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Journal articles on the topic 'Cystic fibrosis; Genetic diseases'
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1
Shelby, Elena-Silvia, Florina Mihaela Nedelea, Tanser Huseyinoglu, Relu Cocos, Mihaela Badina, Corina Sporea, Liliana Padure, and Andrada Mirea. "Innovative therapies in genetic diseases: Cystic fibrosis." Romanian Journal of Pediatrics 70, no. 1 (March 31, 2021): 16–20. http://dx.doi.org/10.37897/rjp.2021.1.3.
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Cystic fibrosis, also named mucoviscidosis, is the most frequent hereditary pulmonary disease and is produced by mutations in the CFTR gene, encoding an anionic channel for chloride and bicarbonate involved in the regulation of salt and bicarbonate metabolisms. Currently, about half of the patients with cystic fibrosis can benefit personalized therapy consisting in modulators, drugs which restore or improve the functionality and stability of CFTR. Moreover, presently, other therapies, such as gene therapy using the CRISP/CAS-9, modified antisense oligonucleotides or the insertion of the wild-type gene using nanolipidic particles or viral vectors, are being developed. This article aims to take stock of the principal types of cystic fibrosis therapies which have been approved or are in clinical trials.
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Chiriac, Anca, Laura Trandafir, Cristian Podoleanu, and Simona Stolnicu. "Cutaneous Manifestations of Cystic Fibrosis." Journal of Interdisciplinary Medicine 3, no. 1 (March 1, 2018): 39–44. http://dx.doi.org/10.2478/jim-2018-0005.
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Abstract Cystic fibrosis (CF) is an autosomal recessive affliction triggered by genetic mutations in the cystic fibrosis transmembrane conductance regulator. The lung and pancreas are the most frequently affected organs in cystic fibrosis, cutaneous involvement is undervalued and underdiag-nosed. Skin lesions observed in patients diagnosed with cystic fibrosis are not well known and can create confusions with other dermatological diseases. The diagnosis of cutaneous lesions as signs of cystic fibrosis by pediatricians or dermatologists, despite their overlapping with different nutritional deficiencies, would allow earlier diagnosis and proper treatment and could improve quality of life and outcomes.
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Biazotti, Maria Cristina Santoro, Walter Pinto Junior, Maria Cecília Romano Maciel de Albuquerque, Litsuko Shimabukuro Fujihara, Cláudia Haru Suganuma, Renata Bednar Reigota, and Carmen Sílvia Bertuzzo. "Preimplantation genetic diagnosis for cystic fibrosis: a case report." Einstein (São Paulo) 13, no. 1 (March 2015): 110–13. http://dx.doi.org/10.1590/s1679-45082015rc2738.
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Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. This disorder produces a variable phenotype including lung disease, pancreatic insufficiency, and meconium ileus plus bilateral agenesis of the vas deferens causing obstructive azoospermia and male infertility. Preimplantation genetic diagnosis is an alternative that allows identification of embryos affected by this or other genetic diseases. We report a case of couple with cystic fibrosis; the woman had the I148 T mutation and the man had the Delta F508 gene mutation. The couple underwent in vitro fertilization, associated with preimplantation genetic diagnosis, and with subsequent selection of healthy embryos for uterine transfer. The result was an uneventful pregnancy and delivery of a healthy male baby.
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Al Arrayed, S. S. "Review of the spectrum of genetic diseases in Bahrain." Eastern Mediterranean Health Journal 5, no. 6 (December 15, 1999): 1114–20. http://dx.doi.org/10.26719/1999.5.6.1114.
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This paper looks at some of the studies on genetic disorders conducted in Bahrain. The disorders covered include: genetic blood disorders, metabolic disorders, chromosomal disorders, including Down syndrome, and cystic fibrosis. The rate of consanguinity in Bahrain and the results of premarital counselling are also discussed
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Saračević, Ediba, and Amira Redžić. "Genetic Examination of Children Suffering from Cystic Fibrosis." Bosnian Journal of Basic Medical Sciences 5, no. 1 (February 20, 2005): 69–71. http://dx.doi.org/10.17305/bjbms.2005.3338.
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CFTR protein (cystic fibrosis trans membrane conductance regulator) is expressed in multiple epithelial tissues, including upper and lower respiratory tracts, pancreas, sweat glands and gastrointestinal tract. More than 800 mutations and 100 polymorphic variants of DNA sequences were identified in patients with CF (Cystic fibrosis) and CFTR- diseases. In this study, genetic CFTR analysis of the children suffering from chronic lung disease (cystic fibrosis) is presented. They are treated and regularly controlled at the Pediatric hospital Sarajevo. CFTR analysis was done in 9 cases, 4 boys (44.4%) and 5 girls (55.55%). There are 3 children (33.3%) in the age group 1 to 3 years, 1 child (11.1%) in the age group 3 to 6 years, 3 children (33.3%) in the age group 6 to 9 years and 2 children (22.2%) in the age group 9 to 12 years. Genetic analysis was conducted at the Medical center for molecular biology School of Medicine, Ljubljana. PCR method with PAGE and direct sequestration on ABI PRISM 31 was applied. The majority of children (7 children, i.e. 7777%) had CFTR mutation Δ F 508 whilst one child had G542X mutation and one child R1174 mutation. The purpose of this study is to emphasize the need for CFTR gene identification in the institutes of our country.
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Patel, Sheylan D., Taylor R. Bono, Steven M. Rowe, and George M. Solomon. "CFTR targeted therapies: recent advances in cystic fibrosis and possibilities in other diseases of the airways." European Respiratory Review 29, no. 156 (June 16, 2020): 190068. http://dx.doi.org/10.1183/16000617.0068-2019.
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Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion transporter that regulates mucus hydration, viscosity and acidity of the airway epithelial surface. Genetic defects in CFTR impair regulation of mucus homeostasis, causing severe defects of mucociliary clearance as seen in cystic fibrosis. Recent work has established that CFTR dysfunction can be acquired in chronic obstructive pulmonary disease (COPD) and may also contribute to other diseases that share clinical features of cystic fibrosis, such as asthma, allergic bronchopulmonary aspergillosis and bronchiectasis. Protean causes of CFTR dysfunction have been identified including cigarette smoke exposure, toxic metals and downstream effects of neutrophil activation pathways. Recently, CFTR modulators, small molecule agents that potentiate CFTR or restore diminished protein levels at the cell surface, have been successfully developed for various CFTR gene defects, prompting interest in their use to treat diseases of acquired dysfunction. The spectrum of CFTR dysfunction, strategies for CFTR modulation, and candidate diseases for CFTR modulation beyond cystic fibrosis will be reviewed in this manuscript.
