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Tankyrase inhibition stabilises AXINs and antagonises the Wnt/β-catenin pathway in adenomatous polyposis coli (APC)-mutated colorectal cancer (CRC), suggesting that tankyrase is a potential therapeutic target for APC-mutated CRC. However, clinical trials on reported tankyrase inhibitors have been severely limited by on-target toxicity in the gastrointestinal (GI) tract. Herein, we report a new tankyrase-selective inhibitor, STP1002, having preclinical antitumour efficacy without on-target toxicity in APC-mutated CRC models.STP1002 was developed and characterised using in vitro and in vivo functional studies; its pharmacokinetics, antitumour efficacy and toxicity were evaluated in vivo.STP1002 showed potent, selective inhibition of tankyrase 1/2 but not of members of the poly (ADP-ribose) polymerase 1/2 (PARP1/2). STP1002 exerted antitumour activity by stabilising AXINs and antagonising the Wnt/β-catenin pathway in a subset of APC-mutated CRC cell lines but not in inhibitor-resistant cells and APC-wild-type CRC cell lines. STP1002 showed favourable pharmacokinetic profiles for oral administration once daily. STP1002 inhibited tumour growth of APC-mutated CRC xenograft animal models but not of APC-wild type models in a dose-dependent manner. The antitumour efficacy of STP1002 was confirmed using APC-mutated CRC patient-derived tumour xenograft models. STP1002 showed no significant on-target toxicity in the GI tract compared to G007-LK, which shows severe ileum toxicity in preclinical animal models.These results demonstrate that STP1002, a novel, orally active tankyrase inhibitor, shows preclinical antitumour efficacy without on-target toxicity in the GI tract. Our data provide a rationale for a clinical trial on STP1002 as a potential tankyrase-targeted drug in patients with APC-mutated CRC.

We investigated the use of a silver reflector embedded with Ni–Cu nanoparticles to achieve low resistance and high reflectivity in GaN-based flip-chip light-emitting diodes. Compared to a single layer of Ag, the NC-NPs/Ag reflector exhibits a higher light reflectance of ~90% at a wavelength of 450 nm, a lower contact resistance of 4.75 × 10−5 II cm2, and improved thermal stability after annealing at 400°C. The NC-NPs formed after the annealing process prevents agglomeration of the Ag layer, while also reducing the Schottky barrier height between the p-GaN layer and metal reflector. The LED fabricated with a NC-NPs/Ag reflector exhibited a forward-bias voltage of 3.13 V and an improvement in light output power of 36.6% (at 20 mA), when compared with the LED composed of a Ag SL. This result indicates that the NC-NPs/Ag reflector is a promising p-type reflector for high-intensity light-emitting diodes.

Mitogen-activated protein kinase (MEK) inhibitors have shown promising results in KRAS-mutated cancers with constitutive activation of the RAS/RAF/MEK pathway. However, the intrinsic and acquired resistance to MEK inhibitors is frequently observed in clinical trials. Wnt/β-catenin signaling hyper-activation is reported to be responsible for such resistance in colorectal cancer (CRC). Herein, we introduce a novel tankyrase inhibitor STP1002 to revert the intrinsic and acquired resistance to MEK inhibitors in KRAS-mutated CRC. Dual combination of STP1002 and MEK inhibitor synergistically reduced the oncogenic activity of KRAS (G12V or G12D)-mutated CRC cell lines. Data also showed that concomitant treatment with STP1002 and MEK inhibitor dramatically inhibited tumor growth of KRAS (G12V)-mutated CRC xenograft animal models. Moreover, the combination treatment sensitized the acquired MEK inhibitor-resistant CRC cells and suppressed the Wnt/YAP pathway which is the bypass mechanism of MEK inhibitor resistance. Dual combination of STP1002 and MEK inhibitor is a promising candidate to overcome resistance to MEK inhibitors in colorectal cancer with KRAS-G12V/G12D mutations. The phase 1 clinical trial study is ongoing in order to show safety margin. Citation Format: Young-Ju Kwon, Dong Young Kim, Uk-Il Kim, Xue Meng, Ho Kyun Lee, Hyung Tae Bang, Jae-Sung Kim, Kyungjin Kim. Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 491.

Radiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδ and/or γ, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδ or γ is not sufficient to completely eliminate solid tumor.We used BR101801, PI3Kδ/γ inhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis.This study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8αOur data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.

As pyrazole and its derivatives have a wide range of biological activities, including anticancer activity, the design of novel pyrazole derivatives has emerged as an important research field. This study describes a novel pyrazole derivative that exerts antitumor and radiosensitizing activities in breast cancer both in vitro and in vivo. We synthesized a novel pyrazole compound N,N-dimethyl-N’-(3-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)azanesulfonamide (PCW-1001) and showed that it inhibited several oncogenic properties of breast cancer both in vitro and in vivo. PCW-1001 induced apoptosis in several breast cancer cell lines. Transcriptome analysis of PCW-1001-treated cells showed that it regulates genes involved in the DNA damage response, suggesting its potential use in radiotherapy. Indeed, PCW-1001 enhanced the radiation sensitivity of breast cancer cells by modulating the expression of DNA damage response genes. Therefore, our data describe a novel pyrazole compound, PCW-1001, with antitumor and radiosensitizer activities in breast cancer.

Although microtubule-associated serine/threonine kinase-like (MASTL) is a promising target for selective anticancer treatment, MASTL inhibitors with nano range potency and antitumor efficacy have not been reported. Here, we report a novel potent and selective MASTL inhibitor MASTL kinase inhibitor-2 (MKI-2) identified in silico through a drug discovery program. Our data showed that MKI-2 inhibited recombinant MASTL activity and cellular MASTL activity with IC50 values of 37.44 nM and 142.7 nM, respectively, in breast cancer cells. In addition, MKI-2 inhibited MASTL kinase rather than other AGC kinases, such as ROCK1, AKT1, PKACα, and p70S6K. Furthermore, MKI-2 exerted various antitumor activities by inducing mitotic catastrophe resulting from the modulation of the MASTL-PP2A axis in breast cancer cells. The MKI-2 treatment showed phenocopies with MASTL-null oocyte in mouse oocytes, which were used as a model to validate MKI-2 activity. Therefore, our study provided a new potent and selective MASTL inhibitor MKI-2 targeting the oncogenic MAST-PP2A axis in breast cancer cells.

Purpose To investigate the preventive effect of colostrum on hepatic fibrosis induced by carbon tetrachloride (CCl4) in mice. Methods Seven-week-old male Balb/C mice were treated with CCl4 with or without a diet of bovine colostrum (BC) for 2 weeks. Hepatic fibrosis was determined using Sirius red staining, α-smooth muscle actin (α-SMA) immunohistochemistry, immunoblot analysis, and quantitative polymerase chain reaction (PCR) for profibrogenic and proinflammatory genes. Hepatocellular injury was assessed through the measurement of serum alanine aminotransferase (ALT) levels. Results Compared to the CCl4 group, the BC4 group had a 55% reduction in fibrosis as demonstrated by Sirius red staining. The BC+CCl4 group also had a significant reduction in α-SMA expression according to immunohistochemistry and immunoblot. On quantitative PCR, the BC+CCl4 group showed significant 8.42-, 21.11-, 0.57-, and 2.90-fold reductions in the expression of Acta2, Col1α1, Tgfβ1, and Tnf-α, respectively, compared to the CCl4 group. The serum ALT level was significantly reduced in the BC+CCl4 group compared to the CCl4 group. Conclusion The present study demonstrated that BC ameliorated CCl4-induced hepatic fibrosis by inhibiting fibrogenesis-related gene expression and also decreased CCl4-induced hepatocyte injury. Therefore, BC might be therapeutically efficacious in preventing hepatic fibrosis in various liver diseases.

