Search

본 연구의 목적은 스트레스 과정 모델을 이론적 기초로 하여, 대학생의 취업 스트레스와 우울감의 관계에서 자아존중감의 매개효과를 검증하는 것이다. 이를 위해 충북 소재 4년제 대학생 300명을 대상으로 면접법을 활용하여 설문조사를 진행하였다. 주요 연구 결과로는 첫째, 대학생의 취업 스트레스는 우울감에 유의한 영향을 미쳤다. 즉, 취업 스트레스가 높을수록 우울감이 높다고 할 수 있다. 둘째, 대학생의 취업 스트레스는 자아존중감에 유의한 영향을 미쳤다. 즉 취업 스트레스가 높을수록 자아존중감이 낮다고 할 수 있다. 셋째, 대학생의 취업 스트레스와 자아존중감이 우울감에 미치는 영향을 살펴보았을 때, 취업 스트레스는 우울감에 통계적으로 유의한 영향을 미치지 않았으며, 자아존중감은 우울감에 통계적으로 유의한 영향을 미쳤다. 즉, 자아존중감이 높을수록 우울감이 낮다고 할 수 있다. 넷째, 대학생의 취업 스트레스와 우울감의 관계에서 자아존중감은 완전매개하였다. 본 연구를 통해 스트레스 과정 모델의 주요 논점을 검증한 것이다. 연구결과를 토대로 대학 내 취업지원 및 집단상담 프로그램 강화를 제언하였다.

In the study, the preparation and electrochemical characterization of screen-printed electrodes (SPE) modified with 4’-mercapto-N-phenylquinone diamine (NPQD) and their behavior as electrocatalysts toward the oxidation of NADH with high stability are described. In particular, NPQD on the SPE substrate was deposited via electro-polymerization. Thus, the modified electrode exhibited a limit of detection (LOD) corresponding to 3.5 µM LOD with a sensitivity corresponding to 0.0076 ± 0.0006 µM/µA in the mouse serum. In all cases, NADH oxidation occurred at potentials approximately corresponding to 0.7 V vs Ag/AgCl electrode, and this indicates a decrease in the overpotential. We used the observations as a point of departure and developed an NADH biosensor based on the electrocatalytic oxidation of NADH. The applicability of the NADH sensor was demonstrated for the first time in 1) selectivity/sensitivity test via complex electrolyte as cell culture medium and 2) inflammatory and fibrotic responses by polyhexamethylene guanidine phosphate via NADH sensing in mouse serum.

With increasing data traffic requirements in vehicular networks, vehicle-to-everything (V2X) communication has become imperative in improving road safety to guarantee reliable and low latency services. However, V2X communication is highly affected by interference when changing channel states in a high mobility environment in vehicular networks. For optimal interference management in high mobility environments, it is necessary to apply deep reinforcement learning (DRL) to allocate communication resources. In addition, to improve system capacity and reduce system energy consumption from the traffic overheads of periodic messages, a vehicle clustering technique is required. In this paper, a DRL based resource allocation method is proposed with remote radio head grouping and vehicle clustering to maximize system energy efficiency while considering quality of service and reliability. The proposed algorithm is compared with three existing algorithms in terms of performance through simulations, in each case outperforming the existing algorithms in terms of average signal to interference noise ratio, achievable data rate, and system energy efficiency.

本稿の目的は，社会文化にみられる高齢者のステレオタイプを分析することである。まず，高齢夫婦が主人公である映画『東京物語』（1953）とそのリメイク作品である『東京家族』（2013）を対象に，登場人物間の人間関係や援助行動，セリフの分析を通して，両映画にみられる違いを明らかにする。次に，映画分析の結果を既存のエイジズム研究で明らかになっている高齢者イメージと比較する。その結果，高齢者は悠々自適，親孝行，援助の対象，孫が好き，女性高齢者の自己犠牲というステレオタイプが明らかになった。しかし一方で，高齢者自身が他の世代を援助する行動は受動的なものから能動的なものへと変化し，その数も増加した。さらに，家族以外の人物による高齢者に対する表現(エイジズム)も多様になってきていることがわかった。, The purpose of this paper is to analyze the stereotype of elderly people found in social culture. First, we identify the difference seen in two films, "Tokyo story" (1953) and its remake work "Tokyo Family" (2013), by analyzing the relationships, support behaviors, dialogues between characters. Then, we compare the result of the above analysis of the image revealed through existing ageism study. As a result, the elderly liked leading easy lives, filial piety, being supported, and grandchildren. Female elderly was revealed as a stereotype of sacrifice. However, the supporting behavior of elderly to other generations has changed from passive to active, and its number has also increased. Furthermore, it became clear that the expression to the elderly (ageism) by non-family member has been varied., 論文(Article)

