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Articles 1 - 30 of 36
Full-Text Articles in Medical Sciences
Phase 1b Study Of Batiraxcept In Combination With Durvalumab In Patients With Platinum-Resistant Ovarian Cancer, Anne Knisely, Emily M Hinchcliff, Elisabeth Gardiner, Reshma Rangwala, Kathryn Lito, Bryan Fellman, Ying Yuan, Anil K Sood, Shannon N Westin, Karen H Lu, Amir A Jazaeri
Phase 1b Study Of Batiraxcept In Combination With Durvalumab In Patients With Platinum-Resistant Ovarian Cancer, Anne Knisely, Emily M Hinchcliff, Elisabeth Gardiner, Reshma Rangwala, Kathryn Lito, Bryan Fellman, Ying Yuan, Anil K Sood, Shannon N Westin, Karen H Lu, Amir A Jazaeri
Student and Faculty Publications
Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71–2.40), and median overall survival (OS) was 4.53 …
Loss Of Cftr Function In Macrophages Alters The Cell Transcriptional Program And Delays Lung Resolution Of Inflammation, Dianne Wellems, Yawen Hu, Scott Jennings, Guoshun Wang
Loss Of Cftr Function In Macrophages Alters The Cell Transcriptional Program And Delays Lung Resolution Of Inflammation, Dianne Wellems, Yawen Hu, Scott Jennings, Guoshun Wang
School of Graduate Studies Faculty Publications
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) gene. The most severe pathologies of CF occur in the lung, manifesting as chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite increasing knowledge of the CF primary defect and the resulting clinical sequelae, the relationship between the CFTR loss of function and the neutrophilic inflammation remains incompletely understood. Here, we report that loss of CFTR function in macrophages causes extended lung inflammation. After intratracheal inoculation with Pseudomonas aeruginosa, mice with a macrophage-specific Cftr-knockout (Mac-CF) were able to mount an …
Inflammatory Activity Of Epithelial Stem Cell Variants From Cystic Fibrosis Lungs Is Not Resolved By Cftr Modulators, Shan Wang, Suchan Niroula, Ashley Hoffman, Melika Khorrami, Melina Khorrami, Feng Yuan, Grace N Gasser, Soon Choi, Bovey Liu, Justin Li, Mark L Metersky, Matthew Vincent, Christopher P Crum, Richard C Boucher, Harry Karmouty-Quintana, Howard J Huang, Ajay Sheshadri, Burton F Dickey, Kalpaj R Parekh, John F Engelhardt, Frank D Mckeon, Wa Xian
Inflammatory Activity Of Epithelial Stem Cell Variants From Cystic Fibrosis Lungs Is Not Resolved By Cftr Modulators, Shan Wang, Suchan Niroula, Ashley Hoffman, Melika Khorrami, Melina Khorrami, Feng Yuan, Grace N Gasser, Soon Choi, Bovey Liu, Justin Li, Mark L Metersky, Matthew Vincent, Christopher P Crum, Richard C Boucher, Harry Karmouty-Quintana, Howard J Huang, Ajay Sheshadri, Burton F Dickey, Kalpaj R Parekh, John F Engelhardt, Frank D Mckeon, Wa Xian
Student and Faculty Publications
Rationale
CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs.
