Browsing by Author "Mathew, Stephen O."
Now showing 1 - 20 of 44
- Results Per Page
- Sort Options
Item A Comparative Analysis of Recruitment Methods used in Randomized Controlled Clinical Drug Trials(2019-05) Garud, Ashwini A.; Mathew, Stephen O.; Goulopoulou, Styliani; Anderson, Jessica; Maynard, BrianClinical trials are a crucial part of any drug development process. The reliability and validity of clinical trials depend on the successful recruitment of subjects. The overall goal of this project was to evaluate the effectiveness of subject recruitment methods used in Randomized Controlled Trials (RCTs) focusing on Major Depressive Disorder (MDD) and Postpartum Depression (PPD) studies. Recruitment methods (on-site and off-site) utilized in these trials were examined for their cost-effectiveness, recruitment return, including the number of subjects enrolled and the number of subjects randomized in the trial and subject demographics. Regarding cost effectiveness, on-site methods were found to be more effective in terms of recruitment return and less costly than off-site for both studies. There was a significant difference in race and gender when subjects were recruited from on-site versus off-site recruitment. For MDD study, a comparatively large number of enrolled and randomized participants were recruited from on-site recruitment methods as compared to off-site, this may be due to the number of physician referrals, indicating that physicians play a major role in subject recruitment. For the Postpartum Depression study, the number of enrolled and randomized subjects from off-site recruitment method was higher than those of on-site methods. Monitoring recruitment strategies implemented in the study and assessing their effectiveness would be helpful in employing strategies for future trials.Item A novel ligand on astrocytes interacts with natural cytotoxicity receptor NKp44 regulating immune response mediated by NK cells(PLOS, 2018-02-15) Bowen, Kelly E.; Mathew, Stephen O.; Borgmann, Kathleen; Ghorpade, Anuja; Mathew, Porunelloor A.NK cells play important role in immunity against pathogens and cancer. NK cell functions are regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells. NK cells were shown to be recruited to the CNS following several pathological conditions. NK cells could impact CNS physiology by killing glial cells and by secreting IFN-gamma. Astrocytes are intimately involved in immunological and inflammatory events occurring in the CNS and reactive astrogliosis is a key feature in HIV-associated neurocognitive disorders. There is little data on NK-astrocyte interactions and ligands expressed on astrocytes that could impact NK cell function. Natural cytotoxicity receptors (NCRs) play a critical role in the cytolytic function of NK cells. Among the NCRs, NKp44 is unique in expression and signal transduction. NKp44 is expressed only upon activation of NK cells and it can mediate both activating and inhibitory signals to NK cells. Here, we have studied the expression and function of natural cytotoxicity receptor NKp44 upon NK-astrocytes interactions in the presence or absence of an HIV peptide (HIV-3S peptide) shown to induce NK cell killing of CD4+ T cells during HIV-infection. Using a fusion protein consisting of the extracellular domain of NKp44 fused to Fc portion of human IgG, we determined the expression of a novel ligand for NKp44 (NKp44L) on astrocytes. Incubation of astrocytes with HIV-3S peptide downregulated NKp44L expression on astrocytes implicating protection from NK mediated killing. Thus, our study showed that NKp44 have a protective effect on astrocytes from NK cell mediated killing during HIV infection and impact astrocyte role in HAND.Item A Quality Improvement Initiative: Evaluating the Impact of Standardized Data Tracking Tools in the Radiation Oncology Clinical Research Office at the University of Texas Southwestern Medical Center(2022-05) Acevedo, Katalina V.; Mathew, Stephen O.; Ranjan, Amalendu P.Developing preventative measures through intentional planning and oversight of clinical trials has the potential to increase efficiency and quality of trial processes and data. This practicum report details a Quality Improvement (QI) initiative evaluating implementation and impact of a standardized data-tracking software on clinical research data compliance in the Radiation Oncology Clinical Research Office at UT Southwestern Medical Center (UTSW). The standardized data tracker evaluated in this study was built through Quickbase, a cloud-based, low-code application development platform specializing in project management and operations optimization. This project evaluated data sets from two active radiation oncology clinical trials using repeated cross-sectional methods to compare rates of data non-compliance and trends in the types of non-compliance exhibited at baseline, one-month, and three-month post data-tracker implementation. Trends in non-compliance were reviewed and preventative measures backed by recommendations from the literature were proposed to facilitate future QI initiatives within the department. The Chi-Squared (X2) Test for Independence was used to determine whether there was a statistical difference in rates of data non-compliance across the three timepoints within studies and overall followed by post-hoc tests consisting of pairwise comparisons with Bonferroni corrections. Overall, statistical analysis revealed a