ALK fusions in small cohorts, or were conducted in vitro and/or in vivo to investigate the function of ALK. One of the suggested theories describes how echinoderm microtubule-associated protein-like 4 (EML4)-ALK variants play a role towards different sensitivities in ALK inhibitors. Until now, there has been no integrated comprehensive study that dissects ALK at the molecular level in a large scale. Here, we report the largest extensive molecular analysis of 158 ALK-rearranged NSCLCs and have investigated these findings in a cell line construct experiment. We discovered that NSCLCs with EML4-ALK short forms (variant 3/others) had more advanced stage and frequent metastases than cases with the long forms (variant 1/others) (p = 0.057, p < 0.05). In vitro experiments revealed that EML4-ALK short forms show lower sensitivity to ALK inhibitors than do long forms. Clinical analysis also showed a trend for the short forms showing worse PFS. Interestingly, we found that breakpoints of ALK are evenly distributed mainly in intron 19 and almost all of them undergo a non-homologous end-joining repair to generate ALK fusions. We also discovered four novel somatic ALK mutations in NSCLC (T1151R, R1192P, A1280V, and L1535Q) that confer primary resistance; all of them showed strong resistance to ALK inhibitors, as G1202R does. Through targeted deep sequencing, we discovered three novel ALK fusion partners (GCC2, LMO7, and PHACTR1), and different ALK fusion partners showed different intracellular localization. With our findings that the EML4-ALK variants, new ALK somatic mutations, and novel ALK-fusion partners may affect sensitivity to ALK inhibitors, we stress the importance of targeted therapy to take the ALK molecular profiling into consideration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Purpose The purpose of this paper is to examine how a company’s symmetrical internal communication efforts could influence its employees’ perception of relationship outcomes with the company and the subsequent employee communication behaviors about the company to others and their turnover intention. Additionally, the mediation effects of employee-organization relationship (EOR) quality between symmetrical internal communication and employee engagement were tested. Design/methodology/approach The study collected the data from a survey of randomly selected 438 individuals who work as sales representatives of the case organization. Respondents were randomly selected through stratified sampling. For the overall statistical procedure, this study adopted the two-step structural equation modeling: on the basis of the final measurement model analysis from confirmatory factor analysis, the proposed structural model was tested using latent variables. Findings The findings of this research clearly demonstrate: employee/internal communication management is linked with employee engagement; employee engagement enhances supportive employee communication behaviors and reduces turnover intention. Also, the mediation results show strong mediation of EORs on the effects of symmetrical internal communication on employee engagement. Research limitations/implications Employees’ communication behaviors such as megaphoning and scouting have special strategic values to organizations. With information seeking, selecting, forwarding, and sharing behaviors of employees, organizations may obtain more valuable information than through formal procedures and channels. Professional literature has long been supporting the importance of fostering positive employee communication behaviors (ECBs), suggesting that WOM and information from the employees deemed as most trustworthy by the external publics. ECBs about their organizations may be viewed as a testament of the quality of EOR. This study results show that employee engagement plays a key role in creating positive ECBs. Practical implications Pragmatically, as noted in the findings, symmetrical communication is an important factor that leads to positive ECB. To facilitate employees’ favorable communication regarding an organization, therefore, the organization needs to practice a two-way, employee-centered symmetrical communication system in its everyday communication management. Communication managers are advised to nurture internal communication practices that listen to the employees and invite their participation in addition to providing complete and fair information to employees. Second, by showing the significant positive influence of EOR on employee engagement and ECB, the finding of the study suggests that strategic relationship management with internal publics affect overall management effectiveness. Hence, organizational managers need to adopt various relationship cultivation strategies in their communication with employees, which have been previously proposed by several studies. Originality/value The findings of the study demonstrated that the effects of employee relationship management and symmetrical internal communication indeed exist beyond ECBs to the actual managerial outcomes. The findings also suggest a three-stage model of employee communication management: employee/internal communication management antecedents; employee engagement; and supportive outcomes of effective employee communication programs, such as supportive/extra ECBs.