Objectives
To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) …
Genome Editing For Cystic Fibrosis, Guoshun Wang
Genome Editing For Cystic Fibrosis, Guoshun Wang
School of Medicine Faculty Publications
Cystic fibrosis (CF) is a monogenic recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator gene (CFTR). Remarkable progress in basic research has led to the discovery of highly effective CFTR modulators. Now ~90% of CF patients are treatable. However, these modulator therapies are not curative and do not cover the full spectrum of CFTR mutations. Thus, there is a continued need to develop a complete and durable therapy that can treat all CF patients once and for all. As CF is a genetic disease, the ultimate therapy would be in-situ repair of the genetic lesions in the …
Impact Of Streptococcus Parasanguinis-Generated Reactive Nitrogen Species On Pseudomonas Aeruginosa Virulence And The Host Response, Joshua J. Baty
Impact Of Streptococcus Parasanguinis-Generated Reactive Nitrogen Species On Pseudomonas Aeruginosa Virulence And The Host Response, Joshua J. Baty
All ETDs from UAB
Streptococcus parasanguinis is an oral commensal bacterium that produces hydrogen peroxide. Hydrogen peroxide can react with endogenous molecules such as nitrite to form reactive nitrogen intermediates (RNI). These S. parasanguinis-mediated RNI have been shown to inhibit oral pathogens such as Streptococcus mutans, Enterococcus faecalis, and Aggregatibacter actinomycetemcomitans. As such, S. parasanguinis plays a protective role in the oral microbial ecosystem by antagonizing and preventing colonization by oral pathogens. In addition to being an important organism for the health of the oral cavity, S. parasanguinis has also been associated with improved outcomes for people with cystic fibrosis. There are two explanations …
Safety And Microbiological Activity Of Phage Therapy In Persons With Cystic Fibrosis Colonized With Pseudomonas Aeruginosa: Study Protocol For A Phase 1b/2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial, Pranita D Tamma, Maria Souli, Michael Billard, Joseph Campbell, Douglas Conrad, Damon W Ellison, Beth Evans, Scott R Evans, Kerryl E Greenwood-Quaintance, Andrey A Filippov, Holly S Geres, Toshimitsu Hamasaki, Lauren Komarow, Mikeljon P Nikolich, Thomas P Lodise, Seema U Nayak, Carmelle Norice-Tra, Robin Patel, David Pride, Janie Russell, Daria Van Tyne, Henry F Chambers, Vance G Fowlerjr, Robert T Schooley, Antibacterial Resistance Leadership Group
Safety And Microbiological Activity Of Phage Therapy In Persons With Cystic Fibrosis Colonized With Pseudomonas Aeruginosa: Study Protocol For A Phase 1b/2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial, Pranita D Tamma, Maria Souli, Michael Billard, Joseph Campbell, Douglas Conrad, Damon W Ellison, Beth Evans, Scott R Evans, Kerryl E Greenwood-Quaintance, Andrey A Filippov, Holly S Geres, Toshimitsu Hamasaki, Lauren Komarow, Mikeljon P Nikolich, Thomas P Lodise, Seema U Nayak, Carmelle Norice-Tra, Robin Patel, David Pride, Janie Russell, Daria Van Tyne, Henry F Chambers, Vance G Fowlerjr, Robert T Schooley, Antibacterial Resistance Leadership Group
Student and Faculty Publications
BACKGROUND: Bacteriophages (phages) are a promising anti-infective option for human disease. Major gaps remain in understanding their potential utility.
METHODS: This is a randomized, placebo-controlled, double-blind study of a single dose of intravenous phage in approximately 72 clinically stable adult cystic fibrosis volunteers recruited from up to 20 US sites with Pseudomonas aeruginosa airway colonization. The single dose of phage consists of a mixture of four anti-pseudomonal phages. Six sentinel participants will be sequentially enrolled with dose escalation of the phage mixture by one log
DISCUSSION: This trial will investigate the activity of phages in reducing P. aeruginosa colony counts …
Cystic Fibrosis Transmembrane Conductance Regulator Modulation May Improve Intestinal Inflammation In Adults With Cystic Fibrosis, Lauren G. Culver
Cystic Fibrosis Transmembrane Conductance Regulator Modulation May Improve Intestinal Inflammation In Adults With Cystic Fibrosis, Lauren G. Culver
Clinical Research in Practice: The Journal of Team Hippocrates
A clinical decision report using:
Ooi CY, Syed SA, Rossi L, Garg M, Needham B, Avolio J, Young K, Surette MG, Gonska T. Impact of CFTR modulation with Ivacaftor on Gut Microbiota and Intestinal Inflammation. Sci Rep. 2018 Dec 13;8(1):17834. https://doi.org/10.1038/s41598-018-36364-6
for a patient with cystic fibrosis experiencing small bowel obstruction.