significant difference in rates on non- compliance across timepoints, suggesting that implementation of the standardized Quickbase data-tracking management tool does significantly decrease rates of non-compliance. Descriptive statistics were performed to characterize the trends in non-compliance within each study across timepoints. This quality improvement project was the first of its kind to formally examine data management trends and practices within the Radiation Oncology Clinical Research Office at UT Southwestern Medical Center. The results provide positive feedback regarding the implementation of a standardized Quickbase data-tracking management tool and characterization of non-compliant data illuminated pressure points in data management workflow that can inform future QI initiatives in shifting data management from its current reactive state to a more proactive data-driven approach. Future work should evaluate the proposed preventative measurements to provide further insight into best practices that can support continuous improvement initiatives within the department.Item Adverse Effects of Lung Cancer Immunotherapy Among Socioeconomically Marginalized Lung Cancer Patients(2022-08) Nwaogbe, Ogochukwu; Mathew, Stephen O.; Basha, Riyaz; Adorboe, AndrewLung cancer remains a major contributor of cancer-related deaths and account for more than half of lung cancer deaths. In the U.S., lung cancer accounts for almost 25% of all U.S. cancer deaths and certain population groups bear a disproportionate burden. Immunotherapy is a novel treatment for lung cancer that has shown improvements in stalling disease progression and overall survival. But these treatments are associated with a plethora of adverse events that can affect any organ in the body. Most of the evidence on the adverse effects associated with immunotherapy is documented from clinical trials which often exclude the socioeconomically marginalized population. Hence little evidence exists on the incidence and range of adverse events in this population group. This study contributes to the evidence on the frequency and types of immunotherapy side effects experienced by socioeconomically marginalized populations.Item An Analysis of Employee Engagement within the Heart and Lung Transplant and Pulmonary Research Department of the Baylor Scott and White Research Institute at Dallas, TX.(2018-12) Lee, Daniel J.; Mathew, Stephen O.; Basha, Riyaz; Khan, Shafaat A.; Martits-Chalangari, Katalin; Martinez, HoracioIntroduction: Employee engagement is an important construct to measure, with positive employee engagement linked to favorable business outcomes such as increased customer satisfaction, increased productivity, and decreased employee turnover. Employees and interns of the Heart and Lung Transplant and Pulmonary Research Department at Baylor Scott and White Research Institute in Dallas, Texas participated in a survey study to gauge engagement levels and identify any process-improvement initiatives that could be implemented to create a better work environment. Methods: An electronic survey was created to assess various engagement drivers. The survey was then administered to employees and interns to assess how well the department was engaging them; it also provided an opportunity for respondents to bring attention to any issues or concerns they had regarding the department. Results: Due to the brevity of the survey, not all engagement drivers could be measured. However, the short length of the survey resulted in a high response rate. Results also showed the department scored high on all engagement drivers that were measured. The small sample size meant statistical analysis was limited to descriptive measures. Action items were also suggested to address the concerns brought to light by the respondents. Conclusion: The engagement drivers measured in the Heart and Lung Transplant and Pulmonary Research Department of the Baylor Scott and White Research Institute in Dallas, Texas show the staff is positively engaged. However, a survey is only a "snap shot" of one moment in time. It is therefore recommended that another survey be conducted after the action items discussed below have been implemented to measure the effects. Short surveys are ideal to get quick responses and a high participation rate. However, a longer, more thorough survey should also be created to gain further insight into all aspects of engagement of the research department. Further research into employee engagement could also be conducted by looking at such demographic factors as age, gender, and years employed at Baylor Scott and White Medical Center. Further research should also attempt to obtain a higher number of participants for greater generalizability and validity.Item Analysis of expression of immune receptors in pediatric acute lymphoblastic leukemia (ALL)(2016-03-23) Mathew, Stephen O.; Mathew, Porunelloor A.; Bowman, Paul; Powers, SheilaAcute Lymphoblastic leukemia (ALL) is the most common type of cancer in children. It is characterized by overgrowth of the lymphocyte precursor (either B cell or T cell) that is nonfunctioning, and crowds out other immune cells. Current treatment options have a success rate of 80-90%. However, those who relapse have a survival rate of only around 25-40%. Also, side effects of current chemotherapy and radiation treatments have been shown to impact the normal growth and development of children. Research has shown that ALL