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Pretto, Luana, Fernanda de-Paris, Alice Beatriz Mombach Pinheiro Machado, Andreza Francisco Martins, and Afonso Luís Barth. "Genetic similarity of Burkholderia cenocepacia from cystic fibrosis patients." Brazilian Journal of Infectious Diseases 17, no. 1 (January 2013): 86–89. http://dx.doi.org/10.1016/j.bjid.2012.09.002.
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Antonova, E. A., A. V. Goryainova, S. Yu Semykin, and T. A. Filatova. "The spectrum of sensitization of children with cystic fibrosis." Experimental and Clinical Gastroenterology, no. 11 (November 20, 2019): 89–92. http://dx.doi.org/10.31146/1682-8658-ecg-171-11-89-92.
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Cystic fibrosis is a hereditary disease that affects the quality of life of patients without proper treatment. It has been established that allergic diseases have become a global public health problem. Due to a variety of clinical manifestations that affect the development, health and quality of life, it is difficult to diagnose. Due to the high incidence of allergic problems, there is the problem of interrelationship of hereditary genetic diseases - cystic fibrosis and spectral sensitization of children suffering from morbidity in order to improve the algorithms, improve the condition and quality of life of patients, due to the appointment of proper diet therapy.
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Markossian, Sarine, Kenny K. Ang, Christopher G. Wilson, and Michelle R. Arkin. "Small-Molecule Screening for Genetic Diseases." Annual Review of Genomics and Human Genetics 19, no. 1 (August 31, 2018): 263–88. http://dx.doi.org/10.1146/annurev-genom-083117-021452.
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The genetic determinants of many diseases, including monogenic diseases and cancers, have been identified; nevertheless, targeted therapy remains elusive for most. High-throughput screening (HTS) of small molecules, including high-content analysis (HCA), has been an important technology for the discovery of molecular tools and new therapeutics. HTS can be based on modulation of a known disease target (called reverse chemical genetics) or modulation of a disease-associated mechanism or phenotype (forward chemical genetics). Prominent target-based successes include modulators of transthyretin, used to treat transthyretin amyloidoses, and the BCR-ABL kinase inhibitor Gleevec, used to treat chronic myelogenous leukemia. Phenotypic screening successes include modulators of cystic fibrosis transmembrane conductance regulator, splicing correctors for spinal muscular atrophy, and histone deacetylase inhibitors for cancer. Synthetic lethal screening, in which chemotherapeutics are screened for efficacy against specific genetic backgrounds, is a promising approach that merges phenotype and target. In this article, we introduce HTS technology and highlight its contributions to the discovery of drugs and probes for monogenic diseases and cancer.
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Montgomery, Samuel T., Marcus A. Mall, Anthony Kicic, and Stephen M. Stick. "Hypoxia and sterile inflammation in cystic fibrosis airways: mechanisms and potential therapies." European Respiratory Journal 49, no. 1 (December 23, 2016): 1600903. http://dx.doi.org/10.1183/13993003.00903-2016.
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Cystic fibrosis is one of the most common autosomal recessive genetic diseases in Caucasian populations. Diagnosisvianewborn screening and targeted nutritional and antibiotic therapy have improved outcomes, however respiratory failure remains the key cause of morbidity and mortality. Progressive respiratory disease in cystic fibrosis is characterised by chronic neutrophilic airway inflammation associated with structural airway damage leading to bronchiectasis and decreased lung function. Mucus obstruction is a characteristic early abnormality in the cystic fibrosis airway, associated with neutrophilic inflammation often in the absence of detectable infection. Recent studies have suggested a link between hypoxic cell death and sterile neutrophilic inflammation in cystic fibrosis and other diseasesviathe IL-1 signalling pathway. In this review, we consider recent evidence regarding the cellular responses to respiratory hypoxia as a potential driver of sterile neutrophilic inflammation in the lung, current knowledge on hypoxia as a pathogenic mechanism in cystic fibrosis and the potential for current and future therapies to alleviate hypoxia-driven sterile inflammation.
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Dolgin, Elie. "Orphan cystic fibrosis drugs find sister diseases." Nature Medicine 17, no. 4 (April 2011): 397. http://dx.doi.org/10.1038/nm0411-397.
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Bergeron, Christelle, and André M. Cantin. "New Therapies to Correct the Cystic Fibrosis Basic Defect." International Journal of Molecular Sciences 22, no. 12 (June 8, 2021): 6193. http://dx.doi.org/10.3390/ijms22126193.
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Rare diseases affect 400 million individuals worldwide and cause significant morbidity and mortality. Finding solutions for rare diseases can be very challenging for physicians and researchers. Cystic fibrosis (CF), a genetic, autosomal recessive, multisystemic, life-limiting disease does not escape this sad reality. Despite phenomenal progress in our understanding of this disease, treatment remains difficult. Until recently, therapies for CF individuals were focused on symptom management. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its product, a protein present at the apical surface of epithelial cells regulating ion transport, allowed the scientific community to learn about the basic defect in CF and to study potential therapies targeting the dysfunctional protein. In the past few years, promising therapies with the goal to restore CFTR function became available and changed the lives of several CF patients. These medications, called CFTR modulators, aim to correct, potentialize, stabilize or amplify CFTR function. Furthermore, research is ongoing to develop other targeted therapies that could be more efficient and benefit a larger proportion of the CF community. The purpose of this review is to summarize our current knowledge of CF genetics and therapies restoring CFTR function, particularly CFTR modulators and gene therapy.
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Engel, Tobias, Paul E. Verweij, Joost van den Heuvel, Dechen Wangmo, Jianhua Zhang, Alfons J. M. Debets, and Eveline Snelders. "Parasexual recombination enables Aspergillus fumigatus to persist in cystic fibrosis." ERJ Open Research 6, no. 4 (September 24, 2020): 00020–2020. http://dx.doi.org/10.1183/23120541.00020-2020.
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Aspergillus fumigatus is a saprobic fungus that causes a range of pulmonary diseases, some of which are characterised by fungal persistence such as is observed in cystic fibrosis (CF) patients. Creation of genetic variation is critical for A. fumigatus to adapt to the lung environment, but biofilm formation, especially in CF patients, may preclude mutational supply in A. fumigatus due to its confinement to the hyphal morphotype. We tested our hypothesis that genetic variation is created through parasexual recombination in chronic biofilms by phenotypic and genetic analysis of A. fumigatus isolates cultured from different origins.As diploids are the hallmark of parasex, we screened 799 A. fumigatus isolates obtained from patients with CF, chronic pulmonary lung disease and acute invasive aspergillosis, and from the environment for spore size. Benomyl sensitivity, nuclear content measurements through fluorescence-activated cell sorting and scanning electron microscopy were used to confirm the diploid state of large size spores. Whole genome sequencing was used to characterise diploid-associated genetic variation.We identified 11 diploids in isolates recovered from six of 11 (55%) CF patients and from one of 24 (4%) chronic aspergillosis patients, but not in 368 isolates from patients with acute Aspergillus infection and the environment. Diploid formation was associated with accumulation of mutations and variable haploid offspring including a voriconazole-resistant isolate.Parasexual recombination allows A. fumigatus to adapt and persist in CF patients, and plays a role in azole resistance development. Our findings are highly significant for understanding the genetics and biology of A. fumigatus in the human lung.
