Anti-cancer effects of disulfiram in head and neck squamous cell carcinoma via autophagic cell death

BACKGROUND: Disulfiram (DSF), which is used to treat alcohol dependence, has been reported to have anti-cancer effects in various malignant tumors. In this study, we investigated the anti-cancer effects and mechanism of DSF in HNSCC. METHODS: Head and neck squamous carcinoma cell lines (FaDu and Hep2) were used to analyze the anti-cancer effects of DSF. The anti-cancer effects of DSF were confirmed in vivo using a xenograft tumor model. RESULTS: The anti-cancer effects of DSF in HNSCC were found to be copper (Cu) dependent. Specifically, DSF/Cu markedly inhibited HNSCC at a concentration of 1 μM. After DSF/Cu administration, production of reactive oxygen species (ROS) was remarkable starting at 0.5 μM, suggesting that the inhibitory effects of DSF/Cu on HNSCC are mediated through the formation of ROS. The levels of phospho-JNK, phospho-cJun and phospho-p38 were increased after DSF/Cu treatment while levels of phospho-Akt were decreased. These results suggested that the inhibitory effects of DSF/Cu on HNSCC cells involve ROS formation and down-regulation of Akt-signaling. Through these molecular mechanisms, DSF ultimately induce the inhibitory effects on HNSCC cell lines mainly through autophagic cell death, not apoptotic cell death. Lastly, we investigated the clinical relevance of DSF/Cu using a HNSCC xenograft animal model, which showed that tumor growth was remarkably decreased by DSF (50 mg/kg injection). CONCLUSION: In treating patients with HNSCC, DSF may contribute to improved HNSCC patient's survival. The characteristic anti-cancer effects of DSF on HNSCC may suggest new therapeutic potential for this medication in HNSCC patients.ope

Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer

BACKGROUND: T cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T cell exhaustion could serve as potential targets for delaying the process and improving ICI efficacy. METHODS: We analyzed the single-cell transcriptome data derived from human melanoma and non-small cell lung cancer (NSCLC) samples and classified the tumor-infiltrating (TI) CD8+ T cell population based on PDCD1 (PD-1) levels, i.e., PDCD1-high and PDCD1-low cells. Additionally, we identified differentially expressed genes as candidate factors regulating intra-tumoral T cell exhaustion. The co-expression of candidate genes with immune checkpoint (IC) molecules in the TI CD8+ T cells was confirmed by single-cell trajectory and flow cytometry analyses. The loss-of-function effect of the candidate regulator was examined by a cell-based knockdown assay. The clinical effect of the candidate regulator was evaluated based on the overall survival and anti-PD-1 responses. RESULTS: We retrieved many known factors for regulating T cell exhaustion among the differentially expressed genes between PDCD1-high and PDCD1-low subsets of the TI CD8+ T cells in human melanoma and NSCLC. TOX was the only transcription factor (TF) predicted in both tumor types. TOX levels tend to increase as CD8+ T cells become more exhausted. Flow cytometry analysis revealed a correlation between TOX expression and severity of intra-tumoral T cell exhaustion. TOX knockdown in the human TI CD8+ T cells resulted in downregulation of PD-1, TIM-3, TIGIT, and CTLA-4, which suggests that TOX promotes intra-tumoral T cell exhaustion by upregulating IC proteins in cancer. Finally, the TOX level in the TI T cells was found to be highly predictive of overall survival and anti-PD-1 efficacy in melanoma and NSCLC. CONCLUSIONS: We predicted the regulatory factors involved in T cell exhaustion using single-cell transcriptome profiles of human TI lymphocytes. TOX promoted intra-tumoral CD8+ T cell exhaustion via upregulation of IC molecules. This suggested that TOX inhibition can potentially impede T cell exhaustion and improve ICI efficacy. Additionally, TOX expression in the TI T cells can be used for patient stratification during anti-tumor treatments, including anti-PD-1 immunotherapy.ope

