Translational Medical Research Commons^™

From Bedside To Bench: Use Of Patient-Derived Xenograft Models To Develop Novel Therapeutic Strategies For Triple-Negative Breast Cancer, Tia H. Turner

Theses and Dissertations

Triple-negative breast cancer (TNBC) is a clinically aggressive disease that is associated with bleak outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative treatment options. Despite decades of major translational research efforts, there has been very little success thus far in the development of effective targeted therapies for this disease. It is imperative to develop novel therapeutic strategies to improve patient outcomes, as well as minimize the toxicity associated with standard-of-care chemotherapeutics. Given that metastatic disease accounts for the vast majority of TNBC-related deaths, a better understanding of therapeutic responses within common sites …

Exploring The Heteromeric Interface Of The 5-Ht2a-Mglu2 Receptor Complex, Mohamed Aarif Abdul Kareem

Theses and Dissertations

Schizophrenia is a serious mental disorder characteristic of several neurotransmitters including dopamine, serotonin, and glutamate being in imbalance. Early therapies focused solely on dopamine antagonism and second-generation antipsychotics focused on the dopamine and serotonin systems and their respective G protein coupled receptor (GPCR) proteins. Although debate for dimerization of certain classes of GPCR exist, the establishment of an mGlu2-5-HT_2A heterocomplex, which is implicated in schizophrenia is of interest. Previous studies have used a mutation-based approach to identify transmembrane domain 4 (TM4) as the domain responsible in mGlu2 for mediating heteromerization before narrowing down the individual amino acids responsible for …

Reply To Lipworth Et Al., Angela M. Moran, Sanjay Ramakrishnan, Catherine A. Borg, Clare M. Connolly, Simon Couillard, Christine M. Mwasuku, Ian D. Pavord, Timothy S.C. Hinks, Lauri Lehtimӓki

Research outputs 2014 to 2021

We thank Dr. Lipworth and colleagues for their interest in our work published recently in the Journal (1). They rightly point out that the biology of asthma attacks is more complex than blood eosinophils alone and that corticosteroids have a wide range of other potentially relevant antiinflammatory effects. However, local treatment with inhaled corticosteroids (ICS) is usually the mainstay of patients with frequent eosinophilic exacerbations, and therefore in the great majority of patients, the key question is what oral corticosteroids (OCS) add to ICS in an acute attack (2) and whether this effect is seen with benralizumab. We suggest that …

The Role Of Histone Chaperone Fact Complex In Base Excision Repair Pathway And Its Therapeutic Potential In Colon Cancer And Medulloblastoma, Heyu Song

Theses & Dissertations

Base excision repair (BER) pathway is required for the removal of damaged bases caused by alkylation, oxidation and ring-saturation. Human apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in BER pathway. Although repair of damaged bases by recombinant APE1 has been well investigated in vitro, how APE1 gains access to damaged bases in the context of chromatin is largely unknown. A prominent member of the histone chaperone family, FACT (Facilitates Chromatin Transcription) is thought to reorganize nucleosomes through the destabilization of multiple intra-nucleosome contacts. FACT complex is composed of two polypeptides identified as SPT16 (Suppressor of Ty 16) and SSRP1 …

Weighing Harms, Benefits, And Alternatives For A Young Man With A Recent Flare Of Ulcerative Colitis, Louise B. Welsh

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Sandborn WJ, Su C, Sands B, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2017 May 4;376(18):1723-1736. doi: 10.1056/NEJMoa1606910

Ranolazine Decreases Weekly Anginal Episodes In Patients With Chronic Stable Angina And Type 2 Diabetes, Hisham Kaddurah

Clinical Research in Practice: The Journal of Team Hippocrates

The author reflects on the meaningful difference between statistical and clinical significance.

Abstracts From The 25th Annual Health Care Systems Research Network Conference, April 8–10, 2019, Portland, Oregon

Journal of Patient-Centered Research and Reviews

The Health Care Systems Research Network (HCSRN) is made up of nonprofit health systems with embedded research departments whose scientists are dedicated to public domain research. The network’s annual conference serves as a forum for research teams to disseminate study findings, stimulate new collaborations, and share insights about conducting research in real-world care settings. Abstracts accepted for presentation at HCSRN 2019 are published in this supplement of Journal of Patient-Centered Research and Reviews, the official scientific journal of the conference.

