상지 웨어러블의 압력 감소를 위한 힘 프로파일과 모멘트암 구조 개발

학위논문 (석사)-- 서울대학교 대학원 : 공과대학 기계공학과, 2019. 2. 조규진.As many occupations such as car mechanics, orchardists, and laparoscopic surgeons require prolonged and repetitive use of their upper body, the prevalence of musculoskeletal disorder in shoulder is particularly high among these professionals. However, a weight compensation of upper extremity can reduce the burden borne by the shoulder. There have been several researches on wearable solutions with rigid structures that reduce the upper limb fatigue, but a user can further benefit with minimal intrusion of workspace and safer interaction when the soft counterpart is applied. As tendon actuation is one of the popular choices among soft wearable robots, the intrinsic issue of axial compression due to the size of the moment arm needs to be addressed. In this paper, a method to reduce the tension-induced compression in upper body soft wearable device is proposed. Unlike the constant moment arm modelling assumed in the previous upper limb wearable device, the added structure on the shoulder increases the moment arm, thus significantly decreasing the tension and compression on anchored region while generating the equal amount of torque. The proposed quasi-zero stiffness mechanism generates a steady tension force which produces resulting sinusoidal torque when coupled with the new moment arm structure.List of Contents Abstract ……………………………………………………i Contents …………………………………………………..iii List of Figures …………………………………………...iv Chapter 1. Introduction …………………………….…1 Chapter 2. Design of Moment Arm Structure ……...4 Chapter 3. Force Generating Mechanism ………….10 Chapter 4. Evaluation ……………………………….13 Part 1. Theoretical …………………………..13 Part 2. Experimental …………………………15 Chapter 5. Conclusion ……………………………….18Maste