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De Rose, Virginia, Kevin Molloy, Sophie Gohy, Charles Pilette, and Catherine M. Greene. "Airway Epithelium Dysfunction in Cystic Fibrosis and COPD." Mediators of Inflammation 2018 (2018): 1–20. http://dx.doi.org/10.1155/2018/1309746.
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Cystic fibrosis is a genetic disease caused by mutations in the CFTR gene, whereas chronic obstructive pulmonary disease (COPD) is mainly caused by environmental factors (mostly cigarette smoking) on a genetically susceptible background. Although the etiology and pathogenesis of these diseases are different, both are associated with progressive airflow obstruction, airway neutrophilic inflammation, and recurrent exacerbations, suggesting common mechanisms. The airway epithelium plays a crucial role in maintaining normal airway functions. Major molecular and morphologic changes occur in the airway epithelium in both CF and COPD, and growing evidence suggests that airway epithelial dysfunction is involved in disease initiation and progression in both diseases. Structural and functional abnormalities in both airway and alveolar epithelium have a relevant impact on alteration of host defences, immune/inflammatory response, and the repair process leading to progressive lung damage and impaired lung function. In this review, we address the evidence for a critical role of dysfunctional airway epithelial cells in chronic airway inflammation and remodelling in CF and COPD, highlighting the common mechanisms involved in the epithelial dysfunction as well as the similarities and differences of the two diseases.
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Lewin, Astrid, Elisabeth Kamal, Torsten Semmler, Katja Winter, Sandra Kaiser, Hubert Schäfer, Lei Mao, et al. "Genetic diversification of persistent Mycobacterium abscessus within cystic fibrosis patients." Virulence 12, no. 1 (January 1, 2021): 2415–29. http://dx.doi.org/10.1080/21505594.2021.1959808.
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Maule, Giulia, Daniele Arosio, and Anna Cereseto. "Gene Therapy for Cystic Fibrosis: Progress and Challenges of Genome Editing." International Journal of Molecular Sciences 21, no. 11 (May 30, 2020): 3903. http://dx.doi.org/10.3390/ijms21113903.
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Since the early days of its conceptualization and application, human gene transfer held the promise of a permanent solution to genetic diseases including cystic fibrosis (CF). This field went through alternated periods of enthusiasm and distrust. The development of refined technologies allowing site specific modification with programmable nucleases highly revived the gene therapy field. CRISPR nucleases and derived technologies tremendously facilitate genome manipulation offering diversified strategies to reverse mutations. Here we discuss the advancement of gene therapy, from therapeutic nucleic acids to genome editing techniques, designed to reverse genetic defects in CF. We provide a roadmap through technologies and strategies tailored to correct different types of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, and their applications for the development of experimental models valuable for the advancement of CF therapies.
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Moore, Kenneth C., Guoshen Wang, Paul McCray, Jian Shao, Tom Moninger, Michael Welsh, and Randy Nessler. "Application of Correlative Microscopy to Genetic Therapy Research of Cystic Fibrosis and Other Human Diseases." Microscopy and Microanalysis 7, S2 (August 2001): 38–39. http://dx.doi.org/10.1017/s143192760002626x.
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Microscopy is an essential tool for developing strategies to use genetic therapy in the treatment of diseases. Negative staining (fig. 1) and cryo-electron microscopy are critical in understanding the structure of native and hybrid vectors to be used as transfer agents. Enzyme cytochemistry is widely used for the detection of markers that aid in determining the rate of gene transfer to cells and tissues. Immunocytochemistry is necessary to identify new gene products. Light, confocal and electron microscopy are used to evaluate pathogenesis, inflammation and cellular changes. For much of the past decade, we have been working to identify the specific gene and cell structure (chloride channel) that is compromised in Cystic Fibrosis patients. Subsequently, appropriate vectors had to be developed for treatment. A significant amount of time and effort has been expended to identify effective viral and other vectors to be used in the transfer of the normal gene construct.In order to facilitate experimentation, we have developed a cell culture system utilizing normal and cystic fibrosis airway epithelia. These cultures are maintained at an air interface and the cells differentiate into the same types found in vivo.
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Sala, Valentina, Alessandra Murabito, and Alessandra Ghigo. "Inhaled Biologicals for the Treatment of Cystic Fibrosis." Recent Patents on Inflammation & Allergy Drug Discovery 13, no. 1 (August 5, 2019): 19–26. http://dx.doi.org/10.2174/1872213x12666181012101444.
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Background:Cystic Fibrosis (CF), one of the most frequent genetic diseases, is characterized by the production of viscous mucus in several organs. In the lungs, mucus clogs the airways and traps bacteria, leading to recurrent/resistant infections and lung damage. For cystic fibrosis patients, respiratory failure is still lethal in early adulthood since available treatments display incomplete efficacy.Objective:The objective of this review is to extend the current knowledge in the field of available treatments for cystic fibrosis. A special focus has been given to inhaled peptide-based drugs.Methods:The current review is based on recent and/or relevant literature and patents already available in various scientific databases, which include PubMed, PubMed Central, Patentscope and Science Direct. The information obtained through these diverse databases is compiled, critically interpreted and presented in the current study. An in-depth but not systematic approach to the specific research question has been adopted.Results:Recently, peptides have been proposed as possible pharmacologic agents for the treatment of respiratory diseases. Of note, peptides are suitable to be administered by inhalation to maximize efficacy and reduce systemic side effects. Moreover, innovative delivery carriers have been developed for drug administration through inhalation, allowing not only protection against proteolysis, but also a prolonged and controlled release.Conclusion:Here, we summarize newly patented peptides that have been developed in the last few years and advanced technologies for inhaled drug delivery to treat cystic fibrosis.
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Comegna, Marika, Giuseppe Maria Maruotti, Laura Sarno, Gustavo Cernera, Monica Gelzo, Maurizio Guida, Fulvio Zullo, Federica Zarrilli, and Giuseppe Castaldo. "Prenatal Diagnosis of Cystic Fibrosis and Hemophilia: Incidental Findings and Weak Points." Diagnostics 10, no. 1 (December 21, 2019): 7. http://dx.doi.org/10.3390/diagnostics10010007.
