MECHANISMS OF CADMIUM-INDUCED AND EPIDERMAL GROWTH FACTOR RECEPTOR MUTATION-DRIVEN LUNG TUMORIGENESIS

Cadmium (Cd) is a ubiquitous pollutant in the environment and a known carcinogen for lung cancer. Cd has been shown to act as a weak mutagen, which suggests that it may exert tumorigenic effect through non-genotoxic ways, such as epigenetic mechanisms. The goal of this project is to investigate the mechanisms of Cd carcinogenesis focusing on the role of lncRNA dysregulations. The Cd-exposed cells formed significantly more colonies in soft agar, displayed cancer stem cell (CSC)-like property and formed tumors in nude mice. Mechanistically, the lncRNA microarray analysis revealed that chronic Cd exposure dysregulates lncRNA expressions. Q-PCR analysis confirmed the significant upregulation of the oncogenic lncRNA DUXAP10 level in Cd-transformed cells. Knockdown of DUXAP10 in Cd-transformed cells significantly reduced their CSC-like property. Further mechanistic studies showed that DUXAP10 activates the Hedgehog pathway to promote Cd-induced CSC-like property. Furthermore, it was determined that chronic Cd exposure upregulates DUXAP10 expression by inducing Pax6 expression. In addition to oncogenic lncRNA upregulation, Cd exposure was also found to downregulate the expression of a tumor suppressive lncRNA MEG3 in Cd-transformed cells. Meanwhile, the levels of DNMTs in Cd-transformed cells were found significantly elevated. Bisulfite-sequencing study revealed that the differentially methylated region (DMR) upstream of MEG3 is hypermethylated in Cd-transformed cells, indicating that the promoted DNMTs activity contributed to downregulation of MEG3. Stably expressing MEG3 in Cd-transformed cells decreased cell proliferation and induced CSC-like property. Further studies showed that MEG3 inhibits cell transformation by limiting cell proliferation and inducing apoptosis. Mechanistic studies revealed that MEG3 reduced cell proliferation by regulating the levels of cell cycle proteins and induced apoptosis by inhibiting the level of Bcl-xL. These findings suggest that dysregulations of lncRNAs play important roles in Cd carcinogenesis. As well as epigenetic dysregulations, we also determined the effect of genetic factor contributing to lung cancer. Enhanced EGFR signaling contributes to 60% of NSCLC cases. However, there is an unmet need to solve acquired resistance to tyrosine kinase inhibitors and low response rate for immunotherapy in lung cancer patients. This study was performed to investigate the role of SOCS3 in EGFR mutation-driven lung cancer and to explore the potential of its regulatory axis as therapeutic target for the development of novel approach. In our transgenic mouse model, overexpression of SOCS3 significantly inhibited tumor formation with mutated EGFR. Further investigation for the underlying mechanism revealed that SOCS3 downregulates YAP protein, which further suppressed Bcl-2 family proteins. External YAP inhibitor was shown to efficiently inhibit the growth of tumor organoids. In vivo studies demonstrated that SOCS3 downregulating YAP leads to less immunosuppressive tumor microenvironment. Lastly, SOCS3 was often found to be silenced in cancers. To mimic this circumstance, the therapeutic efficacy of utilizing external YAP inhibitor combined with anti-PD-L1 was assessed and showed promising outcomes. These results suggest the critical role of SOCS3 as a biomarker for the oncolytic immune environment and provide a novel insight for improving lung cancer immunotherapy

Hydrodynamical Simulations of the Barred Spiral Galaxy NGC 1097

NGC 1097 is a nearby barred spiral galaxy believed to be interacting with the elliptical galaxy NGC 1097A located to its northwest. It hosts a Seyfert 1 nucleus surrounded by a circumnuclear starburst ring. Two straight dust lanes connected to the ring extend almost continuously out to the bar. The other ends of the dust lanes attach to two main spiral arms. To provide a physical understanding of its structural and kinematical properties, two-dimensional hydrodynamical simulations have been carried out. Numerical calculations reveal that many features of the gas morphology and kinematics can be reproduced provided that the gas flow is governed by a gravitational potential associated with a slowly rotating strong bar. By including the self-gravity of the gas disk in our calculation, we have found the starburst ring to be gravitationally unstable which is consistent with the observation in \citet{hsieh11}. Our simulations show that the gas inflow rate is 0.17 M_\sun yr$^{-1}$ into the region within the starburst ring even after its formation, leading to the coexistence of both a nuclear ring and a circumnuclear disk.Comment: 32 pages, 14 figures, 1 table, accepted for publication in the Ap

Holomorphic CFTs and topological modular forms

We use the theory of topological modular forms to constrain bosonic holomorphic CFTs, which can be viewed as $(0,1)$ SCFTs with trivial right-moving supersymmetric sector. A conjecture by Segal, Stolz and Teichner requires the constant term of the partition function to be divisible by specific integers determined by the central charge. We verify this constraint in large classes of physical examples, and rule out the existence of an infinite set of extremal CFTs, including those with central charges $c=48, 72, 96$ and $120$.Comment: 7 pages; v2: references adde