本稿の目的は，エイジズムに関する文献のレビューを行うことである。まず，先行研究の全体的な傾向を把握する。次に，エイジズムの構成要素を分析の枠組みにして日本のエイジズム研究の成果と課題を明らかにする。分析の結果，従来の研究の成果として多様な個人がもつエイジズム意識に関する基礎的データの蓄積が浮かび上がった。しかし，エイジズムに関する理論的考察が不十分であり，おそらくそれゆえに研究の焦点が心理的側面にもっぱら向けられる傾向があり，社会や文化などとの関連性には向けられていない傾向を発見した。これらの結果から，今後，エイジズムの理論的考察を深めるとともに，社会文化的要素を含めた包括的な研究枠組みを構築することが求められていると考える。, The purpose of this paper is to review the research on ageism study in Japan. First, we examine the total tendency of the advanced researches on ageism. Second, we identify the outcomes and remaining issues by reviewing with the analytical framework made by components of ageism. As the result of our analysis, we found that data about various individuals' views toward aging have been accumulated. Theoretical consideration about ageism, however, is insufficient. Perhaps as a result of it, Japanese researches on ageism tend to limit their research focuses only to psychological aspects, but not societal and cultural aspects. It is suggested that research on ageism should have more comprehensive research framework with cultural and societal aspects as well as individual psychological aspects., 論文(Article)

이 연구는 국민 관점에서 대통령의 소통을 어떻게 평가하는지 일련의 지수 개발 절차를 통해 조사하였다. 그결과 대통령의 소통에 대한 평가 요인들은 `대통령의 소통 역량`, `대통령의 정책 소통에 대한 언론의 보도 빈도`, 그리고 `소통 채널의 활용 정도`의 3요인 18문항으로 요약되었다. 다음으로 이러한 소통 평가 요인들이 대통령에 대한 신뢰와 지지도에 어떠한 영향을 미치는지 경로분석을 수행한 결과 세 소통 평가 요인들이 모두 대통령에 대한 신뢰를 매개로 하여 대통령에 대한 지지에 유의미한 영향을 미쳤다. 하지만, 소통 평가 요인들이 지지도에 미치는 직접적인 영향을 고려할 때 단지 대통령의 소통 역량 요인만이 유의미하였고 나아가 직·간접적인 효과의 총합인 총 효과를 살펴볼 때 단지 소통 역량의 요인만이 종합적으로 대통령에 대한 지지도에 유의미한 영향을 미쳤다. 이 같은 결과는 위계적 회귀분석에서도 마찬가지로 관찰되었다. 즉, 소득수준이 높고, 정치 성향이 보수적이며, 지난 대선에서 대통령을 지지한 응답자일수록 지지도가 높은 편이었고, 교육 수준이 높을수록 정부에 대해 보다 비판적 시각을 견지하여 지지도가 낮은 경향을 나타내었으며 이 같은 변인들의 영향력과 더불어 대통령의 소통 역량에 대한 인식과 신뢰도는 지지도에 유의미한 정적 영향을 미침을 다시 확인하였다. 이 같은 결과를 바탕으로 볼 때 이 연구는 대통령의 소통 역량에 대한 국민 인식이 얼마나 중요한지 강조하였다는 점에서 그 차별적 의의를 찾을 수 있다.

To provide high-quality services to the explosion of users in cellular networks, forecasts of users' next location have been studied. But it is difficult to predict users' next location in urban areas because of mobility and dynamic road and traffic condition. To address the problems, it is used that users tend to move based on social relations. If the user's next location is predictable, the traffic changes will be also predictable. It can be applied to various studies, such as base station switching and handover forecasts that can solve energy consumption and service delay problems. In this study, we propose a Markov-based prediction algorithm to forecast the next location of users in H-CRAN (heterogeneous cloud radio access network). We use RRH(radio remote head) trajectory that consists of histories stored serving RRH for each user. Simulation results and discussions demonstrate the prediction accuracy compared with those of autoregressive models.

