• Bisphosphonate-Related Osteonecrosis of the Jaw: From Mechanism to Treatment

      Howie, Rebecca; Department of Cellular Biology and Anatomy (2015-04-20)
      With 55 million prescriptions issued each year, bisphosphonates are the second most prescribed class of drug in the United States. They are widely used to treat diseases with excessive osteoclastic resorption, including post-menopausal osteoporosis, Paget’s disease, and tumor metastasis to bone. Unfortunately, with long term intravenous administration of nitrogen-containing bisphosphonates some patients develop bisphosphonate-related osteonecrosis of the jaw (BRONJ). This debilitating disease has limited treatment options once it has manifested and no mechanism for its development has been elucidated. This dissertation explores the novel concept that bisphosphonates cause osteonecrosis of the jaw by impairing osteocyte-induced osteoclastogenesis and, through the physical accumulation of bisphosphonates in bone, impairing the ability of recruited osteoclasts to attach thereby arresting bone healing. Furthermore, it explores the possibility that chelating agents can be used for the removal of bisphosphonate attachment from bone systemically and locally during extractions, potentially leading to a future preventive treatment. It was found that 13 weeks of 80µg/kg intravenous tail vein injections of Zoledronate followed by two mandibular molar extractions caused the clinical presentation of BRONJ as analyzed by the gross, radiographic, and histological methods. Bone dynamic parameters and TRAP staining suggested an impaired ability for the bone to remodel and defective osteoclast attachment in treated groups that persisted eight weeks after the cessation of treatment. Additionally, it was found through the use of a fluorescently tagged bisphosphonate, that the decalcifying agents cadmium, EDTA, and citric acid all had the ability to cause the significant release of bound bisphosphonate from bone. Finally, this dissertation showed that the migration of monocytes treated with low doses of Zoledronate had increased migration, while their migration to conditioned media of osteocytes treated with Zoledronate was impaired. Collectively, these data suggest that invasive trauma by itself consistently precipitated massive bone necrosis in Zoledronate treated animals, possibly through a bisphosphonate driven alteration of monocyte migration and that the use of decalcifying agents could acutely remove bisphosphonate from bone both systemically and locally. This study establishes and effective rodent model for BRONJ and a possible preventive strategy for the side-effects of bisphosphonates during high-risk situations.
    • Blinding Crystals: Monosodium Urate Crystals and Diabetic Retinopathy

      Amanamba, Udochukwu; Department of Psychological Sciences (Augusta University, 2020-12)
      Diabetic retinopathy (DR) is a common complication of diabetes and the main cause of blindness among adults of working age. Previous studies have established that high blood glucose levels (hyperglycemia) promote chronic sub-clinical inflammation which in turn causes retinal tissue injury and development of DR. It has also been shown that increased levels of uric acid, a by-product of the purine metabolism, generates crystals of monosodium urate (MSU) which could contribute to retinal inflammation and to the development of DR. My honors thesis project focused on investigating the molecular basis of inflammation in diabetic retinopathy (DR), specifically how MSU stimulates sterile inflammation in retinal blood vessels cells and in other retinal cells through the induction of the NLRP3-inflammasome. Human retinal endothelial (HuREC) and Human retinal epithelial cells (HuRPE) were treated with clinically relevant doses of MSU (6mg/dL) or high glucose (HG 25mM) or a combination of both. The expression of NLRP3 inflammasome constituents such as IL-1, NLRP3 protein, Toll-like receptor (TLR4), Gasdermin D (GSDMD) and Thioredoxin-interacting protein (TXNIP) were monitored using Western blotting analysis and ELISA assay. Morphometric analysis and ANOVA statistical approaches were employed to analyze the data. The results obtained showed that HuREC are more responsive to MSU alone than HuRPE. However, in all conditions, MSU significantly potentiated the production of inflammatory constituents of the NLRP3 inflammasome. Overall, the results of my studies support MSU as a contributing factor to the pathogenesis of DR. This suggests that uricemia should be monitored in diabetic patients and hypouricemic drugs could be helpful in combating DR and vision loss in diabetic patients.
    • Blood lead level and risk of asthma.

