픽업 대기 시간의 감소를 위한 강화 학습 기반의 승차 공유 서비스의 매칭 및 요금 책정 알고리즘

학위논문(박사) -- 서울대학교대학원 : 공과대학 건설환경공학부, 2023. 8. 김동규.With the popularization of smartphones, ride-hailing services mediate hailing requests from many users to drivers. They are expected to ease urban problems such as traffic congestion by replacing the demand for private cars. However, contrary to their intended purpose, there exists criticism that ride-hailing services exacerbate negative externalities such as traffic congestion and air pollution. Therefore, it is necessary to alleviate those negative externalities in ride-hailing services. We focus on reducing pickup waiting times, as this also helps decrease negative externalities by reducing the distance traveled by vehicles. This study develops a matching and pricing algorithm to reduce pickup waiting time based on reinforcement learning methods, namely contextual bandits and temporal difference learning. The algorithm iteratively assigns surge multipliers to individual requests and matches the requests to drivers. We apply the proposed algorithm to ride-hailing data in Singapore while investigating the effects of changes in price sensitivity and value term coefficient. The results show similar patterns to the historical matching rate during both peak hours and off-peak hours, demonstrating its applicability in large cities as big as Singapore. Simulations during the morning peak hour show that our proposed model reduces 20 kilograms of carbon dioxide emissions and decreases pickup waiting time by 15% with only a 2% reduction in revenue. By addressing matching, pricing, and reducing pickup waiting time together, this study estimates how much pickup waiting time can be potentially saved and contributes to improving ride-hailing services both in terms of user benefits and reducing externalities.스마트폰의 대중화와 함께, 승차 공유 서비스는 많은 이용자들의 차량 호출을 운전자에게 중개해주고 있다. 이는 자가용 수요를 대체해 교통혼잡 등 도시문제를 완화할 것으로 기대된다. 그러나 애초 취지와 달리 승차 공유 서비스가 교통 혼잡과 대기오염 등 부정적인 외부효과를 악화시킨다는 비판이 제기되고 있다. 따라서, 승차 공유 서비스에서 이러한 부정적인 외부효과를 저감할 필요가 있다. 픽업 대기 시간이 줄어들면 차량이 이동하는 거리가 줄어들어 부정적 외부 효과를 줄일 수 있으므로, 본 연구는 픽업 대기 시간의 감소에 초점을 맞춘다. 본 연구에서는 픽업 대기 시간의 감소를 위하여 강화 학습을 기반으로 한 매칭 및 요금 책정 알고리즘을 개발하였다. 컨텍스츄얼 밴딧과 시간차 학습을 이용하여 개별 호출에 요율을 부여하고 운전자에게 할당하는 작업을 반복적으로 수행하는 알고리즘이다. 개발된 알고리즘은 싱가포르의 승차 공유 서비스 데이터에 적용되었다. 가격 민감도 변화의 영향과 가치항 계수 변화의 영향도 조사하였다. 첨두시간대 뿐만 아니라 비첨두 시간대에도 실제 매칭률과 유사한 매칭률 패턴을 보여 싱가포르와 같은 대도시에서의 적용 가능성을 연구하였다. 오전 첨두 시간에서의 시뮬레이션 결과, 픽업 대기 시간 단축 모델은 픽업 시간을 15% 단축하고, 이산화탄소 배출량을 20kg 절감하며, 수익은 2% 감소하는 데 그쳤다. 본 연구를 통해 동적 요금과 매칭, 픽업 대기 시간 단축을 함께 다뤄 승차 공유 서비스에서 잠재적인 픽업 대기 시간을 얼마나 절약할 수 있는지를 추정하고, 이용자 편익 측면에서 승차 호출 서비스를 개선하는 데 기여하였다.Chapter 1. Introduction 1 1.1. Background 1 1.2. Research Purpose 7 Chapter 2. Literature Review 9 2.1. Concepts 9 2.2. Dynamic Pricing 12 2.3. Negative Externalities 14 2.4. Implications 17 Chapter 3. Methodology 19 3.1. Contextual Bandit 19 3.2. Temporal Difference Learning 23 3.3. Model Formulation 26 Chapter 4. Data Description 33 4.1. Data Tables 33 4.2. Descriptive statistics 38 4.3. Spatial Distribution 39 Chapter 5. Results 43 5.1. Base Model 43 5.2. Pickup Waiting Time Reducing Model 52 5.3. Effect of Changes in Price Sensitivity 56 5.4. Effect of Changes in Value Term Coefficient 61 5.5. Applicability of the Model 69 Chapter 6. Conclusion 73 6.1. Summary 73 6.2. Limitations and Future Research 74 References 75 국문초록 82박