SUMMARY Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CART cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy., Graphical abstract In Brief Avanzi et al. generate CAR T cells that secrete IL-18 and show improved activity in syngeneic hematologic and solid tumor models without prior preconditioning. They further show enhanced recruitment and anti-tumor activity of endogenous T cells.

Due to growing food-related tourism, there is increasing interest about street foods worldwide, including South Korea. Many types of food-related experiences have been considered as one of the significant elements to develop positive perceptions about a destination, and street food has been recognized as a critical clue for encouraging tourists to a destination. Previous scholars mentioned street food as a public health risk element as well as a significant factor to attract tourists&rsquo, attention. Therefore, this study aims to find out how experiential quality of street foods is related to the destination image, life satisfaction, and word of mouth as perceived by tourists in night markets of South Korea. Data was collected from 325 foreigners who visited night markets and have experienced street foods in Korea. This study demonstrates the results of the influence of quality of street foods on tourist experience, on destination image, on life satisfaction, and on word of mouth in Korea. In addition, the result shows a moderating impact of food neophobia on the formulated relationships. There are statistically significant differences between groups with high neophobia perception and low neophobia perception of street foods. Based on the results of this study, we propose not only academic implications for future studies, but also managerial implications for food enterprises and food tourism organizers related to street food.

Lung cancer is second most common cancer in the world. Non Small Cell Lung Cancer (NSCLC) accounts approximately 80-85% of all lung cancer diagnosis. Traditional therapies of this disease were surgical resection, chemotherapy, and radiotherapy, alone or in combination. In addition, targeted therapeutic approach was based on the concept of discovering genetic alterations and the signaling pathways in cancer. Recently, to overcome the critical points for standard therapies, many groups were studied immunotherapeutic approaches, such as programed cell-death protein 1 (PD-1) antibody. However, rational use of these agents has been limited by the lack of a definitive predictive biomarker. Therefore, we identified new target, cancer immunotherapy related gene, CMG by shRNA libraries screening analysis on chemo-agents & target therapy resistant non-small cell lung cancer cells. First of all, we investigated CMG expression by immunohistochemistry in various tissue microarray (TMA). These results show that CMG highly expressed in Lung cancer, Liver cancer, and gastric cancer. We investigated target potentials on lung cancer, liver cancer, and gastric cancer cell lines using in vitro and in vivo assay system. Knockdown of CMG by CMG shRNA was induced cell death in various cancer cell lines. In addition, suppression of CMG was induced tumor size regression in CMG shRNA stable cell lines-derived xenograft model. Based on these results, we synthesized a novel series of CMG therapeutic antibody. CMG therapeutic antibody is a lead antibody for treating Lung cancer patients who express CMG gene. These antibodies have anti-cancer effects and immunotherapeutic effects in lung cancer (NSCLC), liver cancer, and gastric cancer. In addition, the in vivo efficacy of CMG antibody was assessed in mouse lung cancer derived syngeneic mouse model. The CMG antibody was tri-daily i.p. injected and the tumor volume was measured and compared between groups. Dramatic tumor regression was observed in CMG antibody treated group. These results were shown that these antibodies have immunotherapeutic potentials. In conclusion, CMG is a promising target for Lung cancer patients (chemo-agents resistant or PD-1 resistant Lung cancer patienrts). Our antibodies can be promising therapeutic agents for lung cancer, Liver cancer, and gastric cancer. Citation Format: Jai-hee Moon, Dae Hee Lee, Jae-Sik Shin, Joseph Kim, Yoon Sun Park, Seung-Woo Hong, So Hee Lee, Mi Jin Kim, Joonyee Jung, Chun-Ho Park, Sun-Chul Hur, Hyojin Kim, Hyebin Park, Sang Soo Park, Jun Ki Hong, Ji Hee Gong, Jieun Kim, Hyun Ho Lee, Il-Whea Ku, Dong-Hoon Jin. Development of new mechanism based therapeutic antibodies in non-small cell lung 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 2909.