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Because of the progression of genetics and genomics, the demand for prenatal diagnosis (PD) for inherited genetic diseases has increased. However, several incidental findings may emerge during PD, like misattributed paternity, the evidence of disease in a parent, and the possible misinterpretation of the results because of complex alleles or de novo mutations that have several implications. In a retrospective observational study on all the couples referred to our Medical School (1993–2018) for PD of genetic inherited diseases (n = 1502), we selected the cases of PD for cystic fibrosis (CF, n = 239) and hemophilia A and B (HA, HB, n = 47), revising all incidental findings previously mentioned. We found one case in which a technical error led to PD of carrier in two siblings that were born affected by CF, four cases of misattributed paternity, eight cases of asymptomatic parents revealed as affected by CF transmembrane regulator (CFTR)-related disorders, a case of a novel complex allele that could have caused the diagnosis of CF in a carrier fetus, and a case of a de novo mutation in a mother (already a carrier) that caused hemophilia in a child that PD had revealed as healthy. We present these conditions as clinical cases and discuss the technical, clinical, ethical, and legal aspects to be considered.
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Szymczak, Angelika, Piotr Ksiazek, Sylwia Mojsym-Korybska, Wojciech Skorupa, and Albertyna Zbikowska-Machul. "Developing a diagnostic test to identify the selected mutation within the CFTR gene that determines the onset of cystic fibrosis." Current Issues in Pharmacy and Medical Sciences 31, no. 4 (December 1, 2018): 200–203. http://dx.doi.org/10.1515/cipms-2018-0037.
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Abstract Cystic fibrosis is one of the most common genetic diseases among Caucasians due to its prevalence. Modern methods of molecular diagnostics and treatment of the disease allow to prolong the life of patients. In order to apply the appropriate treatment, the genetic basis of this disease should, however, first be known. The most common and the most severe mutation present in the CFTR gene (60-70% of cases) takes the form of an allele. This is responsible for the deletion of phenylalanine in position 508 (Δ508) of the CFTR protein. Determination of mutations in the CFTR gene using molecular techniques makes it possible to identify the causes of the disease in people who do not show the characteristic symptoms of cystic fibrosis.
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Braekeleer, M., C. Allard, J. P. Leblanc, G. Aubin, and F. Simard. "Genetic determinants ofPseudomonas aeruginosa colonization in cystic fibrosis patients in Canada." European Journal of Clinical Microbiology & Infectious Diseases 17, no. 4 (April 1998): 269–71. http://dx.doi.org/10.1007/bf01699984.
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Yan, Ziying, Paul B. McCray Jr, and John F. Engelhardt. "Advances in gene therapy for cystic fibrosis lung disease." Human Molecular Genetics 28, R1 (July 23, 2019): R88—R94. http://dx.doi.org/10.1093/hmg/ddz139.
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Abstract Cystic fibrosis (CF) is a multiorgan recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Gene therapy efforts have focused on treating the lung, since it manifests the most significant life-threatening disease. Over two decades have past since the first CF lung gene therapy trials and significant advances in the therapeutic implementation of pharmacologic CFTR modulators have renewed the field's focus on developing gene therapies for the 10% of CF patients these modulators cannot help. This review summarizes recent progress made in developing vectors for airway transduction and CF animal models required for understanding the relevant cellular targets in the lung and testing the efficacy of gene therapy approaches. We also highlight future opportunities in emerging gene editing strategies that may offer advantages for treating diseases like CF where the gene target is highly regulated at the cellular level. The outcomes of CF lung gene therapy trials will likely inform productive paths toward gene therapy for other complex genetic disorders, while also advancing treatments for all CF patients.
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Beckwith, Jon, and Joseph S. Alper. "Reconsidering Genetic Antidiscrimination Legislation." Journal of Law, Medicine & Ethics 26, no. 3 (1998): 205–10. http://dx.doi.org/10.1111/j.1748-720x.1998.tb01421.x.
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Until approximately twenty years ago, advances in the study of human genetics had little influence on the practice of medicine. In the 1980s, this changed dramatically with the mapping of the altered genes that cause cystic fibrosis (CF) and Huntington disease (HD). In just a few years, these discoveries led to DNA-based tests that enabled clinicians to determine whether prospective parents were carriers of CF or whether an individual carried the Huntington gene and, as a result, would almost certainly develop the disease.Observers interested in the social and economic implications of genetic technology realized that such genetic tests could be used by insurance companies to predict which insurance applicants were likely to become ill or even die from these diseases.
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Vakhlova, Irina V., Anastasia D. Kazachina, and Olga A. Beglyanina. "Case report: a child with cystic fibrosis and phenylketonuria." Russian Pediatric Journal 1, no. 2 (June 12, 2020): 38–44. http://dx.doi.org/10.15690/10.15690/rpj.v1i2.2092.
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Background. In the international clinical practice there have been occasional reports of phenylketonuria (PKU) and cystic fibrosis (CF) found simultaneously in the same patient. Both PKU and CF are the inherited disorders characterized by autosomal recessive type of inheritance. Currently the combination of two or more inherited disorders in one patient is considered to be a clinical rarity.Case description. This is a clinical case of two genetic disorders, CF and PKU, combined in a 5-year old patient who had been followed up since birth. Owing to implementation of neonatal screening for inherited and congenital diseases into clinical practice, during the first month of life the infant was diagnosed with CF (diagnostically significant elevation of immunoreactive trypsin [IRT] at the initial [163.2 ng/mL] and repeat testing on day 21 of life [138.7 ng/mL]) and PKU (phenylalanine [PA] level 15.9 mg/dL). Both disorders have been confirmed by genetic tests, i.e., homozygous DelF508 mutation was found in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and P281L mutation in the phenylalanine hydroxylase (PAH) gene was also present in homozygous state. Child’s parents strictly adhered to dietary and treatment recommendations. By the age of 5 years the child developed symptoms of neurological disorder and disorder of the respiratory system, cognitive impairment and delay in speech development, subclinical epileptiform activity with high risk of epilepsy, and chronic inflammation of the respiratory tract.Conclusion. This case report demonstrates the important role of neonatal screening in early diagnosis and timely start of therapy, and underscores the importance of continuous medication in such genetic disorders as CF and PKU. On the whole, such approach brings about a relative preservation of functioning of the most affected organs and systems. By the age of 5 years the child does not form bronchiectases, shows no signs of chronic hypoxia, nutritional deficiency or pronounced neurologic deficit, and is at low risk for the development of autism spectrum disorder. At the same time, the larger scale and longer-term observations are required in order to make the unequivocal conclusions about the prognosis of these diseases under conditions of modern-day medical follow-up.
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Vakhlova, Irina V., Anastasia D. Kazachina, and Olga A. Beglyanina. "Case report: a child with cystic fibrosis and phenylketonuria." Russian Pediatric Journal 1, no. 2 (June 12, 2020): 38–44. http://dx.doi.org/10.15690/rpj.v1i1.2092.