사설시조의 주제구현 방식 연구

2011년 8월 고전문학 석사학위 논문, 지도교수 조해숙 선생

공정거래위원회를 중심으로

학위논문 (석사) -- 서울대학교 대학원 : 융합과학기술대학원 수리정보과학과, 2021. 2. 이병영.With the rapid development of information and communication technology, digital devices have become an important tool in modern civilization. All data and information are produced and distributed by digital devices, and added value is created through storage and analysis based on digital information. The amount of information produced in the cyber world is exploding beyond imagination as it has recently entered the fourth industrial revolution through the information age. The changes are affecting the methods of investigations by law-regulated bodies such as the prosecution, police, the National Tax Service and the Fair Trade Commission. And for the Fair Trade Commission, which investigates unfair trade practices by companies, so-called collusion, the change is more acute. All information produced by a company is digitalized electronic information, and existing document documents and work logs have long disappeared. Thus, the Fair Trade Commission's investigation has changed to focus on the investigation of digital information. However, the investigation into digital information still has the potential to have side effects that could expose the business secrets of the entity, personal privacy, etc., depending on the method, size, and procedure. In order to minimize such side effects and to strengthen the ability to investigate digital information, the Fair Trade Commission is responding organically by strengthening specialized organizations composed of experts. Digital evidence can be understood to be valuable evidence among digital information. Screening is the most important process that should be addressed in order to prevent the possibility of side effects described above, among cycles from collecting to disposing of digital evidence. In addition, given the increasing trend in the amount and scope of data surveyed, there is a concern that comprehensive collection is likely to involve side effects, although the need for comprehensive collection is greater than for selective collection. This study began with the Fair Trade Commission's consideration of how the comprehensive collection conducted in the course of conducting an administrative investigation to check whether there were any violations of the relevant laws and regulations, and the results of the study recognized the limitations of the keyword analysis methods used mainly in the analysis of digital evidence during the comprehensive collection process and the need for measures to strengthen the management of evidence and guarantee the right to participate in the investigation companies in the process of selecting digital evidence according to the relevance of the case. Based on these limitations and needs, the Fair Trade Commission plans to improve its digital evidence collection and screening procedures. First, we proposed a remote screening framework to expand the right of the subjects to participate. Second, the