of the B cell lineage is particularly resistant to killing by Natural Killer (NK) cells. NK cells are part of the innate immune system and specialize in killing tumor and virally infected cells. NK cell activation is dependent on a balance of inhibitory and activating receptors and their ligands expressed on the target cell. Our laboratory has previously cloned three immune receptors, 2B4, CS1 and LLT1, which have been shown to play a role in cancer, however their significance and role in childhood ALL have not been evaluated. In this study, we evaluated the expression of immune receptors 2B4, CS1, LLT1, NKp30 and NKp46 in pediatric ALL subjects both male and female in the age range of 3 – 18 yrs. ALL subjects and healthy subjects were enrolled at Cook Children’s Hospital and UNT Health Science Center, Fort Worth, TX with informed consent/assent according to IRB approval (UNTHSC IRB# 2008-094 & CCMC IRB# 2008-57). The blood samples were collected and peripheral blood mononuclear cells (PBMC) were isolated and analyzed by flow cytometry and real-time qPCR for expression of immune receptors. ALL subjects showed altered expression of immune receptors in the PBMC as compared to healthy subjects. There was an overall decrease in the expression of 2B4, CS1, LLT1 and NKp46 in the B lymphoblasts of ALL subjects as compared to healthy subjects. Expression and functional analysis of these receptors in a larger sample size will provide valuable insights to conduct future mechanistic studies to investigate the role of these immune receptors in ALL resistance and relapse. Funded by Cancer Research Foundation of North Texas (CRFNT).Item Analysis of Factors that affect Recruitment Process and Effectiveness of Recruitment Methods in Treatment Resistant Depression Study(2019-12) Patel, Eva K.; Mathew, Stephen O.; Mathis, Keisa W.; Maynard, Brian; Anderson, JessicaIntroduction: The following Research Project is a Process Improvement Study to identify the factors affecting the recruitment process and identify best recruitment method in Treatment Resistant Depression Study. Adequate recruitment is essential to any study's success. Most studies report only the effectiveness of recruitment method, but very few report the cost of randomizations. This research project will analyze the effect of different recruitment methods in the Treatment Resistant Depression Study. The study will work on cost analysis which can be critical when deciding which recruitment methods to implement in Randomized Controlled Clinical Trials. Methods: For this research project, a study will be conducted to analyze the factors that affect the recruitment process and compare the effectiveness of different recruitment methods. Factors include demographical data such as age, gender, ethnicity, race and distance from site. Data for this study will be collected from a randomized double blind, active controlled "Treatment Resistant Depression Study" conducted at North Texas Clinical Trials, Fort Worth, TX. Data will include how many subjects were consented, how many of them were enrolled and how many of them failed the screening process. Results: All four recruitment methods were compared, based on the number of subjects referred, enrolled and randomized for the study. Statistical analysis showed that there was no significant difference between subjects referred, enrolled and randomized using all four methods (p-value: 0.1920). Analysis was performed on data which showed a statistically significant difference between the number of subjects referred and randomized through subject database and clinical connection (p-value: 0.0184). Total pooled data revealed race and distance from site being the only predicting factors on the outcome of being screened into the study. II Conclusion: Patient recruitment is a vital component in assuring the success of a clinical trial and can be time consuming. One method of recruitment alone is not sufficient to meet the target enrollment. It was difficult to prove significant effect of all the factors on the recruitment process due to small sample size, but future studies with larger sample size could potentially reveal more significant impact of factors associated with the recruitment process.Item Analysis of Patient Recruitment Methods in Clinical Trials of Different Heart and Lung Diseases(2018-05) Sido, Oghenevovwero V.; Mathew, Stephen O.; Cross, Deanna S.; Felius, Joost; Propps, Jessica; Martits-Chalangari, KatalinPatient recruitment is key to the success of any clinical trial, as clinical trials cannot be conducted without the willful participation of subjects. However, clinical trial recruitment has always been a great challenge in clinical studies. This practicum project conducted over an eight-month period, compares three different methods of subject recruitment into 2 clinical research studies conducted at the Heart & Lung Transplant and Pulmonary Research Department of Baylor Scott & White Research Institute, Dallas. A total of 333 potential subjects were identified via EHR screening or referred by physicians or signed up on the clinical trial portal to be contacted about the study. 