      Joseph, Christine L.M.; Havstad, Suzanne L; Ownby, Dennis R; Peterson, Edward L; Maliarik, Mary; McCabe, Michael J; Barone, Charles; Johnson, Christine Cole; Department of Pediatrics (2005-07-08)
      Asthma and lead poisoning are prevalent among urban children in the United States. Lead exposure may be associated with excessive production of immunoglobulin E, possibly increasing asthma risk and contributing to racial disparities. The objective of this study was to examine racial differences in the association of blood lead level (BLL) to risk of developing asthma. We established and followed a cohort prospectively to determine asthma onset, using patient encounters and drug claims obtained from hospital databases. Participants were managed care enrollees with BLL measured and documented at 1-3 years of age. We used multiple variable analysis techniques to determine the relationship of BLL to period prevalent and incident asthma. Of the 4,634 children screened for lead from 1995 through 1998, 69.5% were African American, 50.5% were male, and mean age was 1.2 years. Among African Americans, BLL > or = 5 and BLL > or = 10 microg/dL were not associated with asthma. The association of BLL > or = 5 microg/dL with asthma among Caucasians was slightly elevated, but not significant [adjusted hazard ratio (adjHR) = 1.4; 95% confidence interval (CI), 0.7-2.9; p = 0.40]. Despite the small number of Caucasians with high BLL, the adjHR increased to 2.7 (95% CI, 0.9-8.1; p = 0.09) when more stringent criteria for asthma were used. When compared with Caucasians with BLL < 5 microg/dL, African Americans were at a significantly increased risk of asthma regardless of BLL (adjHR = 1.4-3.0). We conclude that an effect of BLL on risk of asthma for African Americans was not observed. These results demonstrate the need for further exploration of the complex interrelationships between race, asthma phenotype, genetic susceptibilities, and socioenvironmental exposures, including lead.
    • Blood pressure impacts the renal T cell profile of male and female spontaneously hypertensive rats

      Tipton, Ashlee J.; Department of Physiology (2014-03)
      Of the 68 million Americans with hypertension, fewer than 46% have their blood pressure (BP) adequately controlled and women are more likely than men to have uncontrolled hypertension. This underscores the critical need for new treatment options; however, this is a challenge due to our lack of knowledge regarding the mechanism(s) driving essential hypertension. T cells have been implicated in hypertension in males. Prior to our work, the role of T cells in hypertensive females had been unexplored. We demonstrate that female spontaneously hypertensive rats (SHR) have a decrease in BP in response to an immunosuppressant, supporting an immune component to their hypertension. We further defined a sex difference in the renal T cell and cytokine profile in SHR. Female SHR have a more anti-inflammatory immune profile in their kidneys than males. To gain insight into the mechanisms mediating sex differences in the immune profile, male and female SHR were gonadectomized. Gonadectomy increased pro-inflammatory markers in both sexes and attenuated anti-inflammatory markers particularly in females. Therefore, while both male and female sex hormones promote an anti-inflammatory immune profile, female ii sex hormones contribute greater to their more anti-inflammatory profile, but do not explain the sex difference. To determine the impact of hypertension on the renal immune profile, experiments measured renal T cells and cytokines in hypertensive male and female SHR, normotensive Wistar Kyoto rats (WKY), and SHR treated with antihypertensive therapy. All T cells and cytokines measured were higher in SHR compared to the same sex WKY. Moreover, antihypertensive therapy decreased renal Tregs only in female SHR. These data suggest that increased BP in both sexes is associated with an increase in renal inflammation; however female SHR have a compensatory increase in renal Tregs in response to increases in BP. TGF-β is a key cytokine regulating Treg and Th17 differentiation and we found that female SHR express more TGF-β than males. Experiments assessed if female SHR possessed a sex hormone or BP-mediated increase in renal TGF- β corresponding with increases in Tregs. We determined that loss of female sex hormones and increased BP in female SHR increase renal TGF-β expression. We conclude that BP status drive sex differences in the renal T cell and cytokine profile of SHR.
    • Blurred Lines within the Music Industry: A Different Perspective of Copyright Law and Sampling in the Digital Age

      Wingate, Montrel; Department of History, Anthropology & Philosophy; Turner, Wendy; VanTuyll, Debra; VanTuyll, Hubert; Augusta University (2019-02-13)
      This thesis focuses on the relationship of music and law. Throughout, the debated question is: should the laws of copyright be redefined? The case Williams v. Bridgeport Music, Inc., which focuses on the songs "Blurred Lines" by Robin Thicke and "Got to Give It Up" by Marvin Gaye is the trial central to this thesis. Following a brief history of sampling, Williams v. Bridgeport Music, Inc. is reexamined, challenging the substantiality of the evidence presented. The court proved that the songs have similarities on the surface, yet there is a notable structural difference among the songs. A proposed solution is given, advocating a revision of copyright laws and a substantive similarity test with emphasis on the expert listener rather than the lay listener.
    • Blurred Lines within the Music Industry: A Different Perspective ofCopyright Law and Sampling in the Digital Age

