The University of Maryland Graduate School Baltimore (UMGSB) offers 27 master's and doctoral programs in health, physical, biomedical, medical, and social sciences.

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  • Developing Therapies to Overcome Immunosuppressive Myeloid Cells in the Tumor Microenvironment

    Ceradoy, Justine Anne; Davila, Eduardo, Ph.D.
    Myeloid cells in the tumor microenvironment represent significant barriers to the development of successful cancer immunotherapies. A multi-kinase inhibitor, Regorafenib (Reg), and a DNA-PK inhibitor, NU7441 (NU) were shown in a previous study to reduce expression of immunoinhibitory proteins in adaptive immune cells while increasing stimulatory MHC-I on cancer cells. In this study, we explored whether these drugs could reverse the suppressive activity of myeloid-derived suppressor cells (MDSCs) and alternatively activated macrophages. To test this idea, we used splenocytes from tumor-bearing mice and a human monocytic cell line differentiated into suppressive macrophages and assessed Arginase activity, their ability to suppress effector T cells, and mRNA expression of immunosuppressive and activating markers. We showed that Reg/NU decrease arginase activity and increase immunoactivating markers. These data demonstrate that treatment of suppressive myeloid cells with Reg/NU confers a less suppressive phenotype and leads to the generation of a more activating phenotype.
  • The Role of Nociceptors in Orthodontic Tooth Movement, Pain, and Alveolar Bone Remodeling

    Elnabawi, Omar; Pae, Eung-Kwon
    Objective: To determine the effects of selectively ablating transient receptor potential vanilloid 1 (TRPV1)-expressing nociceptors on orthodontic tooth movement, pain, and alveolar bone remodeling. Methods: Resiniferatoxin (RTX) or vehicle was stereotaxically injected into left trigeminal ganglia in adult C57BL/6 mice. After 1 week, orthodontic spring was placed between left maxillary first molar and upper incisors. Pain level was evaluated by measuring mouse grimace scale (MGS) and bite force before and after 1, 3, and 7 days following the procedures. After 12 days, micro-CT was used to quantify tooth movement and analyzing alveolar bone changes. Results: Experimental tooth movement increased MGS scores and decreased bite force. RTX ablation of TRPV1+ nociceptors attenuated MGS scores and relieved the reduction in bite force. The extent of tooth movement was decreased in RTX-treated group, but interradicular alveolar bone volume was not affected. Conclusion: Selective ablation of TRPV1+ nociceptors significantly decreases tooth movement and pain.
  • A Comparative Study of Preventive Healthcare Behaviors Among African Immigrant Women (AIW) and African American Women (AAW): Barriers and Facilitators of Cervical Cancer Prevention

    Kuffour-Manu, Vera Akosua; Ogbolu, Yolanda; Johantgen, Mary E.
    Abstract Background: Early screening, detection, and treatment of cervical pre-cancerous cells could prevent up to 80% of cervical cancers and reduce cervical cancer mortality by 52% globally. In the United States cervical cancer incidence has decreased by as much as 50% over the past 40 years due to widespread utilization of preventive health services. Yet, health disparities in cervical cancer persist among African immigrant women (AIW) and African American women (AAW) in the US. There is limited research exploring the barriers and facilitators of preventive health services for AIW and AAW. Purpose: To explore perceived barriers and facilitators, and lived experiences of AIW and AAW related to cervical cancer prevention services. Methods: A qualitative study included 14 AIW and 14 AAW, residing in the Washington, DC-Baltimore Metropolitan area. Purposive sampling technique was used to recruit participants from churches,community center, grocery stores and a radio station. A semi-structured interview guide and a demographic questionnare were used for data collection. Data were analyzed using the Intepretative Phenomenological Analysis Method. Nvivo software was used to organize and code the data. Results: The mean age of participants was 41.1(11.9), with most of the women being college educated (93%), with health insurance (96%) that paid for cervical cancer prevention (89%). Many (79%) had not received HPV vaccine and 82% had a pap smear within 1-4years. AIW and AAW data were triangulated and revealed few differences between the groups. Six broad themes emerged grounded in the Health Belief Model. Barriers identified included limited knowledge and awareness of HPV infection, risk, and vaccines; myths related to abstinence, fear, and cleanliness of healthcare facilities; lack of trust and reliance on God for healing. Facilitators included the need to feel safe and healthy; prevent and treat disease; utilize informal and formal support systems; and receive recommendation from providers and public health education related to preventive services. Conclusion: Study findings can be used to mitigate barriers and enhance facilitators to develop culturally tailored interventions for AAW and AIW. The active engagement of health providers, the community and faith based partners can be leveraged to strengthen the development of prevention research.
  • The Role of LRP1 in Inflammation and Vasculopathies