108 patients were referred by physicians, 212 patients were identified via EHR screening and 13 patients signed up on the online clinical trial portal to be contacted for a study. By comparing the method of patient recruitment into clinical studies, we can ascertain what method works best in recruiting patients for clinical trials. The three recruitment methods are: Physician Referral, EHR Screening and Online Portals. We hypothesize that Physician referral is a more successful method for enrolling patients into clinical studies of different heart and lung diseases.Item Autism Spectrum Disorder with and Without Co-Occurring Attention Deficit Hyperactivity Disorder: An Analysis of Pathways to Diagnosis and Intervention in a National Sample(2018-05) Thomi, Morgan S.; Mathew, Stephen O.; Miller, Haylie L.; Patterson, Rita M.; Lovely, Rehana S.Autism Spectrum Disorder (ASD) is diagnosed in 1 out of 68 children. Recent changes to diagnostic guidelines permit clinicians to assign co-occurring diagnoses of ASD and Attention Deficit-Hyperactivity Disorder (ADHD). It is important for researchers and clinicians to be aware of groups vulnerable to delayed or incomplete diagnosis. In this retrospective review of data from the CDC Survey of Pathways to Diagnostics and Services (SPDS) and the National Survey of the Diagnosis and Treatment of ADHD and Tourette Syndrome (DTAT), we sought to assess the impact of race, ethnicity, sex, poverty level, and diagnosing provider type on age of first concern and age of final diagnosis in children diagnosed with ASD, ADHD, and ASD+ADHD. We predicted that age of first concern and age of final diagnosis would vary by sex, race, poverty level, identifier of first symptoms, provider type, and comorbidities. Parents/guardians of 5,959 children aged 3-17 completed the surveys; in the current sample, 2,966 cases were from DTAT and 2,993 were from SPDS. We used a series of ANOVAs to assess differences in the variables of interest by group. Age of first concern was significantly impacted (p [less than] 0.05) by Race, Race x Poverty Level, and Race x Poverty Level x Sex for the ASD+ADHD group. Age of final diagnosis was not significantly impacted (p [greater than] 0.05) by Poverty Level, Race x Poverty Level, and Sex x Race x Poverty Level for the ASD group. Identifier of first symptoms significantly impacted (p [less than] 0.05) age of first concern for all groups, while identifier of first concerns only significantly impacted (p [less than] 0.05) the ASD and ADHD groups. Post-hoc analyses revealed specific patterns of risk. Specific combinations of demographic factors increase vulnerability for later diagnosis. These findings suggest that provider- and patient-centered education is needed to increase surveillance in at-risk populations.Item Blocking LLT1-CD161 interaction enhances natural killer cell-mediated lysis of triple-negative breast cancer cells(2018-03-14) Mathew, Stephen O.; Chaudhary, Pankaj; Mathew, Porunelloor A.; Marrufo, Armando M.Purpose: Triple-negative breast cancer (TNBC) accounts for 20 percent of all breast cancer cases and is known to be the most invasive form of breast cancer. TNBC’s absence of estrogen, progesterone, and human epidermal growth factor-2 receptors makes utilizing hormonal treatments ineffective in suppressing tumor growth. TNBC is associated with poorer prognosis and higher incidences of relapse. Therefore, natural killer cell-mediated immunotherapy shows potential as a treatment option for TNBC. Natural killer cells (NK) are innate lymphoid cells that serves its role in the immune system to eradicate infected and tumor cells. NK cell function is regulated through its receptors interacting with activating and inhibitory ligands on target cells. Lectin-like Transcript-1 (LLT1, CLEC2D) is a counter-receptor that interacts with CD161 (NKRP1A) and inhibits NK cell activation. Our study demonstrated that by blocking TNBC’s LLT1 interaction with CD161 with antibodies increases lysis of TNBCs by NK cells. Methods: We have identified the expression and function of LLT1 on TNBC cell lines MDA-MB-231 and MDA-MB-436 by flow cytometry, western blot, immunofluorescent microscopy, and chromium-release assay. LLT1 expression at the cell surface was decreased through gene knockdown with small interference RNA (siRNA) transfection. Primary NK cells were isolated from peripheral blood mononuclear cells from healthy individuals and then were co-incubated with chromium-labeled TNBCs for quantification of specific lysis of TNBCs by NK cells. Results: Our results have demonstrated a higher expression of LLT1 on TNBCs than non-tumorigenic breast cell line MCF10A. We have shown that blocking LLT1 interaction with CD161 with antibodies on TNBCs have increased lysis of TNBCs by primary NK cells. We have also shown that gene knockdown of LLT1 decreases cell surface expression of LLT1 on TNBCs and increases lysis of TNBCs by NK cells. Conclusions: LLT1 expressed on TNBCs is a ligand that interacts with NK receptor CD161 and sends an inhibitory signal to the NK cell thus serving its role for TNBCs to evade immunosurveillance. Respectively, blocking LLT1 with antibodies on TNBCs and decreasing expression of LLT1 by gene knockdown increases susceptibility of TNBCs to NK cell-mediated lysis. Blocking interaction between LLT1 and CD161 with antibodies activates lysis by NK cells and will open a possible new immunotherapeutic strategy for patients diagnosed with TNBC.Item Building resilience with heart rate variability biofeedback (HRVB): a randomized controlled trial of HRVB to reduce emotional exhaustion/burnout in emergency department and intensive care unit providers(2020-05) Cortez-Neavel, Geordi R.; Jones, Harlan P.; Mathew, Stephen