The Immune Response To Airway Mycosis, Evan Li, Antony Rodriguez, Amber U Luong, David Allen, John Morgan Knight, Farrah Kheradmand, David B Corry
The Immune Response To Airway Mycosis, Evan Li, Antony Rodriguez, Amber U Luong, David Allen, John Morgan Knight, Farrah Kheradmand, David B Corry
Student and Faculty Publications
The allergic airway diseases chronic rhinosinusitis (CRS), allergic fungal rhinosinusitis (AFRS), asthma, allergic bronchopulmonary mycosis/aspergillosis (ABPM/A), and cystic fibrosis (CF) share a common immunological signature marked by T H 2 and TH 17 cell predominant immune responses, the production of IgE antibody, and atypical inflammatory cell infiltrate that includes eosinophils and other innate immune effector cells. Severe forms of these disorders have long been recognized as being related to hypersensitivity reactions to environmental fungi. Increasingly however,environmental fungi are assuming a more primary role in the etiology of these disorders, with airway mycosis, a type of non-invasive airway fungal infection,recognized as …
Exploring Attitudes Towards Newly Approved Therapeutics In Prenatal Genetic Counseling Practice, Charlotte Close
Exploring Attitudes Towards Newly Approved Therapeutics In Prenatal Genetic Counseling Practice, Charlotte Close
Human Genetics Theses
Cystic fibrosis (CF) care has rapidly evolved over the past decade due to the introduction of CFTR modulators and continued quality improvement efforts, yet research from 2013 suggests that prenatal genetic counselors often did not feel knowledgeable discussing newer CF treatments with patients and expressed the need to refer to a CF specialist (Elsas, 2017). Given that the intervening years have allowed for collection of long-term data about CFTR modulators and that the recently approved modulator Trikafta (tez/elx/iva) is available to 90% of the CF population, it is appropriate to re-evaluate the status of prenatal genetic counselors’ awareness of and …
Allergic Bronchopulmonary Aspergillosis In Children, Özge Atay, Suna Asi̇lsoy, Gi̇zem Atakul, Serdar Al, Özge Kangalli Boyacioğlu, Nevi̇n Uzuner, Özkan Karaman
Allergic Bronchopulmonary Aspergillosis In Children, Özge Atay, Suna Asi̇lsoy, Gi̇zem Atakul, Serdar Al, Özge Kangalli Boyacioğlu, Nevi̇n Uzuner, Özkan Karaman
Turkish Journal of Medical Sciences
Background/aim: Allergic bronchopulmonary aspergillus (ABPA) is a lung disease caused by hypersensitivity from Aspergillus fumigatus. Diagnostic criteria, staging systems and treatment methods for ABPA disease have been reported in studies evaluating populations, the majority of which are adult patients. Our study aimed to discuss the use of ABPA diagnostic criteria in children, the success of other alternative regimens to oral corticosteroids in the treatment of ABPA, and the changes that occur during treatment, in the light of the literature. Materials and methods: Between January 2017 and 2020, patients diagnosed with ABPA at the Dokuz Eylül University Child Allergy and Immunology …
Challenges Of Pediatric Disease In Adulthood, Dennis J. Baumgardner, Brian Chicoine
Challenges Of Pediatric Disease In Adulthood, Dennis J. Baumgardner, Brian Chicoine
Journal of Patient-Centered Research and Reviews
Some chronic diseases — such as the rare bone disease X-linked hypophosphatemia, the impetus for a study reported within Volume 7, Issue 2 of the Journal of Patient-Centered Research and Reviews — are diagnosed in childhood but become more symptomatic in adulthood. In this editorial, the challenges, pitfalls, and opportunities regarding the care of adults with childhood-onset chronic diseases are examined using Down syndrome, cystic fibrosis, congenital heart disease, and Hirschsprung disease as examples.