As the representative targeted anticancer drug for colon cancer patients, Erbitux is the EGFR targeted therapeutic antibody and used for treatment of KRAS wild-type colon cancer patients. Even some patients with KRas wt gene did not respond to Erbitux. However, there is no treatment available for Erbitux-resistant patient group with KRAS WT gene, which is almost 50% of KRAS WT gene holders. Recently, our team identified Erbitux primary resistant related proteins named as CRG (Cetuximab-Resistant Gene) by array analysis based Erbitux responder or nonresponder colon cancer patients derived tissues and confirmed by in vitro and in vivo assay system. Based on these results, we synthesized a novel series of CRG targeted inhibitor. CRG inhibitor (CRG i;WM compound) is a lead compound for treating colon cancer patients who do not respond to Erbitux and have KRAS wild-type gene. CRG i has potent in vitro enzyme activity and high anticancer activity against various colon cancer cell lines with good selectivity in in vitro and in vivo system. Furthermore, the compound has good potent ADME/Tox. profiles for optimized lead. CRG i also displays strong anticancer effect in in vivo xenograft models and patient-derived xenograft (PDX) models. In addition, CRG i shows promising signs of overcoming Erbitux resistance in CRG knockout cells-derived xenograft model. We continue to discover improved preclinical candidates with better selectivity and ADME/Tox. profiles and validate predictive biomarker in colon cancer patients. In these efforts, we found some compounds with better profiles than CRG i. We are also trying to develop small molecules having highly potent activity against mutant CRG. In conclusion, active CRG is a promising biomarker and target for Erbitux-resistant KRAS wt colon cancer patients. Our compounds can be promising therapeutic agents for Erbitux-resistant KRAS wt colon cancer patients. Citation Format: Chun-Ho Park, Sun-Chul Hur, Joseph Kim, Dae Hee Lee, Yoon Sun Park, Jae-Sik Shin, Seung-Woo Hong, Jai-Hee Moon, Hyojin Kim, So Hee Lee, Hyebin Park, Joonyee Jung, Mi Jin Kim, Sang Soo Park, Jun Ki Hong, Ji Hee Gong, Jieun Kim, Il-Whea Ku, Hyun Ho Lee, Dong-Hoon Jin. Identification of a novel small-molecule inhibitor for treatment of human colon cancer patients [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 2669.