O.; Gatch, Michael B.; Powers, Mark B.; Warren, Ann MarieCortez-Neavel, Geordi, Building Resilience with Heart Rate Variability Biofeedback (HRVB): A Randomized Controlled Trial of HRVB to Reduce Emotional Exhaustion/Burnout in Emergency Department and Intensive Care Unit Providers. Master of Science in Clinical Research Management, November, 2019, 89 pp., 12 figures, 14 tables, journal entries, references, # titles. PURPOSE: The purpose of this study was to compare perceived emotional exhaustion (assessed through MBI, CD-RISC, PSS, and PHQ-2) between two subject cohorts who received interventions designed to reduce emotional exhaustion through utilization of a Heart rate Variability Biofeedback device, its partner app, and paired technique. We sought to evaluate the effectiveness of HRVB as a means to reduce emotional exhaustion as experienced by emergency and trauma care providers in a single-site, hospital setting (ED and ICU). HYPOTHESIS: The daily use of the HeartMath® HRVB device, Inner Balance application, and Quick Coherence technique over a 4-week period decreases emotional exhaustion in emergency and critical care providers. DESIGN: Providers (RN, PA, NP, MD/DO) working in Baylor University Medical Center's emergency department and intensive-care units participated in a 10-week study, consisting of a 4-week randomized control trial followed by a transition week and additional 5-week study "crossover" extension. RESULTS and CONCLUSIONS: Without the sample size to achieve the desired power of this study, no statistically significant conclusions can be drawn at this time. As of the writing of this thesis, the study is still ongoing, and, thus, new participant data may be included as a result of their completion of the RCT portion.Item Characterization of Markers on Pancreatic and Colon Cancer Stem Cells to Enhance Natural Killer Cell Effector Functions(2021-05) Malaer, Joseph D.; Mathew, Porunelloor A.; Mathew, Stephen O.; Berg, Rance E.; Jones, Harlan P.; Prokai, LaszloDue to advancements in technology and medicine, the average human lifespan in the United States has increased to 79 years since the start of the 20th century. This increase in lifespan is also coupled with an increased risk of developing cancer. While cancer detection and initial treatment has increased the survival of patients, it is not a cure and patients wonder how long they will remain in remission. It is estimated that over 90% of cancer related deaths are due to relapse and metastasis. There is currently a growing body of research that indicates cancer stem cells (CSC) are responsible for relapse and metastasis. CSC are a small subpopulation of cells that retain self-renewal and pluripotency. These cells are also described as being quiescent, which may contribute to their chemotherapy resistance. Additionally, CSC are thought to express ligands to aid in immune evasion mechanisms. Natural Killer (NK) cells are lymphocytes of the innate immune system which function to combat infection and cancer. NK cells, unlike T and B cells, do not require prior sensitization. NK cell function is regulated through activating and inhibitory receptors. Recently, Proliferating Cell Nuclear Antigen (PCNA) was identified as an inhibitory ligand for the natural cytotoxicity receptor NKp44. Lectin-like transcript 1 (LLT1) expression is known to facilitate escape of NK cell effector functions in prostate and breast cancer, and now colorectal cancer. In this study we analyzed the expression of molecules on pancreatic and colon cancer cells that could allow escape from NK cell-mediated immune surveillance. The data presented here demonstrates surface PCNA expressing cells as CSC through co-expression of CSC surface markers CD44 and CD133 as well as overexpression of CSC transcription factors NANOG, SOX-2, and Oct-4. Blocking PCNA or NKp44 alters interferon-ℽ secretion by NK cells when cocultured with pancreatic and colon cancer cells. It is further demonstrated that blocking LLT1 or the PCNA-NKp44 interaction led to an increase in specific lysis of tumor cells. This study suggests that cell surface PCNA could function as a biomarker and an immunotherapeutic target for NK cell mediated killing of pancreatic cancer and colon cancer cells.Item Continuous quality improvement at the clinical research site: implementing methods for coordinators in the Heart and Lung Transplant and Pulmonary department at Baylor Scott and White Research Institute(2020-05) Norgan Radler, Charlene R.; Mathew, Stephen O.; Chaudhary, Pankaj; Martinez, Horacio; Felius, JoostNorgan Radler, Charlene R. Continuous quality improvement at the clinical research site: implementing methods for coordinators in the Heart and Lung Transplant and Pulmonary department at Baylor Scott and White Research Institute Master of Science (Clinical Research Management), April 2020 Introduction: The following research project is a Quality Improvement (QI) study to assess resource utilization for six ongoing clinical trials and evaluate the impact of quality improvement methods on the completion of critical trial activities in the Heart and Lung Transplant and Pulmonary (HLTP) department at Baylor Scott and White Research Institute (BSWRI). Methods: The project design is a case series in which observations were made on research staff before and after an intervention, with no control group. Non-probability sampling with purposeful, maximum variation was used due to the study's