Why Integrating Research and Scholarship into Dental Education Matters

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153679/1/jddj002203372014783tb05683x.pd

Apoptosis and Predisposition To Oral Cancer

The term apoptosis, also known as programmed cell death (PCD), was coined by developmental biologists a number of years ago to describe a form of cell death characterized by several unique morphological and biochemical features. Genetic studies of the round worm Caeneorhabditis elegans, a simple multicellular organism, first revealed apoptosis to be an integral part of the developmental program. Subsequently, the importance of apoptosis in higher organisms was demonstrated in several eukaryotic systems. In mammals, apoptosis is widespread during embryogenesis and in adult tissues. It is required for normal tissue homeostasis and for clonal selection in the immune system. In both developing and adult organisms, apoptosis plays a central role in reinforcing appropriate cellular patterns and in regulating cell number by eliminating cells that are harmful or no longer needed. It is becoming increasingly clear that disruption in the apoptosis pathway can contribute to the development of a number of developmental, inflammatory, degenerative, and neoplastic diseases. The effector arm of the apoptotic program includes members of the Bcl-2 gene family that function as either death agonists or death antagonists. These proteins participate in an elaborate genetically controlled biochemical pathway that functions to maintain tissue and organ homeostasis and serve as a critical defense mechanism to guard against malignant transformation. Cancer is the result of a series of genetic lesions that include activation of oncogenes and inactivation or loss of tumor suppressor genes. Several groups of investigators have observed that deregulated expression of oncogenes can subvert apoptotic pathways, resulting in prolonged cell survival. In pathological settings such as cancer, members of the Bcl-2 gene family are able to synergize with oncogenes and tumor suppressor genes to transform cells. In this review, we describe the process of apoptosis in mammalian cells and define the role and biochemical pathways through which the Bcl-2 gene family induce and/or protect cells from apoptosis. Last, we will discuss the evidence which suggests that alterations in this pathway may play a central role in tumorigenesis by allowing genetically damaged cells normally destined for elimination to persist, predisposing them to additional mutations and driving them to malignancy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66687/2/10.1177_10454411990100020201.pd

Research and Discovery Science and the Future of Dental Education and Practice

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153692/1/jddjde017040.pd

Creation of a Scholars Program in Dental Leadership (SPDL) for Dental and Dental Hygiene Students

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153552/1/jddj0022033720097310tb04805x.pd

Role of Vascular Endothelial Growth Factor in Bone Marrow Stromal Cell Modulation of Endothelial Cells

One of the fundamental principles that underlies tissue-engineering strategies using cell transplantation is that a newly formed tissue must acquire and maintain sufficient vascularization in order to support its growth. Enhancing angiogenesis through delivery of growth factors is one approach to establishing a vascular network to these tissues. In this study, we tested the potential of bone marrow stromal cells (BMSCs) to modulate the growth and differentiation activities of blood vessel precursors, endothelial cells (ECs), by their secretion of soluble angiogenic factors. The growth and differentiation of cultured ECs were enhanced in response to exposure to BMSC conditioned medium (CM). Enzyme-linked immunosorbent assays demonstrated that both mouse and human BMSCs secreted significant quantities of vascular endothelial growth factor (VEGF) (2.4-3.1 ng/106 cells per day). Furthermore, eliminating the activity of BMSC-secreted VEGF with blocking antibodies completely blocked the CM effects on cultured ECs. These data demonstrate that human BMSCs secrete sufficient quantities of VEGF to enhance survival and differentiation of endothelial cells in vitro, and suggest they may be capable of directly orchestrating angiogenesis in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63256/1/107632703762687573.pd

Role of endothelial cell survival and death signals in angiogenesis

Angiogenesis, the process of new microvessel development, is encountered in a select number of physiological processes and is central to the pathogenesis of a wide variety of diseases. There is now convincing evidence that regulated patterns of endothelial cell survival and death, a process known as apoptosis, play a central role in the periodic remodeling of the vasculature, and in the timely evolution and regression of angiogenic responses. In this review we discuss the current evidence suggesting a role for inducers and inhibitors of angiogenesis as well as other mediators that modify endothelial cells functions in the survival and death of endothelial cells. We also discuss how dysregulation of apoptosis can lead to aberrant angiogenesis as demonstrated in the pathogenesis of retinopathy of prematurity and cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41762/1/10456_2004_Article_255969.pd

The response of VEGF-stimulated endothelial cells to angiostatic molecules is substrate-dependent

BACKGROUND: The microenvironment surrounding cells can exert multiple effects on their biological responses. In particular the extracellular matrix surrounding cells can profoundly influence their behavior. It has been shown that the extracellular matrix composition in tumors is vastly different than that found in normal tissue with increased amounts of certain matrices such as collagen I. It has been previously demonstrated that VEGF stimulation of endothelial cells growing on type I collagen results in the induction of bcl-2 expression and enhanced endothelial cell survival. We sought to investigate whether this increased endothelial cell survival resulted in the failure of angiostatic molecules to inhibit angiogenesis. RESULTS: We now demonstrate that VEGF-induced survival on collagen I impairs the ability of three known angiostatic molecules, TSP-1, IP-10 and endostatin to inhibit endothelial cell proliferation. Apoptosis of endothelial cells, growing on collagen I, induced by TSP-1 and IP-10 was also inhibited following VEGF stimulation. In contrast, endostatin induced apoptosis in these same cells. Further analysis determined that endostatin did not decrease the expression of bcl-2 nor did it increase activation of caspase-3 in the presence of VEGF. Alternatively, it appeared that in the presence of VEGF, endostatin induced the activation of caspase-8 in endothelial cells grown on collagen I. Furthermore, only endostatin had the ability to inhibit VEGF-induced sprout formation in collagen I gels. CONCLUSION: These data suggest that TSP-1, IP-10 and endostatin inhibit endothelial cells via different mechanisms and that only endostatin is effective in inhibiting angiogenic activities in the presence of collagen I. Our results suggest that the efficacy of angiostatic treatments may be impaired depending on the context of the extracellular matrix within the tumor environment and thus could impede the efficacy of angiostatic therapies

Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway

AbstractAs tumors continue to grow and exceed their blood supply, nutrients become limited leading to deficiencies in amino acids (AAD), glucose (GD), and oxygen (hypoxia). These alterations result in significant changes in gene expression. While tumors have been shown to overcome the stress associated with GD or hypoxia by stimulating vascular endothelial growth factor (VEGF)-mediated angiogenesis, the role of AAD in tumor angiogenesis remains to be elucidated. We found that in human tumors, the expression of the general control non-derepressible 2 (GCN2, an AAD sensor) kinase is elevated at both protein and mRNA levels. In vitro studies revealed that VEGF expression is universally induced by AAD treatment in all five cell lines tested (five of five). This is in contrast to two other angiogenesis mediators interleukin-6 (two of five) and fibroblast growth factor 2 (two of five) that have a more restricted expression. Suppressing GCN2 expression significantly decreased AAD-induced VEGF expression. Silencing activating transcription factor 4 (ATF4), a downstream transcription factor of the GCN2 signaling pathway, is also associated with strong inhibition of AAD-induced VEGF expression. PKR-like kinase, the key player in GD-induced unfolded protein response is not involved in this process. In vivo xenograft tumor studies in nonobese diabetic/severe combined immunodeficient mice confirmed that knockdown of GCN2 in tumor cells retards tumor growth and decreases tumor blood vessel density. Our results reveal that the GCN2/ATF4 pathway promotes tumor growth and angiogenesis through AAD-mediated VEGF expression and, thus, is a potential target in cancer therapy

Role of C‐X‐C chemokines as regulators of angiogenesis in lung cancer

Lung cancer is the leading cause of malignancy‐related mortality in the U.S. and is predicted to increase over the remainder of this decade. Despite attempts to advance early diagnosis and use combination therapies, the clinical response of this cancer yields an overall 5‐year survival rate of less than 15%. Clearly, new strategies for therapy are indicated. Although carcinogenesis is complex, tumor growth beyond 1–2 mm3 is dependent on angiogenesis. One of the potential mechanisms that allows for tumorigenesis is dysregulation of the balance of angiogenic and angiostatic factors that favors net neovascularization within the primary tumor. Numerous studies have investigated the role of a variety of molecules in the regulation of angiogenesis. Recently, interleukin‐8 (IL‐8), a member of the C‐X‐C chemokine family, has been found to be an angiogenic factor. In contrast, platelet factor 4 (PF4), another C‐X‐C chemokine, has been shown to have angiostatic properties. It is interesting that the major structural difference between IL‐8 and PF4 is the presence of the NH2‐terminal ELR (Glu‐Leu‐Arg) motif that precedes the first cysteine amino acid residue of IL‐8 and is important in ligand/receptor interactions. We hypothesize that angiogenesis associated with tumorigenesis is dependent on members of the C‐X‐C chemokine family acting as either angiogenic or angiostatic factors. This paradigm predicts that the biological balance in the expression of these C‐X‐C chemokines dictates whether the neoplasm grows and develops metastatic potential or regresses. In this review we discuss our recent laboratory findings that support this contention and suggest that further elucidation of the biology of C‐X‐C chemokines in the context of neovascularization of nonsmall cell lung cancer will permit novel targeted therapy aimed specifically at attenuating tumor growth and metastasis. J. Leukoc. Biol. 57: 752–762; 1995.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141888/1/jlb0752.pd

Integrative and collaborative care models between pediatric oral health and primary care providers: a scoping review of the literature

ObjectivesCollaborative and/or integrative care between oral health and primary care providers can increase access to care to a more expansive population, helping to mitigate oral health related disease. The objective of this review was to present and evaluate different types of care models that exist between oral health and primary care providers in pediatric settings.MethodsA literature search was conducted using five databases: MEDLINE/PubMed, ISI Web of Science, Dentistry and Oral Sciences Source, Cochrane Database, and EMBASE, to identify literature from January 1990 to January 2016. Combinations of controlled terms were utilized. Eligible sources targeted pediatric populations ages 1‐17 and provided descriptions of existing collaborative and/or integrative models.ResultsData related to the practice model, oral care provided, level of integration/collaboration and workflow were extracted. Sixteen articles were included that discussed 24 models of collaboration. These models provided ranges of services, but each offered a minimum of oral health risk assessment, oral health instruction, topical fluoride application and assessment for further treatment. These models included different levels of collaboration based off a ranking system created by the authors with 16.6 percent (4) classified as low, 54.2 percent (13) as medium and 29.2 percent (7) as high.ConclusionsExisting care models offered varying services and levels of integration and/or collaboration, but each offered a baseline of oral care. Most of these collaborations were based within Federally Qualified Health Centers and aimed to ease access to care issues.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145544/1/jphd12267.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145544/2/jphd12267_am.pd