담도계암에서 젬시타빈 치료 반응 예측 바이오마커로서의 hENT1

학위논문(박사)--서울대학교 대학원 :의과대학 의학과,2020. 2. 김용태.Background: Gemcitabine is one of the main chemotherapeutic agents for biliary tract cancer (BTC). Expression of human equilibrative nucleoside transporter 1 (hENT1) is considered as a potential predictive biomarker for a gemcitabine response in several cancers. This study aimed to investigate the association between hENT1 expression and the effects of gemcitabine on BTC cell lines and on patients with advanced BTC receiving gemcitabine-based chemotherapy. Methods: Four BTC cell lines, HuCCT1, SNU-478, SNU-1079, and SNU-1196, were tested in this study. mRNA and protein expression levels of hENT1 were measured by quantitative reverse-transcription polymerase chain reaction and western blotting, respectively. Cell viability after gemcitabine treatment was measured in a chemosensitivity assay. For clinical assessment, 40 patients with unresectable or recurrent BTC who were treated with gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) between June 2012 and May 2014 were enrolled. Results: Among the four cell lines, SNU1196 showed the highest mRNA and protein levels of hENT1. Expression of hENT1 had a linear correlation with the log value of the half-maximal inhibitory concentration of gemcitabine. During incubation with gemcitabine, pretreatment with hENT1-specific small interfering RNA (siRNA) resulted in higher cell viability than that in samples pretreated with control siRNA. In a clinical evaluation, there were 22 intrahepatic cholangiocarcinoma, five as perihilar cholangiocarcinoma, 11 as distal bile duct cancer, and two as gallbladder cancers and 15 high-hENT1 and 25 low-hENT1 patients. The median progression-free survival was 24 and 11 weeks among patients with strong and weak intratumoral hENT1 immunohistochemical staining (P = 0.05), and the median overall survival was 52 and 26 weeks (P = 0.15), respectively. Among 22 patients with intrahepatic cholangiocarcinoma, the median PFS was 22 and 7 weeks (P = 0.08) and the median OS was 60 and 21 weeks (P = 0.04) in the high- and low-hENT1 groups, respectively. Conclusion: The current study showed that increased hENT1 expression is associated with a stronger toxic effect of gemcitabine on BTC cell lines. The clinical outcomes suggested that increased intratumoral hENT1 immunohistochemical staining is a possible biomarker predicting better therapeutic effects of gemcitabine on patients with advanced BTC. Further studies are necessary to determine the precise role of hENT1 in BTC.배경: 젬시타빈은 담도계암 치료에서 가장 중요한 약제 중 하나이다. Human equilibrative nucleoside transporter 1 (hENT1)의 발현은 일부 암에서 젬시타빈 치료 반응을 예측하는 잠재적인 바이오마커로 여겨진다. 본 연구는 담도계암 세포주와 젬시타빈 기반 복합항암치료를 받은 진행성 담도계암 환자에서 hENT1 발현과 젬시타빈 효과 사이의 연관성을 평가하고자 한다. 방법: 담도계암 세포주 4종 (HuCCT1, SNU-478, SNU-1079, SNU-1196)에서 hENT1의 mRNA와 단백질 발현을 측정하였다. 젬시타빈 처치 후 세포 생존 능력은 항암제 감수성 분석으로 측정하였다. 임상적인 평가는 2012년 6월에서 2014년 5월 사이에 절제 불가능하거나 혹은 재발한 담도계암 환자 40명에서 젬시타빈 (1000mg/m2)과 시스플라틴 (25mg/m2)으로 치료받은 환자를 대상으로 하였다. 결과: 담관암 세포주 4종 중 SNU 1196이 가장 높은 mRNA와 단백질 발현을 보였다. hENT1 발현은 젬시타빈의 50% 최대 저해 농도 로그값과 선형 상관관계를 보였다. 항암제 주입 전 hENT1 특이 siRNA 전처치는 대조 siRNA 전처치에 비해 높은 세포 생존을 보여주었다. 임상적으로, 간내 담관암 22명, 간문부 담관암 5명, 원위부 담관암 11명, 담낭암 2명이 포함되었다. 종양 내 hENT1의 면역화학염색 발현이 강한 환자군과 약한 환자군에서 중간 무진행생존기간은 24주와 11주 (P=0.05)였고, 중간 전체생존기간은 52주와 26주 (P=0.15)였다. 22명의 간내 담관암 환자에서 중간 문진행생존기간은 22주와 7주 (P=0.08)였고, 중간 전체생존기간은 60주와 21주 (P=0.04)였다. 결론: 본 연구는 hENT1의 증가된 발현이 담도계암 세포주에서 젬시타빈의 강한 독성 효과와 연관되어 있음을 보여주었고, 임상 적으로 증가된 종양 내 hENT1의 면역화학염색이 진행성 담도계암 환자에서 젬시타빈의 더 나은 치료 효과를 예측하는 잠재적인 바이오마커임을 제시하였다.1. Introduction 1 2. Methods 3 3. Results 11 4. Discussion 32 5. References 37 국문 초록 42Docto

A Study on the Relation among Physical Fitness, Physical Activity Levels and Active Ageing on the Elderly

