Life Sciences Commons^™

Survival Advantage Of Both Human Hepatocyte Xenografts And Genome-Edited Hepatocytes For Treatment Of Alpha-1 Antitrypsin Deficiency, Florie Borel, Qiushi Tang, Gwladys Gernoux, Cynthia Greer, Ziqiong Wang, Adi Barzel, Mark A. Kay, Leonard D. Shultz, Dale L. Greiner, Terence R. Flotte, Michael A. Brehm, Christian Mueller

Christian Mueller

Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create …

Evaluating The Therapeutic Efficacy Of Restoring Wild-Type P53 Activity In P53-Mutant Tumors, Connie A. Larsson

Dissertations & Theses (Open Access)

The p53 transcription factor is the most frequently altered in human cancers usually via missense mutations that undermine its transcriptional activity. Clinically, TP53 mutations have been shown to be remarkably predictive of refractoriness to treatment, resulting in poor outcome. Consequently, the development of p53 pathway activating agents is rapidly evolving and gaining more attention in cancer therapeutics research, with several small molecule compounds currently in preclinical and clinical trials. However, it remains largely unknown what types or proportions of p53-mutant tumors will respond to p53 restoration-based therapies.

Using a mouse model of Li Fraumeni syndrome, we genetically restored wild-type …

Sustained Sensitizing Effects Of Tumor Necrosis Factor Alpha On Sensory Nerves In Lung And Airways, Ruei-Lung Lin, Qihai Gu, Mehdi Khosravi, Lu-Yuan Lee

Physiology Faculty Publications

Tumor necrosis factor alpha (TNFα) plays a significant role in the pathogenesis of airway inflammatory diseases. Inhalation of aerosolized TNFα induced airway hyperresponsiveness accompanied by airway inflammation in healthy human subjects, but the underlying mechanism is not fully understood. We recently reported a series of studies aimed to investigate if TNFα elevates the sensitivity of vagal bronchopulmonary sensory nerves in a mouse model; these studies are summarized in this mini-review. Our results showed that intratracheal instillation of TNFα induced pronounced airway inflammation 24 hours later, as illustrated by infiltration of eosinophils and neutrophils and the release of inflammatory mediators and …

The Effects Of Continuous Insulin Pump Therapy On Glycemic Control In Pregnant Type 1 Diabetics, Kimberly Kelsey

Senior Theses

Type 1 Diabetics have various ways of managing their diabetes that have been studied for their effectiveness. Pregnancy in the Type 1 Diabetic has been understudied. It is known that Diabetics in general have poorer pregnancy outcomes because of poor glycemic control. This coupled with the fact that the body needs 3-4 times more insulin as pregnancy comes to an end makes managing blood glucose levels challenging for diabetics (Lowdermilk, 2016, p. 689). For the Type 1 Diabetic, there are two main ways to control diabetes: multiple daily injections using at least two type of insulin and continuous subcutaneous insulin …

Memory Potential, Molecular Characterization, And Translational Applications Of The Novel Theo/Tceo T Cell Phenotype, Todd Bartkowiak, Todd Bartkowiak

Dissertations & Theses (Open Access)

T cells comprise a substantial arm of the immune system and are exquisitely adapted to combat pathogens and tumors. The inflammatory environment largely dictates the nature of T cell response. A hallmark of T cell-mediated immunity is formation of immunological memory; the ability to respond more potently to re-encounter with pathogens. The immune system is also capable of recognizing tumors as foreign, much like viral or bacterial pathogens. Tumors have evolved, though, to generate an immunosuppressive environment to avoid destruction. The field of immunotherapy seeks to overcome immune suppression, in part by targeting T cell co-receptors on the cell surface …

Size, Shape, And Sequence-Dependent Immunogenicity Of Rna Nanoparticles, Sijin Guo, Hui Li, Mengshi Ma, Jian Fu, Yizhou Dong, Peixuan Guo

Center for Research on Environmental Disease Faculty Publications

RNA molecules have emerged as promising therapeutics. Like all other drugs, the safety profile and immune response are important criteria for drug evaluation. However, the literature on RNA immunogenicity has been controversial. Here, we used the approach of RNA nanotechnology to demonstrate that the immune response of RNA nanoparticles is size, shape, and sequence dependent. RNA triangle, square, pentagon, and tetrahedron with same shape but different sizes, or same size but different shapes were used as models to investigate the immune response. The levels of pro-inflammatory cytokines induced by these RNA nanoarchitectures were assessed in macrophage-like cells and animals. It …