    Au, Dianaly; Strickland, Dudley K.; Catania, Selen M.; 0000-0002-8797-833X
    The prevalence of overweight and obesity and a growing aging population has resulted in higher incidences of type 2 diabetes (T2D) and cardiovascular disease (CVD). Although risk factors for T2D and CVD have been known for decades, the molecular mechanisms involved in the pathophysiology of these multifaceted diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is abundantly expressed in several tissues and possesses diverse biological functions, including chylomicron remnant clearance, involvement in insulin signaling and glucose homeostasis, modulation of the inflammatory response, atheroprotection, and maintenance of vascular integrity. We hypothesized that LRP1 may serve as a molecular link between metabolic processes and CVD development and employed tissue-specific LRP1 knockout mouse models to identify potential molecular mechanisms. Studies performed on macrophage-specific LRP1-deficient mice generated on an LDL receptor knockout background (LDLR-/-; macLRP1-/-) and challenged with a Western diet revealed that LRP1 expression in macrophages promotes hepatic inflammation and the development of glucose intolerance and insulin resistance by modulating Wnt signaling. Interestingly, studies performed on smooth muscle-specific LRP1-deficient (smLRP1-/-) mice identified a novel and critical role for LRP1 in modulating vascular smooth muscle cell (VSMC) contraction by regulating calcium signaling events. These results uncovered a potential mechanism by which LRP1 protects against aneurysm development. Studies performed on VSMCs isolated from an aneurysm patient, who also contains two heterozygous missense mutations within the LRP1 gene, showed dysregulation of the TGF-β and p53 signaling pathways. These results provide further biological evidence supporting the association of LRP1 with aortic aneurysms. The role of LRP1 in vascular remodeling was also investigated by inducing remodeling in smLRP1-/- mice using the carotid artery ligation model. Our results suggest that LRP1 protects against excessive vascular remodeling by modulating angiotensin II-mediated signaling. Taken together, this work reveals the complex roles of LRP1 in various tissues and provides evidence supporting LRP1 as a critical molecule that integrates metabolic processes with inflammation and vascular disease.
  • Immunosuppressive Drug Regimens that May Help Improve Survival and Reduce the Risks of Rejection, Infection, and Malignancy after a Lung Transplant

    Wijesinha, Marniker; Hirshon, Jon Mark; 0000-0002-6609-8456
    Background: Median survival among lung transplant recipients is below 6 years, and there is minimal knowledge regarding modifiable factors that may help improve long-term survival. Identifying induction and maintenance immunosuppressive regimens associated with optimal survival can potentially improve outcomes. Methods: We classified lung transplant recipients in the United States from 2003-2016 according to their induction and prophylactic cell cycle inhibitor maintenance therapies, within a tacrolimus-based regimen. We compared the different therapies via multivariable Cox Proportional Hazards models, generating adjusted hazard ratios for death, rejection, infection, and malignancy, the latter three of which utilized semi-competing risks methods. Since prophylactic sirolimus initiation is delayed by up to 1 year post-transplant, adjustments were made to avoid immortal time bias. Multiple imputation was utilized to handle missing data. Results: Sirolimus had the best survival among cell cycle inhibitor maintenance therapies: adjusted Hazard Ratio (HR)=0.71, p=0.003, compared to mycophenolate mofetil [MMF]; chronic rejection incidence was also reduced with sirolimus (HR=0.75, p=0.005). Azathioprine also had slightly better survival than MMF (HR=0.92, p=0.05), and reduced infection incidence (HR=0.62, p<0.0001). Among induction therapies, equine ATG had the best survival: HR=0.79, p=0.003, compared to no induction, as well as reduced rejection (HR=0.75, p=0.02) and infection (HR=0.57, p=0.008) incidence. The combination of induction and maintenance therapies associated with the most favorable survival was sirolimus + tacrolimus maintenance with no induction; HR=0.48, p=0.002 compared to MMF + tacrolimus with induction, and HR=0.41, p<0.0001 compared to MMF + tacrolimus with no induction. Conclusions: Sirolimus initiated in the first year within a tacrolimus-based regimen may significantly improve long-term survival compared to MMF in lung transplant recipients. Out of all combinations of maintenance and induction therapies studied, sirolimus + tacrolimus maintenance with no induction therapy was associated with the best survival. In patients whom sirolimus cannot be utilized for any reason, azathioprine may modestly improve survival compared to MMF. Additional long-term studies in lung transplantation are needed to confirm these findings.
  • Elucidating the Role of Fatty Acid Synthase in Oral Carcinogenesis and Potential Therapeutics

