최저임금 인상이 임금 불평등에 미친 영향 연구

학위논문 (석사) -- 서울대학교 대학원 : 행정대학원 글로벌행정전공, 2021. 2. 박상인.The study estimated the impact of the minimum wage hike in 2018 and 2019 on wage inequality. The difference-in-differences method was used to verify the effect before and after the policy change. South Koreas minimum wage applies to all businesses or workplaces at the same rate nationwide. However, by using the fact that the minimum wage influence rates are different by industry, this paper examined the hypothesis that if the minimum wage was raised - that is, a certain industry had a higher minimum wage influence rate, the industry would have the more improved wage inequality. This project used the influence rate of the minimum wage by industry as an independent variable and the Gini coefficient and inter-decile ratios – P90/P10, P90/P50, and P50/P10 - as dependent variables. The models presented by the study estimated that the 2018 and 2019 minimum wage hike does not have a statistically significant impact on wage inequality overall. Plus, some meaningful presumptions can be found when it is assumed that wage inequality by industry has common trends. The relation between the Gini coefficient and the P90/P10 and the minimum wage increase rate in monthly wages have positive values whereas those in hourly wages have negative values. This means that the monthly wage gap widened while the hourly wage gap is reduced after the minimum wage increased. This implies that the working hours are reduced. From this result, it is presumed that employers have responded to the wage cost burden from the minimum wage increase by reducing working hours. Also, from the results of P90/P50 and P50/P10, it is found that the wage gap between the high-wage group and the middle-wage group has narrowed while the wage gap between the middle-wage group and the low-wage group has widened. This points out that the wages of the middle-wage class may grow higher than the low-wage class or high-wage class after the minimum wage hike due to the spillover effect probably.최저임금은 2015년 이후 연간 7% 수준으로 상승하다가 2018년 16.4%, 2019년 10.9%로 큰 폭 인상되었다. 이 연구는 2018년, 2019년 최저임금 인상이 임금 불평등에 미친 영향을 추정한다. 연구 방법으로는 이중차분법을 사용한다. 비교집단을 산업으로 설정하고 산업별 최저임금 영향률을 독립변수로 사용하며, 임금 불평등의 지표로 지니 계수와 분위수 배율(P90/P10, P90/P50, P50/P10)을 이용한다. 추정 결과, 2018년, 2019년 최저임금 인상이 임금불평등에 미친 영향은 대체적으로 통계적으로 유의하지 않았다. 다만, 이 연구는 데이터 양이 작아 최저임금 영향률 추산에 측정오차가 있을 수 있고 추정식이 단순한 한계를 가진다. 그 밖에 동 연구결과로부터 몇 가지 의미 있는 추가 해석이 가능하다. 임금 분포 내 전체적인 임금 불평등을 나타내는 지니 계수와 P90/P10 배율로부터 시간당 임금의 불평등은 개선되었으나, 월간 임금의 불평등은 확대된 경향을 확인하였다. 저임금 근로자의 시간당 임금 상승에도 불구하고 근로시간이 감소하여 월간 임금, 즉 전체 임금 불평등이 개선되지 않은 것으로 보인다. 이는 고용주들이 최저임금 인상 부담을 근로시간 단축으로 대응한 결과인 것으로 추정된다. 아울러, P90/P50, P50/P10 배율과 최저임금 영향률 간 관계로부터 최저임금 인상이 저임금 근로자의 임금 뿐만 아니라 중위 임금 근로자의 임금 상승까지 영향을 미친 것으로 보이며, 중위 임금 근로자의 임금상승률이 저임금 근로자 및 고임금 근로자의 임금상승률보다 높았던 것으로 추정된다.Chapter 1. Introduction 1 Chapter 2. Theory and Literature Review 6 2.1. Minimum Wage 6 2.2. Wage Inequality 9 2.3. Theoretical Basis 10 2.4. Literature Review 13 Chapter 3. Research Method 21 3.1. Data and Variables 31 3.2. Research Design 34 Chapter 4. Analysis and Finding 38 4.1. Overall Wage Gap 40 4.2. Wage Gap Between Wage Classes 41 4.3. Limitation 43 Chapter 5. Conclusion 45 Bibliography 49 Appendix 52 Abstract in Korean 59Maste