Study of the Conditions that Determine the Formation of Coronal Mass Ejections Using Models of the Coronal Magnetic Field

doctoral thesi

General approach of causal mediation analysis with causally ordered multiple mediators and survival outcome

Causal mediation analysis with multiple mediators (causal multi-mediation analysis) is critical in understanding why an intervention works, especially in medical research. Deriving the path-specific effects (PSEs) of exposure on the outcome through a certain set of mediators can detail the causal mechanism of interest. However, the existing models of causal multi-mediation analysis are usually restricted to partial decomposition, which can only evaluate the cumulative effect of several paths. Moreover, the general form of PSEs for an arbitrary number of mediators has not been proposed. In this study, we provide a generalized definition of PSE for partial decomposition (partPSE) and for complete decomposition, which are extended to the survival outcome. We apply the interventional analogues of PSE (iPSE) for complete decomposition to address the difficulty of non-identifiability. Based on Aalen’s additive hazards model and Cox’s proportional hazards model, we derive the generalized analytic forms and illustrate asymptotic property for both iPSEs and partPSEs for survival outcome. The simulation is conducted to evaluate the performance of estimation in several scenarios. We apply the new methodology to investigate the mechanism of methylation signals on mortality mediated through the expression of three nested genes among lung cancer patients

Causal Mediation Analysis for Difference-in-Difference Design and Panel Data

Advantages of panel data, i.e., difference in difference (DID) design data, are a large sample size and easy availability. Therefore, panel data are widely used in epidemiology and in all social science fields. The literatures on causal inferences of panel data setting or DID design are growing, but no theory or mediation analysis method has been proposed for such settings. In this study, we propose a methodology for conducting causal mediation analysis in DID design and panel data setting. We provide formal counterfactual definitions for controlled direct effect and natural direct and indirect effect in panel data setting and DID design, including the identification and required assumptions. We also demonstrate that, under the assumptions of linearity and additivity, controlled direct effects can be estimated by contrasting marginal and conditional DID estimators whereas natural indirect effects can be estimated by calculating the product of the exposure-mediator DID estimator and the mediator-outcome DID estimator. A panel regression-based approach is also proposed. The proposed method is then used to investigate mechanisms of the effects of the Covid 19 pandemic on the mental health status of the population. The results revealed that mobility restrictions mediated approximately 45 % of the causal effect of Covid 19 on mental health status

物理模型試驗應用於順向坡板岩變形特性之研究

本文主要探討臺灣板岩順向坡變形特性，藉由現場調查、地形分析與物理模型試驗說明板岩不同條件下之重力變形特性，並推估板岩變形過程與潛在崩壞機制。結果顯示，坡趾侵蝕透空與降雨入滲機制為板岩變形之關鍵，其將造成板岩材料強度弱化加速發生變形。此外，板岩變形初始發生於崖頂張力區，坡體將沿著高角度葉理滑移，並於侵蝕弱化帶附近形成剪切破壞或複合型破壞。而變形範圍內具有相當多葉理張開之現象，其將有助於地表水與地下水滲入，促使板岩變形區加速變形至崩壞。This paper focuses on characterizing the deformation of consequent slate slopes in Taiwan. Onsite surveys, terrain analysis, and a physical model test are used to describe the characteristics of gravity-driven deformation under various conditions and identify the process of slate deformation as well as potential failure mechanisms. Slate deformation is shown to begin in the tension zone at cliff tops, wherein the slope body slips along the highly inclined foliation, contributing to shear failure or composite failure near the eroded zone of weakness. The phenomenon of foliation opening is widespread within the area of deformation, enabling surface water and groundwater to seep in, thereby accelerating deformation and failure in the slate deformation zone

Green tea inhibited the elimination of nephro-cardiovascular toxins and deteriorated the renal function in rats with renal failure

Chronic kidney disease (CKD) is a major health problem worldwide. Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are highly protein-bound nephro-cardiovascular toxins, which are not efficiently removed through hemodialysis. The renal excretions of IS and PCS were mediated by organic anion transporters (OATs) such as OAT1 and OAT3. Green tea (GT) is a popular beverage containing plenty of catechins. Previous pharmacokinetic studies of teas have shown that the major molecules present in the bloodstream are the glucuronides/sulfates of tea catechins, which are putative substrates of OATs. Here we demonstrated that GT ingestion significantly elevated the systemic exposures of endogenous IS and PCS in rats with chronic renal failure (CRF). More importantly, GT also significantly increased the levels of serum creatinine (Cr) and blood urea nitrogen (BUN) in CRF rats. Mechanism studies indicated that the serum metabolites of GT (GTM) inhibited the uptake transporting functions of OAT1 and OAT3. In conclusion, GT inhibited the elimination of nephro-cardiovascular toxins such as IS and PCS, and deteriorated the renal function in CRF rats