    Wisniewski, David John; Schneider, Abraham; 0000-0002-7514-7918
    The 5-year overall survival rate in oral squamous cell carcinoma (OSCC) has remained relatively unchanged over decades, due to late stage diagnosis and high recurrence rates. This work investigates two potential contributing risk factors associated with OSCC development: nicotine, present in traditional combustible tobacco cigarettes and electronic nicotine delivery systems, and high glucose as associated with Type II diabetes and hyperglycemia. A novel therapeutic, TVB-3166, for OSCC treatment was also studied through in vitro experiments, which may help improve clinical treatments for fully developed, often late-stage OSCC. Through cell viability and growth assays, scratch assays to mimic in vitro migration, and western blotting, we determined that both nicotine and high glucose caused oral dysplastic keratinocytes to exhibit an increase in malignant-like behavior. High expression levels of fatty acid synthase (FASN), a key de novo lipogenic enzyme, have been implicated in OSCC, and this work presents the first evidence that both nicotine and high glucose markedly increase oral dysplastic keratinocyte FASN expression, which drives epidermal growth factor receptor (EGFR) signaling, a key pro-oncogenic signaling pathway commonly associated with oral carcinogenesis. We also demonstrate that TVB-3166, a novel selective FASN inhibitor, induces apoptosis and reduces in vitro OSCC cell migration. Moreover, TVB-3166 inhibits basal EGFR activity and several other oncogenic signaling proteins. This further establishes a potential role for FASN and EGFR not only in the progression of oral epithelial dysplastic pre-malignant lesions, but in fully-developed OSCC tumors. Overall, this work suggests that both nicotine and high glucose play a role in OSCC progression, specifically as it relates to FASN-dependent EGFR activation. Further, the novel drug TVB-3166 should be investigated in future pre-clinical animal models as a potential adjunct to OSCC therapeutics. Through an improved understanding of risk factors for OSCC development, as well as determination of novel therapeutic strategies, this work aims to improve overall patient survival through prevention of OSCC development, as well as discovery of new adjunctive treatments for fully established tumors.
  • The association between services and recidivism for adjudicated youth with behavioral health problems

    Winters, Andrew Madison; Bright, Charlotte Lyn
    Research consistently shows that a considerable proportion of adjudicated youth have substantial behavioral health problems; however, few studies compare a range of services for adjudicated youth with behavioral health problems and the association with continued offending. Therefore, the purpose of this longitudinal study is to explore the role of services for youth with behavioral health problems, comparing types of services, and the association with continued offending. The sample consisted of adjudicated youth who were placed in an out-of-home setting (N=2277). As such, placement type was used to explore the role of services. Survival analysis was employed to assess the time at risk for recidivism. Multivariate results suggest boys compared with girls, and youth from urban areas are more likely to recidivate, while older youth and youth who were adjudicated for a felony offense were less likely to recidivate. Youth with a high index of mental health problems had a 16% lower hazard of recidivating, and youth with a moderate and high index of aggression had greater than twice the hazard of recidivating. Youth who were placed in community-based residential programs were 24% less likely to recidivate compared with a more secure setting. As the length of placement increased youth were less likely to recidivate, and youth who had multiple placements were more likely to recidivate. This study is among a few studies comparing a range of services for adjudicated youth with behavioral health problems and strengthens the literature on out-of-home placements. Results suggest community-based placements may act as a buffer for continued offending and aggression problems significantly increase the likelihood of further offending. Furthermore, outcomes from this study suggest a tailored service approach for youth with aggression problems prior to justice involvement is needed. This study provides empirical knowledge for practitioners and policy makers by highlighting service pathways for adjudicated youth with behavioral health problems. Further research is needed to explore key decision entry points in the justice system in which services are most effective at reducing ongoing court involvement. Moreover, future research is needed to address how symptoms and services may differ by gender, race and ethnicity, and age.
  • Histomorphometric Analysis of Mouse Growth Plate during Maturation and Senescence.