Factors Associated With Severe Lung Disease In An Adult Population With Cystic Fibrosis: A Single-Center Experience, Berri̇n Er, Ebru Çelebi̇oğlu, Ebru Yalçin, Deni̇z Doğru, Özlem Erden Aki̇, Ömrüm Uzun, Murat Akova, Uğur Özçeli̇k, Nural Ki̇per, Sali̇h Emri̇
Factors Associated With Severe Lung Disease In An Adult Population With Cystic Fibrosis: A Single-Center Experience, Berri̇n Er, Ebru Çelebi̇oğlu, Ebru Yalçin, Deni̇z Doğru, Özlem Erden Aki̇, Ömrüm Uzun, Murat Akova, Uğur Özçeli̇k, Nural Ki̇per, Sali̇h Emri̇
Turkish Journal of Medical Sciences
Background/Aim: The patients with cystic fibrosis (CF) are living longer compared to the past, but respiratory failure is still the most common cause of mortality. The aim of this study is to investigate factors associated with severe lung disease in a cohort of adult patients with CF. Materials and methods: Demographic data, clinical and laboratory findings of the patients aged 18 years and more were collected and the patients were grouped according to forced expiratory volume in 1 s (FEV1) as severe group:
Prospective Evaluation Of Vascular Changes In Acute Respiratory Infections In Children With Cystic Fibrosis, Gökçen Kartal Öztürk, Aykut Eşki̇, Fi̇gen Çelebi̇ Çeli̇k, Seçi̇l Conkar, Fi̇gen Gülen, Esen Demi̇r, Ahmet Keski̇noğlu
Prospective Evaluation Of Vascular Changes In Acute Respiratory Infections In Children With Cystic Fibrosis, Gökçen Kartal Öztürk, Aykut Eşki̇, Fi̇gen Çelebi̇ Çeli̇k, Seçi̇l Conkar, Fi̇gen Gülen, Esen Demi̇r, Ahmet Keski̇noğlu
Turkish Journal of Medical Sciences
Background/aim: Acute exacerbations and chronic inflammation are risk factors for cardiovascular disease (CVD) in cystic fibrosis (CF) patients. The aim of this study was to investigate the effects of acute exacerbation therapy on arterial stiffness in children with CF. Materials and methods: Augmentation index (Aix) and pulse wave velocity (PWV) were measured before and after treatment and 1 month after the end of treatment in patients with acute exacerbation. The relationship between hemodynamic measurements and c-reactive protein (CRP) and pulmonary function tests (PFTs) was investigated. Results: Measurements before and after treatment were evaluated in 27 patients and were repeated in …
Intranasal Peptide-Based Fpva-Klh Conjugate Vaccine Protects Mice From Pseudomonas Aeruginosa Acute Murine Pneumonia, Emel Sen-Kilic, Catherine B. Blackwood, Dylan T. Boehm, Wiliam T. Witt, Aaron C. Malkowski, Justin R. Bevere, Ting Y. Wong, Jesse M. Hall, Shelby D. Bradford, Melinda E. Varney, Fredrick Heath Damron, Mariette Barbier
Intranasal Peptide-Based Fpva-Klh Conjugate Vaccine Protects Mice From Pseudomonas Aeruginosa Acute Murine Pneumonia, Emel Sen-Kilic, Catherine B. Blackwood, Dylan T. Boehm, Wiliam T. Witt, Aaron C. Malkowski, Justin R. Bevere, Ting Y. Wong, Jesse M. Hall, Shelby D. Bradford, Melinda E. Varney, Fredrick Heath Damron, Mariette Barbier
Faculty & Staff Scholarship
Pseudomonas aeruginosa is an opportunistic pathogen causing acute and chronic respiratory infections associated with morbidity and mortality, especially in patients with cystic fibrosis. Vaccination against P. aeruginosa before colonization may be a solution against these infections and improve the quality of life of at-risk patients. To develop a vaccine against P. aeruginosa, we formulated a novel peptide-based P. aeruginosa subunit vaccine based on the extracellular regions of one of its major siderophore receptors, FpvA. We evaluated the effectiveness and immunogenicity of the FpvA peptides conjugated to keyhole limpet hemocyanin (KLH) with the adjuvant curdlan in a murine vaccination and challenge …
The Oxidative Tyrosine Modification, O,O’-Dityrosine, In Lung Disease, Morgan Locy
The Oxidative Tyrosine Modification, O,O’-Dityrosine, In Lung Disease, Morgan Locy
All ETDs from UAB