Learning on Mobile Product Phylogenetic Network

학위논문(박사) -- 서울대학교대학원 : 공과대학 협동과정 기술경영·경제·정책전공, 2024. 2. 이정동."Innovation" is defined as the creation of a new product or the development of a product. Therefore, product innovation has been main research field in the innovation studies, and various studies have been conducted to identify patterns of product innovation and to predict product innovation. In the study of product innovation, an evolutionary approach is often utilized. This is because the various attempts at product innovation, the competition among the various attempts, and the diffusion of the innovations selected in the competition resemble the mechanism of variation - selection - retention in biological evolution. This study aims to evolutionary model this process of product innovation based on data and algorithms. To this end, this study is organized into four main essays. In the first essay, we perform an operational definition of products based on previous product evolution studies. The operational definition allows us to leverage data to transform a product into an object of quantitative analysis. In the second essay, based on the operational definition, this study represents a product as a set of functional modules, which are a set of technical characteristics. In the third essay, constructing a product phylogenetic network by connecting products by using evolutionary relationships between them. In the fourth essay, based on the network, this study explains the product evolution phenomenon and predicts the future product development direction. To verify the appropriateness of the model proposed in this study, an empirical study was conducted on 11,904 mobile products have been released in the global market from 1994 to 2022. This study proposed the following conclusions. First, the unit of combinatorial innovation is the functional modules that comprise a product, not the individual technical characteristics, and innovative products are those with various functional modules. Second, the product phylogenetic network has adequate explanatory power for mobile product innovation histories. Third, the product evolution variables that can be extracted from the network have adequate explanatory power for the product evolution phenomena conceptually proposed by previous studies, suggesting that the product phylogenetic network proposed in this study can serve as a cornerstone for quantitative product evolution research.혁신은 새로운 제품의 탄생 혹은 제품의 발전으로 표현된다. 따라서 제품 혁신은 혁신 연구 분야에 있어서 주된 연구 대상으로 다루어졌으며, 제품 혁신의 정형화된 패턴을 도출하고 제품 혁신의 양상을 예측하는 다양한 연구들이 수행되어져 왔다. 제품 혁신 연구에 있어, 진화적 접근법이 흔히 활용된다. 이는 제품 혁신을 위한 다양한 시도, 다양한 시도들 사이의 경쟁, 그리고 경쟁에서 선택된 혁신의 확산이 생물 진화의 variation – selection – retention 메커니즘과 닮아 있기 때문이다. 본 연구는 이러한 제품 혁신의 과정을 데이터 및 알고리즘에 기반하여 진화적으로 모형화하는데 목적이 있다. 이를 위해 본 논문은 4개의 장으로 구성된다. 첫 번째 장에서는, 선행 제품 진화 연구들에 기반하여 제품에 대한 조작적 정의를 수행한다. 제품에 대한 조작적 정의는 데이터를 활용하여 정량적 분석 대상으로써 제품을 변환할 수 있게 한다. 두 번째 장에서는, 제품에 대한 조작적 정의에 기반하여 제품들을 기술적 특성들의 집합인 기능적 모듈들의 집합으로 표현한다. 세 번째 장에서는, 기능적 모듈들의 집합으로써 제품들과 이들 사이의 진화적 관계성을 연결하는 것으로 제품의 발전 과정을 제품 진화 계통 네트워크로 구축한다. 