    Wilson, Kimberly; Enomoto-Iwamoto, Motomi
    The growth plate (GP) is cartilage tissue at both ends of long bones and plays an essential role for long bone formation and growth. GP changes in overall height, width, zone proportion, cell density and size during skeletal growth and becomes arrested upon skeletal maturation. There is limited information on GP microscopic changes. To establish GP histomorphometric parameters changes throughout skeletal maturation, the tibia of C57Bl/6J mice were evaluated from neonatal to young adult stages. GP histology in the proximal tibia was analyzed regarding total and zone height, width and area. The results showed unique GP changes in width, height and area during growth. The parameters also showed strong correlation with growth rate of the tibia. We studied GP proliferation activity and also found its correlation with tibia growth rate. The results of this study provide groundwork that will aid skeletal research on understanding of GP changes during bone growth.
  • Microglia Regulation of Sexually Dimorphic Amygdala Development

    VanRyzin, Jonathan; McCarthy, Margaret M., 1958-; 0000-0003-2990-6765
    Sex differences in the brain are established early in development and generate lasting changes in brain and behavior, a process known as sexual differentiation. Sexual differentiation of the amygdala produces a highly conserved sex difference in juvenile rough and tumble play behavior; however, the mechanisms underlying this sex difference are unknown. Here, we report that microglia, resident immune cells of the brain, actively shape the sexual differentiation of the amygdala. We found that microglia are more phagocytic in the amygdala of males from postnatal day 0 and 4, during which they also have a higher endocannabinoid (eCB) tone. Administering a masculinizing dose of testosterone to increase the eCB tone in females, or cannabinoid receptor agonists to female pups increased the number of phagocytic microglia and correspondingly decreased the number of newborn cells. Given these data, we hypothesized that microglia control the number of postnatally-born cells in the developing rat amygdala by phagocytosing newborn cells in an endocannabinoid-dependent manner. We found that these phagocytic microglia engulf newly proliferated cells, which are enriched for complement proteins. To directly implicate microglia phagocytosis, we used a function-blocking antibody against the complement receptor 3 (CR3) to prevent phagocytosis. Anti-CR3 antibody treatment increased the number of BrdU+ cells only in males, demonstrating that newborn cells can survive if phagocytosis is prevented. Moreover, administration of cannabinoid receptor antagonists to male pups occluded the effects of phagocytic blockade, suggesting that newborn cell phagocytosis was dependent on the developing ECB tone. Finally, to understand how these early life events manifest changes in the composition of the amygdala, we used a fate mapping approach to phenotype postnatally-born cells at the juvenile age. Our analysis found that the majority of newborn cells differentiated into astrocytes, which were overall higher in density in the posterodorsal region of the medial amygdala, an amygdalar nucleus essential to the integration of social stimuli. Together, these data indicate that sex differences in the local environment of the developing amygdala instruct microglia to actively phagocytose newborn cells as a means to sculpt later life architecture of the amygdala and produce sex differences in social play.
  • Firearm Injuries in Maryland, 2005-2014: Trends, Recidivism, and Costs

    Thurman, Paul; Johantgen, Mary E.; 0000-00022134-8415
    Background: Violent injuries related to firearms are common in the U.S., whether accidental or intentional. Restrictions on use of Federal dollars for research on injury prevention involving firearms has limited our knowledge of how firearm injury impacts the health care system. The objectives of this study are to characterize firearm injuries (FI) in Maryland, quantify recidivism, and to describe hospital treatment and their associated costs for Maryland. Methods: ED and inpatient hospital records utilizing E codes consistent with FI were linked across visits to create unique cases from 2005-2014. Recidivism was defined as any subsequent ED visit or hospitalization for FI. The relationship of social determinants of health derived from US Census data to the rate of FI hospitalization by zip code were examined with generalized linear models, as were FI associated hospital costs. Results: Those with a FI are primarily single young black males, with overall hospitalizations decreasing over the time period. While 9% died in their initial FI, recidivism occurred in 3% of the individuals. Personal Disadvantaged (IRR = 1.13) and Working Disadvantaged (IRR = 1.04) factors were associated with increased rates of FI within zip codes. Hospital costs were significantly predicted by being self-pay/charitable and injury severity, with estimated mean costs for one FI of $47,364. In 2013, FI hospitalizations totaled $14m, of which 25% (n=129) accounted for over $10m. Discussion and Implications: FI hospitalizations are decreasing and are increasingly linked to social determinants of health, which require multifaceted interventions with short term goals of interrupting ongoing violence and long-term goals of preventing future violence. The states are absorbing much of the health cost burden. Further research is needed, which should include developing a registry linking hospitalizations, deaths, and crime data that can be used to evaluate trends and effectiveness of interventions.
  • Effects of Alcohol Exposure during Developmental Phases on Brain Functional Connectivity