학위논문 (석사)-- 서울대학교 대학원 : 체육교육과, 2016. 8. 전태원.본 연구는 활동적 노년과 건강 및 노화관련 혈액 지표와 신체활동량 및 체력 요소의 관계를 파악하여 노인의 활동적 노년기를 위한 기초자료를 제공하는데 목적이 있다. 연구 대상은 서울시 및 서울 근교 도시에 거주하는 만 65세 이상의 노인 456명을 대상으로 하였다. 설문검사, 신체조성, 체력검사, 혈액검사를 실시하였다. 설문 검사는 I-PAQ(International Physical Activity Questionnaire)한국판을 사용하여 신체활동량을 조사하였으며, 활동적 노년 척도를 사용해 활동적 노화를 조사하였다. 신체조성은 신장, 체중, 근육량, 체지방률, 허리/엉덩이/허벅지둘레, 체력 검사는 상•하지 근력, 근지구력, 유연성, 민첩성, 심폐지구력, 평형성을 측정하였다. 혈액 변인은 Glucose, Total Cholesterol(TC), Triglyceride(TG), LDLc(Low density lipoprotein cholesterol), HDLc(High density lipoprotein cholesterol) 농도를 측정하였으며, 노화 관련 변인으로 DHEAs (Dehydroepiandrosterone-sulfate) 농도를 측정하였다. 자료 처리는 Window SPSS 21.0 통계 프로그램을 이용하여 일원분산분석, 상관분석, 다중회귀분석을 실시하였으며, 통계적 유의 수준은 p<.05로 설정하였다. 본 연구를 통하여 얻은 연구 결과는 다음과 같다. 첫째, 혈액변인의 분석결과 남성노인에서 연령군에 따른 DHEAs농도의 차이가 나타났다. 남성 노인에서 혈중지질(HDL, TG, LDL)과 체력요소(유연성, 평형성, 하지 근력, 악력, 심폐지구력), DHEAs와 격렬한 신체활동량과 통계적으로 유의한 상관관계가 나타났다. 활동적 노화와의 상관관계는 남성 노인에서 TC와 참여 영역, 여성 노인에서는 건강영역과 TC, LDL에서 상관관계가 확인 되었다. 둘째, 신체활동 수준에 따른 분석 결과, 남성 노인에서 후기노년기에 갈수록 격렬한 신체활동량이 감소하는 경향(p=.051)을 나타냈다. 여성 노인에서는 후기 노년기에 갈수록 신체활동량이 감소하고 좌업시간이 증가하였다. 여성노인에서 중간•높은 신체활동수준의 집단이 낮은 신체활동 수준 집단에 비하여 DHEAs수치가 높은 것으로 나타났다. 활동적 노화의 측면에서는 남성•여성 노인 모두 높은 신체활동 수준의 집단이 활동적 노화 척도가 높았다. 셋째, 체력에 따른 분석 결과, 남성•여성노인 모두에서 후기 노년기에 갈수록 근육량이 감소하였다. 남성노인은 후기노년기에 갈수록 체력 수준이 떨어졌고 전기(65-74세)-중기(75-84세) 노년기에 비하여 중기(75-84세)-후기(85세 이상) 노년기에 체력이 더욱 급격하게 저하되었다. 여성노인의 경우 모든 연령군에서 체력이 급격하게 저하되었다. 남성•여성 노인 모두 후기 노년기에 갈수록 활동적 노화와 체력의 상관관계가 더욱 높았다. 넷째, 다중 회귀 분석결과, 활동적 노년에 대하여 인구학, 신체활동, 체력, 혈액 변인들을 순차적으로 투입한 결과 성별, 연령, 경제, 평형성, 유연성, 심폐지구력, DHEAs가 활동적 노화에 영향을 미치는 요인으로 나타났으며 체력 변인의 영향력이 가장 크게 나타났다. 결론적으로, 노인의 연령을 전기(65-74세), 중기(75-84세), 후기(85세 이상)로 구분하여 혈액변인, 신체활동량, 체력을 살펴 본 결과 연령증가에 따른 신체활동량, 체력, 혈중지질, 노화관련 혈액변인 등 에서의 부정적인 변화로 인해 집단 간의 차이가 나타났다. 따라서 65세 이상을 동일한 노인으로 바라보는 것 보다는 연령군에 따른 접근과 이에 따른 처방이 필요하다. 또한 이러한 변인 가운데 인구학적(연령, 성별), 신체활동량, 체력(유연성, 평형성, 심폐지구력), DHEAs가 활동적 노화에 영향을 미치는 것으로 나타났다. 따라서 노인의 활동적 노년기를 위하여 신체활동량, 유연성, 평형성, 심폐지구력, DHEAs 등을 유지하고 개선시키기 위한 복합적인 중재가 필요할 것으로 사료된다.The purpose of this study is to investigate the relationship among the active ageing, health and aging-related blood index, physical activity, and physical fitness in order to provide the basic data for the elderly's Active Aging. 456 elderly people aged over 65 were participants who resided in Seoul or cities near Seoul. Questionnaire, body composition, physical fitness test, and blood test were carried out. The questionnaire examined their physical activity quantity by using the Korean version of I-PAQ(International Physical Activity Questionnaire) and examined the active ageing by using the Korean active aging scale. The body composition measured their weight, muscle mass, %body fat, circumference of waist, hip, and thigh, and the physical fitness test measured their strength of the upper and lower body, muscle endurance, flexibility, agility, cardiovascular endurance, and balance. Blood samples were collected to determine blood glucose, Total Cholesterol(TC), Triglyceride(TG), Low density Lipoprotein Cholesterol(LDLc), and High Density Lipoprotein Cholesterol(HDLc), and the DHEAs (Dehydroepiandrosterone Sulfate) concentration was measured as the aging-related index. The one-way ANOVA, correlation analysis, and