Medicine and Health Sciences Commons^™

Cytopenia Among Cml Patients On Imatinib In Kenya: Types, Grades, And Time Course, Angela Mcligeyo, Jamilla Rajab, Mohammed Ezzi, Peter Oyiro, Yatich Bett, Andrew Odhiambo, Matilda Ong’Ondi, Sitna Mwanzi, Mercy Gatua, Naothieno Abinya

Internal Medicine, East Africa

Background: Imatinib mesylate is the gold standard for the treatment of all phases of Philadelphia-positive chronic myeloid leukemia. Patients on imatinib treatment may develop cytopenia due to drug toxicity. This study aimed to determine the types, grades, and time course of cytopenia in CML patients on imatinib at a Nairobi hospital.

Methods: This was a cross-sectional descriptive study of adult patients aged ≥18 years followed up at the Glivec International Patient Access Program (GIPAP) clinic from 2007 to 2015. Patients who developed cytopenia within 12 months of initiating imatinib were eligible. Clinical and hematologic data were retrieved from the patients’ …

Alternative Polyadenylation Modulates Expression Of Pro-Fibrotic Proteins And Contributes To Lung Fibrosis, Junsuk Ko

Dissertations and Theses (Open Access)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease which affects about 5 to 8 million individuals in the world. Despite the high prevalence, there is currently no cure for IPF, and the cause of this disease is still unclear. Our laboratory and collaborators have shown that nudix hydrolase 21 (NUDT21, which is also known as cleavage factor 25, CFIm25) is a key regulator of alternative polyadenylation (APA). NUDT21 depletion causes 3’UTR shortening via APA leading to enhanced mRNA stability and protein translation. This NUDT21 reduction promotes tumor growth in glioblastoma by enhancing expression of oncogenes. Cancer and IPF share …

Vestigial-Like 1 Is A Shared Targetable Cancer-Placenta Antigen Expressed By Pancreatic And Basal-Like Breast Cancers, Sherille Denae Bradley

Dissertations and Theses (Open Access)

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regression by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from tumors of PDAC patients. This led to the identification of a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1), a novel putative TAA demonstrating overexpression in multiple tumor types and low or absent transcript expression in normal tissues with the exception of placenta. VGLL1-specific CTL isolated and expanded from the blood of a male PDAC patient …

Preclinical Studies Of A Novel Idh1 Inhibitor In Acute Myeloid Leukemia (Aml), Vivian Salama

Dissertations and Theses (Open Access)

LY3410738, a novel covalent Isocitrate Dehydrogenase 1 (IDH1) inhibitor in Acute Myeloid Leukemia, it is more effective than Ivosidenib (AG120) and has a potent anti-leukemic effect against IDH1 mutant acute myeloid leukemia in combination with Venetoclax (ABT-199).

Acute myeloid Leukemia (AML) is an aggressive neoplastic blood disorder characterized by proliferation of poorly differentiated cells of myeloid lineage. IDH1 is a cytoplasmic enzyme that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the citric acid cycle. Somatic gain-of-function mutations in IDH1 occur in ~10% of the newly diagnosed AML patients. The neo-enzymatic activity of mutant IDH1 results in accumulation …

Molecular Mechanisms Of Antimicrobial Resistance In Multi-Drug Resistant Enterococci, Ayesha Khan

Dissertations and Theses (Open Access)

Antibiotic resistance is a major global public health threat. Enterococci are recalcitrant, nosocomial pathogens that can be intrinsically resistant to valuable antibiotics, like beta-lactams, or evolve resistance to all existing antimicrobials. The LiaFSR system regulates resistance to cell membrane (CM) stressors like daptomycin (DAP), a front-line drug for multi-drug resistant infections. DAP resistance (DAP-R) in E. faecalis is mediated by CM phospholipid alterations. Emergence of DAP-R often leads to b-lactam resensitization, a phenomenon called the seesaw effect. The molecular mechanism of DAP-R and the seesaw effect are unknown. Here we show that LiaX is a surface exposed protein whose C-terminal …

Hypothalamic Circuits Mediating Consumption And Anxiety, Ryan Cassidy

Dissertations and Theses (Open Access)

From 1960-2016, U.S. obesity prevalence increased 13-40% and diabetes increased from 3-15%. There is an epidemic of metabesity, the aggregate metabolic disorders produced by chronic overeating. Drugs for metabesity were developed in the 1930s with limited effectiveness; agents today rely on the same principles and are similarly ineffective. Particularly surprising has been the failure of satiety enhancers; this indicates it may not be that physiologic hunger drives chronic overeating. Although hunger and satiety affect traditional reward circuitry (Cassidy & Tong 2017), evidence for the primacy of this effect is mixed. Being hungry reduces anxiety-like behavior in mice; whether the …

