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

Incidence and risk factors of readmission after esophagectomy for esophageal cancer

Background: The Esophageal Complications Consensus Group (ECCG) recommends that readmission to a primary or secondary hospital within 30 days of discharge after esophagectomy is an important quality outcome indicator for esophagectomy. This retrospective study was performed to investigate the incidence and risk factors for readmission after esophagectomy. Methods: We retrospectively reviewed 291 patients who received an esophagectomy and mediastinal lymphadenectomy for curative purposes from January 2006 to June 2017. Results: The mean age was 63.02±8.02 years, and there were 264 (90.7%) male patients. Thirty-nine (13.4%) patients were re-admitted within 30 days after discharge. The mean interval from discharge to the readmission was 13.46±9.36. Common causes of readmission were anastomotic stricture that required ballooning (12, 30.7%), wound problem (7, 17.9%), pneumonia (6, 15.4%), and poor oral intake (4, 10.2%). Other causes of readmission were delayed gastric emptying [3], jejunostomy tube problem [2], ileus [2], pain [1], pneumothorax [1], and pleural effusion [1]. On multivariable analysis, anastomotic leakage (odd ratio =2.884, P=0.026) was significantly related to readmission, whereas age, pathologic stage, vocal cord palsy, and neoadjuvant therapy were not related to readmission. Conclusions: Readmission within 30 days after esophagectomy was determined to be related to postoperative anastomotic leakage and wound problems whereas the vocal cord palsy was not.ope

Measuring Surrogate Safety Measures of Individual Vehicles Using RTK-DGPS

학위논문 (석사)-- 서울대학교 대학원 : 건설환경공학부, 2015. 2. 고승영.교통 관련 인적손실과 물적손실이 발생함에 따라, 대다수의 통행이 발생하는 도로교통에서의 안전에 관한 관심이 계속 되어왔다. 도로교통을 운영함에 있어서 각 구간 및 지점에 대한 사전, 사후 조치를 취하기 위하여 도로 구간 상의 위험을 측정하고자 하는 노력의 일환으로 traffic conflict techniques (TCT) 의 도입 이후 지속적으로 발전되어온 차량 주행과 관련한 안전연구 중에서도 surrogate safety measure(SSM)를 이용하여 도로상의 위험을 측정하는 방식은 사고의 직접적인 원인과 연관된 차량의 거동을 분석 대상으로 한다는 장점을 가지고 있다. 그러나 한 지점에 국한된 정보를 이용하기 때문에 위험을 연속적으로 분석하는 데에 제약이 있다. 안전대리변수를 측정하는 데에 제기 되는 문제들로서는 차량궤적을 파악하는 데 있어서의 용이성, 측정결과의 정밀도 및 현실성과 관련한 문제들이 있다. 이러한 문제들 때문에 안전대리변수를 측정하고자 하는 연구에서는 시뮬레이션을 이용한 방법을 주로 사용하여왔으며, 영상처리방식을 이용한 측정이 주를 이루었다. 이러한 기존 측정방법들의 한계를 극복하기 위해 본 연구에서는 RTK-DGPS를 이용하여 time-to-collision(TTC), deceleration rate to avoid collision(DRAC), acceleration noise(AN) 등의 안전대리변수를 측정하는 데에 필요한 문제들을 고려한 방법론을 설정하였다. 본 연구에서는 4차간의 실험을 통해 연속류도로에서의 주행안전도를 알기 위한 안전대리변수를 측정방법론을 수립하였다. 동부간선도로에서의 돌발통계를 활용하여 선정된 월계1교~녹천교, 노원교~수락지하차도 구간과 5년간 고속도로 교통사고 속보자료를 이용하여 선정된 사고다발구간과 대조구간인 영동고속도로 북수원IC-부곡IC, 동군포IC-군포IC를 대상으로 개별 실험차량의 정밀한 궤적자료를 추출하였다. 추출된 궤적자료를 통해 안전대리변수를 측정한 실험을 수행한 결과를 제시하였으며, 돌발통계와 사고자료에 의한 위험구간으로 선정된 구간에서 대조구간 대비 안전대리변수의 변동성이 큰 것으로 나타났다. 이와 관련 기존문헌 결과와의 비교를 통해 본 측정방법론의 함의를 검토하고자 하였다. 본 연구는 향후 다양한 구간 특성 및 운전자 특성에 따른 위험상황을 설명하는 연구와, 위험구간 감지 및 위험한 운전행태의 감지를 통한 사고예방에 활용될 수 있을 것으로 판단된다.제1장 서론 1 1.1 연구의 배경 및 목적 1 1.2 연구의 구성 4 제2장 선행연구 검토 5 2.1 안전대리변수의 개발 5 2.1.1 Time-to-collision (TTC) 8 2.1.2 Deceleration Rate to Avoid Collision 9 2.1.3 Acceleration Noise 10 2.2 안전대리변수의 측정방법 11 2.2.1 시뮬레이션을 이용한 차량궤적자료 구득 13 2.2.2. 실측을 통한 차량궤적자료 구득 15 2.3 선행연구 시사점 및 본 연구와의 차별성 16 제3장 연구 방법론 18 3.1 측정방법론 검토 18 3.1.1 측정장비 특성 18 3.1.2 본 연구의 측정방법론 제시 21 3.2 RTK-DGPS 장비활용 실험설계 25 3.2.1. 1차 실험 25 3.2.2. 2차 실험 26 3.2.3. 3차 실험 28 3.2.4. 4차 실험 31 3.3. RTK-DGPS 활용 실험 수행 34 3.3.1. 1차 실험 34 3.3.2. 2차 실험 34 3.3.3. 3차 실험 36 3.3.4. 4차 실험 37 3.4 수집 자료 처리 41 3.4.1 자료의 일관성 확인 41 3.4.2 속도 자료의 Data Cleaning 기법 43 3.5 RTK-DGPS 궤적자료를 이용한 안전대리변수 계산 44 3.5.1 Time-to-Collision (TTC) 44 3.5.2 Deceleration Rate to Avoid Collision (DRAC) 45 3.5.3 Aceleration Noise (AN) 46 제4장 분석 결과 47 4.1. 경부고속도로 분석 실험 (2차) 47 4.1.1 TTC 측정 결과 48 4.1.2. 가속소음 측정결과 49 4.1.3. DRAC 측졍결과 51 4.2. 동부간선도로 분석 결과(3차) 52 4.2.1. TTC 분석 결과 54 4.2.2. 가속소음 분석 결과 58 4.2.3. DRAC 분석 결과 60 4.3 영동고속도로 실험(4차) 62 4.3.1 TTC 분석 결과 62 4.3.2. 가속소음 산출결과분석 66 4.3.3. DRAC 산출결과분석 69 4.4 종합분석 70 4.4.1. 동부간선도로(3차 실험) 의정부 방향 종합분석 70 4.4.2. 영동고속도로(4차 실험) 인천방향 종합분석 71 4.4.3. 영동고속도로(4차 실험) 강릉방향 종합분석 73 5장 결론 및 향후 연구과제 75 참고문헌 77 Abstract 81Maste