    Tang, Shiyu; Medina, Alexandre E.; Gullipalli, Rao P.
    Fetal alcohol spectrum disorders (FASD) is one of the most common causes of mental disability in the world. There is growing evidence that developmental alcohol exposure can cause reduced cognitive flexibility and alter multisensory processing, suggesting impairments in fronto-striatal and multisensory integrative cortical areas. The central hypothesis is that developmental alcohol exposure leads to impaired connectivity within these areas, and will result in reorganization of the large-scale brain network. We tested this hypothesis with two animal models that are known to exhibit abnormities in cognitive flexibility and sensory processing: (1) a rat FASD model with alcohol exposure from gestational day 6 to 20, similar to human gestation from the first to the late second trimester; (2) a ferret FASD model with alcohol exposure from postnatal day 10 to 30, similar to the third trimester of gestation in humans. These two models mimic alcohol exposure during early and late fetal stage humans. Our study revealed reduced resting-state functional connectivity within fronto-striatal circuit and a visual-tactile circuit in young adult animals with alcohol exposure during early fetal stage. Although alcohol exposure during late fetal stage did not alter the resting-state functional connectivity within fronto-striatal circuit, an increased functional connectivity within the visual-tactile circuit was detected in juvenile animals. Graph theoretical analysis was used to assess the alteration in brain network properties after alcohol exposure during early or late fetal stage. A reduction of large-scale brain network small-worldness was observed following alcohol exposure during early fetal stage. No significant group difference was observed following alcohol exposure during late fetal stage. In conclusion, the results supported the central hypothesis that developmental alcohol exposure alters resting-state functional connectivity within fronto-striatal circuit and visual-tactile circuit and may eventually alter the organization of large-scale brain networks. The timing of alcohol exposure plays an important role in the outcomes and should be taken into consideration in future research, the usage of diagnostic biomarkers and the application of intervention approaches.
  • Medical Costs of Alpha-1 Antitrypsin Deficiency-associated Chronic Obstructive Pulmonary Disease in the United States

    Sieluk, Jan; Mullins, C. Daniel; 0000-0002-1833-0273
    Objectives: The objective of this study was to isolate the healthcare resource utilization and economic burden attributable to the presence of a genetic factor among Chronic Obstructive Pulmonary Disease (COPD) patients with and without Alpha-1 Antitrypsin Deficiency (AATD), twelve months before and after their initial COPD diagnosis. Methods: Retrospective analysis of OptumLabs® Data Warehouse claims (OLDW; 2000 – 2017). The OLDW is a comprehensive, longitudinal real-world data asset with de-identified lives across claims and clinical information. AATD-associated COPD cases were matched with up to 10 unique non-AATD-associated COPD controls. Healthcare resource use and costs were assigned into the following categories: office (OV), outpatient (OP), and emergency room visits (ER), inpatients stays (IP), prescription drugs (RX), and other services (OTH). A generalized linear model was used to estimate total pre- and post-index (initial COPD diagnosis) costs from a third-party payer’s perspective (2018 USD) controlling for age, gender, race/ethnicity, census region, augmentation therapy use, oxygen use, insurance type, year of COPD diagnosis, and Charlson Comorbidity Score. Healthcare resource utilization was estimated using a negative binomial regression. Results: The study population consisted of 8,881 patients (953 cases matched with 7,928 controls). The AATD-associated COPD cohort had higher expenditures and use of OV and OTH services, as well as OV, OP, ER, RX, and OTH before and after the index date, respectively. Adjusted total cost ratios for AATD-associated COPD patients as compared to controls were 2.036 [95% CI: 1.601 – 2.590] and 1.976 [95% CI: 1.550 – 2.517] while the incremental cost difference totaled $6,861 [95% CI: $3,025 - $10,698] an $5,772 [95% CI: $1,940 - $9,604] per patient before and after the index date, respectively. Conclusions: Twelve months before and after their initial COPD diagnosis, patients with AATD incur higher healthcare utilization costs that are double the cost of similar patients without AATD. This study also suggests that increased costs of AATD-associated COPD are not solely attributable to augmentation therapy use. Future studies should further explore the relationship between augmentation therapy, healthcare resource use, and other AATD-associated COPD expenditures.
  • Regulation of Glucokinase in Pancreatic Beta Cells