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

Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer

Background: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). Patients and methods: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). Results: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. Conclusion: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.ope

Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.ope

Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials

Background: Retrospective studies have suggested a potential risk of hyperprogressive disease (HPD) in patients receiving immune checkpoint inhibitors (ICIs). We compared the incidence of HPD during treatment with nivolumab±ipilimumab versus natural tumor progression with placebo in post hoc analyses of two randomized, double-blind clinical trials. Methods: ATTRACTION-2 randomized patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) and progression on ≥2 prior regimens to nivolumab 3 mg/kg Q2W or placebo. CheckMate 451 randomized patients with extensive-disease small cell lung cancer (ED SCLC) and ongoing complete/partial response or stable disease after first-line chemotherapy to nivolumab 240 mg Q2W, nivolumab 1 mg/kg+ipilimumab 3 mg/kg Q3W for four doses then nivolumab 240 mg Q2W, or placebo. Patients receiving ≥1 dose of study drug and with tumor scans at baseline and the first on-treatment evaluation were included in the HPD analyses. HPD definitions were ≥20%, ≥50%, and ≥100% increase in target lesion sum of the longest diameters (SLD) at the first on-treatment assessment. Results: In the ATTRACTION-2 HPD-evaluable population, 243 patients received nivolumab and 115 placebo. Fewer patients receiving nivolumab versus placebo had increases in SLD ≥20% (33.7% vs 46.1%) and ≥50% (6.2% vs 11.3%); similar proportions had increases in SLD ≥100% (1.6% vs 1.7%). In the CheckMate 451 HPD-evaluable population, 177 patients received nivolumab, 179 nivolumab+ipilimumab, and 175 placebo. Fewer patients receiving nivolumab or nivolumab+ipilimumab versus placebo had increases in SLD ≥20% (27.1%, 27.4% vs 45.7%), ≥50% (10.2%, 11.2% vs 22.3%), and ≥100% (2.8%, 2.8% vs 6.3%). Conclusions: Nivolumab±ipilimumab was not associated with an increased rate of progression versus placebo in patients with GC, GEJC, or ED SCLC, suggesting that previous reports of HPD may reflect the natural disease course in some patients rather than ICI-mediated progression. Trial registration number: NCT02538666; NCT02267343.ope

PD-1: Dual guard for immunopathology.

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Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer

BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival. RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).ope

Immune Checkpoint Inhibitors in 10 Years: Contribution of Basic Research and Clinical Application in Cancer Immunotherapy

Targeting immune evasion via immune checkpoint pathways has changed the treatment paradigm in cancer. Since CTLA-4 antibody was first approved in 2011 for treatment of metastatic melanoma, eight immune checkpoint inhibitors (ICIs) centered on PD-1 pathway blockade are approved and currently administered to treat 18 different types of cancers. The first part of the review focuses on the history of CTLA-4 and PD-1 discovery and the preclinical experiments that demonstrated the possibility of anti-CTLA-4 and anti-PD-1 as anti-cancer therapeutics. The approval process of clinical trials and clinical utility of ICIs are described, specifically focusing on non-small cell lung cancer (NSCLC), in which immunotherapies are most actively applied. Additionally, this review covers the combination therapy and novel ICIs currently under investigation in NSCLC. Although ICIs are now key pivotal cancer therapy option in clinical settings, they show inconsistent therapeutic efficacy and limited responsiveness. Thus, newly proposed action mechanism to overcome the limitations of ICIs in a near future are also discussed.ope