Prognostic Significance of EDIL3 Expression and Correlation with Mesenchymal Phenotype and Microvessel Density in Lung Adenocarcinoma

We examined the prognostic significance of Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3) expression and its correlations with mesenchymal phenotype and microvessel density in non-small cell lung carcinoma (NSCLC). A total of 268 NSCLC specimens were evaluated retrospectively by immunohistochemical staining for EDIL3, EMT markers (e-cadherin, β-catenin, and vimentin), and CD31 to measure microvessel density. EDIL3, e-cadherin, β-catenin, and vimentin were expressed in 16%, 22.8%, 3.7%, and 10.1% of the specimens, respectively. The mRNA level of EDIL3 in tumor was correlated with the level of EDIL3 protein expression using immunohistochemistry. In lung adenocarcinoma patients, EDIL3 expression was significantly correlated with low e-cadherin expression, high vimentin expression, and increased microvessel density (P < 0.001, P = 0.001, and P = 0.023, respectively). In lung squamous cell carcinoma patients, EDIL3 expression was significantly correlated with low e-cadherin expression and high vimentin expression (P = 0.021 and P = 0.002, respectively). In lung adenocarcinoma patients, EDIL3 was an independent prognostic factor for overall survival in a multivariate analysis (hazard ratio: 2.552, P = 0.004). EDIL3 is significantly correlated with mesenchymal phenotype, angiogenesis, and tumor progression in lung adenocarcinoma.ope

Dysregulation of T FH-B-T RM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer

Patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations exhibit an unfavorable response to PD-1 inhibitor through unclear mechanisms. Hypothesizing that EGFR mutations alter tumor-immune interactions, we compare tumor-infiltrating lymphocytes between EGFR mutant (EGFR-MT) and wild type (EGFR-WT) tumors through single-cell transcriptomic analysis. We find that B cells, CXCL13-producing follicular helper CD4+ T (TFH)-like cells, and tissue-resident memory CD8+ T (TRM)-like cells decreased in EGFR-MT tumors. The NOTCH-RBPJ regulatory network, which is vital for persistence of TRM state, is perturbed, and the interactions between TFH and B cells through the CXCL13-CXCR5 axis disappear in EGFR-MT tumors. Notably, the proportion of TRM-like cells is predictive for anti-PD-1 response in NSCLC. Our findings suggest that the impairment of TFH-B-TRM cooperation in tertiary lymphoid structure formation, accompanied by the dysregulation of TRM homeostasis and the loss of TFH-B crosstalk, underlies unfavorable anti-PD-1 response in EGFR-MT lung tumors.ope