    Seckinger, Kendra; Rizzo, Mark A.
    Glucose homeostasis is a tightly coordinated process that ensures an adequate source of cellular energy. Blood glucose concentrations are coupled to changes in activity of glucokinase (GCK) in β-cells of the pancreas. GCK acts as the glucose sensor and is responsible for the phosphorylation of glucose that leads to insulin secretion from the pancreas to constrain glucose concentrations within physiologic levels. However, the underlying mechanistic details explaining how GCK maintains this tight control over glucose metabolism are unclear. First we elucidated the role of intracellular Ca2+, particularly Ca2+ mobilized from the endoplasmic reticulum, in GCK activation. We then investigated the cellular regulation of GCK through post-translational S-nitrosylation. Finally, we assessed changes in GCK activity that occur during the development of diabetes. To quantitatively assess this GCK activity in vitro, we used Förster resonance energy transfer (FRET) spectroscopy, fluorescence microscopy and GCK biosensors expressed in cultured pancreatic β-cells and primary mouse islets. This work describes our homotransfer FRET-GCK biosensor and improved data analysis methodology to understand the cellular regulation of GCK activity. To create the homotransfer biosensor, we attached two mVenus fluorescent proteins to GCK and transfected this single-color biosensor into cultured β-cells. We used the inherent polarization of light in combination with FRET principles to precisely measure GCK activation in living cells under various conditions.
  • Repurposing Oxaliplatin for the Treatment of Glioblastoma

    Roberts, Nathan; Woodworth, Graeme
    Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults, accounting for approximately 40% of primary brain tumors. Even with the most aggressive therapy, the mean survival for patients with GBM is still less than 18 months, highlighting the critical need for new therapeutic strategies for this deadly cancer. Among the strategies under consideration is a repurposing of platinum-based chemotherapeutics. Traditionally considered DNA damaging cytotoxic agents, recent findings suggest that platinum-based chemotherapeutics, especially oxaliplatin (OXA), can induce multi-faceted anti-tumor effects, including modulation of cytokines, transcription factors, and tumor immunosuppressive mechanisms, even at lower concentrations that are not directly cytotoxic. Data suggests that a major alternative effect of OXA is the inhibition of signal transducer and activator of transcription 3 (STAT3), a transcription factor at the core of GBM pathobiology. STAT3 signaling is constitutively active in many gliomas and dictates diverse aspects of glioma biology including angiogenesis, invasion, chemotherapeutic resistance, and immunosuppression. STAT3 also controls and co-opts the primary gliomainfiltrating immune cell, the macrophage, which composes up to 40% of the tumor mass. OXA treatment may overcome the pleiotropic glioma-supporting functions of STAT3. It is likely that OXA therapeutic formulations designed to maximize the multi-faceted effects of OXA, including STAT3 inhibition, will have potent anti-GBM effects, including reprogramming of the tumor microenvironment. Although high-dose platinum-based chemotherapeutics have been investigated for CNS tumors, systemic and direct neuronal toxicity at high doses has thus far limited their use. However, new therapeutic delivery strategies including polymeric nanoparticle formulations capable of improving drug delivery to tumor cells, providing a sustained release of chemotherapeutic at the target site, and significantly reducing toxicity are facilitating the adaptation of these compounds in the CNS. We sought to investigate the multi-faceted anti-tumor effects of low-dose OXA in glioma cells and macrophages, with a particular focus on STAT3 modulation. We hypothesized that OXA will reduce STAT3 activity in glioma cells as well as macrophages and that OXA nanoparticle formulations will sustain STAT3 inhibition in vivo, thereby enabling the use of OXA as a biomaterial inhibitor of STAT3 for the treatment of glioma.
  • Advances in Mass Spectrometric Structural Biology Techniques for Pattern Recognition Receptor Ligands of Microbial Origin