Chimeric antigen receptor (CAR) T cell therapy has consistently shown significant results against acute lymphoblastic leukemia (ALL) in clinical trials1. However, results with other hematological or solid malignancies have been far more modest2. These disparate outcomes could be partially due to an inhibitory tumor microenvironment that suppresses CAR T cell function3. Thus, in order to expand the anti-tumor CAR T cell applications, a novel strategy in which these cells are capable of overcoming the hostile tumor microenvironment is needed. The cytokine interleukin-18 (IL-18) induces IFN-γ secretion, enhances the Th1 immune response and activates natural killer and cytotoxic T cells4. Early phase clinical trials that utilized systemic administration of recombinant IL-18 for the treatment of both solid and hematological malignancies have demonstrated the safety of this therapy5. We hypothesize that CAR T cells that constitutively secrete IL-18 could enhance CAR T cell survival and anti-tumor activity, and also activate cells from the endogenous immune system. To generate CAR T cells that constitutively secrete IL-18, we modified SFG-1928z and SFG-19m28mz CAR T cell constructs and engineered bicistronic human and murine vectors with a P2A element to actively secrete the IL-18 protein (1928z-P2A-hIL18 and 19m28mz-P2A-mIL18, respectively). Human and mouse T cells were transduced with these constructs and in vitro CAR T cell function was validated by coculturing the CAR T cells with CD19+ tumor cells and collecting supernatant for cytokine analysis. Both human and mouse CAR T cells secreted increased levels of IL-18, IFN-γ and IL-2. Proliferation and anti-tumor cytotoxic experiments were conducted with human T cells by coculturing CAR T cells with hCD19+ expressing tumor cells. 1928z-P2A-hIL18 CAR T cells had enhanced proliferation over 7 days and enhanced anti-tumor cytotoxicity over 72 hours when compared to 1928z CAR T cells (p=0.03 and 0.01, respectively) Next, the in vivo anti-tumor efficacy of the IL-18 secreting CAR T cell was tested in xenograft and syngeneic mouse models. Experiments were conducted without any prior lympho-depleting regimen. In the human CAR T cell experiments, Scid-Beige mice were injected with 1x106 NALM-6 tumor cells on day 0 and 5x106 CAR T cells on day 1. Survival curves showed a significant improvement in mouse survival with the 1928z-P2A-hIL18 CAR T cell treatment when compared to 1928z CAR T cell (p=0.006). Subsequently, to determine if IL-18 secreting CAR T cells could also improve anti-tumor efficacy in immunocompetent mice, we tested the murine 19m28mz-P2A-mIL18 CAR T cells in a syngeneic mouse model. The C57BL/6 hCD19+/- mCD19+/- mouse model was utilized and injected with 1x106 EL4 hCD19+ tumor cells on day 0 and 2.5 x106 CAR T cells on day 1. Mice treated with 19m28mz-P2A-mIL18 CAR T cells had 100% long-term survival, when compared to 19m28mz (p Our findings demonstrate that anti-CD19 CAR T cells that constitutively secrete IL-18 significantly increase serum cytokine secretion, enhance CAR T cell persistence, induce long-term B cell aplasia and improve mouse survival, even without any prior preconditioning. To our knowledge, this is the first description of an anti-CD19 CAR T cell that constitutively secretes IL-18 and that induces such high levels of T cell proliferation, persistence and anti-tumor cytotoxicity. We are currently investigating other mechanisms by which this novel CAR T cell functions, its interactions with the endogenous immune system, as well as testing its applicability in other tumor types. We anticipate that the advances presented by this new technology will expand the applicability of CAR T cells to a wider array of malignancies. Disclosures Brentjens: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Intruduction Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor outcome and therapeutic challenge. Oral single-agent ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, elicited a response rate of 68% in phase II clinical trial and has been approved by FDA for the treatment of MCL patients who received at least one prior therapy. To increase the response rate, the combination of ibrutinib with rituximab would be an ideal regimen because: (1) Both BTK and CD20 are effective therapeutic targets for MCL; (2) CD20-dependent apoptosis occurs associated with B-cell receptor (BCR) activity. Regardless rituximab-mediated immune response (ADCC and CDC) and ibrutinib-mediated ITK inhibition (Th1 polarization), an important potential effect of ibrutinib and rituximab may enhance the direct anti-MCL cytotoxicity of the combination. Methods and Results We investigated the effects of ibrutinib and/or rituximab in 6 established MCL cell lines and 3 freshly isolated primary MCL cells in vitro. First, ibrutinib, as well as BTK-siRNA, inhibited the growth of MCL cells. Then we found that ibrutinib induced the growth inhibition and apoptosis of most MCL cell lines and primary MCL cells in a dose-dependent manner during 5-7 days of culture (IC50 range from 1.5 to 15 µM). On the other hand, rituximab alone induced 10-30% growth inhibition and apoptosis of both established and primary MCL cells in vitro. Importantly, our results showed that ibrutinib and rituximab combination synergistically induced apoptosis of MCL cells during 5-7 days of culture in vitro. Next, our animal study confirmed the compartmental shift phenomenon mediated by ibrutinib which was similar with the data from clinical study. Briefly, SCID mice were subcutaneously implanted with human fetal bone chips (SCID-hu). After 6 weeks of bone implantation, the freshly isolated MCL cells from patients were directly engrafted into the human fetal bone chips. The engrafted MCL cells produced measurable levels of human β2-microglobulin (β2M) in mouse serum. Once human β2M had been detected in mouse serum, the primary MCL-bearing SCID-hu mice were treatment with 25 mg/kg ibrutinib oral gavage daily. A transient increase of human CD5+CD20+ cells in mouse peripheral blood was detected by flow cytometry from day 8 of treatment, representing a shift of human MCL cells from human fetal bone chip to mouse peripheral blood. At this time, 10 mg/kg rituximab was intravenously administrated every 3 days for total 7 doses. Our results demonstrated that rituximab and ibrutinib combination eradicated MCL cells in vivo and kept mice survival longer than either ibrutinib or rituximab alone. Conclusions Based on our preclinical data of rituximab and ibrutinib combination in vitro and in primary MCL-bearing SCID-hu mice, ibrutinib plus rituximab could be an effective regimen in a clinical trial of relapsed or refractory MCL. Disclosures Off Label Use: Ibrutinib plus rituximab may enhance the direct anti-MCL cytotoxicity. Wang:Pharmacyclics: Honoraria, Research Funding.

