148 research outputs found
Notch Signaling: Mechanistic And Functional Studies In Intestinal Stem Cells And Colorectal Cancer Cells
No full text: The study of stem cell regulation in intestinal and colonic tissues is an area of significant focus within the scientific community, providing mechanistic insight into biological process and offering translational clinical potential. In this thesis we address the contribution of NOTCH signaling in maintaining the stem cell niche by modulating the mode of stem cell division and receptor-ligand interactions for cell-cell communication. Furthermore, we examine NOTCHmediated spatiotemporal recovery of the intestinal stem cell (ISC) niche following single cell ablation. Finally, we demonstrate that elevated NOTCH signaling exists under conditions of physiological stress and in colon cancer initiating cells (CCICs), promoting tumorigenic potential of the intestinal epithelium. Overall, our research highlights the underlying complexities of NOTCH signaling as an essential pathway to maintain intestinal homeostasis and may inspire development of novel CRC therapeutic strategies. Research efforts and findings during my graduate study have been consolidated into the following peer-reviewed publications, of which the four first co-author manuscripts are described in detail in this dissertation. 1. Srinivasan, Tara; Walters, Jewell; Bu, Pengcheng; Than, Elaine B.; Tung, Kuei-Ling; Chen, Kai-Yuan; Panarelli, Nicole; Milsom, Jeff; Augenlicht, Leonard; Lipkin, Steven M; Shen, Xiling. "NOTCH Signaling Regulates Asymmetric Division of Fast- and Slow-Cycling Colon Cancer Initiating Cells." Cancer Research, 2016. (in press) 2. Srinivasan, Tara; Than, Elaine B.; Bu, Pengcheng; Tung, Kuei-Ling; Chen, Kai-Yuan; Augenlicht, Leonard; Lipkin, Steven M.; Shen, Xiling. "NOTCH Signaling Regulates Fast- and Slow-Cycling Intestinal Stem Cells." Scientific Reports, 2016. (in press) 3. Chen, Kai-Yuan*; Srinivasan, Tara*; Choi, Jiahn*; Bu, Pengcheng; Tung, Kuei-Ling; Nishimura, Nozomi; Shen, Xiling. "Dynamic regulation of intestinal stem cell niche recovery in real-time." Cell Systems, 2015. (in review) 4. Murthy, Preetish KL*; Srinivasan, Tara*; Bochter, Skye; Bu, Pengcheng; Cole, Susan; Shen, Xiling. "FRINGE-dependent modification of NOTCH Ligands in Intestinal Stem Cells." 2016. (in preparation) 5. Rothschild, Daniel; Srinivasan, Tara; Aponte-Santiago, Linette; Shen, Xiling; Irving, Allen. "The Ex Vivo Culture and Pattern Recognition Receptor Stimulation of Mouse Intestinal Organoids." JoVE, 2015. (in press) 6. Bu, Pengcheng*; Wang, Lihua*; Chen, Kai-Yuan; Srinivasan, Tara; Lakshminarasimha, Preetish; Tung, Kuei-Ling; Varanko, Anastasia; Ai, Yiwei; Lipkin, Steven; Shen, Xiling. "miR34a and Numb synergize for asymmetric cell fate determination." Cell Stem Cell, 2016 Feb 4;18(2):189-202. 7. Crespo, Miguel; Tsai, Su-Yi; Srinivasan, Tara; Pipalia, Nina; Maxfield, Nina; Lipkin, Steven M; Evans, Todd; Chen, Shuibing. "Colonic Organoids Derived from Human Pluripotent Stem Cells for Modeling Colorectal Cancer and Drug Testing." Nature Medicine, 2015. (in review) 8. Wang, Lihua*; Bu, Pengcheng*; Ai, Yiwel; Srinivasan, Tara; Lipkin, Steven M; Shen, Xiling. "A Long Non-Coding RNA Targets MicroRNA miR-34a to Regulate Colon Cancer Stem Cell Asymmetric Division." eLife, 2016. (in press
Wei sheng bao jian: [24 juan, bu yi]. v.48
No full text羅天益撰 ; [李錫齡輯]宏道書院藏板.Date from preface.Luo Tianyi zhuan ; [Li Xiling ji]Hong dao shu yuan cang ban
sj-docx-2-jva-10.1177_11297298211052528 – Supplemental material for Identifying the impact of the Zone Insertion MethodTM (ZIMTM): A randomized controlled trial
No full textSupplemental material, sj-docx-2-jva-10.1177_11297298211052528 for Identifying the impact of the Zone Insertion MethodTM (ZIMTM): A randomized controlled trial by Chunli Huang, Zhenming Wu, Weihua Huang, Xinghong Zhang, Xiling Lin, Jielin Luo, Lihua Li and Jia Li in The Journal of Vascular Access</p
sj-docx-1-jva-10.1177_11297298211052528 – Supplemental material for Identifying the impact of the Zone Insertion MethodTM (ZIMTM): A randomized controlled trial
No full textSupplemental material, sj-docx-1-jva-10.1177_11297298211052528 for Identifying the impact of the Zone Insertion MethodTM (ZIMTM): A randomized controlled trial by Chunli Huang, Zhenming Wu, Weihua Huang, Xinghong Zhang, Xiling Lin, Jielin Luo, Lihua Li and Jia Li in The Journal of Vascular Access</p
Regulation of intestinal stem cell niche and colon cancer: from biology to therapy