    Oyler, Benjamin; Goodlett, David Robinson, 1960-
    Pattern recognition receptors (PRR) are the innate immune system’s first-line sentinels for distinguishing “self” from “non-self.” Many molecules found in the bacterial cell wall are PRR ligands, including lipopolysaccharide (LPS), cardiolipin (CL), and peptidoglycan (PGN). Molecular structural biology techniques are essential for determining both basic cell biology and host-bacteria interactions through ligand-receptor binding mechanisms. Recent interest in designer PRR ligands or PRR ligand mimetics for use in drug discovery pipelines have given this research more translational value as well. Mass spectrometry (MS) has the unique capability to derive primary structures of ions as well as monitor many different ions in complex mixtures. Several different advances in PRR ligand structure analysis were achieved in this dissertation. First, chemical structure of an LPS-derived vaccine was determined using a top down tandem MS approach. Several different instrumental configurations and methods were employed to demonstrate complementarity of data and broad applicability of the approach. Second, CL from a newly discovered Actinomycete marine sponge symbiont was analyzed and compared to CL from a terrestrial Firmicute to generate hypotheses about host-bacterium interactions. This was the first molecular analysis of any secondary metabolites from this species of bacteria. Third, PGN subunits (muropeptides) from Rickettsia typhi were analyzed in a data dependent global LC-tandem MS approach. This was the first example of PGN structure discovery for R. typhi and the first example of this approach applied to PGN structure elucidation for any Rickettsiae species. All of these developments will help to advance PRR-ligand interaction research – an emerging and promising field for development of novel disease treatment and prevention approaches. Modulation of the innate immune response to bacterial insult is a challenging task without a clear understanding of underlying molecular mechanisms and how they might be manipulated by medicine. One key step in this process is development of sensitive and specific chemical analysis methods fit to acquire unequivocally interpretable data. While all of the methods described herein were applied to specific biological problems, their applicability to other scientific questions is broad.
  • Aging effects on Kinematics, Kinetics, and Neuromuscular Control of Landing Movements in Response to Sudden Loss of Ground Support Surface while Standing

    Sanders, Ozell Phillip; Rogers, Mark William
    Background. With advancing age, the capacity to maintain balance after perturbations deteriorates due to a number of age-related sensorimotor deficits, and likely increases the risk for falls. The unexpected nature of falls triggers startle-like whole body postural responses. Startle responses are characterized by exaggerated whole body postural responses with increased muscle co-activity causing co-contraction during the first trial response (FTR) and normally diminish with repeated exposure due to behavioral habituation. Previous work suggested that age-related abnormalities of exaggerated startle responses and habituation might influence protective balance and startle FTRs to sudden loss of the ground support surface. Furthermore, while startle-like effects in younger adults are modifiable during self-activated (SLF) drop perturbations due to motor prediction, the extent to which this capacity is retained with aging is unknown. Aim. This dissertation 1) compared changes in protective balance and startle responses to unexpected and expected drop perturbations in relation to age during a) FTRs and b) subsequent trials; and 2) determined the modulatory effects of repeated self-triggered drop perturbations on reducing FTR magnitude evoked by externally triggered drop perturbations. Methods. Participants stood atop a moveable platform and received blocks of twelve consecutive trials of externally triggered (EXT) and self-triggered (SLF) drop perturbations. Following the last SLF trial, participants received an additional EXT trial spaced 20 minutes apart to assess retention (EXT RTN) of any modulation effects. Electromyographic (EMG) activity was recorded bilaterally over the sternocleidomastoid (SCM), middle deltoid (DLT), biceps brachii (BIC), vastus lateralis (VL), biceps femoris (BF), medial gastrocnemius (MG), and tibialis anterior (TA). Whole-body kinematics were recorded with motion analysis. Stability in the antero-posterior direction was quantified using the margin of stability (MoS). To quantify landing strategies, the mechanical work performed during drop landings was measured. Results. Incidence of early onset of bilateral SCM activation within 120ms after drop onset was present during the first trial response (FTR) for all participants. Co-contraction indices (CoI) during FTRs between VL and BF as well as TA and MG were significantly greater in older adults compared to young (VL/BF by 26%, p<.05 and TA/MG by 37%, p<0.05). Reduced shoulder abduction between FTR and last trial responses (LTR) was present across both groups and indicative of habituation. Significant age-related differences in landing strategy were present between groups as older adults had greater trunk flexion (p<0.05) and less knee flexion (p<0.05) which resulted in greater peak vGRFs and decreased MoS compared to young adults. Motor prediction via self-triggered drop perturbations (SLF) reduced peak SCM response and VL/BF and TA/MG CoIs (p <0.05) across both groups. Older adults significantly reduced peak vGRFs during SLF FTR compared to EXT FTR (2.40 ± 0.07 vs. 2.74 ± 0.07, p<0.05). Similarly, young adults significantly reduced peak vGRF during SLF FTR compared to EXT FTR (1.43 ± 0.08 vs. 1.83 ± 0.07, p<0.001). Lastly, in both groups, more eccentric work was performed during SLF trials compared to EXT (p <.05). Conclusion. Drop perturbations of standing balance evoke startle-like reactions in young and older adults. Age-associated abnormalities of delayed, exaggerated, and poorly habituated startle/postural FTRs linked with less balance stability and increased joint stiffening with increased impact forces were present among older adults. However, protective balance and startle responses were modulated with motor prediction resulting in reduced knee and ankle co-contraction, reduced ground impact forces and improved balance stability. The observed difference coincided with a reduced SCM response amplitude indicative of a reduced startle influence.
  • Glutathione S-Transferase π Gene Amplification in Oropharyngeal Cancer