Programmed cell death ligand 1 (PD-L1) expression is an important biomarker for predicting response to immunotherapy in clinical practice. Hence, identification and characterization of factors that predict high expression of PD-L1 in patients is critical. Various studies have reported the association of PD-L1 expression with driver genetic status in non-small cell cancer, however, the results have been conflicting and inconclusive. We analyzed the relationship between PD-L1 expression and clinicopathological factors including driver genetic alterations in 1000 resected lung cancers using a clinically validated PD-L1 immunohistochemical assay. PD-L1 expression was significantly higher in squamous cell carcinoma (SCC) compared to adenocarcinomas. PD-L1 expression in adenocarcinoma was associated with higher N-stage, solid histologic pattern, EGFR wild type, and ALK positive, but no significant association with the clinicopathological factors in SCC. EGFR mutant adenocarcinomas with distinctive clinicopathologic features, especially solid histologic pattern and higher stage showed higher PD-L1 expression. To the best of our knowledge, this study is the largest to evaluate the association between PD-L1 expression and clinicopathological and molecular features in lung cancer with a highly prevalent EGFR mutation. Therefore, our results are useful to guide the selection of lung cancer, even EGFR-mutated adenocarcinoma patients with PD-L1 expression, for further immunotherapy.

Solitary fibrous tumors (SFTs) are NAB2-STAT6 fusion-associated neoplasms. There are several subtypes of NAB2-STAT6 fusions, but their clinical significances are still unclear. Moreover, the mechanisms of malignant progression are also poorly understood. In this study, using 91 SFT cases, we examined whether fusion variants are associated with clinicopathological parameters and also investigated the molecular mechanism of malignant transformation using whole-exome sequencing. We detected variant 1b (NAB2ex4-STAT6ex2) in 51/91 (56%) cases and variants 2a/2b (NAB2ex6-STAT6ex16/17) in 17/91 (19%) cases. The NAB2-STAT6 fusion variant types were significantly associated with their primary site (P

// Yu Jin Kim 1 , Sungyoul Hong 2 , Minjung Sung 1 , Min Jeong Park 2 , Kyungsoo Jung 1, 3 , Ka-Won Noh 1, 3 , Doo-Yi Oh 1, 3 , Mi-Sook Lee 1, 3 , Ensel Oh 1, 3 , Young Kee Shin 2, 4 , Yoon-La Choi 1, 3, 5 1 Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Laboratory of Molecular Pathology and Cancer Genomics, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea 3 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea 4 The Center for Anti-cancer Companion Diagnostics, Bio-MAX/N-Bio, Seoul National University, Seoul, Korea 5 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Correspondence to: Yoon-La Choi, email: ylachoi@skku.edu Young Kee Shin, email: ykeeshin@snu.ac.kr Keywords: LYN, dasatinib, lung adenocarcinoma subgroup, SRC, YES Received: March 16, 2016 Accepted: October 01, 2016 Published: October 14, 2016 ABSTRACT Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associated with poor overall survival in a multivariate analysis, and this association was strongest in non-smoker female patients with adenocarcinoma (ADC). In lung ADC cells, LYN expression enhanced cell proliferation, migration, and invasion. Dasatinib inhibited LYN activity and decreased cell viability in LYN-positive ADC cell lines and xenografts. Additionally, we identified the SFKs SRC and YES as candidate dasatinib targets in LYN-negative ADC cell lines. Our findings suggest that LYN is a useful prognostic marker and a selective target of dasatinib therapy in the lung ADC subpopulation especially in female non-smokers with lung ADC.

The study, using a survey of 508 university student publics, investigates (a) the impacts and mechanisms that a relationship has on a public’s perceptions and behavior around an issue and (b) how relationship types impact a public’s perception toward a tuition increase issue differently. The situational theory of publics was used as a theoretical framework. The results generally supported the theories. More important, the findings indicated that a communal relationship and an exchange relationship had different impacts on problem recognition, constraint recognition, and involvement recognition.

Purpose – The purpose of this paper is to explain the benefits of charitable sport events and examines how consumer involvement in the cause, attitude toward the event, and event-sponsor fit influence corporate image (CI) and corresponding purchase intention (PI). Design/methodology/approach – The conceptual model developed in this research consolidates various constructs related to sponsors and events into a single comprehensive framework, thus offering an integrated view of the factors that determine consumers’ perceptions of a sponsorship and their attitudes toward a sponsor. Data were collected from participants in the Pink Ribbon Love Marathons (PRLM) held in Seoul, South Korea. A total of 650 female subjects (mean age=41.2, SD=12.5) participated in this investigation. Findings – The findings indicate that CI plays a significant role as a partial mediator within a reciprocal relationship between participants’ event perception and patronage intention. Sponsoring a well-targeted event might have a positive impact on CI and PI. Originality/value – What makes this study unique is the application of previous research examining cause-related sport sponsorship from a sport participant’s perspective. From a practical standpoint, the findings of this study reveal the importance of corporate communication in CSR.