multiple regression analysis were carried out through means of Window SPSS 21.0 statistics program, and the statistical significance was set at p<.05. The result of this study is as follows. First, as a results of the analysis of blood, there were significant differences in DHEAs concentration following the age group of elderly men. The blood lipid(HDL, TG, and LDL), physical fitness(flexibility, balance, lower and upper body strength, and cardiovascular endurance), and DHEAs showed a statistically significant correlation with the vigorous physical activity. The correlation appeared between the TC and participation area of the elderly men, and between the health area and TC, LDL of the elderly women. Second, as a result of the analysis following the physical activity level, the vigorous physical activity quantity tended to decrease(p=.051) as it went to the old-old age of the elderly men. In the case of the elderly women, the total physical activity quantity decreased and the sedentary time increased as it went to the old-old age. This revealed that the DHEAs concentration of the group of middle/high physical activity level was higher than that of the group of the low physical activity level in the elderly women. In terms of the active ageing, the active ageing scale of the group of high physical activity level was both high in elderly men and women. Third, as a result of the analysis following the physical fitness, the muscle mass decreased as it went to the old-old age both in the elderly men and women. The physical fitness level of elderly men declined as it went to the old-old age and the physical fitness declined more rapidly in the middle-old and old-old period compared to the young-old and middle-old period. As for the elderly women, the physical fitness declined rapidly in all age groups. The correlation between the active aging and physical fitness was much higher as it went to the old-old period in both male and female elderly people. Fourth, as a result of the multiple regression analysis, sex, age, economic status, balance, flexibility, cardiovascular endurance, and DHEAs appeared as factors influencing the active ageing while the influence of the physical fitness variable was the biggest. In conclusion, these results showed a difference in the physical activity, physical fitness, and blood variable among the elderly groups classified into young-old group, middle-old group, and old-old group. Particularly, they rapidly decreased in the middle-old period. Therefore, the concern for the elderly men after the middle-old period is more required. For Active Aging, the comprehensive treatment of include the demographic variables and blood index is needed, mainly to improve physical fitness through the increase of physical activity.I. 서 론 1 1. 연구의 필요성 1 2. 연구 목적 5 3. 연구 가설 5 4. 연구의 제한점 6 Ⅱ. 이론적 배경 7 1. 활동적 노화 7 2. 건강과 혈중지질 및 혈당 17 3. 노화와 호르몬 20 Ⅲ. 연구 방법 22 1. 연구 대상 22 2. 연구 설계 24 3. 측정 도구 25 4. 검사 절차 26 5. 자료 분석 31 IV. 연구 결과 32 1. 연구 대상자의 특징 32 2. 혈액변인과 활동적 노화 35 3. 신체활동 수준과 활동적 노화 44 4. 체력과 활동적 노화 50 5. 인구학, 혈액, 신체활동, 체력 변인과 활동적 노화 71 V. 논의 74 1. 혈액변인과 활동적 노화 74 2. 신체활동과 활동적 노화 77 3. 체력과 활동적 노화 78 4. 인구학, 혈액, 신체활동, 체력 변인과 활동적 노화 80 VI. 결론 및 제언 82 1. 결론 82 2. 제언 83 참고 문헌 85 Abstract 97 부록 100Maste