qualitative research design. Metrics were collected regarding the completion of key trial activities of subject screening, subject enrollment, and data entry before and after intervention using a spreadsheet tool. Collected metrics were reviewed to identify areas for improvement and QI interventions were designed and implemented to reallocate resources as appropriate. The data was maintained in a run chart to monitor changes during the pre-intervention and post-intervention periods. Statistical analysis was performed on the data to evaluate the effect of the intervention. Results: The Wilcoxon Signed-Rank test was used to statistically analyze differences in medians of activity metrics across all studies before and after intervention. All variables improved in the direction of the applied interventions except time screening subjects and data entered in the electronic data capture (EDC) system. Median differences were found statistically non-significant, except the combined variable of number of open queries and case report forms (CRF) not entered weekly which demonstrated a statistically significant decrease following intervention. Median time screening subjects demonstrated a non-significant decrease following intervention while median number of subjects screened showed a non-significant increase. Median time enrolling subjects and median number of subjects enrolled increased post intervention, but statistical testing was not performed due to the small sample size below the minimum critical threshold required. Median time entering data in the EDC demonstrated a non-significant increase following intervention while median number of CRFs entered in the EDC showed a non-significant decrease. Conclusion: Implementation of the quality improvement process for clinical research staff provided a tool for our site to continuously assess and improve trial outcomes. Five of the seven variables receiving quality improvement interventions improved in the direction of the intervention, with one demonstrating a statistically significant difference. The small sample size used may have decreased the power of the study to detect statistical significance. Future studies should be completed to apply the quality improvement methodology used to a larger sample size. In conclusion, this study established 'proof of concept' for the completion of future, larger-scale quality improvement projects at our research site.Item Development and In Vitro Characterization of Gemcitabine Loaded Nanoparticles for Pancreatic Cancer Therapy(2021-05) Pham, Jennifer H.; Ranjan, Amalendu P.; Fudala, Rafal; Mathew, Stephen O.Pancreatic Ductal Adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths worldwide and the most common type of pancreatic malignancy (90%). With a poor five-year survival rate of only 5-8%, complete surgical resection remains the only curative treatment. However, most patients are diagnosed at a later stage where chemotherapy and radiotherapy are the only options. Gemcitabine is the FDA-approved treatment for PDAC, but the current therapy leads to more severe side effects due to the instability of gemcitabine in the blood stream and its poor membrane permeability. Nanoparticles are effective in cancer therapy because they allow modifications that make for a more effective delivery method and also reduces the toxicity to normal tissue. In this proposed study, we aim to formulate, optimize and evaluate the in vitro effectiveness of gemcitabine loaded nanoparticles in a PDAC cell line in order to improve the effectiveness of current chemotherapy treatments for pancreatic ductal adenocarcinoma. We found out of the three types of nanoplatforms used for encapsulating gemcitabine (GEM-NPs): polymeric, liposomal and lipid polymer hybrid, the liposomal nanoparticles were the most effective in the encapsulation of gemcitabine according to the physicochemical properties, such as average particle size, zeta potential, drug loading and encapsulation efficiency. In vitro functional evaluation of liposomal formulation was done in a PDAC cell line (PANC-1). This study suggests that the use of liposomal nanoparticles is the most beneficial in the encapsulation and delivery of gemcitabine.Item Differential Expression of LLT1, SLAM Receptors CS1 and 2B4 and NCR Receptors NKp46 and NKp30 in Pediatric Acute Lymphoblastic Leukemia (ALL)(MDPI, 2023-02-26) Powers, Sheila B.; Ahmed, Nourhan G.; Jose, Roslin; Brezgiel, Marissa; Aryal, Subhash; Bowman, W. Paul; Mathew, Porunelloor A.; Mathew, Stephen O.Acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer. Most patients (85%) develop B-cell ALL; however, T-cell ALL tends to be more aggressive. We have previously identified 2B4 (SLAMF4), CS1 (SLAMF7) and LLT1 (CLEC2D) that can activate or inhibit NK cells upon the interaction with their ligands. In this study, the expression of 2B4, CS1, LLT1, NKp30 and NKp46 was determined. The expression profiles of these immune receptors were analyzed in the peripheral blood mononuclear cells of B-ALL and T-ALL subjects by single-cell RNA sequencing data obtained from the St. Jude PeCan data portal that showed increased expression of LLT1 in B-ALL and T-ALL subjects. Whole blood was collected from 42 pediatric ALL subjects at diagnosis and post-induction chemotherapy and 20 healthy subjects, and expression was determined at the mRNA and cell surface protein level. A significant increase in cell surface LLT1 expression in T