Early Dexamethasone Administration In Adults With Suspected Meningitis Lowers Morbidity And Mortality, Dana Siegel

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of de Gans J, van de Beek D, Investigators EDiABMS. Dexamethasone in adults with bacterial meningitis. New Eng J Med. 2002;347(20):1549-1556. doi: 10.1056/NEJMoa021334.

Coordinating An Oncology Precision Medicine Clinic Within An Integrated Health System: Lessons Learned In Year One, Michael A. Thompson, Jennifer J. Godden, Deborah Wham, Antony Ruggeri, Michael P. Mullane, Amanda Wilson, Shamsuddin Virani, Scott M. Weissman, Brenda Ramczyk, Pamela Vanderwall, James L. Weese

Journal of Patient-Centered Research and Reviews

Precision medicine is a term describing strategies to promote health and prevent and treat disease based on an individual’s genetic, molecular, and lifestyle characteristics. Oncology precision medicine (OPM) is a cancer treatment approach targeting cancer-specific genetic and molecular alterations. Implementation of an OPM clinical program optimally involves the support and collaboration of multiple departments, including administration, medical oncology, pathology, interventional radiology, genetics, research, and informatics. In this review, we briefly introduce the published evidence regarding OPM’s potential effect on patient outcomes and discuss what we have learned over the first year of operating an OPM program within an integrated health …

How Do Teachers Use Comics To Promote Engagement, Equity, And Diversity In Science Classrooms?, Camilla Matuk, Talia Hurwich, Amy Spiegel, Judy Diamond

World of Viruses

Equitable learning opportunities are critical to the goals of science education. However, major curriculum standards are vague on how to achieve equity goals, and educators must often develop their own resources and strategies to achieve equity goals. This study examines how educators used a comic book series designed to interest youth in virology as a way to make science more broadly appealing to their diverse students. We begin with the notion of Pedagogical Design Capacity, which describes a dynamic relationship between teachers and their tools and the ability for teachers to perceive and leverage affordances of artifacts as tools in …

Effects Of The Dual Orexin Receptor Antagonist Dora-22 On Sleep In 5xfad Mice, Marilyn J. Duncan, Hannah Farlow, Chairtra Tirumalaraju, Do-Hyun Yun, Chanung Wang, James A. Howard, Madison N. Sanden, Bruce F. O'Hara, Kristen J. Mcquerry, Adam D. Bachstetter

Neuroscience Faculty Publications

Introduction: Sleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevant mouse model, 5XFAD.

Methods: Wild-type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA-22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y-maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, respectively.

Results: In 5XFAD mice, DORA-22 significantly increased light-phase sleep without reducing Aβ levels, …

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …

Coping With Chronic Fungal Rhinosinusitis: Diagnosis To Therapy, Veronica Corcino, Leslie Beavin, Shengli Lu, Ashley Ross, Carmen V. Sciortino Jr.

The University of Louisville Journal of Respiratory Infections

No abstract provided.

Implementing A Pre-Exposure Prophylaxis Intervention For Safer Conception Among Hiv Serodiscordant Couples: Recommendations For Health Care Providers, Mari-Lynn Drainoni, Dea L. Biancarelli, Ashley A. Leech, Meg Sullivan, Angela R. Bazzi

Journal of Health Disparities Research and Practice

Couples in HIV serodiscordant relationships frequently desire children. Although partners who are virally suppressed pose almost no risk of transmitting HIV to their partners, partners who are inconsistently on therapy may transmit HIV to their partners when attempting to conceive. Pre-exposure prophylaxis (PrEP) is an available safer conception strategy for these couples but is not consistently offered. We sought to better understand barriers to PrEP implementation for couples seeking conception and patient perceptions on what providers could do to encourage use. We conducted in-depth, qualitative interviews with 11 participants representing six couples taking PrEP for safer conception in a safety-net …