measure was proposed to grant access to information that could harm the legal interests of the employees of the investee and its employees through comprehensive collection. Third, phased screening of digital evidence was proposed. This paper means that by redefining the procedures of collection and screening steps during the process of processing digital evidence by the Fair Trade Commission, and thus proposing measures to guarantee the right of participation of the subjects, the Fair Trade Commission can strengthen the internal stability of the management of evidence data in the investigation process, and the opportunity for the suspect to participate in the process of processing evidence data is expanded.정보통신기술의 급격한 발전에 따라 현대 문명에서 디기털기기는 빼놓을 수 없는 중요한 도구가 되었다. 모든 자료와 정보는 디지털기기에 의해 생산, 유통되고, 디지털정보의 저장, 분석을 통해 부가가치가 창출되고 있다. 정보화시대를 거쳐 최근 4차 산업 혁명시대에 돌입하면서 사이버 세계에서 생산되는 정보의 양은 상상할 수 없을 만큼 폭발적으로 증가하고 있다. 이러한 변화는 공정위, 검찰, 경찰 및 국세청 등 법률에서 규제하는 행위에 대한 조사를 통해 사실관계를 밝혀야하는 기관의 조사 방법에도 영향을 주고 있다. 특히 기업을 대상으로 불공정거래행위, 부당한 공동행위 등을 조사하는 공정거래위원회의 경우 이러한 변화를 더욱 급격하게 체감할 수 밖에 없다. 기업에서 생산되는 모든 정보는 디지털화된 전자정보이고, 기존의 서류문서나 업무일지 등은 사라진 지 오래되었다. 따라서 공정거래위원회의 조사는 디지털정보에 대한 조사 위주로 변화하게 되었다. 그러나 디지털정보에 대한 조사는 그 방법과 규모, 절차 등에 따라서 기업의 영업기밀, 개인의 프라이버시 등이 노출되는 부작용이 발생할 가능성도 상존한다. 이러한 부작용을 최소화하고, 디지털정보에 대한 조사 역량을 강화화기 위하여 공정거래위원회는 전문가로 구성된 전문 조직을 강화하는 등 유기적으로 대응하고 있다. 디지털증거는 디지털정보 중 증거 가치가 있는 것으로 이해할 수 있다. 디지털증거를 수집부터 폐기까지의 사이클 중에서 위에서 기술한 부작용이 발생할 수 있는 가능성을 차단하기 위해 가장 중요하게 다뤄져야하는 과정이 디지털증거의 선별절차이다. 또한 조사 대상 자료의 양과 범위가 늘어나는 추세를 볼 때 선별수집보다 포괄수집의 필요성이 커지고 있지만 포괄수집의 경우 부작용을 수반할 가능성이 커지는 우려가 있다. 본 연구는 공정거래위원회가 소관 법령에 위반한 행위가 있는지 여부를 확인하기 위하여 행정조사를 실시하는 과정에서 행해지는 포괄수집이 적절하게 운영될 수 있는 방안에 대한 고민으로부터 시작되었으며, 연구결과 포괄수집 과정에서 대면 선별 절차의 한계점과 피조사인의 의사와는 상관없이 사건과 무관한 기업의 영업비밀이나 피조사인의 소속 임직원의 프라이버시와 관련된 자료에 대한 처리 방안을 강화할 필요성, 포괄수집에 의해 확보한 디지털정보들 중에서 사건관련성이 있는 디지털증거만을 수집하기 위한 선별 시 주요 증거들이 사장될 수 있는 문제점을 인식하였다. 이러한 한계점, 필요성 및 문제점을 기초로 공정거래위원회의 디지털증거 수집 및 선별 절차를 개선하기 위한 방안으로 첫째, 원격 선별 프레임워크를 제안하여 피조사인의 참여권을 확대하는 방안을 모색하였고, 둘째, 포괄수집으로 인해 피조사인과 피조사인의 소속 임직원들의 법익을 해할 수 있는 정보에 대한 접근제한권한을 피조사인에게 부여하는 방안을 제안하였으며, 셋째, 디지털증거의 단계적 선별 방안을 제안하였다. 본 논문은 공정거래위원회가 디지털증거를 처리하는 과정 중 수집 및 선별 단계의절차를 재정립하고, 그에 따라 피조사인의 참여권 보장방안을 제안함으로써 공정거래위원회는 조사 과정에서 증거자료 관리의 내실을 강화할 수 있고, 피조사인은 증거자료 처리 과정의 참여 기회가 확대된다는 데 그 의의가 있다.목 차 제1장 서론 1 제2장 디지털증거의 특성 4 제1절 디지털증거의 개념 4 제2절 디지털증거의 특성 5 1. 매체독립성 5 2. 비가시성 비가독성 6 3. 취약성 6 4. 대용량성 7 5. 전문성 8 6. 네트워크 관련성 8 제3절 디지털증거의 증거능력 8 1. 동일성 9 2. 무결성 10 3. 진정성 11 4. 신뢰성 12 제3장 공정거래위원회 사건 처리의 개관 13 제1절 공정거래위원회의 연혁 13 제2절 공정거래위원회의 성격 및 권한 14 제3절 공정거래위원회 사건 처리 절차 16 1. 사건의 인지 17 2. 사전심사 18 3. 심사착수 후 조사 및 심사 19 4. 안건상정 19 5. 심의 준비 20 6. 위원회 심의 및 의결 21 7. 처분에 대한 불복절차 22 제4절 공정거래위원회 사건조사 22 제5절 공정거래위원회의 디지털포렌식 24 1. 디지털포렌식 관련 법제 24 2. 공정거래위원회의 디지털증거 수집 관련 규정 25 3. 선별수집 27 4. 포괄수집 28 5. 디지털증거 포괄수집의 중요성 29 제4장 디지털증거 포괄수집의 쟁점 31 제1절 디지털증거 수집에 대한 피조사인의 참여권 보장 문제 31 제2절 피조사인의 법익 침해 가능성 32 제3절 사건 관련성 판단상 쟁점 33 제5장 디지털 증거 선별 절차의 개선 방안 35 제1절 디지털증거 선별 방법 확대 35 제2절 디지털정보 접근 제한권 부여 38 제3절 디지털증거의 단계적 선별 방안 40 제6장 결론 42 참고문헌 44 Abstract 46Maste