Mtor Kinase Inhibition Effectively Decreases Progression Of A Subset Of Neuroendocrine Tumors That Progress On Rapalog Therapy And Delays Cardiac Impairment, Melissa A. Orr-Asman, Zhengtao Chu, Min Jiang, Mariah Worley, Kathleen Lesance, Sheryl E. Koch, Vinicius S. Carreira, Hanan M. Dahche, David R. Plas, Kakajan Komurov, Xiaoyang Qi, Carol A. Mercer, Lowell B. Anthony, Jack Rubinstein, Hala E. Thomas

Internal Medicine Faculty Publications

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice …

Nanoparticle Delivery Of Mir-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells Via Targeting C22orf28 Directly, Xiaoti Lin, Weiyu Chen, Fengqin Wei, Binhua P. Zhou, Mien-Chie Hung, Xiaoming Xie

Molecular and Cellular Biochemistry Faculty Publications

Rationale: Cancer stem cells (CSCs) have been implicated as the seeds of therapeutic resistance and metastasis, due to their unique abilities of self-renew, wide differentiation potentials and resistance to most conventional therapies. It is a proactive strategy for cancer therapy to eradicate CSCs. Methods: Tumor tissue-derived breast CSCs (BCSC), including XM322 and XM607, were isolated by fluorescence-activated cell sorting (FACS); while cell line-derived BCSC, including MDA-MB-231.SC and MCF-7.SC, were purified by magnetic-activated cell sorting (MACS). Analyses of microRNA and mRNA expression array profiles were performed in multiple breast cell lines. The mentioned nanoparticles were constructed following the standard molecular cloning …

Disaggregating The Relative Influence Of Genetic, Environmental And Individual Factors On Lcl And Hdl Cholesterols And Bmi For A Sample Of African American (Aa) Mothers And Daughters, C. Jayne Brahler, Jewel Harden, Michelle Mchone, Matthew Soules, Eric Evans, Ann Alyanak, Fred Diakpieng, Paul M. Vanderburgh

Paul M. Vanderburgh

There are many reports about the associations between blood lipids, body mass index (BMI) and dietary cholesterol intakes both within the individual and between related individuals. The purpose of this descriptive research project was to investigate the relationships between LDL and HDL cholesterols, body mass index and dietary cholesterol intakes for a sample of African American (AA) mothers and their daughters and to attempt to separate the contribution of genetic versus environmental factors. Mother and daughter participants (n =42 and 66, respectively) were 12-14-hours fasted when blood samples were drawn, heights and weights measured, and 24 hour food recalls completed.

Perceived Stress Levels May Impact Upper Extremity Function Among Women Treated For Breast Cancer, Mary Insana Fisher, Anne Fleischer, Lynn Hendricks, Megan Mcclure, Kim Parent, Renee Roberts

Physical Therapy Faculty Publications

Purpose/Hypothesis: Women treated for breast cancer report ongoing upper extremity disability with functional limitations; however, objective measures do not appear to explain the extent of perceived dysfunction. The purpose of this study was to investigate the relationship between perceived stress level, fear of physical activity, self-reported upper extremity function, and objective measures of upper extremity function including range of motion (ROM), strength, and muscular endurance, among women treated for breast cancer.

Number of Subjects: 25

Materials/Methods: Women diagnosed with stage I-III breast cancer in the past 12-60 months were evaluated using the Disabilities of the Arm, Shoulder and Hand (DASH), …

Rehabilitation Of An Injured Golden Eagle (Aquila Chrysaetos): A Case Study, Fida Muhammad Khan, Fakhar-I- Abbas, Abu Ul Hassan Faiz

Journal of Bioresource Management

Habitat destruction and anthropogenic activities cause wild birds to migrate towards urban areas in search of food and sometimes nesting in high-roof buildings, where they are caught by local people using different techniques and are further used for hunting or recreational purposes. An injured Golden Eagle (Aquila chrysaetos) was found entangled in bushes near the vicinity of Balkasar Research Complex, Chakwal, Pakistan. After complete physical examination, a wound on the right wing and closed leg fracture was diagnosed. The successful treatment was done by anti-parasitic and anti-bacterial drugs with careful monitoring. Splint was adjusted after aligning the fractured …

Investigation Of The Safety Of Focused Ultrasound-Induced Blood-Brain Barrier Opening In A Natural Canine Model Of Aging, Meaghan Anne O'Reilly, Ryan Matthew Jones, Edward Barrett, Anthony P. Schwab, Elizabeth Head, Kullervo Hynynen

Sanders-Brown Center on Aging Faculty Publications

Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits.