본 연구에서는 제4차 산업혁명의 특징 및 미래신산업 발굴을 위한 해양분야의 기회영역별 해양과학기술을 분석하고, 해양 중심의 지속가능한 발전을 위해 향후 추진방향을 전망하고자 한다. 기술혁신을 기반으로 한 4차 산업혁명 기술에 접목될 수 있는 해양분야는 빅데이터, 증강현실, 드론, 로봇 등의 신기술과 IoT 기술의 융복합을 중심으로 가속화 되고 있다. 현재 해양 R&D 중점개발 기술은 미래해양자원, 해양청정에너지, 해양환경, 해양생명공학, 해양장비개발 및 인프라 구축, 해양과학조사 및 예보, 해양안전 및 교통시설, 첨단항만·물류 기술개발, 대형 연구인프라 구축 등에 투자되고 있다. 하지만, 안전한 해양공간 조성, 해양환경 개선 등을 위해 Safety 항만기술, 빅데이터 활용 해양예보 기술, 해양생태계 건강성 복원 기술, 인공지능 해저로봇기술 등이 기회영역 분야로 주목받고 있다. 또한, 신산업 분야의 핵심기술을 선도하고자 수공양용 무인이동체 기술, ICT기반 해양레포츠 서비스 및 고부가가치 해양레저장비 기술, 극한지 활용 장비·소재 기술, 해양수산자원을 활용한 신물질 기술 및 해양수산 바이오 팩토리 기술, 해양플랜트 운영·해체 기술 등이 거론되고 있다. 마지막으로 해운물류·항만, 수산 등 기존 산업분야의 위기를 극복하고 신성장동력을 창출하기 위해, IoT기반 해운·항만·물류서비스 개발, 선박 자율운항 기술, ICT 활용 스마트 양식기술, 해저구조물 건설 핵심기술개발 등이 제안되고 있다.

The circadian clock control of CONSTANS (CO) transcription and the light-mediated stabilization of its encoded protein coordinately adjust photoperiodic flowering by triggering rhythmic expression of the floral integrator flowering locus T (FT). Diurnal accumulation of CO is modulated sequentially by distinct E3 ubiquitin ligases, allowing peak CO to occur in the late afternoon under long days. Here we show that CO abundance is not simply targeted by E3 enzymes but is also actively self-adjusted through dynamic interactions between two CO isoforms. Alternative splicing of CO produces two protein variants, the full-size COα and the truncated COβ lacking DNA-binding affinity. Notably, COβ, which is resistant to E3 enzymes, induces the interaction of COα with CO-destabilizing E3 enzymes but inhibits the association of COα with CO-stabilizing E3 ligase. These observations demonstrate that CO plays an active role in sustaining its diurnal accumulation dynamics during Arabidopsis photoperiodic flowering.

The Korean government is considering the implementation of the marine debris pollution abatement technology program (MDPATP) to mitigate the negative impacts of marine debris and systematically manage marine debris through scientific researches such as monitoring and environmental impact assessment of marine debris. In this regard, this study attempts to analyze the economic feasibility of the MDPATP in order to provide policy-maker with useful information. To this end, the indices for economic feasibility such as net present value (NPV), benefit/cost (B/C) ratio, and internal rate of return (IRR) are presented. The results show that NPV, B/C ratio, and IRR are computed to be 45.7 billion won, 2.72, and 17.12%, respectively, which are bigger than 0, 1.0, and 5.5%, and that the MDPATP passes the cost-benefit analysis. Thus, it is concluded that it is socially profitable to conduct the MDPATP.