이하선 암 치료에서 이하선 절제술의 범위, 경부 절제술 및 보조 방사선 치료의 적응증

This paper analyzed previous research data to identify the most important issues to be considered during treatment of parotid gland cancer (PGC) and reviewed recent advancements in techniques in parotid surgery. For successful treatment of PGC, a preoperative surgical plan should be designed with consideration of the histologic characteristics and anatomical complexity of the tumor, and the functional and anatomical integrity of the facial nerve should be carefully inspected during surgery and damage to the nerve minimized. The need for adjuvant radiotherapy should be determined based on intraoperative findings and pathologic findings of the specimen after surgery. To optimize treatment outcomes for PGC, the extent of surgery and adjuvant radiotherapy should be decided according to histologic characteristics and risk stratification.ope

Incidence of Acute Endophthalmitis after Intravitreal Antivascular Endothelial Growth Factor Injection in Age-related Macular Degeneration

Purpose: Antivascular endothelial growth factor (anti-VEGF) agents are routinely intravitreously injected to treat neovascular age-related macular degeneration (AMD). Postoperative endophthalmitis, a side effect after intravitreal anti-VEGF injection, has been reported to have a low incidence but may threaten vision. In this study, we aimed to analyze the incidence of acute endophthalmitis after intravitreal anti-VEGF injection and associated risk factors in patients with neovascular AMD in South Korea. Methods: Using the health claims data recorded in the Korean National Health Insurance System database, we identified newly developed neovascular AMD cases from 2010 through 2019. Acute endophthalmitis was defined as a case of invasive treatment for accompanying symptoms. All statistical analyses were performed with a significance level p < 0.05. To find risk factors, we used univariate and multivariable Poisson regression. Results: The overall incidence of acute endophthalmitis was 0.019% (p = 0.21) during the 10-year period: 0.025% for aflibercept injection and 0.014% for ranibizumab injection. The incidence was higher in metropolitan city residents than in Seoul (incidence rate ratio [IRR], 1.96; 95% confidence interval [CI], 1.02-3.79; p = 0.04) and was higher for aflibercept injections than for ranibizumab injections (IRR, 1.82; 95% CI, 1.17-2.82; p = 0.01). However, in multivariate analysis, only aflibercept injections showed a significant effect on the incidence of acute endophthalmitis (IRR, 1.80; 95% CI, 1.16-2.79; p = 0.01). Conclusions: The incidence of acute endophthalmitis after intravitreal anti-VEGF injections was generally low, and aflibercept was revealed as a significant risk factor.ope

Guidelines for the Surgical Management of Oral Cancer: Korean Society of Thyroid-Head and Neck Surgery

Korean Society of Thyroid-Head and Neck Surgery appointed a Task Force to provide guidance on the implementation of a surgical treatment of oral cancer. MEDLINE databases were searched for articles on subjects related to "surgical management of oral cancer" published in English. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. The quality of evidence was rated with use RoBANS (Risk of Bias Assessment Tool for Nonrandomized Studies) and AMSTAR (A Measurement Tool to Assess the Methodological Quality of Systematic Reviews). Evidence-based recommendations for practice were ranked according to the American College of Physicians grading system. Additional directives are provided as expert opinions and Delphi questionnaire when insufficient evidence existed. The Committee developed 68 evidence-based recommendations in 34 categories intended to assist clinicians and patients and counselors, and health policy-makers. Proper surgical treatment selection for oral cancer, which is directed by patient- and subsite-specific factors, remains the greatest predictor of successful treatment outcomes. These guidelines are intended for use in conjunction with the individual patient's treatment goals.ope

Machine learning-based prediction model using clinico-pathologic factors for papillary thyroid carcinoma recurrence

This study analyzed the prognostic significance of clinico-pathologic factors, including the number of metastatic lymph nodes (LNs) and lymph node ratio (LNR), in patients with papillary thyroid carcinoma (PTC), and attempted to construct a disease recurrence prediction model using machine learning techniques. We retrospectively analyzed clinico-pathologic data from 1040 patients diagnosed with PTC between 2003 and 2009. We analyzed clinico-pathologic factors related to recurrence through logistic regression analysis. Among the factors that we included, only sex and tumor size were significantly correlated with disease recurrence. Parameters such as age, sex, tumor size, tumor multiplicity, ETE, ENE, pT, pN, ipsilateral central LN metastasis, contralateral central LNs metastasis, number of metastatic LNs, and LNR were input for construction of a machine learning prediction model. The performance of five machine learning models related to recurrence prediction was compared based on accuracy. The Decision Tree model showed the best accuracy at 95%, and the lightGBM and stacking model together showed 93% accuracy. Among those factors mentioned above, LNR and contralateral LN metastasis were used as important features in all machine learning prediction models. We confirmed that all machine learning prediction models showed an accuracy of 90% or more for predicting disease recurrence in PTC. LNR and contralateral LN metastasis were used as important features for constructing a robust machine learning prediction model. In the future, we have a plan to perform large-scale multicenter clinical studies to improve the performance of our prediction models and verify their clinical effectiveness.ope