Perinatal Nicotine With Or Without Early Life Influenza Infection Leads To Lung Dysfunction With Age., Ryan Carroll Mcallister

Electronic Theses and Dissertations

Obstructive Airway Diseases (OADs) affect millions of people worldwide, and are characterized by chronic inflammation and tissue remodeling in the lung. It has been proposed that the development of OAD is greatly influenced (and perhaps pre-determined) by early life events, such as maternal smoking or a viral infection. However, direct evidence of this is limited and the mechanisms involved remain unclear. Our laboratory previously developed a murine model of perinatal nicotine exposure, and reported that nicotine leads to airway remodeling and decreased pulmonary function in the offspring. We discovered these effects were mediated through the α7 nicotinic acetylcholine receptor (nAChR). …

Trichuris Muris Whey Acidic Protein Induces Type 2 Protective Immunity Against Whipworm, Neima Briggs

Dissertations and Theses (Open Access)

Human whipworm (Trichuris trichiura) infects approximately 1 in 15 people worldwide, representing the leading infectious cause of colitis and subsequent, inflammatory bowel disease (IBD). Current control measures focused on mass deworming have had limited success due to low drug efficacies. Vaccination would be an ideal, cost-effective strategy to induce protective immunity, leading to control of infection and transmission. Here we report the identification of whey acidic protein, a whipworm secretory protein, as a strong immunogen for inducing protective efficacy in a surrogate mouse T. muris infection model. The near full-length recombinant WAP protein (rTm-WAP49), as well …

Epigenetic Alterations Mediate Ipsc Normalization Of Dna-Repair Expression And Tnr Stability In Huntington's Disease, Peter A. Mollica, Martina Zamponi, John Reid, Deepak Sharma, Alyson E. White, Roy C. Ogle, Robert D. Bruno, Patrick C. Sachs

School of Medical Diagnostics & Translational Sciences Publications

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat (TNR) expansion within the HTT gene. The mechanisms underlying HD-associated cellular dysfunction in pluripotency and neurodevelopment are poorly understood. We had previously identified downregulation of selected DNA repair genes in HD fibroblasts relative to wild-type fibroblasts, as a result of promoter hypermethylation. Here, we tested the hypothesis that hypomethylation during cellular reprogramming to the induced pluripotent stem cell (iPSC) state leads to upregulation of DNA repair genes and stabilization of TNRs in HD cells. We sought to determine how the HD TNR region …

Doacs Least Harmful For Patients With Calciphylaxis On Hemodialysis Needing Anticoagulation, Mona Fayad

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of King BJ, El-Azhary RA, Mcevoy MT, et al. Direct oral anticoagulant medications in calciphylaxis. International Journal of Dermatology. 30 August 2017;56(1):1065-1070. doi: 10.1111/ijd.13685

Food Insecurity And Pre-Hypertension, Pre-Diabetes In Adult Women: Results From The 2007-2010 National Health And Nutrition Examination Survey, Michelle L. Redmond, Phd, Ms, Fanglong Dong, Phd, Philip Twumasi-Ankrah, Phd, Robert B. Hines, Phd, Mph, Lisette T. Jacobson, Phd, Mpa, Ma, Elizabeth Ablah, Phd, Mph, Judy Johnston, Ms, Rd/Ld, Tracie C. Collins, Md, Mph, Mhcds

Journal of Health Disparities Research and Practice

Background

Being food insecure is generally defined as the limited or uncertain availability of safe and nutritious foods and is linked to poor nutrition and fully progressed diet-sensitive chronic diseases. However, little is known about the association between food insecurity and pre-clinical disease such as pre-hypertension and pre-diabetes. This study sought to examine the associations between food insecurity and pre-clinical disease among a racially/ethnically diverse population of women.