Department of Energy Policy, Graduate School of Energy & Environment, Seoul National University of Science & Technology, 232 Gongreung-Ro, Nowon-Gu, Seoul, 139-743, Korea Marine Policy Development Office, Korea Institute of Marine Science & Technology Promotion, 87 Nonhyeon-Ro, Seocho-Gu, Seoul, 137-941, Korea요 약 : 정부는 훼손된 해양생태계의 현황 및 원인을 파악하고 생태계 기능 복원 및 손실 방지 전략을 수립하기 위해 해양생태계 복원기술개발 사업의 시행을 고려하고 있다. 사업 시행 여부에 대한 판단을 위해서는 이 사업에 대한 경제적 타당성 분석이 필수적으로 요구된다. 이에 본 연구에서는 조건부 가치측정법(CVM, contingent valuation method)을 적용하여 사업 수행의 경제적 타당성을 분석하고자 한다. 지불의사 유도방법으로 유인일치적인 양분선택형 모형을 이용하되, 지불의사액 추정모형으로 영(0)의 응답을 명시적으로 다룰 수 있는 스파이크 모형을 적용한다. CVM 적용을 위한 설문조사는 미국 해양대기청의 지침에 따라 전국 1,000가구를 대상으로 일대일 개별면접을 통해 2013년에 시행되었다. 분석결과 연간 가구당 평균 지불의사액은 5,414원으로 추정되었다. 이 값을 전국으로 확장하면 향후 5년 동안 연간 약 986억원에 달한다. 이 값과 해양생태계 복원기술개발 사업의 투자비 정보를 이용하여 경제성을 분석한 결과, 순현재가치, 편익/비용 비율, 내부수익률은 각각 3,378억원, 5.20, 65.9%로 산정되어 각각 0, 1.0, 5.5%를 상회하므로 이 사업은 비용-편익 분석을 통과한다. 핵심용어 : 해양생태계 복원기술개발 사업, 경제적 타당성, 조건부 가치측정법, 지불의사액, 비용-편익 분석Abstract : The Korean government is considering implementation of the marine ecosystem restoration technology program (MERTP) to analyze the current status of the marine ecosystems and causes for the ecosystem deterioration as well as to eventually establish a master strategic plan for restoring ecosystem functions and preventing ecosystem functional loss. In order to determine likelihood of successful implementation, it is essential to perform an analysis of the economic feasibility of the program. The present study assessed economic feasibility of the MERTP. To this end, the dichotomous choice contingent valuation (CV) method is used. In particular, dichotomous choice (DC) format is employed as a method of eliciting willingness-to-pay (WTP) response to incentive-compatible mechanisms. The study also employed the spike model to deal with zero WTP responses from the DC CV survey. This survey of 1,000 randomly selected households in accordance with the guidelines provided by the National Oceanic and Atmospheric Administration (USA) was carried out nationwide in 2013. And, the respondents were asked in person-to-person interviews about their WTP for implementing the MERTP. The results showed that the annual mean WTP was estimated to be 5,414 won per household. Consequently, the annual benefit from the MERTP would be about 98.6 billion won for the next five years. Economic feasibility assessment utilizing the MERTP investment cost and expansion cost of the value provided that net present value, benefit/cost ratio, and internal rate of return are 337.8 billion won, 5.20, and 65.9%, respectively, which are bigger than 0, 1.0, and 5.5%, and that the MERTP passes the cost-benefit analysis. Key Words : Marine ecosystem restoration technology program, Economic feasibility, Contingent valuation method, Willingness to pay, Cost-benefit analysis1) First Author : yjkwon@seoultech.ac.kr, 02-970-6960Corresponding Author : shyoo@seoultech.ac.kr, 02-970-6802