Multiplexed Crispr Libraries For Cancer Functional Genomics, Jintan Liu

Dissertations and Theses (Open Access)

High-throughput forward genetic screenings are invaluable tools to systematically explore genetic interactions and to link gene disruption with disease contexts. The adaptation of CRISPR/Cas9 has improved the sensitivity and specificity of functional screenings. Despite this advance, there remains a long-standing need to improve functional screenings with smaller and more versatile pooled libraries. Capitalizing on the inherent multiplexing capability of a class 2 CRISPR enzyme AsCpf1, we developed a multiplexed, high throughput screening strategy that has avoided the usual trade-off between library size and library penetration, allowing library minimization without sacrificing gene targeting efficiency. We optimized the AsCpf1 protein for functional …

Bayesian Adaptive Designs And Versatile Software Platform For Early Phase Clinical Trials, Yanhong Zhou

Dissertations and Theses (Open Access)

This research is dedicated to improve the efficiency of Bayesian adaptive designs for early phase clinical trials. Phase I clinical trials can be conducted using algorithm-based (also known as rule-based), model-based, or model-assisted designs. Numerous studies have shown that model-assisted designs have the simplicity of algorithm-based designs while possessing the great performance of the model-based designs. Despite the desirable properties of current model-assisted designs, their use is still limited. More importantly, they can fall short of tackling some emerging challenges brought by the development of novel therapies. Thus, there is a pressing need for model-assisted designs that can complement the …

Receptor Tyrosine Kinases-Mediated Acquired Parp Inhibitor Resistance In Breast Cancer, Mei-Kuang Chen

Dissertations and Theses (Open Access)

Leveraging compromised DNA damage repair (DDR) pathways commonly found in tumor cells, a classic strategy in cancer therapy is inducing excessive DNA damage to cause cancer cell death. Small molecule poly(ADP-ribose) polymerase (PARP) inhibitors (PARP-is) have been approved for clinical use in treating breast cancer and ovarian cancer patients bearing DDR-deficient tumors with mutations in breast cancer susceptibility genes (BRCA^m). However, accumulating evidences show that both intrinsic and acquired resistances to PARP-is exist in clinic and pre-clinical animal models. Therefore, I developed panels of cells with acquired PARP-is resistance from PARP-is-sensitive triple negative breast cancer (TNBC) cell …

Factors That Impact Uptake Of Carrier Screening By Male Reproductive Partners Of Female Prenatal Patients, Wendi Betting

Dissertations and Theses (Open Access)

Carrier screening is a genomic technology that is used to identify individuals who are carriers of autosomal recessive conditions. Despite published recommendations, the majority of male partners do not complete carrier screening after their female partner is identified to be a carrier. Previous studieshave examined reasons why women elect or decline carrier screening, but there have been few published studies that examine factors that influence a male partner’s decision to elect or decline carrier screening, particularly when the female has been identified as a carrier. The aim of the study was to determine the factors that influence the uptake of …

Heterogeneous Nuclear Ribonucleoprotein K (Hnrnp K) Overexpression And Its Interaction With Runx1 Rna In Acute Myeloid Leukemia, Marisa Aitken

Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) is an often devastating hematologic malignancy with 5-year overall survival lingering near 20%. Acquiring a deeper understanding of molecular underpinnings of leukemogenesis will provide a basis for developing more effective therapeutic strategies for patients with AML.

Here, we identified overexpression of hnRNP K as a recurrent abnormality in a subset (~20%) of AML patients. High levels of this RNA-binding protein associated with inferior clinical outcomes in de novo AML. Thus, to evaluate its putative oncogenic capacity in myeloid disease, we overexpressed hnRNP K in murine hematopoietic stem and progenitor cells isolated from fetal liver cells (FLCs). …

Assessing Patient Attitudes To Ward Genetic Testing For Hereditary Hematologic Malignancy, Addison Johnson

Dissertations and Theses (Open Access)

Since 2003, more than 15 genes have been identified to predispose to hereditary hematologic malignancy (HHM). Although the diagnostic yield of germline analysis for leukemia is similar to solid tumors, referral for genetic evaluation in adults with leukemia is underperformed. Identifying HHM is important for prognostication, treatment, and donor selection for hematopoietic stem cell transplant. No studies have examined leukemia patients’ attitudes toward genetic testing for HHM. This study aimed to assess leukemia patients’ attitudes toward genetic testing and elicit current perceived distress due to a leukemia diagnosis. Data were elicited through an electronic survey sent to 5,513 patients diagnosed …