    Sadegh, Nahal Mir; Zou, Ying, M.D., Ph.D.; Mitchell, Braxton D.; 0000-0002-4025-1678
    Head and neck cancers make up about 3% of all new cancer cases in the United States. In addition to the traditional risk factors such as tobacco and alcohol use, recent studies have shown that Human Papillomavirus (HPV) is another risk factor for this type of cancer. Since Traditional prognostic markers such as tumor extent and size are not adequate for risk stratification, clinically relevant and practical biomarkers are needed, especially in the context of non-HPV related cancers, in order to define high-risk patients who might benefit from more aggressive treatment strategies. This project explores the suitability of GSTP1 gene amplification as a biomarker for risk stratification in a subset of head and neck cancers, oropharyngeal cancer (OPC), by evaluating the suitability of a previously established algorithm for defining GSTP1 gene amplification and using that information to evaluate GSTP1 gene amplification status as a prognostic indicator for OPC patients.
  • Pediatric Cell-Mediated Immune System and Response to Ty21a Typhoid Vaccination Compared to Adults

    Rudolph, Mark Edward; Sztein, Marcelo B.; 0000-0002-0942-0349
    Typhoid fever is a life-threatening disease caused by the human-restricted pathogen Salmonella enterica serovar Typhi (S. Typhi). The oral live-attenuated Ty21a typhoid vaccine protects against this severe disease by eliciting robust, multifunctional cell mediated immunity (CMI), shown to be associated with protection in wild-type S. Typhi challenge studies. Ty21a induces S. Typhi-responsive CD8+ and CD4+ T cells but little is known about the response to this vaccine in children. To address this important gap in knowledge, we have used mass cytometry to analyze pediatric and adult pre- and post-Ty21a vaccination T cells with both an HLA-E restricted and an autologous S. Typhi-antigen presentation model. Here, using conventional supervised analytical tools, we show adult T cells are more multifunctional at baseline than those obtained from children. Moreover, pediatric and adult T cells respond similarly to Ty21a vaccination, but adult responders remain more multifunctional. The use of the unsupervised dimensionality reduction tools allowed us to confirm these findings, as well as to identify increases and decreases in well-defined specific CD4+ and CD8+ T cell populations that were not possible to uncover using the conventional gating strategies. These findings evidenced age-associated maturation of multifunctional S. Typhi-responsive T cell populations, including those which have previously shown to be associated with protection from, and/or delayed onset of, typhoid disease. Further, in depth analysis of control stimulation conditions also found age-associated multifunctional T cell heterogeneity. These findings are likely to play an important role in improving pediatric vaccination strategies against S. Typhi and other enteric pathogens.
  • Graduate Research Conference 1996

    University of Maryland, Baltimore. University of Maryland Baltimore County Graduate Student Association (1996-05-01)
    The Graduate Student Research Day (GSRD) is a one-day conference that provides graduate students from the University of Maryland Baltimore County (UMBC) and the University of Maryland at Baltimore (UMAB) the opportunity to present results of their ongoing research to peers, faculty members, the University of Maryland community at large, and other interested parties. Co-sponsored by theUMBC and UMAB Graduate Student Associations (GSA), the GSRD event provides a forum for the exchange of information and ideas. With 130 scheduled presentations, GSRD 96 has the highest level of participation in the history of this event.
  • Graduate Research Conference 1993

    University of Maryland, Baltimore. Graduate Student Association (1993-05-05)
    This is the program and collection of abstracts for poster and oral presentations for the 15th Annual GRC. This conference offers researchers, be they graduate students, professional students, or postdoctoral fellows, the opportunity to present their discoveries to a diverse audience. Our unique combination of research across various professional schools and disciplines allows basic scientists, informaticists, social scientists, nurses, and policy researchers to intermingle and discuss their research in an interdisciplinary setting.

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