네 번째 장에서는 제품 진화 계통 네트워크에 기반하여, 제품 진화 현상을 설명하고 미래 제품 발전 방향에 대한 예측을 수행한다. 논문에서 제안하는 모형의 적절성을 검증하기 위해, 1994년부터 2022년까지 글로벌 마켓에 출시된 11,904개의 모바일 제품에 대한 실증연구를 수행하였다. 이를 통해 다음 결론들을 도출하였다. 첫 번째로, 조합적 혁신의 단위는 제품을 구성하는 개별 기술적 특성이 아니라 제품을 구성하는 기능적 모듈이며 혁신적 제품은 다수의 기능적 모듈을 보유한 제품이다. 두 번째로, 제품 진화 계통 네트워크는 실제 모바일 제품 혁신 사례에 대한 적절한 설명력을 가진다. 세 번째로, 제품 진화 계통 네트워크에서 추출할 수 있는 제품 진화 변수들은 선행 제품 진화 연구들에서 개념적으로 제시한 제품 진화 현상에 대한 적절한 설명력을 가지며, 이는 본 연구가 제안한 제품 진화 계통 네트워크가 정량적 제품 진화 연구의 주춧돌 역할을 할 수 있음을 시사한다.Abstract iii Contents v List of Tables . ix List of Figures xi Chapter 1. Introduction 1 1.1 Research background and motivation 1 1.2 Research purpose and outline of the study 4 Chapter 2. Literature review on product evolution 8 2.1 Theoretical background 8 2.1.1 Product evolution in innovation studies 8 2.1.2 Previous literature on product innovation 9 2.1.3 Evolutionary approach for product innovation 11 2.2 Methodological background 17 2.2.1 Methodology for product evolution . 17 Chapter 3. Conceptual background for product evolution 20 3.1 Definition of product 20 3.1.1 Technical and service characteristics in a product 20 3.1.2 Functional modules 23 3.2 Principle for product evolution 28 3.2.1 Descent with modification 28 3.2.2 Combinatorial innovation . 29 Chapter 4. Representation method for product . 32 4.1 Introduction 32 4.2 Model 35 4.2.1 Heterogeneous product gene network . 35 4.2.2 Product gene embedding 38 4.2.3 Functional module. 41 4.2.4 Model summary . 43 4.3 Empirical research 43 4.3.1 Data: Mobile product 43 4.3.2 Result 47 4.3.3 Validation 70 4.3.4 Implication 74 4.4 Sub-conclusion 78 Chapter 5. Product phylogenetic network 82 5.1 Introduction 82 5.2 Model 85 5.2.1 Evolutionary relationship between products 85 5.2.2 Product phylogenetic network (PPN) 88 5.2.3 Evolutionary path for product evolution: Product lineage 92 5.2.4 Product phylogenetic tree (PPT) 98 5.2.5 Model summary 101 5.3 Empirical research . 101 5.3.1 Mobile product phylogenetic network . 101 5.3.2 Sub-PPN of mobile product 110 5.3.3 Lineage of mobile product . 114 5.3.4 Mobile product phylogenetic tree 125 5.3.5 Validation 135 5.4 Sub-conclusion . 141 Chapter 6. Product Speciation . 143 6.1 Introduction 143 6.2 Product Speciation . 145 6.2.1 Conceptual background 145 6.2.2 Product speciation in product phylogenetic network 151 6.2.3 Speciation index 156 6.3 Empirical research . 158 6.3.1 Vertical inheritance & horizontal gene transfer in mobile product 158 6.3.2 Mobile product taxon 164 6.3.3 Mobile product speciation 176 6.4 Strategy for product development: Speciation coordinate . 193 6.5 Sub-conclusion . 210 Chapter 7. Conclusion . 215 7.1 Summary of the study 215 7.2 Implications 217 7.3 Limitation and future studies 219 Bibliography 222 Appendix 1: Embedding results of five metapaths mobile HPGN 236 Appendix 2: Dimensionality reduction 242 Appendix 3: Product gene embedding hyperparameter experiment . 247 Appendix 4: Distance measures 253 Appendix 5: Hierarchical clustering . 255 Appendix 6: Robustness check for representation method 257 Appendix 7: Product innovativeness . 265 Appendix 8: Mixed effect model 271 Abstract (Korean) 274박