Methods: Aged dogs naturally accumulate plaques and show …

Evolution Of The Alpha-1 Antitrypsin Muscle Gene Therapy: Translation From Clinical Trial To Benchtop And Back Again, Alisha M. Gruntman, Gwladys Gernoux, Gensheng Wang, Janet Benson, Jeff Chulay, Dave Knop, Christian Mueller, Terence R. Flotte

Christian Mueller

Alpha-one antitrypsin (AAT) deficiency is a genetic disease affecting the lungs due to inadequate anti-protease activity in the pulmonary interstitium. On-going human trials use intra-muscular delivery of adeno-associated virus (rAAV1), allowing expressing myofibers to secrete normal (M)AAT protein. In the Phase IIa trial, patients in the highest dose cohort (6x1012vg/kg) were given 100 intra-muscular (IM) injections of undiluted vector, with serum AAT levels still substantially below target levels. Previous work has shown that delivering rAAV vector to the musculature via limb perfusion leads to widespread gene expression in myofibers. We hypothesize that widespread delivery would result in an overall increase …

The Effect Of Target-Specific Biomolecules In Breast Cancer, Mohannad Garoub

FIU Electronic Theses and Dissertations

Cancer is the second leading cause of mortality in the United States and the World, therefore, early effective prevention, diagnosis, and therapy is needed. Estrogens play a major role in the initiation and progression of breast cancer. Elevated lifetime exposure to estrogens is associated with an increased risk of developing breast cancer. Estrogens through influencing mitochondria contribute to estrogen induced breast carcinogenesis; however, the exact mitochondrial mechanisms underlying the estrogen carcinogenic effect in breast tissue are not clearly understood. For this dissertation, the mitotoxic and cytotoxic effects of triphenylphosphonium cation (TPP) and Origanum majorana organic extract (OME) as well as …

5 Year Expression And Neutrophil Defect Repair After Gene Therapy In Alpha-1 Antitrypsin Deficiency, Christian Mueller, Gwladys Gernoux, Alisha M. Gruntman, Florie Borel, Emer P. Reeves, Roberto Calcedo, Farshid N. Rouhani, Anthony Yachnis, Margaret Humphries, Martha Campbell-Thompson, Louis M. Messina, Jeffrey D. Chulay, Bruce Trapnell, James M. Wilson, Noel G. Mcelvaney, Terence R. Flotte

Christian Mueller

Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%-3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%-2.5% of the target level from …

Effects Of Phosphodiesterase 3a Modulation On Murine Cerebral Microhemorrhages, Rachita K. Sumbria, Vitaly Vasilevko, Mher Mahoney Grigoryan, Annlia Paganini-Hill, Ronald Kim, David H. Cribbs, Mark J. Fisher

Pharmacy Faculty Articles and Research

Background: Cerebral microbleeds (CMB) are MRI-demonstrable cerebral microhemorrhages (CMH) which commonly coexist with ischemic stroke. This creates a challenging therapeutic milieu, and a strategy that simultaneously protects the vessel wall and provides anti-thrombotic activity is an attractive potential approach. Phosphodiesterase 3A (PDE3A) inhibition is known to provide cerebral vessel wall protection combined with anti-thrombotic effects. As an initial step in the development of a therapy that simultaneously treats CMB and ischemic stroke, we hypothesized that inhibition of the PDE3A pathway is protective against CMH development.