Methods

Using data from 2007-2010 NHANES, we examined associations between food security and pre-clinical disease among women 18-65 years. Chi-square tests were used to examine differences in demographic variables. Bivariate and multivariable …

A Study Of Acoustically Activated Nanodroplets, Songita Choudhury

Theses & Dissertations

Current treatment of acute myocardial infarction (AMI), which is the main pathophysiological event leading to death in the United States, has advanced considerably with the introduction of emergent percutaneous interventions, but there remains an urgent need for novel techniques to rapidly and accurately detect infarcted or ischemic tissue that results from AMI. Ultrasound contrast agents, also known as microbubbles (MB), have become commonplace in echocardiography. However, MBs are purely intravascular tracers and unable to cross endothelial barriers due to size. The limitations of MBs, namely size and short circulation times within the human body, led to the development of phase-change …

Muc4 Based Immunotherapy For Pancreatic Cancer, Kasturi Banerjee

Theses & Dissertations

Pancreatic Cancer (PC) is a lethal disease claiming approximately 45000 lives in the US in 2018, and it establishes an elaborate immunosuppressive tumor microenvironment that aids in disease pathogenesis. Immunotherapy has emerged as a strategy to target tumor cells by reprogramming patient’s immune system. Challenges present in PC immunotherapy are: i) identifying a tumor-associated antigen that could be targeted, ii) identifying adjuvants that could efficiently deliver antigens, iii) eliciting robust anti-tumor responses and iv) overcoming peripheral tolerance and immunosuppression elicited by the tumor.

Firstly, we detected circulating autoantibodies to MUC4 present in PC patients and observed that IgM autoantibodies to …

Investigating Ampk Signalling Regulation Of Autophagy In A Model Of Ovarian Tumour Dormancy, Jeremi Laski

Western Research Forum

Investigating AMPK signalling regulation of autophagy in a model of ovarian tumour dormancy

Jeremi Laski and Trevor G. Shepherd

Background:

Ovarian cancer is the most deadly gynecologic malignancy in women. A particular subset of this disease, epithelial ovarian cancer (EOC), is responsible for over 70% of all diagnosed ovarian cancer cases, yet the mechanisms governing disease progression are poorly understood. One of the unique hallmarks of EOC metastasis lies in the process of spheroid formation, whereby tumour cells aggregate into larger 3D structures. These EOC spheroids have been shown to be metabolically dormant, while concurrently up-regulating autophagy (cellular waste …

Microrna 1207-3p In Prostate Cancer, Dibash Das

Dissertations, Theses, and Capstone Projects

Prostate cancer (PCa) is the most commonly diagnosed male cancer and the second leading cause of cancer-related death for men in the United States. Understanding the molecular mechanisms involved in progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC) is a major challenge. MicroRNAs (miRNAs), are known to be dysregulated in PCa. MicroRNA-1207-3p (miR-1207-3p) is encoded by the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of miR-1207-3p in PCa is unclear. We have discovered that miR-1207-3p is significantly underexpressed in PCa cell lines …

Examining Differences In Hpv Awareness And Knowledge And Hpv Vaccine Awareness And Acceptability Between U.S. Hispanic And Island Puerto Rican Women, Daisy Y. Morales-Campos Phd, Robin Vanderpool

Journal of Health Disparities Research and Practice

Background: In 2015, only 42% of Puerto Rican (PR) girls aged 13-17 and 44% of U.S. Hispanic girls aged 13-17 were vaccinated with all three Human Papillomavirus (HPV) vaccine doses. These percentages were far lower than the Healthy People 2020 goal of 80% of girls aged 13-15 completing the vaccine series. The purpose of this study was to examine potential differences in HPV awareness and knowledge and HPV vaccine awareness and acceptability between a population-based sample of U.S. Hispanic and island Puerto Rican women.

Methods: We restricted our analyses to female respondents from the Health Information National Trends Survey (HINTS) …

The Role Of Ceramide In Neutrophil Elastase Induced Inflammation In The Lungs, Sophia Karandashova

Theses and Dissertations

Alterations to sphingolipid metabolism are associated with increased pulmonary inflammation, but the impact of inflammatory mediators, such as neutrophil elastase (NE), on airway sphingolipid homeostasis remains unknown. NE is a protease associated CF lung disease progression, and can be found in up to micromolar concentrations in patient airways. While sphingolipids have been investigated in the context of CF, the focus has been on loss of cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we present a novel observation: oropharyngeal aspiration of NE increases airway ceramides in mice. Using a previously characterized mouse model of NE-induced inflammation, we demonstrate that NE …