E prostanoid receptor 4 를 발현하는 큰포식세포의 Cxcl1 생산을 통한 염증성 대장염의 점막회복 유도 기전 연구

학위논문(박사)--서울대학교 대학원 :의과대학 의학과,2020. 2. 석승혁.Restoration of epithelial barrier function prevents chronic inflammation upon facing intestinal microflora when tissue damages have occurred. Dysfunctional tissue regeneration is commonly considered to be a cause of inflammatory bowel diseases (IBDs). Macrophage is a fundamental component of wound healing, however, the key elements for generating a tissue regenerating phenotype of intestinal macrophage remain elusive. Here I found that E prostanoid receptor 4 (EP4) expression in macrophages is critically required for tissue regeneration in a damaged intestinal milieu. Csf1r-Cre/Esr1EP4fl/fl mice did not go through appropriate tissue regeneration with shortened colon length and prolonged disease activity index after recovery phase of dextran sodium sulfate induced colitis model. EP4+ macrophages are marked by high CD206 expression and high intracellular cAMP level at the resolution phase of colitis, implicating a functional significance of EP4 in the formation of wound healing macrophages. RNA sequencing from sorted macrophages identified a Cxcl1 secreted from EP4+ intestinal macrophages as a driving factor for the epithelial proliferation from regenerating crypts via the PGE2/EP4/MAPK signaling axis. These studies thus define an important role of EP4 expression on intestinal macrophages to revive damaged epithelium.장 조직이 손상되었을 때 장 상피세포 장벽의 회복은 장관내 미생물 균총을 격리하여 만성적인 염증이 일어나는 것을 막아준다. 따라서 장 조직의 재생이 제대로 일어나지 않으면 장관내 미생물에 대한 면역반응이 지속적으로 일어나 염증성 대장염을 야기하게 되며 질환으로부터의 완전한 회복을 위해서는 손상된 장 조직이 적절한 재생을 거쳐 해부학적 장벽을 형성해야 한다. 큰포식세포는 상처 치유의 기본적인 요소 중에 하나로 잘 알려져 있으나 장에 있는 큰포식세포의 조직 재생 능력에 기여하는 주요한 요소가 무엇인지에 대해서는 잘 알려져 있지 않다. 본 연구에서는 큰포식세포에서 지질매개인자인 PGE2의 수용체 중 하나인 EP4 수용체의 발현이 손상 받은 장 조직 재생에 핵심적으로 관여하는 것을 증명하였다. 먼저 큰포식세포 특이적으로 EP4를 발현하지 않는 마우스 (Csf1r-Cre/Esr1EP4fl/fl)를 제작하여 대장염을 일으킨 후 장염의 회복기에 여전히 짧은 장 길이 및 높은 질병 활성도 등을 확인하여 장염의 회복이 잘 일어나지 않음을 확인하였다. 또한 EP4 를 발현하는 큰포식세포는 CD206를 높게 발현하고 있었으며 세포 내 cAMP 를 많이 발현하고 있었다. 이는 EP4가 상처치유 큰포식세포 형성에 중요한 기능을 하고 있음을 암시하고 있다. 더 나아가 회복기 시기의 큰포식세포에 대한 대단위 유전체 분석을 통하여 EP4 신호전달 체계에 의한 큰포식세포의 조직재생능력 향상과 연관 있는 분자생물학적 기전을 확립하고자 하였다. 대단위 유전체 분석을 통하여 Cxcl1 의 발현이 Csflr-EP4-/- 마우스 유래 장 큰포식세포에서 크게 감소하는 것을 확인하였으며, Cxcl1 이 PGE2/EP4/MAPK 신호전달 체계를 통해서 crypt 의 분열을 도와 장 상피세포 분열을 촉진시킬 수 있음을 확인하였다. 본 연구결과로 염증성 대장염 모델의 조직 수복 시기에 조직의 적절한 재생이 이루어지기 위하여 EP4에 의한 큰포식세포의 PGE2/EP4/MAPK 신호전달체계 활성이 필요함을 확인하고 장 손상에 대한 재생 유도 반응의 전체적인 세포간 네트워크에서 큰포식세포가 Cxcl1생산을 통하여 관여하는 분자생물학적 기전을 새롭게 밝혔다.Introduction 1 Materials and Methods 4 Results 12 Discussion 58 References 63 Abstract in Korean 67Docto

Effects of medial septum deep brain stimulation for memory recovery in a memory impaired rat model established by 192 IgG-saporin injection