*, ** Graduate School of Energy & Environment, Seoul National University of Science & Technology, 232 Gongreung-Ro, Nowon-Gu, Seoul, 139-743, Korea*** Environment and Economics Assessment Section, Korea Institute of Ocean Science & Technology, 787 Haean-Ro, Sangnok-gu, Ansan, 426-744, Korea요 약 : 본 연구는 금강 하구 관리에 대한 합리적 결론을 도출하기 위하여 하구의 환경가치를 추정하였다. 추정 방법은 하구의 세부적인 속성을 평가하기 위하여 다속성 효용이론에 근거한 조건부 가치측정법을 적용하였다. 또한 하구 인근지역(전북, 충남) 400가구와 전국 13개 광역지자체(전북, 충남, 제주도 제외)지역 600가구를 무작위로 추출하여 일대일 개별면접을 통해 금강 하구 관리방안에 대해 얼마나 지불할 의사가 있는지를 조사하였다. 응답자들은 전반적으로 조건부 시장을 잘 받아들였으며, 가구당 연 평균 지불의사액은 금강하구 인근지역의 경우 1,497원, 전국 13개 광역지자체 지역의 경우 4,343원으로 분석되어 지역에 따라 큰 차이가 났다. 이 값을 해당 지역의 모집단으로 확장한 결과, 각각 연간 21.3억 원 및 701.5억 원이었다. 이러한 정량적인 값은 금강 하구관리 정책에 대한 합리적인 의사결정에 유용한 자료로 활용될 수 있을 것이다. 핵심용어 : 금강 하구, 환경가치, 지불의사액, 다속성 효용이론, 조건부 가치측정법 Abstract : The current study attempted to assess the environmental value of Geum-river estuary for rational management decision-making. To investigate the comprehensive properties of the Geum-river estuary, we applied the contingent valuation method based on multi-attribute utility theory. We surveyed a randomly selected sample of 400 and 600 households of the Geum-river estuary-neighboring area (Jeollabuk-do, Chungcheongnam-do), and other nation-wide large districts (except Jeollabuk-do, Chungcheongnam-do, and Jeju-do), respectively, and carried out person-to-person interviews with subjects on their willingness-to-pay for the estuary conservation and management program. Respondents, overall, accepted the contingent market system and were willing to contribute a significant amount, that is 1,497 won for the residents from the Geum-river estuary-neighboring area and 4,343 won for the residents from other nation-wide large districts on average, per household per year. These results implied that there were large difference between the two groups. The aggregate values of the Geum-river estuary for the estuary-neighboring area and other nation-wide large districts amount to 2.13 and 70.15 billion won, respectively, per year. This quantitative value deduced from the current study, could be a useful baseline fact for any decision-making process particularly in the establishment of management policies for the Geum-river estuary. Key Words : Geum-river estuary, Environmental value, Willingness to pay, Multi-attribute utility theory, Contingent valuation method 1)

Background Plants constantly monitor changes in photoperiod or day length to trigger the flowering cycle at the most appropriate time of the year. It is well established that photoperiodic flowering is intimately associated with the circadian clock in Arabidopsis. In support of this notion, many clock-defective mutants exhibit altered photoperiodic sensitivity in inducing flowering. LATE ELONGATED HYPOCOTYL (LHY) and its functional paralogue CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) constitute the core of the circadian clock together with TIMING OF CAB EXPRSSION 1 (TOC1). While it is known that TOC1 contributes to the timing of flowering entirely by modulating the clock function, molecular mechanisms by which LHY and CCA1 regulate flowering time have not been explored. Results We investigated how LHY and CCA1 regulate photoperiodic flowering through molecular genetic and biochemical studies. It was found that LHY-defective mutants (lhy-7 and lhy-20) exhibit accelerated flowering under both long days (LDs) and short days (SDs). Consistent with the accelerated flowering phenotypes, gene expression analysis revealed that expression of the floral integrator FLOWERING LOCUS T (FT) is up-regulated in the lhy mutants. In addition, the expression peaks of GIGANTEA (GI) and FLAVIN-BINDING, KELCH REPEAT, F-BOX PROTEIN 1 (FKF1) genes, which constitute the clock output pathway that is linked with photoperiodic flowering, were advanced by approximately 4 h in the mutants. Furthermore, the up-regulation of FT disappeared when the endogenous circadian period is matched to the external light/dark cycles in the lhy-7 mutant. Notably, whereas CCA1 binds strongly to FT gene promoter, LHY does not show such DNA-binding activity. Conclusions Our data indicate that the advanced expression phases of photoperiodic flowering genes are associated with the clock defects in the lhy mutants and responsible for the reduced photoperiodic sensitivity of the mutant flowering, demonstrating that LHY regulates photoperiodic flowering via the circadian clock, similar to what has been shown with TOC1. It is notable that while LHY regulates photoperiodic flowering in a similar manner as with TOC1, the underlying molecular mechanism would be somewhat distinct from that exerted by CCA1 in Arabidopsis. Electronic supplementary material The online version of this article (doi:10.1186/s12870-016-0810-8) contains supplementary material, which is available to authorized users.