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Background. In the international clinical practice there have been occasional reports of phenylketonuria (PKU) and cystic fibrosis (CF) found simultaneously in the same patient. Both PKU and CF are the inherited disorders characterized by autosomal recessive type of inheritance. Currently the combination of two or more inherited disorders in one patient is considered to be a clinical rarity.Case description. This is a clinical case of two genetic disorders, CF and PKU, combined in a 5-year old patient who had been followed up since birth. Owing to implementation of neonatal screening for inherited and congenital diseases into clinical practice, during the first month of life the infant was diagnosed with CF (diagnostically significant elevation of immunoreactive trypsin [IRT] at the initial [163.2 ng/mL] and repeat testing on day 21 of life [138.7 ng/mL]) and PKU (phenylalanine [PA] level 15.9 mg/dL). Both disorders have been confirmed by genetic tests, i.e., homozygous DelF508 mutation was found in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and P281L mutation in the phenylalanine hydroxylase (PAH) gene was also present in homozygous state. Child’s parents strictly adhered to dietary and treatment recommendations. By the age of 5 years the child developed symptoms of neurological disorder and disorder of the respiratory system, cognitive impairment and delay in speech development, subclinical epileptiform activity with high risk of epilepsy, and chronic inflammation of the respiratory tract.Conclusion. This case report demonstrates the important role of neonatal screening in early diagnosis and timely start of therapy, and underscores the importance of continuous medication in such genetic disorders as CF and PKU. On the whole, such approach brings about a relative preservation of functioning of the most affected organs and systems. By the age of 5 years the child does not form bronchiectases, shows no signs of chronic hypoxia, nutritional deficiency or pronounced neurologic deficit, and is at low risk for the development of autism spectrum disorder. At the same time, the larger scale and longer-term observations are required in order to make the unequivocal conclusions about the prognosis of these diseases under conditions of modern-day medical follow-up.
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Vakhlova, Irina V., Anastasia D. Kazachina, and Olga A. Beglyanina. "Case report: a child with cystic fibrosis and phenylketonuria." Russian Pediatric Journal 1, no. 2 (June 12, 2020): 38–44. http://dx.doi.org/10.15690/rpj.v1i2.2092.
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Background. In the international clinical practice there have been occasional reports of phenylketonuria (PKU) and cystic fibrosis (CF) found simultaneously in the same patient. Both PKU and CF are the inherited disorders characterized by autosomal recessive type of inheritance. Currently the combination of two or more inherited disorders in one patient is considered to be a clinical rarity.Case description. This is a clinical case of two genetic disorders, CF and PKU, combined in a 5-year old patient who had been followed up since birth. Owing to implementation of neonatal screening for inherited and congenital diseases into clinical practice, during the first month of life the infant was diagnosed with CF (diagnostically significant elevation of immunoreactive trypsin [IRT] at the initial [163.2 ng/mL] and repeat testing on day 21 of life [138.7 ng/mL]) and PKU (phenylalanine [PA] level 15.9 mg/dL). Both disorders have been confirmed by genetic tests, i.e., homozygous DelF508 mutation was found in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and P281L mutation in the phenylalanine hydroxylase (PAH) gene was also present in homozygous state. Child’s parents strictly adhered to dietary and treatment recommendations. By the age of 5 years the child developed symptoms of neurological disorder and disorder of the respiratory system, cognitive impairment and delay in speech development, subclinical epileptiform activity with high risk of epilepsy, and chronic inflammation of the respiratory tract.Conclusion. This case report demonstrates the important role of neonatal screening in early diagnosis and timely start of therapy, and underscores the importance of continuous medication in such genetic disorders as CF and PKU. On the whole, such approach brings about a relative preservation of functioning of the most affected organs and systems. By the age of 5 years the child does not form bronchiectases, shows no signs of chronic hypoxia, nutritional deficiency or pronounced neurologic deficit, and is at low risk for the development of autism spectrum disorder. At the same time, the larger scale and longer-term observations are required in order to make the unequivocal conclusions about the prognosis of these diseases under conditions of modern-day medical follow-up.
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van Heeckeren, Anna M., Mark Schluchter, Lintong Xue, Juan Alvarez, Steven Freedman, Judith St. George, and Pamela B. Davis. "Nutritional Effects on Host Response to Lung Infections with Mucoid Pseudomonas aeruginosa in Mice." Infection and Immunity 72, no. 3 (March 2004): 1479–86. http://dx.doi.org/10.1128/iai.72.3.1479-1486.2004.
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ABSTRACT In cystic fibrosis, a recessive genetic disease caused by defects in the cystic fibrosis conductance regulator (CFTR), the main cause of death is lung infection and inflammation. Nutritional deficits have been proposed to contribute to the excessive host inflammatory response in both humans and Cftr-knockout mice. Cftr-knockout mice and gut-corrected Cftr-knockout mice expressing human CFTR primarily in the gut were challenged with Pseudomonas aeruginosa-laden agarose beads; they responded similarly with respect to bronchoalveolar lavage cell counts and levels of the acute-phase cytokines tumor necrosis factor alpha, interleukin-1β (IL-1β), and IL-6. Wild-type mice fed the liquid diet used to prevent intestinal obstruction in Cftr-knockout mice had inflammatory responses to P. aeruginosa-laden agarose beads similar to those of wild-type mice fed an enriched solid diet, so dietary effects are unlikely to account for differences between wild-type mice and mice with cystic fibrosis. Finally, since cystic fibrosis patients and Cftr-knockout mice have an imbalance in fatty acids (significantly lower-than-normal levels of docosahexaenoic acid), the effects of specific supplementation with docosahexaenoic acid of wild-type and Cftr-knockout mice on their inflammatory responses to P. aeruginosa-laden agarose beads were tested. There were no significant differences (P = 0.35) in cumulative survival rates between Cftr-knockout mice and wild-type mice provided with either the liquid diet Peptamen or Peptamen containing docosahexaenoic acid. In conclusion, diet and docosahexaenoic acid imbalances alone are unlikely to explain the differences in the host response to lung infections with mucoid P. aeruginosa between mice with cystic fibrosis and their wild-type counterparts.
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Плотникова, О. М., and М. Ю. Скоблов. "MicroRNA role in hereditary genetic diseases." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 9(218) (September 30, 2020): 5–17. http://dx.doi.org/10.25557/2073-7998.2020.09.5-17.