의과대학/박사The possibility of using deep brain stimulation (DBS) for memory enhancement was recently reported; however, the mechanisms underlying its effects are not precisely understood. This study was performed to find the therapeutic effects and mechanism of DBS using a memory impaired rat model. First, a spatial memory impaired rat model mimicking the cholinergic deficit in Alzheimer’s disease was established. Second, the effects of medial septum (MS)-DBS on this memory impaired rat model were investigated. Furthermore, to detect the stage of the memory process that was affected, DBS was delivered at different times. In the first experiment, 192 IgG-saporin was infused into the cerebral ventricle to cause selective cholinergic damage. Two weeks later, cholinergic denervation caused spatial memory impairment in the Morris water maze test and glucose hypometabolism of the cingulate cortex in the [F-18] fluorodeoxyglucose PET study. In the second experiment, a 60-Hz stimulation was delivered to the MS to confirm the therapeutic effects of MS-DBS. During the 2-week stimulation, MS-DBS enhanced spatial memory and increased the number of doublecortin immunopositive cells in the hippocampus. Next, to detect the stage of the memory process affected by MS-DBS, stimulation was delivered at different times: pre-stimulation, 5days of before the water maze test; training-stimulation, 5days after the start of the training phase for the water maze; probe-stimulation, 2 h of stimulation shortly before the probe test of the water maze. The most effective memory restoration occurred in the pre-stimulation group in which the latency of the training phase was similar to that of the normal group. Moreover, the pre-stimulation group had a better recalled of the platform position than the other stimulation groups. An increase in the level of brain derived neurotrophic factor (BDNF) was observed in the pre-stimulation group that was maintained in both the frontal cortex and hippocampus. The level of glutamic acid decarboxylase 65/67, an enzyme that catalyzes the decarboxylation of glutamate to GABA, was reduced in the hippocampus. However, acetylcholinesterase activity in the pre-stimulation group was not different from the lesion group. These results suggest that the spatial memory improvement associated with MS-DBS is mainly correlated with increased BDNF expression in the frontal cortex and hippocampus, rather than with direct electrical stimulation of cholinergic or GABAergic neurons in the hippocampus. Taken together, the memory impairment caused by cholinergic denervation could be improved by MS-DBS (60Hz). Additionally, it has a significant correlation with the up-regulation of BDNF expression and neurogenesis. Based on the results of this study, the use of MS-DBS during the early stage of disease is thought to restore spatial memory impairments.ope

Which one will you choose; open, laparoscopic, or robotic transduodenal ampullectomy?: a case report

Transduodenal ampullectomy (TDA) is the treatment of choice for large premalignant lesions of the ampulla of Vater (AoV). With the development of surgical techniques, various methods, including the open, laparoscopic, and robotic approaches, for performing TDA have emerged. Herein, we report four consecutive cases treated with open, laparoscopic, and robotic TDA, with technical pitfalls and future perspectives of TDA in treating premalignant lesions of the AoV. The surgical techniques and principles for TDA were the same regardless of the surgical approaches. After surgery, none of the patients showed any abnormal findings or complications, except for digestive problems. All these surgical approaches are appropriate for patients requiring TDA; however, minimally invasive TDA, particularly the robotic approach is ideal. Considering the surgical complexity of TDA, the robotic approach is considered to be effective.ope

Iroquois Homeobox 1 Acts as a True Tumor Suppressor in Multiple Organs by Regulating Cell Cycle Progression

Iroquois homeobox 1 (IRX1) belongs to the Iroquois homeobox family known to play an important role during embryonic development. Interestingly, however, recent studies have suggested that IRX1 also acts as a tumor suppressor. Here, we use homozygous knockout mutants of zebrafish to demonstrate that the IRX1 gene is a true tumor suppressor gene and mechanism of the tumor suppression is mediated by repressing cell cycle progression. In this study, we found that knockout of zebrafish Irx1 gene induced hyperplasia and tumorigenesis in the multiple organs where the gene was expressed. On the other hands, overexpression of the IRX1 gene in human tumor cell lines showed delayed cell proliferation of the tumor cells. These results suggest that the IRX1 gene is truly involved in tumor suppression. In an attempt to identify the genes regulated by the transcription factor IRX1, we performed microarray assay using the cRNA obtained from the knockout mutants. Our result indicated that the highest fold change of the differential genes fell into the gene category of cell cycle regulation, suggesting that the significant canonical pathway of IRX1 in antitumorigenesis is done by regulating cell cycle. Experiment with cell cycle blockers treated to IRX1 overexpressing tumor cells showed that the IRX1 overexpression actually delayed the cell cycle. Furthermore, Western blot analysis with cyclin antibodies showed that IRX1 overexpression induced decrease of cyclin production in the cancer cells. In conclusion, our in vivo and in vitro studies revealed that IRX1 gene functionally acts as a true tumor suppressor, inhibiting tumor cell growth by regulating cell cycle.ope

