Adv Exp Med Biol
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Subpopulations of cancer cells with stem cell-like characteristics, termed cancer stem cells, have been identified in a wide range of human cancers. Cancer stem cells are defined by their ability to self-renew as well as recapitulate the original heterogeneity of cancer cells in culture and in serial xenotransplants. Not only are cancer stem cells highly tumorigenic, but these cells are implicated in tumor resistance to conventional chemotherapy and radiotherapy, thus highlighting their significance as therapeutic targets. ⋯ More specifically, the core stem cell signaling pathways, such as the Wnt, Notch and Hedgehog pathways, also critically regulate the self-renewal and survival of cancer stem cells. While the oncogenic functions of Notch pathway have been well documented, its role in cancer stem cells is just emerging. In this chapter, we will discuss recent advances in cancer stem cell research and highlight the therapeutic potential of targeting Notch in cancer stem cells.
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The complement system plays a major role in innate immune defenses against infectious agents, but exaggerated activation of complement can lead to severe tissue injury. Systemic (intravascular) activation of complement can, via C5a, lead to neutrophil (PMN) activation, sequestration and adhesion to the pulmonary capillary endothelium, resulting in damage and necrosis of vascular endothelial cells and acute lung injury (ALI). Intrapulmonary (intraalveolar) activation of complement can cause ALI that is complement and PMN-dependent, resulting in a cytokine/chemokine storm that leads to intense ALI. ⋯ There is accumulating evidence that C5a may suppress inflammatory responses or divert them from Th1 to Th2 responses, impacting the innate immune system. Finally, in experimental polymicrobial sepsis, there is evidence that many of the adverse outcomes can be linked to the roles of C5a and engagement of its two receptors, C5aR and C5L2. These observations underscore the diversity of effects of C5a in a variety of inflammatory settings.
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Intervertebral disc (IVD) degeneration is a disease of the discs connecting adjoining vertebrae in which structural damage leads to degeneration of the disc and surrounding area. Degeneration of the disc is considered to be a normal process of aging, but can accelerate faster than expected or be precipitated by other factors. ⋯ We will provide a brief overview of the anatomic, cellular, and molecular structure of the IVD, and delve into the cellular and molecular pathophysiology surrounding IVD degeneration. We will then highlight some of the newest developments in stem cell, protein, and genetic therapy for IVD degeneration.
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Advancement of in vitro osteogenesis, or the production of bone, is a complex process that has significant clinical implications. Surgical intervention of several spinal disorders entails decompression of the spinal cord and nerves which can lead to subsequent biomechanical instability of the spine. Spinal arthrodesis (fusion) is often required to correct this instability and necessary to eliminate the resulting pathological motion of vertebral segments. ⋯ Here, we describe their individual roles, as well as pose novel concepts on how their collective role may be the optimal strategy to improve upon in vitro osteogenesis and whether this could also be translated to improved bone formation in vivo. Further, we discuss the various molecular markers that are available for cell identification and the tissue engineering strategies that could replicate the osteoinductive, osteoconductive and osteoproductive milieuthat is available in autograft. Finally, we present a broad primer on the possible integration of cellular, molecular and tissue engineering strategies to improve osteogenesis and the future trends that may bring the promise seen in the laboratory to fruition in preclinical animal models.