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На сегодняшний день известно около 7000 наследственных заболеваний. Однако современные методы ДНК диагностики выявляют причину возникновения заболеваний примерно в 40% случаев. Отчасти это обусловлено сложностью и большим разнообразием молекулярных механизмов их патогенеза. МикроРНК являются одним из мощнейших регуляторов экспрессии генов. Однако участие их в патогенезе наследственных заболеваний пока недостаточно изучено из-за сложностей поиска таких нарушений. В данной работе проведён анализ описанных механизмов патогенеза наследственных заболеваний, опосредованных нарушениями регуляции экспрессии генов посредством микроРНК. Такие случаи были выявлены при таких наследственных заболеваниях как муковисцидоз, миодистрофия Дюшенна, бета-талассемия, глаукома, лице-лопаточно-плечевая миодистрофия Ландузи-Дежерина, болезнь Гиршпрунга, синдром Ретта, синдром Туретта, пемфигус (болезнь Хейли-Хейли). To date, about 7,000 hereditary diseases are known. However, modern diagnostic methods reveal the cause of the disease in about 40% of cases. This is partly due to the complexity and wide variety of molecular mechanisms of pathogenesis. MicroRNAs are one of the most powerful genes expression regulators. But their participation in the pathogenesis of hereditary diseases has not yet been studied enough because of the difficulties in finding such disorders. In this work, we collected and analyzed pathogenesis of hereditary diseases mediated by dysregulation of gene expression by microRNA. such cases have been identified for such hereditary diseases as cystic fibrosis, Duchenne muscular dystrophy, beta-thalassemia, glaucoma, facioscapulohumeral muscular dystrophy Landouzy-Dejerine, Hirschsprung disease, Rett syndrome, Tourette syndrome, pemphigus (Hailey-Hailey disease).
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Miller, Aaron C., Alejandro P. Comellas, Douglas B. Hornick, David A. Stoltz, Joseph E. Cavanaugh, Alicia K. Gerke, Michael J. Welsh, Joseph Zabner, and Philip M. Polgreen. "Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions." Proceedings of the National Academy of Sciences 117, no. 3 (December 27, 2019): 1621–27. http://dx.doi.org/10.1073/pnas.1914912117.
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Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001–2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions.
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Shelby, Elena-Silvia, and Andrada Mirea. "INNOVATIVE THERAPIES IN GENETIC DISEASES: SPINAL MUSCULAR ATROPHY." Romanian Journal of Pediatrics 70, no. 2 (June 30, 2021): 108–13. http://dx.doi.org/10.37897/rjp.2021.2.4.
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Spinal muscular atrophy is a congenital neuromuscular disease characterized by the deterioration of the motor neurons located mainly in the anterior horns of the spinal cord, leading to progressive muscle weakness and atrophy. Globally, SMA is, after cystic fibrosis, the second cause of death due to a a genetic disease in the pediatric population. Over 95% of the total cases of SMA are represented by 5q SMA, caused by biallelic mutations in the SMN1 gene (5q13.2), the rest of the SMA types being called, generically, non-5q SMA. Currently, a few genetic targeted therapies are available for 5q SMA, while other innovative therapies are still in clinical trials. Early diagnosis and treatment of 5q SMA have an essential role in preventing the onset and evolution of symptoms and can save the life of the patient and prevent debilitating sequelae. This article aims to briefly describe the cause and symptomatology of 5q SMA as well as to make a short review of the genetic therapies available for this disease.
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Poore, T. Spencer, Gina Hong, and Edith T. Zemanick. "Fungal Infection and Inflammation in Cystic Fibrosis." Pathogens 10, no. 5 (May 18, 2021): 618. http://dx.doi.org/10.3390/pathogens10050618.
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Fungi are frequently recovered from lower airway samples from people with cystic fibrosis (CF), yet the role of fungi in the progression of lung disease is debated. Recent studies suggest worsening clinical outcomes associated with airway fungal detection, although most studies to date are retrospective or observational. The presence of fungi can elicit a T helper cell type 2 (Th-2) mediated inflammatory reaction known as allergic bronchopulmonary aspergillosis (ABPA), particularly in those with a genetic atopic predisposition. In this review, we discuss the epidemiology of fungal infections in people with CF, risk factors associated with development of fungal infections, and microbiologic approaches for isolation and identification of fungi. We review the spectrum of fungal disease presentations, clinical outcomes after isolation of fungi from airway samples, and the importance of considering airway co-infections. Finally, we discuss the association between fungi and airway inflammation highlighting gaps in knowledge and future research questions that may further elucidate the role of fungus in lung disease progression.
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Pompilio, Arianna, Vincenzo Savini, Ersilia Fiscarelli, Giovanni Gherardi, and Giovanni Di Bonaventura. "Clonal Diversity, Biofilm Formation, and Antimicrobial Resistance among Stenotrophomonas maltophilia Strains from Cystic Fibrosis and Non-Cystic Fibrosis Patients." Antibiotics 9, no. 1 (January 2, 2020): 15. http://dx.doi.org/10.3390/antibiotics9010015.
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The intrinsic antibiotic resistance of Stenotrophomonas maltophilia, along with its ability to form biofilm both on abiotic surfaces and host tissues, dramatically affects the efficacy of the antibiotic therapy. In this work, 85 S. maltophilia strains isolated in several hospital of central Italy and from several clinical settings were evaluated for their genetic relatedness (by pulsed-field gel electrophoresis, PFGE), biofilm formation (by microtiter plate assay), and planktonic antibiotic resistance (by Kirby–Bauer disk diffusion technique). The S. maltophilia population showed a high genetic heterogeneity: 64 different PFGE types were identified, equally distributed in cystic fibrosis (CF) and non-CF strains, and some consisted of multiple strains. Most of the strains (88.2%) were able to form biofilm, although non-CF strains were significantly more efficient than CF strains. CF strains produced lower biofilm amounts than non-CF strains, both those from respiratory tracts and blood. Non-CF PFGE types 3 and 27 consisted of strong-producers only. Cotrimoxazole and levofloxacin were the most effective antibiotics, being active respectively against 81.2% and 72.9% of strains. CF strains were significantly more resistant to piperacillin/tazobactam compared to non-CF strains (90% versus 53.3%), regardless of sample type. Among respiratory strains, cotrimoxazole was more active against non-CF than CF strains (susceptibility rates: 86.7% versus 75%). The multidrug resistant phenotype was significantly more prevalent in CF than non-CF strains (90% versus 66.7%). Overall, the multidrug-resistance level was negatively associated with efficiency in biofilm formation. Our results showed, for the first time, that in S. maltophilia both classical planktonic drug resistance and the ability of biofilm formation might favor its dissemination in the hospital setting. Biofilm formation might in fact act as a survival mechanism for susceptible bacteria, suggesting that clinical isolates should be routinely assayed for biofilm formation in diagnostic laboratories.
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Egic, Amira, Zeljko Mikovic, Vesna Mandic, and Natasa Karadzov. "Prenatal diagnosis of meconium ileus and meconium peritonitis: Indications for cystic fibrosis testing." Srpski arhiv za celokupno lekarstvo 139, no. 7-8 (2011): 527–30. http://dx.doi.org/10.2298/sarh1108527e.