Methods: The effect of PDE3A pathway inhibition was studied in the inflammation-induced and …

Identification Of A Nucleoside Analog Active Against Adenosine Kinase-Expressing Plasma Cell Malignancies, Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J. Barelli, Michelle A. Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H. Shoemaker, J. David Warren, Olivier Elemento, Kenneth M. Kaye, Ethel Cesarman

Pharmacy Faculty Articles and Research

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase–inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we …

Recombinant Aav Serotype And Capsid Mutant Comparison For Pulmonary Gene Transfer Of Alpha-1-Antitrypsin Using Invasive And Noninvasive Delivery, Rejean Liqun Wang, Thomas J. Mclaughlin, Travis Cossette, Qiushi Tang, Kevin Foust, Martha Campbell-Thompson, Ashley Martino, Pedro Cruz, Scott Loiler, Christian Mueller, Terence R. Flotte

Christian Mueller

Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing alpha-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 x 1010 vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar …

An Objective Assessment Of The Variability In Number Of Drops Per Bottle Of Glaucoma Medication, Daniel B. Moore, Judy Beck, Richard J. Kryscio

Ophthalmology and Visual Science Faculty Publications

Background: The purpose of this study is to evaluate the number of eyedrops available per bottle of a variety of commonly prescribed glaucoma medications.

Methods: Six bottles of each glaucoma medication were tested: three each in the vertical and horizontal orientations. Bottles were housed in a customized force gauge apparatus designed to mimic ballpoint fingertip contact with a bottle. At a standard rate, all drops were expressed from each bottle and counted with an automated drop counter. Simultaneously, bottle volume was measured and drop size and number were also estimated. The main outcome measures were: total number of drops, volume …

Modeling Hiv Dynamics Following 3bnc117 Antibody Infusion, Samantha Erwin

Biology and Medicine Through Mathematics Conference

No abstract provided.

Tumor Necrosis Factor Α Inhibition For Alzheimer's Disease, Rudy Chang, Kei-Lwun Yee, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Tumor necrosis factor α (TNF-α) plays a central role in the pathophysiology of Alzheimer’s disease (AD). Food and Drug Administration–approved biologic TNF-α inhibitors are thus a potential treatment for AD, but they do not cross the blood-brain barrier. In this short review, we discuss the involvement of TNF-α in AD, challenges associated with the development of existing biologic TNF-α inhibitors for AD, and potential therapeutic strategies for targeting TNF-α for AD therapy.

The Regulation Of Rotavirus–Infected Ht29.F8 And Ma104 Cells Treated With Arachidin 1 Or Arachidin 3, Caleb M. Witcher

Electronic Theses and Dissertations

Rotavirus (RV) infections cause severe life threatening diarrhea in young children and immunocompromised individuals. Several effective vaccines have been developed for young children but are not protective against all strains of RV, and there are no anti-RV therapeutics. Our laboratory has discovered a decrease in the number of infectious simian RV particles (SA114f) in human intestinal cell line, HT29.f8 cells with the addition of either of two stilbenoids, arachidin-1 (A1) or arachidin-3 (A3). This suggests effects on the host cell and RV replication. We examined the cellular effects of human RV strain (Wa) on a human intestinal cell line (HT29.f8) …

Mapping The Interaction Between Lrrc59 And Cip2a Oncoprotein, Tamika C. Reed

Graduate School of Biomedical Sciences Theses and Dissertations

The oncogene cancerous inhibitor of protein phosphatase 2A (CIP2A) has been shown to promote oncogenesis through numerous protein-protein interactions. CIP2A was initially found to be a direct inhibitor of the PP2A tumor suppressor protein; however, new research has demonstrated that CIP2A can act independently of PP2A through protein-protein interactions resulting in deregulation of the cell cycle and the development of therapeutic drug resistance, tumorigenesis, and cell proliferation. It has been shown that leucine rich repeat containing 59 protein (LRRC59) binds to and is required for the nuclear translocation of CIP2A, thereby making this interaction a target for drug therapy. Thus, …

The Effect Of Photoactivated Tmp On Burkholderia Cepacia Biofilms, Reyna G. Osorio, Chandra N. Swiech, Tracy L. Collins

The Research and Scholarship Symposium (2013-2019)

Burkholderia cepacia is an opportunistic pathogen that causes infections in immunocompromised individuals such as cystic fibrosis patients. B. cepacia infections are typically characterized by the formation of complex communities of cells known as biofilms. Because B. cepacia biofilms are difficult to eradicate using antibiotics, it is important to pursue alternative treatment methods. Photodynamic therapy (PDT) is a type of therapy that uses light, a photosensitizer, and oxygen to elicit cell death through the production of reactive oxygen species. PDT has been shown in previous studies to be successful in killing both Pseudomonas aeruginosa and Staphylococcus aureus. In this study, we …