본 연구는 최근 기업 경영에서 그 중요성이 커지고 있는 조직과 사내 구성원 간의 관계성을 중심으로 내부공중의 균형적인 커뮤니케이션 인식이 관계성 및 기업 평판 인식, 그리고 직원들의 커뮤니케이션 행동에 미치는 영향을 살펴보았다. 연구를 위해 국내 대기업 총 25곳에 재직 중인 일반 직원 416명을 대상으로 설문조사를 실시한 결과, 균형적인 내부 커뮤니케이션 인지는 조직－직원 관계성에 긍정적인 영향을 미쳤으며, 조직－직원 관계성 인식은 사원들의 소속 조직 평판 인식과 커뮤니케이션 행동에도 유의미한 영향을 미치는 것으로 나타났다. 또한 직원들의 평판 인식도 커뮤니케이션 행동에 영향을 미쳤다. 더 나아가, 조직－사원 관계성의 각 차원에 따라 그 영향력에 차이가 있었고, 직원들의 내부적인 평판 인식 역시 차원 별로 커뮤니케이션 행동에 차별적인 영향을 미치는 것을 알 수 있었다. 이러한 연구 결과는 균형적 사내 커뮤니케이션 및 전략적 관계 관리의 중요성과 효과를 보여준다.

Amplification and overexpression of MDM2 and CDK4 are well-known diagnostic criteria of well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). Although it was reported that depletion of MDM2 or CDK4 decreased proliferation in DDLPS cell lines, it remains unclear whether MDM2 and CDK4 induce WDLPS/DDLPS tumorigenesis. We examined whether MDM2 and/or CDK4 produce WDLPS/DDLPS using transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRASv12). In vitro functional experiments revealed that co-overexpression of MDM2 and CDK4 plays key roles in tumorigenesis by increasing cell growth and migration and inhibiting adipogenic differentiation potency compared to sole expression of MDM2 or CDK4. Using mouse xenograft models, we found that co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can develop proliferative DDLPS in vivo. Our results suggest that co-overexpression of MDM2 and CDK4 induces DDLPS tumour potency in transformed human BMSCs by accelerating cell growth and migration and blocking adipogenetic potential incooperation with multiple genetic factors.

Given that the choice of breastfeeding is not available to every mother, in spite of its advantages, in this article we examine the factors influencing the use of infant formula in South Korea. We draw on data from a national survey of South Korean mothers conducted in 2009, to show that while maternal use of infant formula feeding was affected by socio-economic factors such as education, income and employment status, it was also influenced by mothers’ perception of risks of infant formula. We found that the way mothers perceived the safety of formula milk’s raw materials was a key factor influencing their decisions about formula feeding, while their perceptions of the safety of the manufacturing facilities and the distribution system was less influential. The mothers in the survey perceived that product safety was more important than considerations such as convenience and economic value of infant formula. We argue that the priority which Korean mothers give to considerations of the risk/safety of infant ...

The concept of corporate social responsibility (CSR) is very meaningful in a culture such as that of the Republic of Korea, where individual ethics are grounded in Confucianism, which emphasizes humanism and altruism. We examined the mediating role of emotion in the relationships among participants' perceptions of CSR, their attitude toward philanthropic corporate sponsorship of a sporting event, and of the sponsoring company's brand equity. We conducted a survey with 251 participants in a charitable sports event held in Seoul, South Korea, which was sponsored by a major Korean company. The results of analysis of the data collected provide an understanding of how strong brand equity of the sponsoring company was generated among participants. The findings also shed light on the mediating role of emotion in the relationship between the company's brand equity and 2 major participant cognitive factors of attitude toward an event and perception of CSR. Results indicate that sponsoring a charitable sporting event targeted at certain types of consumers can be an effective marketing tool for a company to build brand equity.

Additional file 1: Table S1. Subtype and source of soft tissue cell lines. Table S2. Cell culture medium. Table S3. Primer sets of qRT-PCR. Table S4. Correlation of IHC with 3 anti-PD-L1 clones in UPS tissues (A) N = 46 (without N/A), correlation coefficient. (B) N = 100 (with N/A), correlation coefficient. (C) N = 13 (with positive expression cases in A), correlation coefficient.

Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLCs) show good clinical response to ALK inhibitors. However, some ALK-rearranged NSCLC patients show various primary responses with unknown reasons. Previous studies focused on the clinical aspects of ALK fusions in small cohorts, or were conducted in vitro and/or in vivo to investigate the function of ALK. One of the suggested theories describes how echinoderm microtubule-associated protein-like 4 (EML4)-ALK variants play a role towards different sensitivities in ALK inhibitors. Until now, there has been no integrated comprehensive study that dissects ALK at the molecular level in a large scale. Here, we report the largest extensive molecular analysis of 158 ALK-rearranged NSCLCs and have investigated these findings in a cell line construct experiment. We discovered that NSCLCs with EML4-ALK short forms (variant 3/others) had more advanced stage and frequent metastases than cases with the long forms (variant 1/others) (p = 0.057, p0.05). In vitro experiments revealed that EML4-ALK short forms show lower sensitivity to ALK inhibitors than do long forms. Clinical analysis also showed a trend for the short forms showing worse PFS. Interestingly, we found that breakpoints of ALK are evenly distributed mainly in intron 19 and almost all of them undergo a non-homologous end-joining repair to generate ALK fusions. We also discovered four novel somatic ALK mutations in NSCLC (T1151R, R1192P, A1280V, and L1535Q) that confer primary resistance; all of them showed strong resistance to ALK inhibitors, as G1202R does. Through targeted deep sequencing, we discovered three novel ALK fusion partners (GCC2, LMO7, and PHACTR1), and different ALK fusion partners showed different intracellular localization. With our findings that the EML4-ALK variants, new ALK somatic mutations, and novel ALK-fusion partners may affect sensitivity to ALK inhibitors, we stress the importance of targeted therapy to take the ALK molecular profiling into consideration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

Focusing on academic institutions in higher education as the research context, this study examined the relations of key factors affecting students’ supportive behavioral intentions toward the university (e.g., giving gifts as alumni, continuing education, and giving referrals regarding the university). Based on the literature from various disciplines, this study proposed four factors are critical influencing such intentions: (1) students’ communication behavior with the university, (2) perceived quality of educational experience, (3) evaluations of the relationship with the university, and (4) university reputation. The data in this study were collected using a survey of current undergraduate students (N = 336) who were attending a private university in Seoul during Fall 2005. Structural equation modeling (SEM) was used to analyze the proposed model. Regarding overall results, the proposed model can be retained as a valid model based on data-model fits: Eight hypotheses were supported in this study, but not the effect of students’ educational experience on university reputation. The findings suggest that to foster students’ supportive behavior, universities need to cultivate a good relationship with their students and to obtain favorable reputation held by students, while ensuring active communication behavior of students and the quality of students’ educational experience.

Although the concepts of image and reputation have been increasingly emphasized in the fields of public relations and marketing, the association of these 2 concepts has not been empirically studied within the public relations domain. Furthermore, although significant research into corporate image has been established, relatively less image research has been conducted on service-oriented organizations such as universities. The purpose of this study is to assess the impact of institutional image and image-related constructs on students' supportive attitude, which represents the student's commitment to and identification with the organization. After identifying the components that construct corporate image, the study examines the relationships among these constructs under the concept of corporate image. It also attempts to analyze the impact of this image in order to understand its influence on student recruitment, and to describe the strategic implications for university communication management. Structural...

SNS에 대한 폭발적 관심과 함께 많은 기업들이 SNS를 사용해 공중들과 관계를 구축하고자 하지만, 상호작용성과 대화성과 같은 SNS의 매체적 특성이 제대로 활용되지 않는 경우가 많다. 이에 본 연구는 PR 관점에서 기업 커뮤니케이션 차원의 SNS의 사용 현황과 효과를 살펴보았으며, 특히 글로벌 환경에서 문화적 특성이 SNS 운영과 관리에 어떻게 전략적으로 적용되어야 하는가에 대해 탐색하였다. 이를 위해 한국에 진출한 다국적 기업과 한국 기업 총 45개의 기업 페이스북 페이지 사용방식을 온라인 관계 관리의 틀에서 비교하였으며, 선행 연구의 틀에 기반하여 각 기업 페이스북 페이지에 포스팅 된 메시지의 내용에 대해 기업 커뮤니케이션 전략과 메시지 목적, 상호작용성, 관계 구축 전략, 그리고 참여 전략 등을 항목화하여 분석하였다. 연구 결과 기업들은 기업 커뮤니케이션 차원보다는 마케팅적 차원에서 페이스북을 활발하게 사용하는 것으로 나타났으며, 이용자 반응 면에서도 기업 메시지보다는 제품/서비스 관련 메시지들이 효과적인 것으로 나타났다. 또한 본 연구의 결과는 페이스북 사용 방식의 문화적 차이를 보여줄 뿐만 아니라, 커뮤니케이션 목적에 따라 메시지 전략이 정교화되어야 함을 시사한다.