      Wingate, Montrel; Department of History, Anthropology, & Philosophy (Augusta University, 2019-05)
      This thesis focuses on the relationship of music and law. Throughout, the debated question is: should the laws of copyright be redefined? The case Williams v. Bridgeport Music, Inc., which focuses on the songs "Blurred Lines" by Robin Thicke and "Got to Give It Up" by Marvin Gaye is the trial central to this thesis. Following a brief history of sampling, Williams v. Bridgeport Music, Inc. is reexamined, challenging the substantiality of the evidence presented. The court proved that the songs have similarities on the surface, yet there is a notable structural difference among the songs. A proposed solution is given, advocating a revision of copyright laws and a substantive similarity test with emphasis on the expert listener rather than the lay listener.
    • Boobi: An Eight-Part Teleplay

      Garcia, Jasmine; Department of Communications (Augusta University, 2017-12)
    • Bound Relativistic Motion in One Dimension

      Dains-McGahee, Sydney; Department of Mathematics (Augusta University, 2021-05)
      This project is a mathematical study of the relativistic dynamics of particles in one dimension moving under forces derivable from a potential. These motions and their nonrelativistic counterparts are described by Hamiltonian systems of differential equations. These Hamiltonian systems are in general nonlinear. Linear algebraic and differential equations are quite easy to solve – their solutions can be determined exactly – although the same cannot be said for nonlinear equations whose solutions can only be approximated (most of the time, with certain exceptions). We use numeric approximations to explore the relativistic and nonrelativistic simple harmonic oscillator and find that, unlike in the nonrelativistic case, the relativistic simple harmonic oscillator is not isochronous. We further study what happens to the period as the energy increases and then extend to exploring and comparing relativistic and nonrelativistic motions and periods for systems with forces given by power law potentials.
    • BrdU-positive cells in the neonatal mouse hippocampus following hypoxic-ischemic brain injury.

      Bartley, John H; Soltau, Thomas; Wimborne, Hereward J. C.; Kim, Sunjun; Martin-Studdard, Angeline; Hess, David C.; Hill, William D; Waller, Jennifer L.; Carroll, James E; Department of Pediatrics; et al. (2005-03-24)
      BACKGROUND: Mechanisms that affect recovery from fetal and neonatal hypoxic-ischemic (H-I) brain injury have not been fully elucidated. The incidence of intrapartum asphyxia is approximately 2.5%, but the occurrence of adverse clinical outcome is much lower. One of the factors which may account for this relatively good outcome is the process of neurogenesis, which has been described in adult animals. We used a neonatal mouse model to assess new cells in the hippocampus after H-I injury. RESULTS: Neonatal mice underwent permanent unilateral carotid ligation on the seventh postnatal day followed by exposure to 8% hypoxia for 75 minutes. The presence of new cells was determined by bromodeoxyuridine (BrdU) incorporation into cells with sacrifice of the animals at intervals. Brain sections were stained for BrdU in combination with neuronal, glial, endothelial and microglial stains. We found a significant increase in BrdU-positive cells in the neonatal mouse hippocampus in the injured area compared to the non-injured area, most prominent in the dentate gyrus (DG) (154.5 +/- 59.6 v. 92.9 +/- 32.7 at 3 days after injury; 68.9 +/- 23.4 v. 52.4 +/- 17.1 at 35 days after injury, p < 0.0011). Among the cells which showed differentiation, those which were stained as either microglial or endothelial cells showed a peak increase at three days after the injury in the DG, injured versus non-injured side (30.5 +/- 17.8 v. 2.7 +/- 2.6, p < 0.0002). As in the adult animal, neurogenesis was significantly increased in the DG with injury (15.0 +/- 4.6 v. 5.2 +/- 1.6 at 35 days after injury, p < 0.0002), and this increase was subsequent to the appearance of the other dividing cells. Numbers of new oligodendrocytes were significantly higher in the DG on the non-injured side (7.0 +/- 24.2 v. 0.1 +/- 0.3, p < 0.0002), suggesting that oligodendrocyte synthesis was reduced in the injured hippocampus. CONCLUSION: These findings demonstrate that the neonatal animal responds to brain injury with neurogenesis, much like the adult animal. In addition, H-I insult leads to more neurogenesis than hypoxia alone. This process may play a role in the recovery of the neonatal animal from H-I insult, and if so, enhancement of the process may improve recovery.
    • The c-MYC oncogene deregulates global DNA methylation and hydroxymethylation to control genome-wide gene expression for tumor maintenance in leukemia/lymphoma