Nephrotoxicity In Patients With Or Without Cystic Fibrosis Treated With Polymyxin B Compared To Colistin, Ryan L. Crass, Wilbur Cliff Rutter, Donna R. Burgess, Craig A. Martin, David S. Burgess

Pharmacy Practice and Science Faculty Publications

Nephrotoxicity is the primary adverse effect of the polymyxins. The relative rates of toxicity of polymyxin B and colistin have not been fully elucidated, especially in patients with cystic fibrosis (CF). A retrospective cohort study of adults treated with polymyxin B or colistin for at least 48 h was conducted. The primary endpoint was the incidence of kidney injury assessed by RIFLE (i.e., risk, injury, failure, loss, end-stage renal disease) criteria. Risk factors for kidney injury were evaluated using multivariate Cox regression. A total of 414 patients were evaluated, 220 of whom had CF. In patients without CF, there was …

Toward A Research Agenda For Oncology Physical Therapy, Lucinda Pfalzer, Nicole L. Stout, Shana Harrington, Mary Insana Fisher

Physical Therapy Faculty Publications

Research Round-up: Cancer survivors frequently experience cancer treatment–related functional impairments and disability. While a growing body of evidence supports the effectiveness of rehabilitation interventions for these individuals, there are significant gaps in the existing literature and no interdisciplinary agreement on the priorities for cancer rehabilitation research. In 2016, the Oncology Section revised its strategic plan and set an objective to create an oncology rehabilitation research agenda for the physical therapy (PT) profession. To achieve this goal, the scope of the agenda, a development and review process, and dissemination plan need to be developed.

Colicins - A Sound Antimicrobial Approach For The Prevention Of Catheter-Associated Urinary Tract Infections, Sandra M. Roy

Doctoral Dissertations

The emergence and spread of antibiotic resistance has created one of the greatest challenges in fighting infectious disease. We address the rise of antibiotic-resistant pathogens by examining the evolutionary history of a class of resistance determinants, the SHV b-lactamases. We isolated the genes that encode the SHV beta-lactamases (bla_SHV genes) from clinical settings and from an environment essentially devoid of antibiotic use. Our data suggests that, counter to current dogma, the use of antibiotics in the clinic is not creating these resistance genes; genes for antibiotic resistance already exist in nature and our use of antibiotics in clinical …

Effect Of Exercise Position On Percent Changes In Serratus Anterior Muscle Thickness, Joseph M. Day

Physical Therapy Faculty Publications

Objective: A reliable method for measuring SA thickness with ultrasound imaging has been reported, yet the ability to detect differences in levels of contractility has yet to be established. The purpose of this study was to determine if there are differences in the percent change in thickness of the SA during four different exercise positions performed by healthy individuals.

Design: Observational study

Setting: Laboratory

Participants: Twenty-eight healthy participants, mean age 26 (SD 4, 57% female, 100% right handed)

Methods: Volunteers were positioned in a standardized sitting posture and anatomical landmarks were marked for ultrasound probe positioning. Two resting and two …

The [E]Motionless Body No Longer: Tracing The Historical Intersections Of Mental Illness And Movement In The American Asylum, Holly Adele Herzfeld

Senior Projects Spring 2017

Senior Project submitted to The Division of Multidisciplinary Studies of Bard College.

Vocal Function Exercises For Normal Voice: With And Without Semi-Occlusion, Megan Suzanne Brown

Theses and Dissertations--Communication Sciences and Disorders

The primary purpose of this investigation was to explore the effects of varying degrees of vocal tract semi-occlusion in Vocal Function Exercises (VFEs) on attainment of pre- established maximum phonation time (MPT) goals in individuals between the ages of 18 and 45 with normal voice. Individuals were randomized into three experimental groups: the traditional VFE with a semi-occluded vocal tract (SOVT), modified /o/ with partial occlusion, and modified /a/ without significant occlusion. For six weeks, the participants completed the four exercises two times each, twice daily on corresponding vocal tract postures assigned by group. Results indicated significant change in percent …