B7-H4 is a recently discovered B7 family member that has inhibitory effects on T-cell immunity. However, the reverse signalling mechanism of the B7-H4-expressing cells remains unclear. Previous work has shown that B7-H4 expression was enhanced on B cells following Epstein-Barr virus (EBV) infection, and engagement of cell-surface-expressed B7-H4 induces cell death of EBV-transformed B cells. Here we found that B7-H4 was constitutively expressed on EBV-positive lymphoma cells, Raji and IM-9 cells, but was not expressed on EBV-negative lymphoma cells (Ramos). Engagement of B7-H4 significantly reduced cell growth of Raji and IM-9 cells and resulted in cell cycle arrest at G0-G1 phase in a dose- and time-dependent manner. To clarify the mechanism of cell cycle arrest via activation of B7-H4, cell cycle regulatory factors were examined by reverse transcription-polymerase chain reaction and immunoblotting. We found that B7-H4 triggered down-regulation of CDK4/6 and up-regulation of p21 expression at both protein and RNA levels. Furthermore, CDK2 and cyclin E/D expression was down-regulated by B7-H4 triggering. Additionally, the down-regulation of phospho-AKT and phospho-cyclin E were clearly detected in B7-H4-activated Raji cells, but the phosphorylation of p53 was constitutively maintained. These results indicate that B7-H4-mediated signalling on EBV-positive B-cell lymphoma cells modulates the cell cycle through down-regulation of the AKT pathway. Consequently, B7-H4 may be a new potential target for use in EBV-positive lymphoma therapy.

SRC family kinases (SFKs) have a strong rationale as a clinical strategy in non-small cell lung cancer (NSCLC). Unfortunately, the reviewed study showed disappointing activity of SFK inhibitor dasatinib in molecularly unselected patient cohort. Therefore, the studies in NSCLC should be investigated to identify patients more likely to benefit from dasatinib either as monotherapy or in combination with other agents. Here, we considered that LYN may play specific roles in lung cancer and therefore analysed survival prognosis according to the expression of LYN and the effect of dasatinib on the inhibition of cell growth and LYN activity. We evaluated LYN expression by immunohistochemistry on 446 NSCLCs using paraffin-embedded tissues. Elevated LYN expression level of NSCLCs, especially in adenocarcinoma, female, and non-smoker, affected poor overall survival (OS, P=0.036). In lung adenocarcinoma cell lines, LYN expression impacted on cell proliferation, migration and invasion. Dasatinib treatment resulted in decreased cell viability in most of these cell lines. Also, we found that dasatinib suppressed active tyrosine phosphorylation of LYN. In the resistant cell lines, H23 and SK-LU-1, which showed elevated epidermal growth factor (EGFR) and MET activities, combined treatment of EGFR or MET inhibitor with dasatinib revealed the synergistic effects on decreased cell viability. Our findings highly suggest that LYN has potential as a new selected target molecule of SFKs in the treatment of NSCLCs. Citation Format: Yu Jin Kim, Minjung Sung, Min Jeong Park, Young Kee Shin, Yoon-La Choi. LYN is a new prognostic and therapeutic target in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2785. doi:10.1158/1538-7445.AM2014-2785

CM1(centrocyte/-blast marker I) defined by a mAb developed against concanavalin-A activated PBMC, is expressed specifically on a subpopulation of centroblasts and centrocytes of human germinal center(GC) B cells. Interestingly cisplatin or PMA induced CM1 expression on cervical cancer cell (Hela 229). In addition, we observed the existence of CM1 in cervical cancer patients' tissues. In this study, we observed the function of CM1 induced by cisplatin on cervical cancer cells. So we designed to investigate the enhancement of the chemoresponse to cisplatin by anti-CM1 mAb treatment in human cervical cancer Hela 229 cells. We observed that CM1 ligation with anti-CM1 mAb enhanced the apoptosis of Hela cells pre-treated with cisplatin and induced the expression of both FasL and Fas in theses cells. Furthermore, anti-Fas blocking antibody, ZB4, blocked CM1-mediated apoptosis effectively in Hela cells. Caspase-8 inhibitor, z-IETD effectively blocked CM1-induced cell death. And CM1 ligation down-regulated expression of procaspase-8 and PARP. RT-PCR results showed up-regulated the expression of Bax and Bad and down-regulated the expression of Bcl-2. The release of cytochrome c and the translocation to nucleus of endoG and AIF were showed by confocal micoscopy. Based on these findings, it can be concluded that CM1 might act as an effective apoptosis inducer in chemotherapy of cervical cancer by regulating the expression of various apoptosis-related genes via Fas/FasL pathway.