      Poole, Candace Jean; Biomedical Sciences (Augusta University, 2019-05)
      Aberrant DNA methylation is a characteristic feature of tumor cells. However, our knowledge of how DNA methylation patterns are established and maintained to contribute to tumorigenesis is limited. Inactivation of the c-MYC oncogene triggers tumor regression in T-cell acute lymphoblastic leukemia (T-ALL) resulting in dramatic changes to the chromatin landscape including DNA methylation. In this study, I investigated how MYC regulates DNA methylation and hydroxymethylation patterns to contribute to gene expression programs important for tumor maintenance in T-ALL and Burkitt lymphoma. I report that MYC maintains 5-methylcytosine (5mC) and 5-hydroxy-methylcytosine (5hmC) patterns by regulating the DNA methylation machinery, which is important for gene expression in T-ALL. DNA methyltransferases (DNMTs) initiate 5mC marks, while Ten-eleven translocation methylcytosine dioxygenases (TETs) oxidize 5mC to produce 5hmC as an intermediate modification, ultimately leading to active DNA de-methylation. I demonstrated that DNMT1 and DNMT3B are MYC target genes and that their expression is dependent on high MYC levels. Knockdown of DNMT3B in T-ALL reduced cell proliferation through cell cycle arrest and caused the reactivation of gene transcription through reversing promoter/CpG island methylation. Furthermore, I demonstrated that TET1 and TET2 expression is MYC-dependent, as high TET1 and low TET2 levels depend on oncogenic MYC. Knockdown of TET1 in T-ALL reduced cell proliferation through cell cycle arrest and caused genome-wide changes in 5mC and 5hmC corresponding to changes in gene programs important for ribosomal biosynthesis and protein synthesis. In contrast, ectopic expression of TET2 reduced tumor cell proliferation through apoptosis/necrosis and caused genome-wide changes in 5mC and 5hmC corresponding to changes in transcriptional regulatory gene programs. My finding that a coordinated interplay between components of the DNA methylation machinery is necessary for MYC-driven tumor maintenance highlights the potential of targeting specific DNMT or TET proteins for therapeutic strategies.
    • Calpain-2 Activates Akt via the TGF~ 1-mTORC2 Pathway in Pulmonary Artery Smooth Muscle Cells

      Abeyrathna, Prasanna; Deparment of Pharmacology and Toxicology (8/23/2016)
      Calpain is a family of calcium-dependent nonlysosomal neutral cysteine endopeptidases. Akt is a serine/threonine kinase that belongs to the AGC kinases and plays important roles in cell survival, growth, proliferation, angiogenesis, and cell metabolism. Both calpain and Akt are downstream signaling molecules of platelet-derived growth factor (PDGF) and mediate PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) in pulmonary vascular remodeling. We found that inhibition of calpain-2 using the calpain inhibitor MDL28170 and calpain-2 siRNA attenuated Akt phosphorylation at serine-473 (S473) and threonine-308 (T308) as well as collagen synthesis and cell proliferation ofPASMCs induced by PDGF. Overexpression of calpain-2 in PASMCs induced dramatic increases in Akt phosphorylation at S4 73 and T308. Moreover, knockout of calpain attenuated Akt phosphorylation at S473 and T308 in smooth muscle of pulmonary arterioles of mice with chronic hypoxic pulmonary hypertension. The cell-permeable specific TGF~ receptor inhibitor SB431542 attenuated Akt phosphorylation at both S473 and T308 induced by PDGF and overexpressed calpain- 2 in PASMCs. Moreover, SB-431452 and knock down of ALK5 significantly reduced PDGF-induced collagen synthesis and cell proliferation of PASMCs. Nevertheless, neutralizing extracellular TGF~l using a cell-impermeable TGF~l neutralizing antibody did not affect PDGF-induced Akt phosphorylation at S473 and T308. Further, inhibition of mTORC2 by knocking down its component protein Rictor prevented Akt phosphorylation at S473 and T308 induced by PDGF and overexpressed calpain-2. These data provide the first evidence supporting that calpain-2 up-regulates PDGF-induced Akt phosphorylation via an intracrine TGF~ 1/mTORC2 mechanism.
    • CaMKIIβ association with F-actin in developing cortical neurons