cells, monocytes and NK cells was observed. Increased expression of CS1 and NKp46 was observed on monocytes of ALL subjects at diagnosis. A decrease of LLT1, 2B4, CS1 and NKp46 on T cells of ALL subjects was also observed post-induction chemotherapy. Furthermore, mRNA data showed altered expression of receptors in ALL subjects pre- and post-induction chemotherapy treatment. The results indicate that the differential expression of the receptors/ligand may play a role in the T-cell- and NK-cell-mediated immune surveillance of pediatric ALL.Item Dysfunctional neuroimmune pathways promote the development and maintenance of lupus hypertension(2020-05) Pham, Grace S.; Mathis, Keisa W.; Rickards, Caroline A.; Goulopoulou, Styliani; Cunningham, J. Thomas; Ma, Rong; Mathew, Stephen O.Hypertension afflicts nearly half of the adults in the United States and the majority of cases have no known cause. Chronic inflammation has been implicated in the development and maintenance of hypertension, and autoimmunity may comprise one of its sources. Hypertension is highly prevalent in the autoimmune disease systemic lupus erythematosus (SLE), in which chronic aberrant inflammation may be a causative factor. Endogenous neuroimmune pathways, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cholinergic anti-inflammatory pathway, likely contribute to this phenomenon. The HPA axis is a classical neuroimmune mechanism that senses peripheral inflammation via afferent vagal fibers, culminating in the release of the anti-inflammatory hormone cortisol. Previous studies have characterized HPA axis dysfunction in SLE, but less is known about how this dysregulation specifically impacts the hypertension that occurs in the setting of SLE. A second neuroimmune interaction, the cholinergic anti-inflammatory pathway, is an efferent vagus nerve-to-spleen mechanism that relies on T cell-produced acetylcholine to quell inflammation in acute settings and may be hypoactive in chronic inflammatory diseases like SLE. Notably, both of these neuroimmune mechanisms depend on vagus nerve function, identifying the vagus as a potential target for neuromodulation. Furthermore, the relationship between chronic inflammation and hypertension validates the investigation of neuroimmune pathway dysfunction towards novel mechanisms of hypertension. Herewithin, the HPA axis and cholinergic anti-inflammatory pathway are investigated using the well-established NZBWF1 mouse model of lupus hypertension. Our findings are that (1) administration of an inflammatory stimulus that activates vagal afferents elicits comparable neuronal activation in the paraventricular nucleus of the hypothalamus, compared to control mice, despite heightened peripheral inflammation; (2) amplification of efferent vagus nerve activity reduces blood pressure and renal inflammation; and (3) chronic unilateral vagotomy paradoxically results in decreased blood pressure and renal inflammation. Taken together, these findings identify dysfunction in two neuroimmune pathways while demonstrating that interventions targeting these pathways may have therapeutic benefits in lupus hypertension. In terms of future impact, these results may promote continuing inquiry in a more recently discovered neuroimmune pathway (i.e., cholinergic anti-inflammatory pathway), as well as reinstate curiosity in an older, abandoned area of research (i.e., HPA).Item Evaluation of NK Cell – Astrocyte Interactions: Potential Role in HIV-Associated Neurocognitive Disorders and HIV- Associated Dementia(2015-05-01) Bowen, Kelly E.; Mathew, Porunelloor A.; Mathew, Stephen O.; Hodge, Lisa M.NK cells play important roles in immunity against pathogens and cancer. NK cell functions are regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells. During pathological conditions, NK cells were shown to be recruited to the CNS and could impact CNS physiology by killing glial cells and by secreting IFN-g. Astrocytes are intimately involved in immunological and inflammatory events occurring in the CNS and reactive astrogliosis is a key feature in HIV-associated neurocognitive disorders (HAND). There is little data on NK cell-astrocyte interactions and ligands expressed on astrocytes that could impact NK cell function. This study aimed to identify NK-associated ligands expressed by human astrocytes that confer this NK-directed cytotoxicity of astrocytes and assay the cytotoxicity differences in presence and absence of HIV 3S peptide. Using a fusion protein consisting of the extracellular domain of NKp44 fused to Fc portion of human IgG, we determined the expression of a novel ligand for NKp44 (NKp44L) on astrocytes. Incubation of astrocytes with 3S peptide downregulated NKp44L expression on astrocytes implicating protection from NK mediated killing. Thus, our study demonstrated that NKp44 has a protective effect on astrocytes from NK cell mediated killing during HIV infection. Astrocytes could also secrete cytokines that affect the expression of NK receptors on NK cells. We evaluated the expression of receptors on NK cells after co-culture with astrocytes. CD38 expression was increased on primary NK cells after incubation with astrocytes. CD38 is expressed on both NK cells and astrocytes and has an important implication in HIV-1 infection. Blocking CD38 signaling in our studies decreased astrocyte lysis, suggesting CD38 signaling has important implications in NK-astrocyte interactions. Future studies