Optimal sequence of systemic therapy after sorafenib failure in patients with hepatocellular carcinoma

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Persistence of Hepatocellular Carcinoma Risk after Hepatitis C Virus Eradication

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Risk Factors for Surgery in Patients with Intestinal Behçet's Disease During Anti-Tumor Necrosis Factor-Alpha Therapy

Purpose: Behçet's disease (BD) is a chronic inflammatory immune-mediated disease involving multiorgan systems. Gastrointestinal (GI) manifestations of BD include abdominal pain, vomiting, GI bleeding, fistula formation, obstruction, and perforation that might require surgery. Recently, anti-tumor necrosis factor-alpha (anti-TNF-α) therapy has been shown to have favorable outcomes in patients with intestinal BD who are refractory to conventional therapy. This study sought to figure out the risk factors for undergoing surgery during anti-TNF-α therapy in patients with intestinal BD. Materials and methods: In this retrospective analysis of intestinal BD patients who were treated with anti-TNF-α, we collected the baseline patient data including comorbidities, clinical, endoscopic, and radiologic characteristics, and the Disease Activity Index for Intestinal Behçet's Disease at the time of anti-TNF-α initiation. Each potential risk factor was compared. For multivariate analysis, Cox regression was used. Results: A total of 62 patients were considered eligible for analysis, and 15 of them (24.1%) underwent surgery. In univariate analysis, the presence of extraintestinal manifestation, such as joint symptoms and erythrocyte sedimentation rate (ESR), were significantly associated with surgery during therapy. In multivariate analysis, drug response within 4 weeks [hazard ratio (HR), 64.59], skin and joint manifestation (HR, 10.23 and HR, 6.22), geographic ulcer (HR, 743.97), and ESR >42.5 mm/h (HR, 9.16) were found to be factors predictive of undergoing surgery during anti-TNF-α therapy. Conclusion: We found five risk factors predictive of surgery in patients with intestinal BD receiving anti-TNF-α therapy, which can guide physicians in selecting appropriate patients between anti-TNF-α therapy and early surgery.ope

Appraisal of Long-Term Outcomes of Liver-Directed Concurrent Chemoradiotherapy for Hepatocellular Carcinoma with Major Portal Vein Invasion

Backgrounds and aims: Molecular-targeted agents are acceptable standards to treat advanced-stage hepatocellular carcinoma (HCC), however, their therapeutic benefit, ie, sorafenib, was significantly offset in case of major vessel invasion. Liver-directed concurrent chemo-radiotherapy (LD-CCRT) provided favorable outcomes in terms of survivals and tumor shrinkage, so, we appraised its long-term therapeutic efficacy. Patients and methods: Advanced HCC patients with portal vein invasion (main trunk or the 1st order branch) were enrolled. During a 5-week radiotherapy course, concurrent hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and leucovorin was administered through an implanted port on the first and last 5 days. Four weeks after LD-CCRT, a maintenance HAIC using 5-fluorouracil and cisplatin was administered every 4 weeks. Results: Among 152 patients, the objective response rates as the best response by modified Response Evaluation Criteria In Solid Tumors were 48.0% after LD-CCRT and 55.3% during subsequent HAIC maintenance. After LD-CCRT, biological responses in alpha-fetoprotein and protein induced by the absence of vitamin K or antagonist-II levels were achieved in 46.2% and 52.6%, respectively. Sixteen patients (10.5%) underwent curative resection or liver transplantation after down-staging. Median overall survival and progression-free survival were 13.5 and 6.9 months, respectively. Conclusion: LD-CCRT followed by maintenance HAIC yielded favorable survival outcomes in advanced HCC patients with major portal vein invasion. Through initial tumor reduction, LD-CCRT induced down-staging with subsequent curative treatment feasible in 10.5% of patients, resulting in long-term survival. Further prospective trials are warranted to confirm these results.ope