Genetic Counselors' Approaches To Direct-To-Consumer Genetic Testing For Hereditary Breast Cancer, Sarah Burke

Dissertations and Theses (Open Access)

Given the increasing availability of health-related direct-to-consumer genetic testing (DTC-GT) and third-party interpretation (TPI) services, it is likely that genetic counselors (GCs) will continue to encounter consumers that require follow-up counseling for their results. The National Comprehensive Cancer Network recommends clinical-grade genetic testing to confirm commercial results; however, the type of testing that GCs select remains uncharacterized. Therefore, we aimed to describe the specific recommendations that cancer GCs make for confirmatory genetic testing in probands who have already obtained DTC-GT results or TPI data that reported a BRCA1/2 pathogenic variant. We recruited 80 GCs specializing in hereditary cancer and administered …

Modulation Of Pi3k-Akt Pathway In Colorectal Cancer, Maliha Nusrat

Dissertations and Theses (Open Access)

The phosphatidylinositol-3-kinase (PI3K) signaling pathway is activated in 20-40% colorectal cancers (CRC) through PTEN loss (PTEN^loss) and PIK3CA mutations (PIK3CA^mut). Allosteric AKT inhibition with MK2206 monotherapy has been ineffective in CRC patients. We investigated the impact of MK2206 on pharmacodynamic (PD) markers and signaling pathways using reverse phase protein array (RPPA) on (1) paired tumor biopsies from a clinical trial of MK2206 in PI3K-altered metastatic CRC, (2) PTEN^lossCRC patient derived xenografts (PDX) treated with MK2206 or carrier, and (3) MK2206-treated cell lines. PD inhibition was deep in cell lines, less but significant in …

Investigating Medical Examiners' Practices: Genetic Evaluation For Fatal Acute Aortic Dissection, Bradley Power

Dissertations and Theses (Open Access)

Acute thoracic aortic dissection (TAD) is a life-threatening event with a hereditary component. Currently, pathogenic variants in 11 genes associated with aortic aneurysm and dissection predispose to a heritable form of disease thereby conferring an increased risk for TAD. Genetic testing plays a pivotal role not only in diagnosis, but also in risk stratification for relatives and medical management to prevent premature death from dissection. Due to its high fatality rate, medical examiners and coroners (ME/Cs) may be the first to identify TAD cases and initiate genetic testing for the decedent and at-risk relatives. ME/Cs were surveyed using three clinical …

Impact Of Epa And Dha Supplementation And 15-Lox-1 Expression On Colitis And Colitis-Associated Colorectal Cancer, Jonathan Jaoude

Dissertations and Theses (Open Access)

Inflammatory bowel disease (IBD) patients not only suffer from colitis but also from increased morbidity and mortality of colitis-associated colorectal cancer (CAC). The enzyme 15-lipoxygenase-1 (15-LOX-1) is crucial to converting omega-3 fatty acid derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to resolvins, potent anti-inflammatory products. 15-LOX-1 effects on the conversion of EPA and DHA to resolvins that subsequently exert anti-inflammatory and anti-tumorigenic effects have received little attention. To address this knowledge gap, we hypothesize that 15-LOX-1 expression in colonic epithelial cells is essential for resolvin biosynthesis from EPA and DHA to modulate immunophenotype, limit inflammation, promote resolution, and help …

Frequency Of Copy Number Variants Involving The Sex Chromosomes In A Clinical Setting, Autumn Vara

Dissertations and Theses (Open Access)

Copy number variants (CNVs) are a common finding in the clinical setting and contribute to both genetic variation as well as disease. Recently, studies have described the accumulation of multiple CNVs as a disease modifying mechanism. While it has been characterized how additional CNVs may play a role in phenotype, in which ways and to what extent sex chromosomes are involved has not been fully described. We performed a secondary data analysis using the DECIPHER database on 2,273 de-identified individuals with 2 CNVs. CNVs were designated primary and secondary based on our criteria and characteristics of both CNV groups were …

Exosomal Communication By Metastatic Osteosarcoma Cells Modulates Alveolar Macrophages To An M2 Tumor-Promoting Phenotype And Inhibits Tumoricidal Functions, Kerri Wolf

Dissertations and Theses (Open Access)