providing novel insights into the role of NK cells in the pathogenesis of HAND and other brain disorders might result in the development of NK cell based therapies for brain pathologies.Item Examination of Ventilation Before and After Advanced Airway Placement During Continuous Chest Compressions Cardiopulmonary Resuscitation(2020-05) Gordon, Teresa R.; Hodge, Lisa M.; Sumien, Nathalie; Mathew, Stephen O.Purpose: The aim of this project was to identify a method to measure ventilation during continuous chest compressions CPR that will improve outcomes for resuscitation attempts on out of hospital cardiac arrest patients Hypothesis: It is possible to identify ventilation waveforms using defibrillator bioimpedance and adequate ventilation prior to placement of an advanced airway during continuous chest compressions is associated with better outcomes. Design: Defibrillator files from 4 Resuscitation Outcomes Consortium sites were examined for evidence of ventilations. The number of ventilations, placement of an advanced airway, return of spontaneous circulation, initial heart rhythm, and ventilation rates were recorded. Results and Conclusion: It is feasible to identify ventilations during continuous chest compressions CPR using bioimpedance. There was no significant difference between ventilation before and after an advanced airway was placed. The association between ventilation and outcome is undetermined.Item Expression and Function of Ligands for Natural Killer Cell Receptors on Triple-negative Breast Cancer Cells(2018-08) Marrufo, Armando M.; Mathew, Porunelloor A.; Mathew, Stephen O.; Jones, Harlan P.; Phillips, Nicole R.Triple-negative breast cancer (TNBC) accounts for 20 percent of all breast cancer cases and is known to be the most invasive form of breast cancer. TNBC's absence of estrogen, progesterone, and human epidermal growth factor-2 receptors makes utilizing hormonal treatments ineffective in suppressing tumor growth. TNBC is associated with poorer prognosis and higher incidences of relapse. Therefore, natural killer cell-mediated immunotherapy shows potential as a treatment option for TNBC. Natural killer cells (NK) are innate lymphoid cells that serves its role in the immune system to eradicate infected and tumor cells. NK cell function is regulated through its receptors interacting with activating and inhibitory ligands on target cells. Lectin-like Transcript-1 (LLT1, CLEC2D) is a ligand that interacts with NKRP1A (CD161) and inhibits NK cell activation. Proliferating Cell Nuclear Antigen (PCNA) is a ligand that interacts with NKp44 and inhibits NK cell activation. We have identified the expression and function of LLT1 and PCNA on TNBC cell lines by flow cytometry, western blot, immunofluorescent microscopy, and chromium-release assay. Our results have demonstrated a higher expression of LLT1 and PCNA on TNBCs than non-tumorigenic breast cell line MCF10A. We have shown that blocking LLT1 interaction with NKRP1A with antibodies and gene knockdown of LLT1, respectively, on TNBCs have increased lysis of TNBCs by primary NK cells. We have also shown that blocking PCNA interaction with NKp44 with antibodies have enhanced killing of TNBCs by NK cells. LLT1 and PCNA expressed on TNBCs sends an inhibitory signal to the NK cell thus serving its role for TNBCs to evade immunosurveillance. Blocking LLT1-NKRP1A or PCNA-NKp44 with antibodies enhances lysis by NK cells and may open a novel immunotherapeutic strategy for patients diagnosed with TNBC.Item Expression of Immune Receptors in Response to Chemotherapy Treatment in B and T Acute Lymphoblastic Leukemia(2023) Ahmed, Nourhan; Mathew, Stephen O.Acute Lymphoblastic Leukemia (ALL) represents the most common pediatric cancer. Most patients (85%) develop B-cell ALL, however, T-cell ALL tends to be more aggressive and show less promising prognosis. Significant improvements in chemotherapy regimens caused a leap in the 5-year survival rates to surpass 90%. However, relapse significantly lowers the chances of survival to less than 50% due to resistance developed by malignant cells to chemotherapy. Natural Killer (NK) cells represent the cytotoxic compartment of innate immunity. As opposed to T cells, NK cells can recognize and kill malignant cells without the need for antigen presentation. NK cells currently represent a promising immunotherapy alternative to traditional chemotherapy. They directly kill cancer cells through activation/inhibition signals or through cytokine release and mediating an adaptive response. As targets of interest for our research, we chose LLT1, CD155 and PCNA as NK-inhibitory receptors and CS1, 2B4 as activation receptors. Previously, we have shown a significant decrease of LLT1, 2B4 and CS1 on T lymphoblasts of ALL patients collected from 42 subjects after induction chemotherapy and compared with samples from 20 healthy subjects. Based on the preliminary data, in this study we are investigating the effect of chemotherapy on the expression of those activating and inhibitory receptors. Cell surface protein expression and mRNA expression of these NK receptors pre- and post-Doxorubicin and Vincristine treatment of B and T ALL cell lines have been analyzed. Resistance to chemotherapy is one of the major reasons for failure of treatment in cancer recurrence. However, the cytotoxic potential of NK cells can be harnessed to overcome the chemo-resistance seen in leukemic cells.
- «
- 1 (current)
- 2
- 3
- »