The oxidative tyrosine modification, o,o′-dityrosine, has been identified in various pathologic conditions associated with oxidative stress in mammalian systems, and demonstrated to be important in physiologic processes in invertebrate organisms. The formation of o,o’-dityrosine is catalyzed by a heme peroxidase (hPx) in the presence of hydrogen peroxide (H2O2). The understanding of this stable, covalent tyrosine modifica-tion in lung biology is limited. Oxidative stress has been implicated in the pathogenesis of various lung diseases, including interstitial lung disease (ILD) and cystic fibrosis (CF). We observed that the oxidative protein modification, o,o’-dityrosine, was markedly ele-vated in the circulating plasma of ILD patients …
Mucus Adhesion As A Therapeutic Target In Cystic Fibrosis, Courtney Fernandez Petty
Mucus Adhesion As A Therapeutic Target In Cystic Fibrosis, Courtney Fernandez Petty
All ETDs from UAB
Cystic fibrosis (CF) is a genetic disease resulting from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is an ion channel responsible for proper movement of chloride and bicarbonate ions across the apical cell surface. Defective CFTR results in an absence of bicarbonate transport, which functions in part to chelate Ca2+, a divalent cation found in abundance in mucin granules in normal conditions; this yields a hyperviscous and adhesive mucus on the respiratory and gastrointestinal tracts of patients with CF. Bronchial mucins are glycosylated proteins with neutral and negative sugars modified by negatively charged sialic and neuraminic …
Molecular Characterization Of The Rare Cftr Mutation P67l As A Model For Genotype-Specific Drug Development And Personalized Medicine In Cystic Fibrosis, Carleen Mae Pomperada Sabusap
Molecular Characterization Of The Rare Cftr Mutation P67l As A Model For Genotype-Specific Drug Development And Personalized Medicine In Cystic Fibrosis, Carleen Mae Pomperada Sabusap
All ETDs from UAB
The traditional CFTR functional defect subcategories (i.e. protein misfolding, gating, conductance, etc.) are sometimes inadequate for determining patients most likely to benefit from emerging modulator treatment. We employ the P67L variant as emblematic of ways a thorough biochemical analysis of a rare CF defect can guide new therapeutic approaches, help predict drug response, and facilitate clinical precision. Historically, P67L has been designated a class IV conductance abnormality (i.e., malformed ion pore). In contrast, our studies demonstrate P67L disrupts CFTR protein maturation, prompts misfolding, causes gating defects, and exhibits wild-type like conductance. We show that P67L CFTR is robustly rescued by …
Pseudomonas Aeruginosa Sabotages The Generation Of Host Proresolving Lipid Mediators, Becca A. Flitter, Kelli L. Hvorecny, Emiko Ono, Taylor Eddens
Pseudomonas Aeruginosa Sabotages The Generation Of Host Proresolving Lipid Mediators, Becca A. Flitter, Kelli L. Hvorecny, Emiko Ono, Taylor Eddens
Dartmouth Scholarship
Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4 (15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4 transcellular biosynthesis and function. In the airway, 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate …
Effect Of Inhaled Steroids On Clinical And Inflammatoryparameters In Children With Cystic Fibrosis, Zeynep Seda Uyan, Gökseni̇n Ünlügüzel Üstün, Goncagül Haklar, Erkan Çakir, Sedat Oktem, Refi̇ka Ersu, Bülent Taner Karadağ, Fazi̇let Karakoç, Eli̇f Dağli
Effect Of Inhaled Steroids On Clinical And Inflammatoryparameters In Children With Cystic Fibrosis, Zeynep Seda Uyan, Gökseni̇n Ünlügüzel Üstün, Goncagül Haklar, Erkan Çakir, Sedat Oktem, Refi̇ka Ersu, Bülent Taner Karadağ, Fazi̇let Karakoç, Eli̇f Dağli
Turkish Journal of Medical Sciences