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Introduction. More recently, the regions of increased abdominal echogenicity such as echogenic bowel, meconium ileus and meconium peritonitis have been associated with an increased prevalence of a variety of unfavourable outcomes including chromosomal abnormalities, cytomegalovirus infection, intestinal obstruction, anorectal malformations and cystic fibrosis. Earlier prenatal examinations of these severe autosomal recessive diseases had been suggested only to families with history of cystic fibrosis. Recently, systemic examination has been introduced by ultrasound with bowel hyperechogenicity where the fetus is the index case for genetic disease. Risk for cystic fibrosis with this ultrasonography findings ranges from 0-33%. Outline of Cases. Two patients are presented, aged 24 and 29 years, both primigravide. The first one had ultrasonography finding of meconium peritonitis revealed at the 37th week of gestation and the other meconium ileus revealed on ultrasonography at the 29th week of gestation. Both patients had prenatal testing of foetal blood obtained by cordocenthesis, both had normal kariotype and were negative for cytomegalovirus infection. Parental DNA testing for the 2nd patient showed that parents were not carriers for the 29 most frequent mutations. Both neonates had intestinal obstruction, underwent surgery and early postoperative course was normal. Hystopathological finding suggested a possibility of cystic fibrosis for the 1st patient, but parents did not want to be tested and for the 2nd one congenital bowel stenosis as a cause of intestinal obstruction. Conclusion. Ultrasonographic echogenic bowel is an indication for invasive procedures for foetal blood testing for chromosomal abnormalities, congenital infections and parental testing for cystic fibrosis. Only if parental heterozygosity is proven foetus should be tested.
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Węgrzyn, Grzegorz, Joanna Jakóbkiewicz-Banecka, Magdalena Gabig-Cimińska, Ewa Piotrowska, Magdalena Narajczyk, Anna Kloska, Marcelina Malinowska, et al. "Genistein: a natural isoflavone with a potential for treatment of genetic diseases." Biochemical Society Transactions 38, no. 2 (March 22, 2010): 695–701. http://dx.doi.org/10.1042/bst0380695.
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Genistein [4′,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a natural isoflavone occurring in many plants known to possess various biological activities, ranging from phyto-oestrogenic to antioxidative actions. Recent studies indicated that this isoflavone can also be considered as a drug for as yet untreatable genetic diseases. In the present review, we discuss a plausible use of genistein in treatment of two genetic disorders: CF (cystic fibrosis) and MPS (mucopolysaccharidosis). Although various biological actions of genistein are employed in these two cases, in vitro studies, tests on animal models and pilot clinical trials suggest that this plant-derived compound might be a real hope for patients suffering from severe inherited disorders with relatively complicated pathomechanisms, including those affecting the central nervous system.
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Malysh, Artem, Fedir Prytkov, Nataliia Morozova, and Mykhailo Tkachenko. "ОСОБЛИВОСТІ ПРОМЕНЕВОЇ ДІАГНОСТИКИ УРАЖЕННЯ ЛЕГЕНЬ ПРИ МУКОВІСЦИДОЗІ." Ukrainian Scientific Medical Youth Journal, no. 2(110) (June 27, 2019): 13–20. http://dx.doi.org/10.32345/usmyj.2(110).2019.13-20.
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Our method was used to clarify the possibilities of diagnostic in case of cystic fibrosis and the installation of a computer tomography place in a diagnostic algorithm. Consequently we have analyzed the results of cases of 5 patients at the age from 19 to 25 years with the diagnosis of cystic fibrosis confirmed by sweat samples and genetic investigations. From September 2017 to 2018, the patients were placed in the infection epidemic department No. 2 of Oleksandrivskiy Clinical Hospital die to complications of the main disease. The patients were in the group of middle and high level of severity, respiratory failure II, III stages. These patients were dynamically examined by digital radiography of the chest cavity organs “Radrex” by Toshiba. All of the patients were united by an young age, asthenic and low nutrition body structure, short stature and prolonged anamnesis from early childhood, anamnesis of respiratory diseases, acute respiratory viral infections, bronchitis, sinusitis of the maxillary antrum. It was proved that the results obtained by radiography are typical for CF, but not specific, as well as they could be found in other diffuse lung diseases. After multispiral Computer tomography scan, we have found the main symptoms of cystic fibrosis, such as: total systemic damage of bronchopulmonary structures, two-sides character of pulmonary bronchiectasis . The presence of pronounced dilation of the bronchi of all orders, at least 200% of the original size, with a consolidation and thickening of their walls: a symptom of "ring" and the symptom of "paired strips" and filling of abruptly dilated bronchi of all calibers with a viscous secretion and as a result of this the mucous plugs are formed.
Conclusion. The results of the X-ray examination are typical for CF and not specific, as well as for other diffuse pulmonary diseases. Computer tomography can be used for diagnostics of thin structurally functional particles characteristic for cystic fibrosis. It has also been established that the expression of morphological changes of cystic fibrosis are increased with the age of the patients. CT scan is the most useful for the detection morphological and functional changes for cystic fibrosis. Moreover, the CT scan is able to improve the early diagnoses for lungs pathology among the adolescent and the adults, and decrease the period of expectation of the result of the treatment.
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Chirgwin, Michael E., Margaret R. Dedloff, Alina Maria Holban, and Monica C. Gestal. "Novel Therapeutic Strategies Applied to Pseudomonas aeruginosa Infections in Cystic Fibrosis." Materials 12, no. 24 (December 7, 2019): 4093. http://dx.doi.org/10.3390/ma12244093.
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Cystic fibrosis (CF) is one of the most prevalent genetic diseases and a total of 1700 different genetic mutations can cause this condition. Patients that suffer this disease have a thickening of the mucus, creating an environment that promotes bacterial infections. Pseudomonas aeruginosa is a ubiquitous bacterium, which is frequently found in the lungs of CF patients. P. aeruginosa is known for its high level of antibiotic resistance as well as its high rate of mutation that allows it to rapidly evolve and adapt to a multitude of conditions. When a CF lung is infected with P. aeruginosa, the decay of the patient is accelerated, but there is little that can be done apart from controlling the infection with antibiotics. Novel strategies to control P. aeruginosa infection are imperative, and nanotechnology provides novel approaches to drug delivery that are more efficient than classic antibiotic treatments. These drug delivery systems are offering new prospects, especially for these patients with special mucus conditions and bacterial characteristics that limit antibiotic use.
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Girón Moreno, Rosa María, Marta García-Clemente, Layla Diab-Cáceres, Adrián Martínez-Vergara, Miguel Ángel Martínez-García, and Rosa Mar Gómez-Punter. "Treatment of Pulmonary Disease of Cystic Fibrosis: A Comprehensive Review." Antibiotics 10, no. 5 (April 23, 2021): 486. http://dx.doi.org/10.3390/antibiotics10050486.