      Lin, Yu-Chih; Department of Pharmacology and Toxicology (2008-08)
      Calcium/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase that is best known for its role in synaptic plasticity and memory .. Although multiple roles of CaMKII have been identified in the hippocampus, its role in the developing cerebral cortex is less well understood. Immunostaining showed Ca~KII~, but not CaMKIIa was expressed in embryonic day 18 (E 18) cortical neurons at 4 days in vitro (DIV) and localized to a F-actin rich cytoskeletal structure we termed "micro spike". Further characterization of micro spikes revealed that micro spikes were composed of bundled actin, and were stable over time. Besides CaMKII~, several actin binding proteins, such as Arp3, cortactiti"and ~1-integrin were also colocalized in microspikes. Fluorescence recovery after photo bleaching (FRAP) analyses showed different dynamics of actin and CaMKII~ in microspikes compared to dendrite spines. The colocalization of CaMKII~ and F-actin in microspikes was dependent on the F-actin binding domain and the oligomerization domain. FRAP analyses confirmed the association of CaMKIIP with F-actin in microspikes was via the F-actin binding domain. This association was altered by the co-expression of CaMKIIa. FRAP analyses with stabilized F-actin using jasplakinolide or cytochalasin-D further indicated CaMKIIP, but not CaMKIIa, had a strong interaction with stable F-actin. Inhibiting calmodulin binding on CaMKII using a CaMKII inhibitor, KN93, dissociated CaMKIIP from stable F-actin. Increasing CaMKIIP activity with KCl or an active form of CaMKIIP, CaMKIIPT287D, also dissociated CaMKIIP from stable F-actin. A calmodulin binding mutant, CaMKIIPA303R, or a kinase dead mutant, CaMKIIPK43R, however, did not recover differently from wildtype CaMKIIp. The differential binding of CaMKIIP with F-actin shown in FRAP analyses correlated with CaMKIIP enrichment in microspikes and the prominence of microspikes. While overexpressed CaMKIIP increased the number of cells with microspikes, knockdown of CaMKIIP with shRNA reduced it. Taken together, these data suggested that CaMKIIP is associated with F-actin in cortical neurons, and this association is regulated by CaMKIIa and calcium signals · contributing to the stability of micro spikes.
    • Can novel Apo A-I polymorphisms be responsible for low HDL in South Asian immigrants?

      Dodani, Sunita; Dong, Yanbin; Zhu, Haidong; George, Varghese; Department of Medicine (2010-03-19)
      Coronary artery disease (CAD) is the leading cause of death in the world. Even though its rates have decreased worldwide over the past 30 years, event rates are still high in South Asians. South Asians are known to have low high-density lipoprotein (HDL) levels. The objective of this study was to identify Apolipoprotein A-I (Apo A-I) polymorphisms, the main protein component of HDL and explore its association with low HDL levels in South Asians. A pilot study on 30 South Asians was conducted and 12-h fasting samples for C-reactive protein, total cholesterol, HDL, low-density lipoprotein (LDL), triglycerides, Lipoprotein (a), Insulin, glucose levels, DNA extraction, and sequencing of Apo A-I gene were done. DNA sequencing revealed six novel Apo A-I single nucleotide polymorphisms (SNPs) in South Asians, one of which (rs 35293760, C938T) was significantly associated with low (<40 mg/dl) HDL levels (P = 0.004). The association was also seen with total cholesterol (P = 0.026) and LDL levels (P = 0.032). This pilot work has highlighted some of the gene-environment associations that could be responsible for low HDL and may be excess CAD in South Asians. Further larger studies are required to explore and uncover these associations that could be responsible for excess CAD risk in South Asians.
    • Cancer Stressors and Protective Factors: Predictors of Stress Experienced During Treatment for Childhood Cancer