Surgical Outcomes of Sialendoscopy-Assisted Approaches for Removal of Parotid Gland Stones

Background and Objectives With the introduction of sialendoscopy, minimal invasive surgery has become possible for the removal of sialoliths, although sialendoscopic removal of parotid stones remains a surgical challenge. Sialendoscopic stone removal can be differently applied according to the location and size of stones. This study was conducted to evaluate the surgical outcomes of sialaendoscopic stone removal and to provide a strategy for choosing an adequate surgical approach according to the characteristics of parotid stones. Subjects and Method A retrospective study was conducted of 43 patients with parotid sialolithiasis who were treated by sialendoscopic stone removal between March 2017 and January 2021. Surgical techniques were classified into sialendoscopy alone (SA), sialendoscopy-assisted transoral approach (STO), and sialendoscopy-combined retroauricular approach (SRA). The parotid gland stones were categorized by size, location, and multiplicity. Results Of the 43 patients, 13 patients underwent SA, 10 received STO, and 20 were treated with different SRA approaches. The SRA approaches included three distal, seven proximal, and ten intraglandular stone removal cases. The success rate of stone removal was 92% (12 cases) by SA, 90% (9 cases) by STO, and 100% (20 cases) by SRA. In cases of SA and STO, all patients had distant stones except for one who had proximal stones. Postoperative complications including pain, swelling, wound dehiscence, sialocele, duct stricture, and facial palsy mainly occurred in cases treated with SRAs. Conclusion Appropriate use of various sialendoscopy-assisted approaches is mandatory to preserve the gland and minimize surgical complications in patients with different features of parotid gland stones.ope

Survival Benefits From Surgery for Stage IVa Head and Neck Squamous Cell Carcinoma: A Multi-institutional Analysis of 1,033 Cases

Objectives: Head and neck squamous cell carcinomas (HNSCs) are frequently diagnosed at the locoregional advanced stage (stage IVa), but controversy remains regarding whether stage IVa HSNCs should be treated with upfront surgery or definitive chemoradiation therapy (CRT). The purpose of this study was to compare overall survival (OS) and disease-free survival (DFS) in patients with stage IVa HNSC treated primarily by surgery with curative intent with/without (neo)adjuvant treatment (surgery group) versus those treated primarily with CRT (CRT group). Methods: We reviewed data of 1,033 patients with stage IVa HNSC treated with curative intent at 17 cancer centers between 2010 and 2016. Results: Among 1,033 patients, 765 (74.1%) received upfront surgery and 268 (25.9%) received CRT. The 5-year OS and DFS rates were 64.4% and 62.0% in the surgery group and 49.5% and 45.4% in the CRT group, respectively. In multivariate analyses, OS and DFS were better in the surgery group than in the CRT group (odds ratio [OR] for death, 0.762; 95% confidence interval [CI], 0.592-0.981; OR for recurrence, 0.628; 95% CI, 0.492-0.802). In subgroup analyses, the OS and DFS of patients with oropharyngeal cancer were better in the surgery group (OR for death, 0.548; 95% CI, 0.341-0.879; OR for recurrence, 0.598; 95% CI, 0.377-0.948). In the surgery group, patients with laryngeal cancer showed better OS (OR for death, 0.432; 95% CI, 0.211-0.882), while those with hypopharyngeal cancer DFS was improved (OR for recurrence, 0.506; 95% CI, 0.328-0.780). Conclusion: A survival benefit from surgery may be achieved even in patients with stage IVa HNSC, particularly those with oropharyngeal and laryngeal cancer. Surgery led to a reduction in the recurrence rate in patients with hypopharyngeal cancer.ope