Detecting Open Source-Code Plagiarism

소스코드 표절은 원본자료의 출처를 분명히 밝히지 않고 자신의 것처럼 사용하는 행위를 말하는데, 학생이 제출하는 과제에서부터 산업 현장의 프로그램 일부 또는 전체에 이르기까지 소스코드 표절 범위는 매우 다양하다. 이러한 표절 문제는 인터넷 매체의 발달로 인해 더욱더 만연해지고 있고, 오픈 소스코드는 소스코드의 공개를 통해 사용, 복제, 수정, 배포가 자유롭다는 강점을 바탕으로 전 세계적으로 그 영역이 확대되고 있다. 자유지향적인 오픈 소스코드에도 지켜야 하는 라이센스와 요구조건이 있다. 그러나 그 오픈 소스코드들이 가지고 있는 요구조건들을 무시한 채, 아니면 본의 아니게 라이센스들의 요구조건들을 어기고 오픈 소스를 상업적으로 사용하는 사례들이 점점 많아지고 있다. 이를 위해서는 오픈 소스코드 표절에 대한 탐지가 효과적이고 강력히 수행되어야만 한다. 다시 말해 불법 복제코드를 효과적으로 검출할 수 있는 탐지 프로그램의 개발과 활용이 문제 해결의 핵심이라고 할 수 있다. 기존의 소스코드 표절 기법은 학생들의 프로그램과제 표절 검사를 위한 단순한 프로그램이기 때문에, 오픈 소스코드 표절을 감지하는 툴로 사용하기에는 실행속도가 한없이 길거나, 많은 오픈 소스코드들 중에서 표절을 탐지하기에는 많은 제약이 따른다. 또한 소스코드를 찾아주는 Google 코드 검색은 줄 단위 검색을 제공하고 있기 때문에, 파일이나 패키지 단위의 검색으로 사용하기에는 불편함이 있다. 따라서 본 논문에서는 기존의 소스코드 표절 기법으로 탐지가 어려운 문제점과 Google 코드 검색의 줄 단위 검색의 불편함을 해결하기 위해 사용자들이 편리하게 오픈 소스코드 표절을 탐지할 수 있는 Google 코드 검색 Data API를 사용한 패키지 단위의 오픈 소스코드 표절에 대한 기법과 프로그램을 개발하였다.;Source code plagiarism means a practice of using the source without clarifying the source of original work like the own thing. A range of source plagiarism ranging from an assignment submitted by students to the part or entirety of the industrial field’ s program becomes very diverse. Such the plagiarism problem is spreading more and more due to a development of Internet media. In recent years, many domestic and foreign firms have executed their business by utilizing the open source. However, many firms have increasingly used the open source for the commercial use by violating the requisites of licenses ignoring the license of open source. But, because the measures for detecting or preventing it are still insufficient, the study on the open source code plagiarism detection is required. In this paper, we propose effective open source code plagiarism detection method by using Google Code Search API. The existing method of detecting thesource code plagiarism is analyzed, and an experiment and evaluation is conducted by proposing the effective detection method and implementing the application program. Then, a conclusion and a future research development direction are explained.I. 서론 = 1 1.1 연구 배경 및 목적 = 1 1.2 연구 내용 = 2 II. 관련 기술 및 연구 동향 = 3 2.1 오픈 소스코드와 라이센스 = 3 2.2 표절 탐지 기법 = 8 2.3 오픈 소스 탐지 기술 = 14 III. 오픈 소스코드 표절 탐지 기법 = 18 3.1 전처리 과정 = 19 3.2 Google 코드 검색 Data API 요청 및 응답결과 = 24 IV. 시스템 구현 = 25 4.1 시스템 구성 = 25 4.2 시스템 메소드 = 27 4.3 실행 = 29 4.4 성능평가 = 32 V. 결론 및 향후 과제 = 34 참고문헌 = 36 ABSTRACT = 3