Osteosarcoma metastasizes to the lung, and there is a link between the predominance of tumor promoting immunosuppressive M2 macrophages in the metastases and poor patient survival. By contrast, M1macrophage predominance correlates with longer survival. M2 macrophages can be induced by various stimuli in the tumor microenvironment, including exosomes, which are 40- to 150-nm vesicles that are involved in intercellular communication and contribute to tumor progression and immune evasion. Recognizing that tumor cells can influence the tumor microenvironment to make it more permissive and because of the link between M2 dominance and curtailed patient survival, we evaluated the effect of …

Genetic Counselors' Experiences With And Approaches To Discordant Genotypic And Phenotypic Sex Detected Via Non-Invasive Prenatal Testing, Emily Stiglich

Dissertations and Theses (Open Access)

As the use of non-invasive prenatal testing becomes more ubiquitous during pregnancy, genetic counselors (GCs) will see clients more frequently for discordant sex identification via non-invasive prenatal testing (NIPT-DSI). Thus, it is imperative to investigate what GCs consider important when counseling about NIPT-DSI and assess how GCs perceive their role in such cases. Prenatal and pediatric GCs were surveyed regarding previous experiences of NIPT-DSI, comfort levels of topics relating to NIPT-DSI, and perceived importance of potential discussion topics in a counseling session (n = 108). The survey consisted of two vignettes, presenting cases of NIPT-DSI identified prenatally in one …

Loss Of Caspase-8 Function In Combination With Smac Mimetic Treatment Sensitizes Head And Neck Squamous Carcinoma To Radiation Through Induction Of Necroptosis., Burak Uzunparmak

Dissertations and Theses (Open Access)

Caspase-8 (CASP8) is one of the most frequently mutated genes in Head and Neck Squamous Carcinomas (HNSCC), and mutations of CASP8 are associated with poor overall survival. The distribution of these mutations in HNSCC suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a unique cell death mechanism. Here, we evaluated how CASP8 regulates necroptosis in HSNCC using cell line models and syngeneic mouse xenografts. In vitro, knockdown of CASP8 rendered HNSCCs susceptible to necroptosis induced by a second mitochondria-derived activator of caspase (SMAC) mimetic, Birinapant, when combined …

An Exploration Of Neuroanatomical Signatures Of Pediatric Bipolar Disorder Using Structural Neuroimaging, Jonika Tannous

Dissertations and Theses (Open Access)

Bipolar Disorder (BD) is diagnosed using the Diagnostic and Statistical Manual (DSM) criteria, which relies heavily on symptomatology. This method, however, lends itself to error due to variance in symptom expression and is further complicated during childhood and adolescence- a period marked by major anatomical and behavioral changes. Therefore, in order to institute early and effective interventions, it is imperative that we develop more objective methods of mood disorder characterization and diagnosis. Two proposed solutions for accomplishing this task include 1) the generation of normative development models to assess BD risk and 2) data-driven clustering of patients based on specific …

Mcp-1 Release Modulation Through Interaction Of Pulmonary Endothelial Cells And Mesenchymal Stromal Cells, Kaavya Giridhar

Dissertations and Theses (Open Access)

Background: Ischemic stroke is a leading cause of death and long-term disability

around the world. Current treatment options are limited to the administration of

tissue plasminogen activator (tPA) and/or endovascular therapy, administered within

a limited time window. However, cell-based therapies such as mesenchymal stromal

cells (MSCs) have increasingly shown great promise for ischemic stroke recovery

with some therapies already in various stages of clinical trials. Intravenous (IV)

administration of the MSCs leads to the entrapment of these MSCs in the lungs.

These entrapped MSCs interact with the pulmonary endothelial cells (PECs) and

could modulate the immune response through the release …

Development Of Fully Balanced Ssfp And Computer Vision Applications For Mri-Assisted Radiosurgery (Mars), Jeremiah Sanders

Dissertations and Theses (Open Access)

Prostate cancer is the second most common cancer in men and the second-leading cause of cancer death in men. Brachytherapy is a highly effective treatment option for prostate cancer, and is the most cost-effective initial treatment among all other therapeutic options for low to intermediate risk patients of prostate cancer. In low-dose-rate (LDR) brachytherapy, verifying the location of the radioactive seeds within the prostate and in relation to critical normal structures after seed implantation is essential to ensuring positive treatment outcomes.