Musical Realization of Poetic Image: <Gaspard de la Nuit> by Maurice Ravel

학위논문(석사) -- 서울대학교대학원 : 음악대학 음악과, 2022. 8. 주희성.본고는 프랑스 태생의 작곡가 모리스 라벨 (Maurice Ravel, 1875-1937)의 피아노 작품 에 나타난 시적 이미지에 관한 논문이다. 라벨은 프랑스 시인 알로와스 베르트랑(Aloysius Bertrand, 1807-1841)의 시집 『밤의 가스파르: 램브란트와 카로 풍의 환상 (Gaspard de la Nuit: Fantaisies à la manière de Rembrandt et de Callot)』을 읽고 감명받아 1908년 피아노 작품 를 작곡하였다. 라벨 의 각 곡 첫머리에는 베르트랑의 시가 삽입되어 있다. 본고에서는 라벨 의 구조와 악곡에 나타난 시적 이미지의 음악적 구현을 베르트랑의 시 와 연관하여 살펴보았다. 라벨 는 ‘옹딘(Ondine)’, ‘교수대(Le Gibet)’, ‘스카르보(Scarbo)’로 구성되어 있으며, 세 곡의 구조는 베르트랑 시의 내용에 따라 분석될 수 있다. 라벨의 악곡에 나타난 시상의 청각적 구현을 화성과 음형, 악상 변화, 텍스추어의 대비, 음정 관계에서 살펴보았고, 시의 성격과 내용이 라벨의 작품에 어떻게 적용되었는지 알아보았다. 베르트랑 시 『밤의 가스파르』의 내용과 라벨 구조의 거시적인 연관성을 제시하였고, 각 절에 대응되는 패시지의 화성, 악상 변화, 텍스추어의 차이 등을 미시적으로 분석하였다.This thesis explored relation between the piano solo piece , composed by the French composer Maurice Ravel(1875-1937), and collections of poems 『Gaspard de la Nuit: Fantaisies à la manière de Rembrandt et de Callot』 by the French poet Aloysius Bertrand(1807-1841). Ravel’s , composed in 1908, is based on three different poems from Bertrand’s, each of which are placed before their corresponding movements. This study examines similarities of the structure between the poem and the music, by aligning the visuals that Bertrand offers in his poem to the musical expressions that Ravel wrote. Ravel’s consists of three movements which are, ‘Ondine’, ‘Le gibet’ and ‘Scarbo’. The structure of each movement can be analyzed by the contents of the original poems by Bertrand. This study looks into the musical interpretation of the visuals from Bertrand’s poems, by researching the tools that Ravel utilized such as a variety of harmonies, timbre, contrast of texture, relations of pitch collections, etc. The undeniable relationship between Bertrand’s and Ravel’s work should affect how one interprets Ravel’s . To avoid a vague conceptualization of images given in each part of , it is the performer’s responsibility to carefully study both the works of Bertrand and Ravel. In doing so, performers could better present the images of each scene and the characters of each movement.Ⅰ. 서 론 1 Ⅱ. 본 론 3 1. 작품배경 3 2. 시적 이미지와 라벨 &lt;밤의 가스파르&gt;의 구조 6 2. 1. '옹딘(Ondine)' 6 2. 2. '교수대(Le gibet)' 27 2. 3. '스카르보(Scarbo)' 40 Ⅲ. 결 론 59 부 록 61 참고문헌 68 Abstract 70석

Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death

Microglial cells are activated during excitotoxin-induced neurodegeneration. However, the in vivo role of microglia activation in neurodegeneration has not yet been fully elucidated. To this end, we used Ikkbeta conditional knockout mice (LysM-Cre/Ikkbeta(F/F)) in which the Ikkbeta gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IkappaB kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (Ikkbeta(F/F)), and lipopolysaccharide-induced proinflammatory gene expression was also compromised. Kainic acid (KA)-induced hippocampal neuronal cell death was reduced by 30% in LysM-Cre/Ikkbeta(F/F) mice compared with wild-type mice. Reduced neuronal cell death was accompanied by decreased KA-induced glial cell activation and subsequent expression of proinflammatory genes such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/Ikkbeta(F/F) mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-alpha and IL-1beta expression. Based on these data, we concluded that IKK/nuclear factor-kappaB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediatorsope

Transfection of arginine decarboxylase gene increases the neuronal differentiation of neural progenitor cells

Growing evidence suggests that the clinical use of neural progenitor cells (NPCs) is hampered by heterogeneity, poor neuronal yield and low survival rate. Recently, we reported that retrovirus-delivered human arginine decarboxylase (hADC) genes improve cell survival against oxidative insult in murine NPCs in vitro. This study investigates whether the induced expression of hADC gene in mNPCs induces any significant change in the cell fate commitment. The evaluation of induced hADC gene function was assessed by knockdown of hADC gene using specific siRNA. The hADC gene delivery triggered higher expression of N-CAM, cell adhesion molecule and MAP-2, neuronal marker. However, the hADC gene knockdown showed downregulation of N-CAM and MAP-2 expression suggesting that hADC gene delivery favors cell fate commitment of mNPCs towards neuronal lineage. Neurite outgrowth was significantly longer in the hADC infected cells. The neurotrophic signal, BDNF aided in the neuronal commitment, differentiation, and maturation of hADC-mNPCs through PI3K and ERK1/2 activation. The induction of neuron-like differentiation is believed to be regulated by the expression of GSK-3β and Wnt/β-catenin signaling pathways. Our findings suggest that hADC gene delivery favors cell fate commitment of mNPCs towards neuronal lineage, bring new advances in the field of neurogenesis and cell therapy.ope

Recovered changes in the spleen by agmatine treatment after transient cerebral ischemia

Stroke or cerebrovascular injury is the leading cause of disability and the third leading cause of deaths worldwide. After the initial ischemic injury, sympathetic signals are transmitted to the spleen and a compromised blood-brain barrier, coupled with expression of adhesion molecules by the vascular endothelial cells permits an influx of peripheral immune cells. This influx of peripheral immune cells into the brain exacerbates the local brain inflammatory response, leading to enhanced neurodegeneration. Agmatine is a primary amine formed by decarboxylation of L-arginine synthesized in the mammalian brain. In this study, we determined the effect of agmatine on the immune response in the spleen after transient cerebral ischemia. Twenty-three hours after transient cerebral ischemia, the white pulp area was reduced and the number of CD11b(+) macrophages and CD4(+)CD25(+) regulatory T cells (T reg cells) were increased in the spleens in the experimental group as a result of alteration of the immune response in the spleen, as regulated by inflammatory cytokines. In the agmatine treatment group (100 mg/kg IP), the contraction of white pulp was diminished and the number of CD11b(+) macrophages and CD4(+)CD25(+)T reg cells were decreased. Twenty-three hours after transient cerebral ischemia, the brain infarction area was significantly reduced (5.51±1.63% of the whole brain) in the agmatine treatment group compared to 15.02±4.28% of the whole brain in the experimental control group. These results suggest that agmatine treatment can reduce brain infarction through minimizing neuroinflammation and can lessen the danger of post-stroke infection from depression of the immune system after stroke.ope

Agmatine Attenuates Nitric Oxide Synthesis and Protects ER-structure from Global Cerebral Ischemia in Rats

In ischemic strokes, apoptosis is caused by excitotoxicity, ionic imbalance, oxidative/nitrosative stress, and apoptotic-like pathways. Nitric oxide (NO), a free radical, is elevated after ischemic insult. NO, which is generated primarily by neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), promotes neuronal damage following ischemia. Evidence obtained in recent years has demonstrated that endoplasmic reticulum (ER)-mediated cell death plays an important role in cerebral ischemia. Agmatine is an endogenous substance synthesized from L-arginine by arginine decarboxylase (ADC) and is present in mammalian brain. We had previously reported that agmatine contributes to neuroprotection against ischemic injury. In continuation of our earlier work, we intended to investigate whether agmatine protects brain from transient global ischemia, and also tried to determine the neuroprotective mechanism of agmatine. Twenty minutes of transient global ischemia was induced by 4 vessel occlusion (4-VO). Agmatine (100 mg/kg, IP) was administered simultaneously with reperfusion. Samplings of brain were done at 6, 24, 48, and 72 h after reperfusion to determine the effect of agmatine on ischemic injured hippocampus. ER-damage was also investigated using electron microscope. Results showed that agmatine treatment prevented delayed neuronal cell death in hippocampal CA1 neurons after global cerebral ischemia. It also blocked NOS expression in the rat brain. Agmatine induced the increased expression of glucose-regulated protein 78 (Grp78). These results suggest that agmatine inhibits the production of NO by decreasing the expression of nNOS and iNOS on global forebrain ischemia and the neuroprotective effect of agmatine were concerned with the ER stress-mediated conditionope