No full text136 pagesThe intestine is one of the fastest regenerative tissues in the body, and homeostasis of the tissue requires robust regulations of intra- and inter-cellular signaling. The stem cells reside at crypt bottom of intestinal epithelium serve as the workhorse of tissue regeneration and keep the tissue homeostasis. When dysregulated events occur to normal intestine cells, cancerous cells often emerge with unchecked cell growth and perturbed cell death, and escape from rigorous mechanisms of cellular signaling regulations. Colorectal cancer (CRC) is one of the most common cause of cancer deaths. Current treatments include surgery and chemotherapy, but disease recurrence occurs frequently. The continuous renewal of intestinal epithelium relies on the presence of intestinal stem cells that could be at the origin of CRC and contribute to therapy resistance and metastases. Several cell signaling pathways and regulatory elements involve in both intestinal cell homeostasis and tumorigenesis. My studies focus on understanding the regulation in intestinal stem cell niche and applying transcriptome and chromatin accessibility profiling to investigate drug resistance in colon cancer. Tissue homeostasis requires rigorous control mechanisms for stem cell division and maintenance of a stable stem cell niche. In the intestinal stem cell (ISC) niche, ISCs and Paneth cells form a stable pattern to control stem cell behavior. However, how is the stem cell niche pattern dynamically regulated and maintained in a rapid regenerative environment still remains unclear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. This study highlights the importance of Notch 1 positive feedback mechanisms in spatiotemporal control of the stem cell niche. Patients with advanced colorectal cancer (CRC) develop chemoresistance to current standard-of-care therapies. We used patient-derived organoids (PDO) from metastatic CRC patients and integrated chromatin and transcriptomic profiling to show that resistant tumor cells remodel their chromatin in response to chemotherapy. Personalized therapy with pharmacological inhibitor of FGFR1 or OXTR, two novel targets for resistant CRC, circumvents oxaliplatin resistance. This study demonstrates the combination of PDO and integrated chromatin/transcriptomic analysis as a potential precision medicine platform to overcome chemoresistanc
The Logic of Homophily Dynamics in Heterogeneous Networks: Axiomatization, Model Checking and Validity Checking
No full textSocial networks have received considerable attention from the modal logic community. In this article, we study and characterize one of the most important principles in the field of social networks. Homophily, which means similarity breeds association, reveals the nature of social organization. In order to be able to express similarity and association together, we generalize the basic network and then define the heterogeneous network. The heterogeneous network is also defined to provide a good foundation for the use of logical approaches. The Logic of Homophily LHG,M that we propose in this article is based on Computation Tree Logic and Formal Concept Analysis. LHG,M describes the homophily dynamics of the heterogeneous networks at a specified similarity coefficient. Furthermore, we not only axiomatize the LHG,M and prove that the axiom system LHG,Mn is sound and complete, but we also prove that the model checking and the validity checking for LHG,M are both PSPACE-complete
Dynamic Temporal Logic of Subjective Homophily
No full textHomophily, which means similarity breeds association, is one of the most fundamental principles in social organization. However, in some cases, homophily is not significant, because actors’ perceptions of others differ from the real situation. In this article, we use the term “subjective homophily” to describe the homophily where the perceived similarity of objects is considered. In addition, we also consider social influence, which is closely related to homophily and represents the diffusion of some attributes through associations. In short, the dynamic temporal logic LoSHG,MSC we propose in this article is based on computation tree logic (CTL), which is used to describe the evolution of networks by subjective homophily, and dynamic logic (DL), which provides the dynamic update operator for representing active social influence. Furthermore, we prove that the model checking problem and the validity checking problem for LoSHG,MSC are both PSPACE-complete. Finally, we use an example, named false consensus, to illustrate how logic captures the subjective homophily evolution of networks and the impact of active social influence on evolution and structure
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