      Hockenberry-Eaton, Marilyn; Department of Physiological and Technological Nursing (1992-05)
      The purpose of this study was to evaluate cancer stressors and protective factors as predictors of stress experienced during treatment for childhood cancer. The conceptual framework evolved from the stress and coping literature and childhood cancer research. A convenience sample of 44 children between 6 ½ and 13 ½ years of age receiving treatment for cancer were evaluated during two clinic visits. Protective factors included the child’s self-perception, coping strategies, perceived social support, and family environment. Cancer stressors include acute stressors represented by the type of treatment received during two clinical visits. Chronic stressors were evaluated by the child’s perception of stressors related to the cancer experience. Responses to stressors were assessed by physiologic and psychologic indicators of stress. Physiologic measures include epinephrine, norepinephrine, and cortisol measures of urine and psychologic measures of state and trait anxiety. No significant differences were found in the physiologic or psychologic response to stressors in relation to the type of treatment received during either clinic visit. Epinephrine and norepinephrine were elevated for children during both clinic visits. Stepwise multiple regression analyses revealed that family expressiveness and the child’s perceived global self-worth were the best predictors of epinephrine levels. Family activities and recreation and family intellectual cultural orientation were the best predictors of state anxiety. The intensity of chronic cancer stressors, family activities and recreation, family intellectual cultural orientation, the child’s perception of physical appearance, and presence of family conflict had the greatest effect of trait anxiety. This study is the first to examine the child’s perception of chronic cancer stressors and protective factors associated with treatment for cancer. The findings provide insight into the importance of the interactions among the nature of the stressor, perceptual meaning of the stressor, and physiologic and psychologic responses to stressors that may affect long-term adjustment to childhood cancer.
    • Cannabidiol protects retinal neurons by preserving glutamine synthetase activity in diabetes.

      El-Remessy, Azza B.; Khalifa, Yousef; Ola, S; Ibrahim, Ahmed S.; Liou, Gregory I.; Department of Ophthalmology; Vision Discovery Institute (2010-08-31)
      PURPOSE: We have previously shown that non-psychotropic cannabidiol (CBD) protects retinal neurons in diabetic rats by inhibiting reactive oxygen species and blocking tyrosine nitration. Tyrosine nitration may inhibit glutamine synthetase (GS), causing glutamate accumulation and leading to further neuronal cell death. We propose to test the hypothesis that diabetes-induced glutamate accumulation in the retina is associated with tyrosine nitration of GS and that CBD treatment inhibits this process. METHODS: Sprague Dawley rats were made diabetic by streptozotocin injection and received either vehicle or CBD (10 mg/kg/2 days). After eight weeks, retinal cell death, M?�ller cell activation, GS tyrosine nitration, and GS activity were determined. RESULTS: Diabetes causes significant increases in retinal oxidative and nitrative stress compared with controls. These effects were associated with M?�ller cell activation and dysfunction as well as with impaired GS activity and tyrosine nitration of GS. Cannabidiol treatment reversed these effects. Retinal neuronal death was indicated by numerous terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL)-labeled cells in diabetic rats compared with untreated controls or CBD-treated rats. CONCLUSIONS: These results suggest that diabetes-induced tyrosine nitration impairs GS activity and that CBD preserves GS activity and retinal neurons by blocking tyrosine nitration.
    • Canonical Wnt Signaling in Antigen Presenting Cells Regulates Microbiota-Induced Inflammation and Immune Cell Homeostasis in the Colon