A Study on the Establishment of Standard Service Model Provided by Korea Coast Guard at Fishing Port

Many modern civilizations are doing economical activities at the ocean more frequently than ever. At home and abroad, conflicts in interests are increasing among the neighboring nations, reflecting the emphasis of ocean development, such as the acquisition of ocean resources. In addition, the demand of the K.C.G. (Korea Coast Guard) is drastically increasing due to a number of government-led ocean protection policies and the proclamation of EEZ (Exclusive Economic Zone) among Korea, China, and Japan, which brought in the expansion of administrative ocean zone. The K.C.G. comes to the center of protecting ocean sovereignty as well as supporting the value-adding process with numerous duties, such as security enhancement, environmental conservation, and resource management of the ocean. The K.C.G. is being asked to provide the fishermen, main clients of it, with the proper information management from their standpoint. As the importance of ocean resource multiplies, the demands from the clients are getting diversified and their expectations higher along with ocean activities. Therefore, The constant increase of activities in both visible and invisible forms has expanded the needs of security enforcement in the ocean. In response to the demands of security and safety in the ocean, the K.C.G. is providing the ocean security service supplying the demands in real-time by installing police stations with many subordinate branch offices along the coastal area. However, due to the limited budgets and resources available, providing high-quality security services has its limits . This research, thereby, proposes plausible direction of the standard service model of K.C.G. for the change from the operation-oriented service to the client-oriented service at the Fishing ports through the efficient allocation and distribution of the resources available. Chapter 1 describes the background, objective, scale, and the method of research, followed by Chapter 2 analyzing the current operational status of the K.C.G. by classifying the volunteer activities of fishery-related operation, security and safety security issues, environmental protection, and other public cooperation. Chapter 3 clarifies the friendly relations with the public in order to exam the fishermen's awareness of the K.C.G. based on the four main indices: the level of satisfaction, credibility, awareness and friendliness. Feasible implications were derived from the survey of the fishery workers and the analysis of those indices. Next, Chapter 4 surveys and analyzes the current, required, and demanded workloads and achievement of K.C.G. at Fishing ports by classifying its operations in 7 fields, including ocean security, then by using a calculating formula. Chapter 5 and the last chapter present a model regarding the standardization of the services at Fishing ports in terms of organization, operational resources, education, and improvement of awareness, etc. Thus, they cover the conversion of the operational system services from unit-oriented ones to client-oriented, function-oriented, and the region-oriented ones based on the result of the previous researches. This conversion has proposed the characteristics and functions of the operational, organizational model of the K.C.G. in towns and cities, which was integrated systematically and functionally. Besides, the prediction of officer education are presented, which is necessary in organizing the manpower and equipment and doing the client-oriented services to deal with the changes in security environment of the future and provide the demander-oriented security services around each police station. Also, another model is presented to promote the insufficient awareness of the operations of K.C.G. at Fishing ports. The newly developed service standard model is expected to upgrade the recognition of the Fishing port users for K.C.G., because this system can cope with the accidents and crimes more quickly and provide region-close services by turning the previous separated and unorganized operations into each regional operational unit. Furthermore, this model suggests further development of standard model by taking a regionally limited examination and analysis on current operational status, awareness and other factors. Although there is a limit to applying the currently proposed model to the entire fishing ports in the nation at this point, we can expect the great chance of establishing the customized standard model of the K.C.G.'s security service that will be able to be applied to the each Fishing port in Korea before long. And it can be accomplished by reapplying current research to larger scopes by the types of the Fishing ports, body of the water, then building the methods which make it possible to standardize the operations of the K.C.G in quality and quantity nationwide. Finally, the service standardization is expected to make more efficient the allocation of the limited resources of the K.C.G. and improve the operational efficiency.제1장 서론 = 1 1.1 연구의 배경 및 목적 = 1 1.2 연구의 범위와 방법 = 2 1.3 논문의 구성 = 3 제2장 어업관련 해양경찰 업무 개관 = 5 2.1 모델지역 = 5 2.2 모델지역의 해양경찰 = 7 2.3 어업관련 해양경찰 업무 = 7 제3장 어항에서 해양경찰 업무 현황 = 15 3.1 어항에서 해양경찰 업무량 = 15 3.1.1 의의 = 15 3.1.2 업무량 = 16 3.2 업무량 평가 = 22 제4장 어업종사자의 해양경찰 업무 친숙도 조사 = 33 4.1 친숙도 개념 = 33 4.2 조사대상 및 방법 = 34 4.3 친숙도 평가 및 분석 = 34 4.4 시사점의 도출 = 37 제5장 해양경찰서비스 표준모델 = 46 5.1 조직 모델 = 46 5.2 업무 모델 = 49 5.3 자원모델 = 56 5.4 교육모델 = 57 5.5 친숙도 향상 모델 = 59 제6장 결론 = 64 참고문헌 = 6