간세포암에서의 YAP/TAZ 발현정도와 간세포암에 YAP/TAZ 저해가 미치는 효과

Hepatocellular carcinoma is the most common malignancy in liver cancer and is the second leading cause of death worldwide. Despite surgical resection of early stage HCC, recurrence rate is high and prognosis is poor. Hippo signaling is a tumor suppressive pathway and its inactivation leads to tissue overgrowth and tumorigenesis via YAP- and TAZ- mediated transcriptional activation. Here, I investigated the expression levels of YAP and TAZ in patient-derived HCC tissue and identified the effects of YAP/TAZ inhibition depending on the baseline YAP/TAZ expression when combined with sorafenib using patient-derived multicellular tumor spheroid (MCTS) model. HCC tissue was obtained from surgical resection of HCCs and YAP/TAZ expression was analyzed using western blot. Primary HCC cell lines were established from patient-derived tissue. I selected six patient-derived HCC cell lines according to YAP/TAZ expression and they were classified into three groups depending on the YAP/TAZ expression on western blot: high, medium, low. Then, I generated multicellular tumor spheroid (MCTS) by mixing patient-derived HCC cells and stroma cells (LX2, WI38, and HUVECs) at a 3:1:1:1 ratio in ultra-low attachment plates. I assessed the YAP/TAZ expression from protein extracted from MCTS. TAZ expression was major in monolayer HCCs (2D culture) and YAP expression shown from tissue western blot reappeared in MCTS. I analyzed the cell viability upon 48hours of following drug treatment: sorafenib, sorafenib with CA3 0.1μM, and CA3 (novel YAP1 inhibitor). We confirmed that out of six patient-derived HCC cell lines, cell lines with high YAP/TAZ expression at MCTS level responded more sensitively to the combination therapy (Sorafenib + CA3 0.1μM) despite potent cytotoxic effect of CA3 exhibited in all of the patient-derived HCCs. MCTS with medium or low YAP/TAZ expression did not show difference in drug sensitivity: sorafenib vs. sorafenib combined with CA3 0.1µm. In conclusion, targeting YAP/TAZ inhibition using novel YAP1 inhibitor CA3 could be a promising therapeutic strategy to enhance sensitivity to sorafenib especially in HCCs with high YAP/TAZ expression at MCTS. 간세포암은 전세계에서 두번째로 흔한 암 사망원인이다. 조기 간세포암의 치료는 국소적 치료나 수술적 간절제이며, 간절제에도 재발의 위험은 높으며 예후는 불량하다. Hippo signaling은 종양억제 신호기전으로 이 신호기전이 억제될 때 YAP과 TAZ 활성화를 통한 암발생에 기여한다고 알려져 있다. YAP/TAZ를 표적으로 암치료제에 대한 연구가 이루어지고 있으며, 효과가 있다고 알려져 있다. YAP 발현정도가 불량한 예후 및 약물저항성과도 연관이 있어, 환자들의 간암조직의 YAP/TAZ 발현 정도가 약물저항성에 영향을 미칠 것이란 가정하 YAP/TAZ 저해제인 CA3를 기존 간암치료제인 소라페닙과 병합하여 약물처리를 하여 YAP/TAZ 저해제가 YAP/TAZ발현정도에 따라 약물저항성 극복에 미치는 영향을 연구하였다. 수술적으로 절제하여 얻은 환자들의 간암조직을 이용하여 간암조직에서의 YAP/TAZ 단백질 발현정도를 확인하였다. 간암조직으로부터 간암세포를 분리하여 환자유래 간암세포와 간주위 기질세포(LX2, WI38, HUVEC)를 동시에 배양하여 실제 간암의 환경을 잘 구현하는 환자유래 multicellular tumor spheroid model (MCTS)를 구축하였다. 2D culture 간암세포와 MCTS(3D culture)에서 2D에서는 발현되지 않은 YAP이 MCTS(3D)에서는 발현되는 것을 확인하였다. 이는 2D에서의 YAP/TAZ발현이 실제 간암에서 발현되는 것과의 차이가 있음을 확인시키고 간암세포뿐 아니라 주위기질세포와의 상호작용이 실제 종양환경에 중요함을 말해준다. YAP/TAZ 발현정도를 YAP/TAZ 단백질 발현의 높고 낮음에 따라 고발현, 중간발현, 저발현군으로 구분하여 소라페닙 단독, CA3 단독요법의 약물반응을 확인하였고, 그 결과 CA3단독요법에는 YAP/TAZ 발현정도와 무관하게 매우 잘 반응하는 것을 확인하였다. YAP/TAZ 고발현군에서 소라페닙과 CA3 0.1 병합요법이 소라페닙 단독치료에 비해 약물반응성이 증가한데 반해 YAP/TAZ 저발현군이나 중간발현군에서는 차이가 없었다. 환자유래 간암세포를 이용하여 MCTS를 구축하였고, 이를 이용하여 CA3를 이용한 YAP/TAZ 저해가 YAP/TAZ 고발현 MCTS에서 소라페닙의 약물반응성을 증가시켰다.open박

YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation

Background and aims: HCC is the most predominant type of liver cancer affecting 800,000 people globally each year. Various small-molecule compounds targeting diverse oncogenic signaling pathways have been tested for patients with HCC, and clinical outcomes were not satisfactory. In this study, we investigated molecular signaling that determines the efficiency of drug delivery into HCC. Approach and results: Hydrodynamics-based transfection (HT) was performed to develop mouse models for HCC induced by various oncogenes. Mice bearing liver cancer were treated with verteporfin at 5 weeks after HT. Multicellular HCC organoid (MCHO) models were established that contained various types of stromal cells, such as hepatic stellate cells, fibroblasts, and endothelial cells together with HCC cells. Tumor organoids were treated with verteporfin, and distributions of the drug in the organoids were assessed using fluorescence microscopy. Murine HCC models developed by HT methods showed that a high Yes-associated protein/Transcriptional co-activator with PDZ-binding motif (YAP/TAZ) activity in HCC cells impaired verteporfin penetration into the cancer. Activation of tumor stroma was observed in HCC with a high YAP/TAZ activity. Consistent with the findings in the in vivo models of HCC, MCHOs with activated YAP/TAZ signaling showed stromal activation and impaired penetration of verteporfin into the tumor organoids. Inhibition of YAP/TAZ transcriptional activity in HCC cells significantly increased drug penetration into the MCHO. Conclusions: Drug delivery into liver cancer is impaired by YAP/TAZ signaling in tumor cells and subsequent activation of stroma by the signaling. Disrupting or targeting activated tumor stroma might improve drug delivery into HCC with an elevated YAP/TAZ activity.restrictio