      Swafford, Daniel Joseph; Department of Biochemistry and Molecular Biology / Cancer Center (8/3/2018)
      Aberrant Wnt/β-catenin-signaling occurs in several inflammatory diseases including inflammatory bowel disease (IBD) and IBD-associated colon carcinogenesis. However, its role in shaping mucosal immune responses to commensals in the gut remains unknown. Here, we investigated the importance of canonical Wnt signaling in CD11c+ antigen presenting cells (APCs) in controlling intestinal inflammation. Using a mouse model of ulcerative colitis, we demonstrated that canonical Wnt-signaling in intestinal CD11c+ antigen presenting cells (APCs) controls intestinal inflammation by imparting an anti-inflammatory phenotype. Genetic deletion of Wnt co-receptors, low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in CD11c+ APCs in mice (LRP5/6ΔCD11c mice) resulted in enhanced intestinal inflammation with increased histopathological severity of colonic tissue. This was due to microbiota-dependent increased production of pro-inflammatory cytokines and decreased expression of immune regulatory factors such as IL-10, retinoic acid (RA), and IDO. In addition, loss of LRP5/6-mediated signaling in CD11c+ APCs resulted in altered microflora and T cell homeostasis, which led to a loss of systemic tolerance to oral antigen. Furthermore, our study demonstrates that conditional activation of β-catenin in CD11c+ APCs in LRP5/6ΔCD11c mice resulted in reduced acute intestinal inflammation with decreased histopathological severity of colonic tissue. Loss of canonical Wnt signaling in CD11c+ APCs also results in an increase in colonic polyp formation and exacerbation of chronic inflammation/injury. This was also heavily dependent on the presence and composition of the gut microbiota, as fecal transfers from LRP5/6ΔCD11c mice to floxed control (LRP5/6FL/FL) mice that were administered an antibiotic cocktail produces a polyp load and weight loss similar to that of LRP5/6ΔCD11c mice without treatment. Additionally, our study demonstrates that conditional activation of β-catenin in CD11c+ APCs in LRP5/6ΔCD11c mice reduces severity of inflammation-associated colon carcinogenesis in these mice. Furthermore, we show that treatment of LRP5/6ΔCD11c mice with either RA or IL-10 reduces severity of inflammation-associated colon carcinogenesis. Mechanistically, RA and IL-10 may independently reduce key inflammatory factors at the acute phase of colitis. These results ultimately reveal a mechanism by which intestinal APCs control intestinal inflammation and immune homeostasis via the canonical Wnt signaling pathway, which may serve as a promising target for chronic inflammatory disorders.
    • Carcinomatous Meningitis: The Natural History of Successfully Treated Metastatic Bladder Cancer

      Tadepalli, S.; Coleman, Teresa; Hackett, Ladawn A.; Liles, G.B.; Department of Medicine; Department of Pathology (2011-08-24)
      Carcinomatous meningitis due to bladder cancer is a rare entity reported only in case reports. Optimal therapy is thus poorly defined with earlier cases reporting an unsuccessful outcome. Here we report a case of late carcinomatous meningitis secondary to transitional cell carcinoma (TCC) of the bladder occurring in a patient in complete remission. He was successfully treated with intrathecal methotrexate and whole brain irradiation and experienced prolonged survival after treatment. With modern chemotherapy increasing complete remissions and survival rates in patients with TCC, more and more patients are being reported with carcinomatous meningitis. We raise the question of whether central nervous system prophylaxis should be considered in patients with TCC achieving a complete remission to chemotherapy in the metastatic setting.
    • Case Selection Criteria for use with Resin-Infiltrative Treatment of Enamel Decalcification

      Raley, N; Clayton, Ashley; Fortson, WM; Deleon, E; Rueggeberg, FA; Department of Orthodontics, Department of Restorative Sciences (Augusta University, 2019)
      Although one of the primary aims for many orthodontic patients is to achieve improvement in their dental esthetic condition, a high percentage of these patients develop unesthetic, white spot lesions (WSL) during the course of treatment. These lesions develop due to enamel decalcification resulting from bacterial plaque accumulation around difficult to clean brackets and overlying wires and ligation devices. Acids produced locally in this retained plaque will decalcify enamel along the peripheral border of the bonded bracket. Quite often, despite repeated admonishment by the clinician to the patient to take extra care in cleansing these susceptible locations, patients return with large plaque deposits around the brackets, and evidence of the early stages of enamel decalcification: the so-called “white spot lesion” (WSL). The problem becomes obvious at the time of bracket removal, when, although the teeth may now be arranged in near-to-perfect alignment and occlusion, large, white areas of enamel decalcification are prominently displayed, denoting the exact location of where the bonded bracket used to be.
    • Case Study: Legalize It All

      Wilder, Corneshia S.; Department of Sociology, Criminal Justice & Social Work (2017-03)
      Currently, there are over 20 states in the United States that made using marijuana legal for medical purposes. With nearly half of the states legalized marijuana, some believe that stronger illegal drugs, such as cocaine and meth, should be legalized. Dan Baum, a writer, wrote an article in Harper’s Magazine that it is time to “legalize it all”. Other do not believe that harder drugs should be legalized. Mark Kleiman, a public policy expert and professor, predicts that alcohol and cocaine addiction will rise if harder drugs become legal. Is it ethically permissible to legalize harder drugs in the United States? In my presentation, I am going to explain the case in detail. It will include information about the stakeholder and how each stakeholder will be affected. I will also explain my viewpoint of the case by using theories and statistics to explain my position in the case.