First Case of Esophagectomy Using a Robotic Single-Port System for Laryngo-Esophagectomy

A 58-year-old female patient was diagnosed with hypopharyngeal cancer with extension to the invasion of the upper esophagus. After 2 cycles of durvalumab as neoadjuvant therapy, total laryngo-esophagectomy using a single-port (SP) system via a subcostal incision was done. The operation was completed within 41 minutes, and the patient recovered without esophagectomy-related complications. The patient received total laryngectomy and esophagectomy using a robotic SP system via a 3-cm-long subcostal incision and gastric pull-up under laparotomy. During the postoperative period, the patient suffered from anastomotic leakage, but recovered with vacuum therapy. Here, we report the first successful human case of esophagectomy using an SP system.ope

Guidelines for Tracheostomy From the Korean Bronchoesophagological Society

The Korean Bronchoesophagological Society appointed a task force to develop a clinical practice guideline for tracheostomy. The task force conducted a systematic search of the Embase, Medline, Cochrane Library, and KoreaMed databases to identify relevant articles, using search terms selected according to key questions. Evidence-based recommendations for practice were ranked according to the American College of Physicians grading system. An external expert review and a Delphi questionnaire were conducted to reach a consensus regarding the recommendations. Accordingly, the committee developed 18 evidence-based recommendations, which are grouped into seven categories. These recommendations are intended to assist clinicians in performing tracheostomy and in the management of tracheostomized patients.ope

Initial experience with and surgical outcomes of da Vinci single-port system in general thoracic surgery

Background: The da Vinci single-port system (SPS) (Model SP1098, Intuitive Surgical Inc., Sunnyvale, CA, USA) has been used in genitourinary and general surgical procedures; however, its clinical application in general thoracic surgery has not been attempted. This retrospective study investigated the clinical outcomes of SPS in general thoracic surgery. Methods: After approval from the Ministry of Food and Drug Safety in Korea, the surgical details of SPS in simple thoracic surgeries at two independent institutions were collected and retrospectively reviewed. Results: Overall, 17 surgeries were performed using SPS without conversion to multiport surgery. The patients included six males, and the overall median age was 52 years (range, 28-83 years). The commonest pathological diagnoses were thymoma (8 cases) and benign cystic lesions (6 cases). The approach for SPS was subxiphoid, subcostal, and intercostal in 11, 4, and 2 cases, respectively. All patients underwent the surgeries without complications. The median operation time and peak pain score were 120 minutes (range, 58-250 minutes) and 3 (range, 2-4). The median duration of in situ chest tube and hospital stay was 1 day (range, 1-2 days) and 3 days (range, 2-7 days), respectively. SPS showed a shorter duration of in situ chest tube and hospital stay than robotic single-site surgeries. Conclusions: The application of SPS in the field of general thoracic surgery is feasible and can be successful. Although this study reported preliminary data and the cases were relatively simple, advanced and complex procedures should be attempted with the SPS in the near future.ope

Gene mutation discovery research of non-smoking lung cancer patients due to indoor radon exposu

Although the incidence and mortality for most cancers such as lung and colon are decreasing in several countries, they are increasing in several developed countries because of an unhealthy western lifestyles including smoking, physical inactivity and consumption of calorie-dense food. The incidences for lung and colon cancers in a few of these countries have already exceeded those in the United States and other western countries. Among them, lung cancer is the main cause of cancer death in worldwide. The cumulative survival rate at five years differs between 13 and 21 % in several countries. Although the most important risk factors are smoking for lung cancer, however, the increased incidence of lung cancer in never smokers(LCINS) is necessary to improve knowledge concerning other risk factors. Environmental factors and genetic susceptibility are also thought to contribute to lung cancer risk. Patients with lung adenocarcinoma who have never smoking frequently contain mutation within tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene. Also, K-ras mutations are more common in individuals with a history of smoking use and are related with resistance to EFGR-tyrosine kinase inhibitors. Recently, radon(Rn), natural and noble gas, has been recognized as second common reason of lung cancer. In this review, we aim to know whether residential radon is associated with an increased risk for developing lung cancer and regulated by several genetic polymorphisms.ope