Rituximab in combination with hyperfractionated cyclophosphamide, vincristine, doxorubicin (DOX), and dexamethasone has been a successful frontline therapy for aggressive mantle cell lymphoma (MCL), a distinct and heterogeneous subtype of non-Hodgkin lymphoma, with complete remission rates as high as 87% in patients at or below 65 years of age. However, the efficacy of rituximab in combination with hyperfractionated cyclophosphamide, vincristine, DOX, and dexamethasone comes at the expense of severe grade III-IV toxic effects, and its use is limited by de novoor acquired multidrug resistance. Berubicin (WP744; BRN) is a clinically evaluated analog of DOX that, like DOX, stabilizes cleavable complexes between DNA and topoisomerase II, leading to irreversible double-strand DNA breaks and abrogation of DNA religation. In contrast to DOX, BRN overcomes multidrug resistance by circumventing efflux mediated by ATP-binding cassette proteins like P-glycoprotein and MRP-1. BRN is also the first anthracycline derivative to effectively cross the blood-brain barrier, with demonstrated phase 1 responses in brain cancer patients. Our MCL studies demonstrated that treatment with BRN decreased cell growth threefold to sixfold more potently than DOX in all tested MCL cell lines (Mino, Jeko-1, SP53, and Granta 519) and four MCL patient samples by arresting MCL cell-cycle progression at the G2/M phase and inducing extensive apoptosis. Moreover, in a Western blot assay, Jeko-1 and Mino cells exhibited activation of caspase-3 and caspase-9 and cleavage of poly(ADP-ribose) polymerase over time, pointing to the presence of a mitochondria-mediated apoptosis pathway in BRN-treated MCL cell lines. We then assessed the in vivo activity of BRN, using DOX as a control, in MCL-bearing severe combined immunodeficient (SCID) and SCID-hu mice. Our results indicated that SCID mice given 10 mg/kg DOX survived no more than 15 days after treatment, whereas all mice given 10 mg/kg BRN survived up to 63 days after treatment. On the other hand, when BRN and DOX were administered at lower doses of 5 mg/kg in a SCID-hu MCL mouse model, similar survival durations for BRN and DOX were observed. In summary, our studies demonstrate that BRN is highly potent against MCL in vitro and displays a wider therapeutic window than DOX, delivering very promising in vivo activity in both SCID and SCID-hu MCL models. These results indicate that BRN should be evaluated in the treatment of other lymphomas and seriously considered as an effective replacement for DOX in MCL treatment. BRN’s success in Phase 1 studies in glioma patients and observed safety and effectiveness in MCL models warrant further investigation of its clinical use and combination with existing therapies in MCL patients. Disclosures Priebe: MD Anderson: Waldemar Priebe holds patents and has a financial interest in the development of berubicin. Patents & Royalties.

Introduction Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor outcome and therapeutic challenge. Oral single-agent ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, elicited a response rate of 68% in phase II clinical trial and has been approved by FDA for the treatment of MCL patients who received at least one prior therapy. To increase the possibility of therapeutic potential, the investigation of BTK-dependent/independent signaling pathways is needed. Methods and Results Using both established MCL cell lines and primary MCL cells as a model system, our data demonstrated that ibrutinib effectively inhibited BTK phosphorylation along with quick STAT3 inactivation within 30 minutes of ibrutinib incubation at a dose lower than 100nM. Since the results clearly indicated that ibrutinib inhibited both BTK and STAT3 activation in MCL cells, we next elucidated the function and action between BTK and STAT3. Using a validated BTK-specific siRNA, we knocked down BTK to test the legitimacy of the relationship between BTK and STAT3. The results showed that transient knockdown of BTK significantly inhibited STAT3 phosphorylation in MCL cells. Next, the results from both immunoprecipitation and confocal microscopy showed that STAT3 was BTK-associated transcription protein indicating that BTK could function as a kinase upstream of STAT3, in a similar manner to the JAK/STAT pathway. Since STAT3 is predominately known as the downstream protein of the IL-6/JAK pathway, we examined whether there is a cross-talk between the BTK-STAT3 and the JAK-STAT3 pathways in MCL cells. After stimulation of MCL cells with IgM or IL-6, ibrutinib only inhibited IgM-induced STAT3 activation but not IL-6-induced STAT3 activation. Even with an increased dose of ibrutinib, the basal level of STAT3 phosphorylation remains detectable in MCL cells due to IL-6 autocrine. However, ibrutinib plus JAK inhibitor completely inactivated STAT3 and synergistically inhibited the growth of MCL cells. These data indicate that there are two independent pathways, BCR-BTK and IL6-JAK, which lead to STAT3 activation without cross-talk in MCL cells. Conclusions Our results may lead to the development of more effective combination therapy to block both BCR-BTK and IL-6-JAK signaling pathways for relapsed or refractory MCL. Disclosures Wang: Pharmacyclics: Honoraria, Research Funding.

Doctor of Philosophy in Social Welfare, Doshisha University