One current gap in knowledge is how to simultaneously image the prostate, surrounding anatomy, and radioactive seeds within the …

Case Presentation On Periampullary Cancer And Ampullectomy, Tetiana Soloviova

Publications and Research

Periampullary cancer is a complex disease of heterogenous origin. This is cancer arising within 2 cm of the papilla of Vater and includes pancreatic, ampullary, biliary and duodenal cancers. Duodenal cancer has the highest estimated 5-year survival (49%), followed by ampullary cancer (45%), distal bile duct cancer (27%), and pancreatic cancer (18%). (Ray-Offor, 2019, ¶ 1)

Surgical And Oncological Implications Of Aberrant Arterial Anatomy In Patients Undergoing Pancreatoduodenectomy, Muhammad Rizwan Khan, Saleema Begum, Dawar Burhan Khan, K. M. Inam Pal

Section of General Surgery

Whipple's pancreatoduodenectomy is a complex surgical procedure and any aberrant arterial anatomy may have serious surgical implications. The objective of our study was to analyse the frequency of aberrant hepatic artery and compare the outcomes in patients with normal anatomy. Clinical data and computed tomography scans of 45 consecutive patients who underwent Whipple's procedure from 2007 to 2016 were reviewed. Group 'A' included patients with aberrant hepatic artery while group 'B' with normal anatomy. Aberrant hepatic artery was present in 11 (24%) patients and type V was the most common variant (n=5, 45%). Morbidity rate in group A was 82% …

Artifact Identification For Blood Pressure And Photoplethysmography Signals In An Unsupervised Environment, Pooi Khoon Lim

Student Works (2020-2029)

Physiological signals play a significant role in clinical diagnosis, it always acts as a major input of a decision support system. However, the physiological signal is easily corrupted by different factors especially motion artifacts. Several research works have been tried to recover the underlying physiological signal by suppressing the artifact. However, not much attention has been paid to situation where the artifact is too extreme and the artifact suppression is not possible. In this situation, physiological signal quality must be evaluated before any further assessment. In this study, an automated artifact detection algorithm was developed for Blood Pressure and PPG …

Synthesis, Cytotoxicity And Apoptosis Studies On Nickel And Zinc Derivatives Of Testosterone-N4-Substituted-Thiosemicarbazones, Mok Piew Heng

Student Works (2020-2029)

The side effects of cisplatin such as toxicities are mainly due to the lack of selectivity of this chemotherapeutic agent. In order to increase the selectivity of an anticancer agent, hormone molecule that targets a specific receptor may be utilized. This research aimed to prepare cytotoxic Schiff base compounds (and their nickel and zinc complexes) with testosterone and derivatives of thiosemicarbazide, which are potentially selective towards cancerous cells. Three Schiff base ligands (TM, TF, and TP) were made from the conjugation of testosterone with three derivatives of thiosemicarbazide (N4= methyl, fluorophenyl, and ethylphenyl) and their respective nickel (NM, NF, and …

Managing Stress In A Constantly-Changing Workforce, Lorri Burch-Hubbard

Electronic Theses and Dissertations

When staffing reductions occur in the workplace, staff left behind may face increased stress, may not be given the support they need to manage the feelings caused by the reduction. This study was conducted to evaluate the impact of stress caused by staffing reductions has on medical technologists (MT), medical technicians (MLT) and respiratory therapists (RT), and to identify any common methods of stress management used by those staff who remain in the organization.

Literature research showed the negative impact stress can have on individuals when it is not addressed, such as decreased work performance, health issues, and even the …

Health And Academic Achievement In College And University Students, Amber Beane

Electronic Theses and Dissertations

The purpose of this non-experimental quantitative correlational study was to investigate the relationship between academic achievement and health in a national sample of college students using quantitative data analysis. Specifically, the researcher analyzed the relationship between three health-promoting behaviors (physical activity, strength training, and fruit and vegetable consumption), three negative health behaviors (cigarette, e-cigarette, and opioid use) and obesity with GPA.

Cross-sectional data on student health collected from the American College Health Association’s National College Health Assessment II (ACHA-NCHA-II) and completed by 426,650 college students from 650 U.S. colleges during the semesters between 2015 and 2019 formed the foundation for …

Examination Of Perceptions Of Weight Loss And Weight Loss Methods, Andrew Seiber

Electronic Theses and Dissertations

The purpose of this study was to examine individuals’ perceptions of weight loss and weight loss methods. Respondents were employees and customers attending health/wellness events at local supermarkets in June, July, and August 2019. Participants completed a survey to assess their understanding and perceptions of weight loss and methods used to achieve weight loss. The majority of participants were white females, 60 years or older with a college degree and a Body Mass Index (BMI) classified as overweight or obese. Data revealed most participants had a variety of misconceptions relating to weight loss and weight loss methods that were obscure …