Background/aim: The effectiveness of inhaled corticosteroids (ICSs) in cystic fibrosis (CF) is controversial. The aim of this study was to investigate the effect of an ICS on bronchial hyperreactivity (BHR), oxidative status, and clinical and inflammatory parameters in CF patients. Materials and methods: CF patients were randomized to receive either 2 mg/day nebulized budesonide or 0.9% normal saline as placebo for 8 weeks. Results: Twenty-nine CF patients (mean age: 10.5 $\pm$ 2.9 years) were enrolled in the study. There was no statistically significant difference between the two groups at the end of 8 weeks in terms of symptoms, pulmonary function, …
Emerging Pathogens In Cystic Fibrosis Patients At Virginia Commonwealth University Medical Center (Vcumc), Emily M. Hill
Emerging Pathogens In Cystic Fibrosis Patients At Virginia Commonwealth University Medical Center (Vcumc), Emily M. Hill
Theses and Dissertations
Cystic fibrosis (CF) is an autosomal recessive disorder affecting 70,000 individuals worldwide. This disease is characterized by the buildup of mucus in the airways leading to chronic lung infections resulting in pulmonary failure and death in 95% of CF patients. Routine surveillance of CF pathogens using traditional microbiology culture guides management and treatment of CF patients. Molecular profiling studies have revealed emerging pathogens that may play a role in CF lung disease by either directly causing infection or upregulating the virulence factors of classic CF pathogens, such as P. aeruginosa; however, routine CF culture protocols have not been modified …
Pseudomonas Aeruginosa Reduces Vx-809 Stimulated F508del-Cftr Chloride Secretion By Airway Epithelial Cells, Bruce A. Stanton, Bonita Coutermarsh, Roxanna Barnaby, Deborah Hogan
Pseudomonas Aeruginosa Reduces Vx-809 Stimulated F508del-Cftr Chloride Secretion By Airway Epithelial Cells, Bruce A. Stanton, Bonita Coutermarsh, Roxanna Barnaby, Deborah Hogan
Dartmouth Scholarship
Background:
P. aeruginosa is an opportunistic pathogen that chronically infects the lungs of 85% of adult patients with Cystic Fibrosis (CF). Previously, we demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE) cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second) by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation. We propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and …
Coculture Of Staphylococcus Aureus With Pseudomonas Aeruginosa Drives S. Aureus Towards Fermentative Metabolism And Reduced Viability In A Cystic Fibrosis Model, Laura M. Filkins, Jyoti A. Graber, Daniel G. Olson, Emily L. Dolben, Lee Lynd, Sabin Bhuju, George A. O'Toole
Coculture Of Staphylococcus Aureus With Pseudomonas Aeruginosa Drives S. Aureus Towards Fermentative Metabolism And Reduced Viability In A Cystic Fibrosis Model, Laura M. Filkins, Jyoti A. Graber, Daniel G. Olson, Emily L. Dolben, Lee Lynd, Sabin Bhuju, George A. O'Toole
Dartmouth Scholarship
The airways of patients with cystic fibrosis are colonized with diverse bacterial communities that change dynamically during pediatric years and early adulthood. Staphylococcus aureus is the most prevalent pathogen during early childhood, but during late teens and early adulthood, a shift in microbial composition occurs leading to Pseudomonas aeruginosa community predominance in ∼50% of adults. We developed a robust dual-bacterial in vitro coculture system of P. aeruginosa and S. aureus on monolayers of human bronchial epithelial cells homozygous for the ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) mutation to better model the mechanisms of this interaction. We show that P. …
The I507-Atc→Att Silent Codon Change Contributes To The Misfolding Of ∆F508 Cftr, Vedrana Bali
The I507-Atc→Att Silent Codon Change Contributes To The Misfolding Of ∆F508 Cftr, Vedrana Bali
All ETDs from UAB
Synonymous codon changes (SCCs) do not alter the amino acid sequence of proteins, but may significantly change the phenotype. The frequency of synonymous codons is species- and gene-specific, described as codon usage bias (CUB). Over the past 50 years, research has shown that SCCs affect protein biogenesis, development of human disorders and the function of recombinant proteins developed for therapeutic applications. However, the molecular mechanisms by which SCCs alter the function of gene products are not completely understood. In Chapter 2 we summarize present knowledge in this field. The most common cause of cystic fibrosis (CF) is the deletion of …