Primary Tumor Suppression and Systemic Immune Activation of Macrophages through the Sting Pathway in Metastatic Skin Tumor

Purpose: Agonists of the stimulator of interferon genes (STING) play a key role in activating the STING pathway by promoting the production of cytokines. In this study, we investigated the antitumor effects and activation of the systemic immune response of treatment with DMXAA (5,6-dimethylxanthenone-4-acetic acid), a STING agonist, in EML4-ALK lung cancer and CT26 colon cancer. Materials and methods: The abscopal effects of DMXAA in the treatment of metastatic skin nodules were assessed. EML4-ALK lung cancer and CT26 colon cancer models were used to evaluate these effects after DMXAA treatment. To evaluate the expression of macrophages and T cells, we sacrificed the tumor-bearing mice after DMXAA treatment and obtained the formalin-fixed paraffin-embedded (FFPE) tissue and tumor cells. Immunohistochemistry and flow cytometry were performed to analyze the expression of each FFPE and tumor cell. Results: We observed that highly infiltrating immune cells downstream of the STING pathway had increased levels of chemokines after DMXAA treatment. In addition, the levels of CD80 and CD86 in antigen-presenting cells were significantly increased after STING activation. Furthermore, innate immune activation altered the systemic T cell-mediated immune responses, induced proliferation of macrophages, inhibited tumor growth, and increased numbers of cytotoxic memory T cells. Tumor-specific lymphocytes also increased in number after treatment with DMXAA. Conclusion: The abscopal effect of DMXAA treatment on the skin strongly reduced the spread of EML4-ALK lung cancer and CT26 colon cancer through the STING pathway and induced the presentation of antigens.ope

YH29407 with anti-PD-1 ameliorates anti-tumor effects via increased T cell functionality and antigen presenting machinery in the tumor microenvironment

Among cancer cells, indoleamine 2, 3-dioxygenase1 (IDO1) activity has been implicated in improving the proliferation and growth of cancer cells and suppressing immune cell activity. IDO1 is also responsible for the catabolism of tryptophan to kynurenine. Depletion of tryptophan and an increase in kynurenine exert important immunosuppressive functions by activating regulatory T cells and suppressing CD8+ T and natural killer (NK) cells. In this study, we compared the anti-tumor effects of YH29407, the best-in-class IDO1 inhibitor with improved pharmacodynamics and pharmacokinetics, with first and second-generation IDO1 inhibitors (epacadostat and BMS-986205, respectively). YH29407 treatment alone and anti-PD-1 (aPD-1) combination treatment induced significant tumor suppression compared with competing drugs. In particular, combination treatment showed the best anti-tumor effects, with most tumors reduced and complete responses. Our observations suggest that improved anti-tumor effects were caused by an increase in T cell infiltration and activity after YH29407 treatment. Notably, an immune depletion assay confirmed that YH29407 is closely related to CD8+ T cells. RNA-seq results showed that treatment with YH29407 increased the expression of genes involved in T cell function and antigen presentation in tumors expressing ZAP70, LCK, NFATC2, B2M, and MYD88 genes. Our results suggest that an IDO1 inhibitor, YH29407, has enhanced PK/PD compared to previous IDO1 inhibitors by causing a change in the population of CD8+ T cells including infiltrating T cells into the tumor. Ultimately, YH29407 overcame the limitations of the competing drugs and displayed potential as an immunotherapy strategy in combination with aPD-1.ope