Age-Dependent Changes In Oxygen Supply And Demand Of Rat Spinotrapezius Muscle, Sami C. Dodhy

Theses and Dissertations

Because of the aerobic nature of cellular metabolism in mammalian organisms, a continuous supply of oxygen is necessary to maintain normal physiological function. As organisms age, their metabolic rates generally decline and there are accompanying alterations in the structure and function of the microcirculation, as this part of the cardiovascular system is especially important for oxygen exchange. The overall Oxygen Transport System can be considered as being composed of two complementary components: one for Oxygen Demand and one for Oxygen Supply. The purpose of the current work is to describe the age-dependent changes in both oxygen demand and oxygen supply …

Effects Of The Na-Cl Co-Transporter (Ncc) In Western Diet Induced Metabolic And Cardiac Dysfunction, Zachary S. Cutter

Theses and Dissertations

Interleukin-18 (IL-18) is a pro-inflammatory cytokine known to be involved in maintaining metabolic homeostasis; however, also capable of inducing cardiac dysfunction. Additionally, IL-18, has been shown to bind to a novel receptor, the Na-Cl Co-transporter (NCC). We hypothesized that NCC mediates IL-18 metabolic and cardiac signaling in mice. Using male C57BL/6J mice, we compared the metabolic and cardiac function changes after at least 8 weeks of high-saturated fat high sugar diet (Western Diet) in NCC knockout (NCCKO), IL-18 knockout (IL-18KO), and wild-type mice. We show that NCCKO mice have significantly increased body weight gain from baseline, no difference in fasting …

Conference Proceedings: Aurora Scientific Day 2017

Journal of Patient-Centered Research and Reviews

This supplement includes select abstracts presented at the 43rd Annual Aurora Scientific Day research symposium on May 24, 2017. Aurora Scientific Day hosts a forum for original research conducted by faculty, fellows, residents, and other allied health professionals affiliated with Aurora Health Care, an integrated health system headquartered in Milwaukee, Wisconsin.

Generation Of A Patient-Derived Brain Metastasis Breast Cancer Cell Line Via Novel Orthotopic Injection Placement And Serial Mouse Transplantation To Develop Pdx Mouse Model, Amber L. Lacrosse, Denise M. Coley, Paul J. Mintz, Santhi D. Konduri, Richard A. Rovin, Amin B. Kassam

Journal of Patient-Centered Research and Reviews

Background: The incidence of brain metastasis appears to be increasing, potentially due to advanced technology that aids early diagnosis. Patient-derived xenografts (PDX) have high translational value, as these models retain key functional characteristics of the patient tumor. PDX models are useful to understand the molecular basis of tumorigenesis and to identify new treatment targets. However, generating a first-line PDX model is challenging as engraftment failure is high. Serial transplanting tumor tissue via mouse-to-mouse propagation increases engraftment rates and decreases PDX development time. Herein we report methods to generate a PDX cell line from patient-derived tumor tissue that includes the cerebral …

Lung Cytokines And Systemic Inflammation In Patients With Copd., Alessandra Morello Gearhart, Rodrigo Cavallazzi, Paula Peyrani, Timothy L. Wiemken, Stephen P. Furmanek, Andrea Reyes-Vega, Umair Gauhar, Hiram Rivas-Perez, Jesse Roman, Julio A. Ramirez, Rafael Fernandez-Botran

Faculty and Staff Scholarship

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by lung and systemic inflammation. The role of cytokines in local and systemic inflammation in COPD is not well understood. This study aimed to compare plasma and bronchoalveolar lavage (BAL) fluid cytokine levels in COPD and non-COPD subjects with the intent of better understand their potential roles in driving local and systemic inflammation.

Methods: This cross-sectional study analyzed data from 65 subjects: 31 with COPD confirmed by spirometry and 34 non-COPD controls. All subjects underwent spirometry, plasma sample collection, and bronchoscopy/BAL. Levels of 21 inflammatory cytokines were measured in the plasma (systemic …