Pouring Salt On A Wound: Pseudomonas Aeruginosa Virulence Factors Alter Na+ And Cl− Flux In The Lung, Alicia E. Ballok, George A. O'Toole
Pouring Salt On A Wound: Pseudomonas Aeruginosa Virulence Factors Alter Na+ And Cl− Flux In The Lung, Alicia E. Ballok, George A. O'Toole
Dartmouth Scholarship
Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen with multiple niches in the human body, including the lung. P. aeruginosa infections are particularly damaging or fatal for patients with ventilator-associated pneumonia, chronic obstructive pulmonary disease, and cystic fibrosis (CF). To establish an infection, P. aeruginosa relies on a suite of virulence factors, including lipopolysaccharide, phospholipases, exoproteases, phenazines, outer membrane vesicles, type III secreted effectors, flagella, and pili. These factors not only damage the epithelial cell lining but also induce changes in cell physiology and function such as cell shape, membrane permeability, and protein synthesis. While such virulence factors are important in …
Epoxide-Mediated Cifr Repression Of Cif Gene Expression Utilizes Two Binding Sites In Pseudomonas Aeruginosa, Alicia E. Ballok, Christopher D. Bahl, Emily L. Dolben, Allia K. Lindsay, Jessica D. St. Laurent, Deborah Hogan, Dean Madden, George A. O'Toole
Epoxide-Mediated Cifr Repression Of Cif Gene Expression Utilizes Two Binding Sites In Pseudomonas Aeruginosa, Alicia E. Ballok, Christopher D. Bahl, Emily L. Dolben, Allia K. Lindsay, Jessica D. St. Laurent, Deborah Hogan, Dean Madden, George A. O'Toole
Dartmouth Scholarship
Pseudomonas aeruginosa secretes an epoxide hydrolase virulence factor that reduces the apical membrane expression of ABC transporters such as the cystic fibrosis transmembrane conductance regulator (CFTR). This virulence factor, named CFTR inhibitory factor (Cif), is regulated by a TetR-family, epoxide-responsive repressor known as CifR via direct binding and repression. We identified two sites of CifR binding in the intergenic space between cifR and morB, the first gene in the operon containing the cif gene. We have mapped these binding sites and found they are 27 bp in length, and they overlap the -10 and +1 sites of both the cifR …
Prevalence Of Streptococci And Increased Polymicrobial Diversity Associated With Cystic Fibrosis Patient Stability, L. M. Filkins, T. H. Hampton, A. H. Gifford, M. J. Gross, D. A. Hogan, M. L. Sogin, H. G. Morrison, B. J. Paster, G. A. O'Toole
Prevalence Of Streptococci And Increased Polymicrobial Diversity Associated With Cystic Fibrosis Patient Stability, L. M. Filkins, T. H. Hampton, A. H. Gifford, M. J. Gross, D. A. Hogan, M. L. Sogin, H. G. Morrison, B. J. Paster, G. A. O'Toole
Dartmouth Scholarship
Diverse microbial communities chronically colonize the lungs of cystic fibrosis patients. Pyrosequencing of amplicons for hypervariable regions in the 16S rRNA gene generated taxonomic profiles of bacterial communities for sputum genomic DNA samples from 22 patients during a state of clinical stability (outpatients) and 13 patients during acute exacerbation (inpatients). We employed quantitative PCR (qPCR) to confirm the detection of Pseudomonas aeruginosa and Streptococcus by the pyrosequencing data and human oral microbe identification microarray (HOMIM) analysis to determine the species of the streptococci identified by pyrosequencing. We show that outpatient sputum samples have significantly higher bacterial diversity than inpatients, but …
Combination Of 16s Rrna Variable Regions Provides A Detailed Analysis Of Bacterial Community Dynamics In The Lungs Of Cystic Fibrosis Patients, Melissa S. Doud, Michael Light, Gisela Gonzalez, Giri Narasimhan, Kalai Mathee