폐암세포에서 표피성장인자 수용체-티로신 키나아제 억제제와 선택적인 사이클로옥시게나제-2 억제제의 병합치료 효과

학위논문 (박사)-- 서울대학교 대학원 의과대학 의학과, 2017. 8. 한성구.Introduction: To overcome the acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs), various strategies have been explored in preclinical and clinical setting. Cyclooxygenase(COX)-2 inhibitors have been reported to suppress cell growth and to lead to apoptosis of various cancer cells by EGFR down-regulation. In the present study, we assessed whether the combination of celecoxib, a COX-2 inhibitor, and EGFR-TKIs could overcome the acquired resistance in lung cancer cells. Materials and Methods: The EGFR-mutated lung cancer cell lines(HCC827 and PC-9) and drug-resistant cell lines (HCC827/GR, HCC827/ER, PC-9/GR and PC-9/ER) were used. Celecoxib and COX-2 siRNA were used as COX-2 inhibitor. Reversible EGFR-TKIs, gefitinib and erlotinib, and EGFR siRNA were used as EGFR inhibitor. Western blotting was employed to investigate the expression of proteins involved with EGFR signaling. Results: Addition of celecoxib treatment enhances sensitivity to EGFR-TKIs in parental HCC827 and PC-9 cells harboring with EGFR activating mutation. Combined celecoxib and gefitinib treatment overcame gefitinib resistance via the inhibition of the phosphorylation of MET, EGFR and Akt in HCC827/GR cells. In HCC827/ER cells, combination treatment with erlotinib and celecoxib inhibited the expression of AXL, p-Akt and Erk. We evaluated the ability of combination treatment with gefitinib or erlotinib, and celecoxib to inhibit the proliferation of PC-9 cells with an EGFR T790M mutation. These combinations showed an additive growth inhibition in PC-9/GR cells and a synergistic growth inhibition in PC-9/ER cells through the suppression of EGFR and Akt activities. Conclusions: The combination of EGFR-TKIs and celecoxib may be a new strategy to overcome the acquired resistance to EGFR-TKIs in lung cancer.Abstract ----------------------------------------------- i Contents --------------------------------------------- iii List of figures ----------------------------------------- iv List of abbreviations and symbols ---------------------- vi 1. Introduction ----------------------------------------- 1 2. Materials and methods ------------------------------ 4 3. Results --------------------------------------------- 9 4. Discussion ---------------------------------------- 14 5. References ---------------------------------------- 19 국문초록 --------------------------------------------- 51Docto

Induction Chemotherapy as a Prognostication Index and Guidance for Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: The Concept of Chemo-Selection (KCSG HN13-01)

Purpose: Certain patient subgroups who do not respond to induction chemotherapy (IC) show inherent chemoresistance in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). This study aimed to assess the prognostic value of IC, and role of IC in guiding the selection of a definitive locoregional therapy. Materials and methods: Out of the 445 patients in multi-institutional LA-HNSCC cohort, 158 (36%) receiving IC were enrolled. The study outcome was to assess overall survival (OS) through IC responsiveness and its role to select subsequent treatments. Results: Among 135 patients who completed subsequent treatment following IC, 74% responded to IC (complete response in 17% and partial response in 58%). IC-non-responders showed 4.5 times higher risk of mortality than IC-responders (hazard ratio, 4.52; 95% confidence interval, 2.32 to 8.81; p < 0.001). Among IC-responders, 84% subsequently received definitive concurrent chemoradiotherapy (CCRT) and OS was not differed by surgery or CCRT (p=0.960). Regarding IC-non-responders, 54% received CCRT and 46% underwent surgery, and OS was poor in CCRT (24-month survival rate of 38%) or surgery (24-month survival rate of 63%). Conclusion: Response to IC is a favorable prognostic factor. For IC-responders, either surgery or CCRT achieved similar survival probabilities. For IC-non-responder, multidisciplinary approach was warranted reflecting patients' preference, morbidity, and prognosis.ope