Improvements in Memory after Medial Septum Stimulation Are Associated with Changes in Hippocampal Cholinergic Activity and Neurogenesis

Deep brain stimulation (DBS) has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS) electrode implantation (sham stimulation); group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.ope

Short and long-term outcomes of minimally invasive central pancreatectomy: Comparison with minimally invasive spleen-preserving subtotal distal pancreatectomy

Background: Central pancreatectomy(CP) is more complex surgery and higher complication rate than distal pancreatectomy(DP). However, with the development of minimally invasive surgery, CP has become a safer surgery technique. In this study, we compare minimally invasive CP(MI-CP) and Minimally invasive spleen-preserving subtotal DP(MI-SpSTDP) to figure out the short-term and long-term outcomes of MI-CP. Methods: From March 2007 to June 2020, 36 cases of MI-SpSTDP and 23 cases of MI-CP were performed for benign and borderline malignant pancreatic tumors in Severance hospital. The occurrence of postoperative pancreatic fistula(POPF) and Clavian-Dindo classification grade 3 or more in the two group was investigated, and the Controlling nutritional status scores(CONUT score) before and 1-year after surgery were compared to determine the long-term outcomes of exocrine function. Results: There was no difference in postoperative complications including POPF between the two groups(17.4% vs 5.1%, p = 0.294). And there were no statistical differences in either the MI-CP group (0.74 ± 0.75 vs. 0.78 ± 0.99, p = 0.803) or the MI-SpSTDP group (0.86 ± 0.83 to 0.61 ± 0.59, p = 0.071). Conclusions: MI-CP had longer operation time and hospital stay and is safe and effective in preserving endocrine and exocrine functions in treatment of benign or borderline tumors located at the neck or proximal body of the pancreas.ope

Aberrant Hedgehog ligands induce progressive pancreatic fibrosis by paracrine activation of myofibroblasts and ductular cells in transgenic zebrafish

Hedgehog (Hh) signaling is frequently up-regulated in fibrogenic pancreatic diseases including chronic pancreatitis and pancreatic cancer. Although recent series suggest exclusive paracrine activation of stromal cells by Hh ligands from epithelial components, debates still exist on how Hh signaling works in pathologic conditions. To explore how Hh signaling affects the pancreas, we investigated transgenic phenotypes in zebrafish that over-express either Indian Hh or Sonic Hh along with green fluorescence protein (GFP) to enable real-time observation, or GFP alone as control, at the ptf1a domain. Transgenic embryos and zebrafish were serially followed for transgenic phenotypes, and investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), in situ hybridization, and immunohistochemistry. Over-expression of Ihh or Shh reveals virtually identical phenotypes. Hh induces morphologic changes in a developing pancreas without derangement in acinar differentiation. In older zebrafish, Hh induces progressive pancreatic fibrosis intermingled with proliferating ductular structures, which is accompanied by the destruction of the acinar structures. Both myofibroblasts and ductular are activated and proliferated by paracrine Hh signaling, showing restricted expression of Hh downstream components including Patched1 (Ptc1), Smoothened (Smo), and Gli1/2 in those Hh-responsive cells. Hh ligands induce matrix metalloproteinases (MMPs), especially MMP9 in all Hh-responsive cells, and transform growth factor-ß1 (TGFß1) only in ductular cells. Aberrant Hh over-expression, however, does not induce pancreatic tumors. On treatment with inhibitors, embryonic phenotypes are reversed by either cyclopamine or Hedgehog Primary Inhibitor-4 (HPI-4). Pancreatic fibrosis is only prevented by HPI-4. Our study provides strong evidence of Hh signaling which induces pancreatic fibrosis through paracrine activation of Hh-responsive cells in vivo. Induction of MMPs and TGFß1 by Hh signaling expands on the current understanding of how Hh signaling affects fibrosis and tumorigenesis. These transgenic models will be a valuable platform in exploring the mechanism of fibrogenic pancreatic diseases which are induced by Hh signaling activation.ope

GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma

Background: Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. Method: In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. Results: PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19-9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19-9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. Conclusion: Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.ope