Combination Of 16s Rrna Variable Regions Provides A Detailed Analysis Of Bacterial Community Dynamics In The Lungs Of Cystic Fibrosis Patients, Melissa S. Doud, Michael Light, Gisela Gonzalez, Giri Narasimhan, Kalai Mathee
Department of Biological Sciences
Chronic bronchopulmonary bacterial infections remain the most common cause of morbidity and mortality among patients with cystic fibrosis (CF). Recent community sequencing work has now shown that the bacterial community in the CF lung is polymicrobial. Identifying bacteria in the CF lung through sequencing can be costly and is not practical for many laboratories. Molecular techniques such as terminal restriction fragment length polymorphism or amplicon length heterogeneity-polymerase chain reaction (LH-PCR) can provide many laboratories with the ability to study CF bacterial communities without costly sequencing. The aim of this study was to determine if the use of LH-PCR with multiple …
Survey Of Adult Cystic Fibrosis Patients And Parents Of Cystic Fibrosis Patients On Nutrition Education, Dixie Lea Durham
Survey Of Adult Cystic Fibrosis Patients And Parents Of Cystic Fibrosis Patients On Nutrition Education, Dixie Lea Durham
Boise State University Theses and Dissertations
Cystic fibrosis (CF) is an inherited disorder affecting more than 30,000 Americans, primarily Caucasians (CF Foundation, n.d.a). A defective gene on the seventh chromosome is inherited from the mother and the father. This gene causes the body to produce an abnormal protein that leads to thick, sticky mucus that is secreted by the lungs, pancreas, liver, sweat glands, and reproductive organs. The pancreas normally excretes enzymes that aid in the digestion of food, however this function is impaired in CF, and therefore CF patients must ingest replacement enzymes (CF Foundation, n.d.a). Despite advances in treatment, including replacement enzymes, under-nutrition and …
Corr4a And Vrt325 Do Not Reduce The Inflammatory Response To P. Aeruginosa In Human Cystic Fibrosis Airway Epithelial Cells, Laleh Talebian, Bonita Coutermarsh, Jacqueline Y. Channon, Bruce A. Stanton
Corr4a And Vrt325 Do Not Reduce The Inflammatory Response To P. Aeruginosa In Human Cystic Fibrosis Airway Epithelial Cells, Laleh Talebian, Bonita Coutermarsh, Jacqueline Y. Channon, Bruce A. Stanton
Dartmouth Scholarship
P. aeruginosa chronically colonizes the lung in CF patients and elicits a proinflammatory response. Excessive secretion of IL-6 and IL-8 by CF airway cells in response to P. aeruginosa infection in the CF airway is though to contribute to lung injury. Accordingly, the goal of this study was to test the hypothesis that Corr4a and VRT325, investigational compounds that increase ΔF508-CFTR mediated Cl− secretion in human CF airway cells, reduce the pro-inflammatory response to P. aeruginosa.
Acute Pancreatitis As An Atypical Presentation Of Henoch-Schonlein Purpura And Cystic Fibrosis, Murat Çakir, Beri̇l Di̇lber, Mukaddes Kalyoncu, Embi̇ya Di̇lber, Ayşe Aksoy, Erol Erduran
Acute Pancreatitis As An Atypical Presentation Of Henoch-Schonlein Purpura And Cystic Fibrosis, Murat Çakir, Beri̇l Di̇lber, Mukaddes Kalyoncu, Embi̇ya Di̇lber, Ayşe Aksoy, Erol Erduran
Turkish Journal of Medical Sciences
Acute pancreatitis (AP) is a rare clinical entity in childhood. Two children, aged 10 and 14 years, were hospitalized for acute abdominal pain. Clinical and laboratory findings were compatible with AP. Both patients were given supportive medications. Two days after admission, the first patient had purpuric lesions on both buttocks and lower extremities, and occult bleeding. The clinical picture was consistent with Henoch-Schonlein purpura, with pancreatitis and gastrointestinal involvement. The patient’s clinical condition improved rapidly after administration of prednisolone. The second patient had digital clubbing on physical examination, and positive sweat chloride test results led to the diagnosis of cystic …