Here, we report a method for high-sensitivity fluorescence imaging of iron, which demonstrates the abundance and distribution of iron in plant tissues more precisely than conventional histochemical staining procedures. The fluorescence turn-on method is rapid (

What happened under the rubric of small-government reform slogans during the era of cutback management in Japan and Korea? This paper analyzes and discusses the structural changes of the central state apparatus, and provides implications to the constraints and opportunities of administrative reforms in Japan and Korea. Applying the ‘bureau-shaping model’ of Patrick Dunleavy, we find substantive validity for the bureau-shaping strategy in both countries; both state apparatus have been shaping their delivery agencies into transfer, contract and control agencies. However, the degree of changes was not enough (especially, in Japan) to strongly test the hypotheses of the bureau-shaping model. Now, structural changes of the state apparatus in both countries are expected to be more radical than those in past years. And the explanatory power of the bureau-shaping model is anticipated to be greater in the future.

Longer life time is required to commercial hybrid vehicle than that of passenger hybrid electric vehicle, like conventional commercial and private vehicle. On the respect of electric motor of hybrid powertrain, the lifetime of electric motor mostly depends on the two factors; electric insulation degradation and fatigue of bearings. In electric motor design, especially used in commercial hybrid powertrain, the reliability and lifetime estimation is very crucial in order to meet the lifetime requirement.

Runyon group IV atypical mycobacteria, Mycobacterium fortuitum, is an environmental organism and is capable of producing a variety of clinical infections such as cutaneous infection, abscess and pulmonary and ocular infection. Rarely, it has been a documented cause of peritonitis in patients receiving continuous ambulatory peritoneal dialysis (CAPD). We report a case of M. fortuitum peritonitis in a patient undergoing CAPD and emphasize the importance of mycobacterial cultures in patients with CAPD-associated peritonitis whose routine culturing yields no organisms repeatedly.

The aqueous extract of European mistletoe (Viscum album, L.) has been used in cancer therapy. The purified mistletoe lectins, main components of mistletoe, have demonstrated cytotoxic and immune-system-stimulating activities. Korean mistletoe (Viscum album L. coloratum), a subspecies of European mistletoe, has also been reported to possess anticancer and immunological activities. A galactose- and N-acetyl-D-galactosamine-specific lectin (Viscum album L. coloratum agglutinin, VCA) with Mr 60 kDa was isolated from Korean mistletoe. Mistletoe preparations have been given subcutaneously due to the low stability of lectin in the gastrointestinal (GI) tract. In the present study, we investigated the possibility of alginate/chitosan microcapsules as a tool for oral delivery of mistletoe lectin. In addition, our strategy has been to develop a system composed of stabilizing cores (granules), which contain mistletoe lectin, extract or powder, coated by a biodegradable polymer wall. Our results indicated that successful incorporation of VCA into alginate/chitosan microcapsules has been achieved and that the alginate/chitosan microcapsule protected the VCA from degradation at acidic pH values. And coating the VCA with polyacrylic polymers, Eudragit, produced outstanding results with ideal release profiles and only minimal losses of cytotoxicity after manufacturing step. The granules prepared with extract or whole plant produced the best results due to the stability in the extract or whole plant during manufacturing process.

The three fractions of inulase differing in isoelectric pH were isolated from a strain ofAspergillusniger by isoelectric focussing and characterized in their temperature stability. These fractions had distinguishable thermal stability. Among them, one fraction (pI 5.2) having main activity showed a high thermal stability comparable to that of the Novozyme 230 (Novo A/S, Denmark) at 60°C.