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Cystic fibrosis (CF) is a genetic disease that causes absence or dysfunction of a protein named transmembrane conductance regulatory protein (CFTR) that works as an anion channel. As a result, the secretions of the organs where CFTR is expressed are very viscous, so their functionality is altered. The main cause of morbidity is due to the involvement of the respiratory system as a result of recurrent respiratory infections by different pathogens. In recent decades, survival has been increasing, rising by around age 50. This is due to the monitoring of patients in multidisciplinary units, early diagnosis with neonatal screening, and advances in treatments. In this chapter, we will approach the different therapies used in CF for the treatment of symptoms, obstruction, inflammation, and infection. Moreover, we will discuss specific and personalized treatments to correct the defective gene and repair the altered protein CFTR. The obstacle for personalized CF treatment is to predict the drug response of patients due to genetic complexity and heterogeneity of uncommon mutations.
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Lepage, Mathieu L., Antoine Mirloup, Manon Ripoll, Fabien Stauffert, Anne Bodlenner, Raymond Ziessel, and Philippe Compain. "Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores." Beilstein Journal of Organic Chemistry 11 (May 6, 2015): 659–67. http://dx.doi.org/10.3762/bjoc.11.74.
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The synthesis and photophysical properties of the first examples of iminosugar clusters based on a BODIPY or a pyrene core are reported. The tri- and tetravalent systems designed as molecular probes and synthesized by way of Cu(I)-catalysed azide–alkyne cycloadditions are fluorescent analogues of potent pharmacological chaperones/correctors recently reported in the field of Gaucher disease and cystic fibrosis, two rare genetic diseases caused by protein misfolding.
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Zarrilli, Federica, Ausilia Elce, Manuela Scorza, Sonia Giordano, Felice Amato, and Giuseppe Castaldo. "An Update on Laboratory Diagnosis of Liver Inherited Diseases." BioMed Research International 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/697940.
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Liver inherited diseases are a group of genetically determined clinical entities that appear with an early chronic liver involvement. They include Wilson’s disease (hepatolenticular degeneration), hereditary hemochromatosis, and alpha-1-antitrypsin deficiency. In addition, cystic fibrosis, although it is not specifically a liver disease, may cause a severe liver involvement in a significant percentage of cases. For all these pathologies, the disease gene is known, and molecular analysis may contribute to the unequivocal diagnosis. This approach could avoid the patient invasive procedures and limit complications associated with a delay in diagnosis. We review liver inherited diseases on the basis of the genetic defect, focusing on the contribution of molecular analysis in the multistep diagnostic workup.
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Maitra, Rangan, Perumal Sivashanmugam, and Keith Warner. "A Rapid Membrane Potential Assay to Monitor CFTR Function and Inhibition." Journal of Biomolecular Screening 18, no. 9 (May 7, 2013): 1132–37. http://dx.doi.org/10.1177/1087057113488420.
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The cystic fibrosis transmembrane conductance regulator (CFTR) protein is an important regulator of ion transport and fluid secretion in humans. Mutations to CFTR cause cystic fibrosis, which is a common recessive genetic disorder in Caucasians. Involvement of CFTR has been noted in other important diseases, such as secretory diarrhea and polycystic kidney disease. The assays to monitor CFTR function that have been described to date either are complicated or require specialized instrumentation and training for execution. In this report, we describe a rapid FlexStation-based membrane potential assay to monitor CFTR function. In this assay, agonist-mediated activation of CFTR results in membrane depolarization that can be monitored using a fluorescent membrane potential probe. Availability of a simple mix-and-read assay to monitor the function of this important protein might accelerate the discovery of CFTR ligands to study a variety of conditions.
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Schneider, Ines, Anne Marie Queenan, and Adolf Bauernfeind. "Novel Carbapenem-Hydrolyzing Oxacillinase OXA-62 from Pandoraea pnomenusa." Antimicrobial Agents and Chemotherapy 50, no. 4 (April 2006): 1330–35. http://dx.doi.org/10.1128/aac.50.4.1330-1335.2006.
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ABSTRACT Pandoraea spp. are gram-negative, glucose nonfermenting rods detectable in blood cultures and sputa of cystic fibrosis patients. They are resistant to various antibiotic groups, with imipenem being the only active β-lactam. We isolated an imipenem-resistant (MIC, 64 μg/ml) Pandoraea pnomenusa strain from a cystic fibrosis patient. Cloning and sequencing identified two β-lactamases of Bush group 2d, namely, the known OXA-33, located on an integron, and the novel carbapenem-hydrolyzing oxacillinase OXA-62. OXA-62 is only distantly related to other oxacillinases (OXA-50 being closest with 43% amino acid identity). It hydrolyzes penicillins, oxacillin, imipenem, and meropenem but not expanded-spectrum cephalosporins. The bla OXA-62 gene is chromosome located. No transposable elements were found in its genetic neighborhood. With OXA-62-specific primers, bla OXA-62 could be identified in all P. pnomenusa strains and appears to be species specific. This additional mechanism of carbapenem resistance further complicates the treatment of infections caused by P. pnomenusa.
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Yagci, S., G. Hascelik, D. Dogru, U. Ozcelik, and B. Sener. "Prevalence and genetic diversity of Staphylococcus aureus small-colony variants in cystic fibrosis patients." Clinical Microbiology and Infection 19, no. 1 (January 2013): 77–84. http://dx.doi.org/10.1111/j.1469-0691.2011.03742.x.
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Peabody, Jacelyn E., Ren-Jay Shei, Brent M. Bermingham, Scott E. Phillips, Brett Turner, Steven M. Rowe, and George M. Solomon. "Seeing cilia: imaging modalities for ciliary motion and clinical connections." American Journal of Physiology-Lung Cellular and Molecular Physiology 314, no. 6 (June 1, 2018): L909—L921. http://dx.doi.org/10.1152/ajplung.00556.2017.
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The respiratory tract is lined with multiciliated epithelial cells that function to move mucus and trapped particles via the mucociliary transport apparatus. Genetic and acquired ciliopathies result in diminished mucociliary clearance, contributing to disease pathogenesis. Recent innovations in imaging technology have advanced our understanding of ciliary motion in health and disease states. Application of imaging modalities including transmission electron microscopy, high-speed video microscopy, and micron-optical coherence tomography could improve diagnostics and be applied for precision medicine. In this review, we provide an overview of ciliary motion, imaging modalities, and ciliopathic diseases of the respiratory system including primary ciliary dyskinesia, cystic fibrosis, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis.
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Enikanolaiye, Adebola, and Monica J. Justice. "Model systems inform rare disease diagnosis, therapeutic discovery and pre-clinical efficacy." Emerging Topics in Life Sciences 3, no. 1 (March 13, 2019): 1–10. http://dx.doi.org/10.1042/etls20180057.
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Abstract Model systems have played a large role in understanding human diseases and are instrumental in taking basic research findings to the clinic; however, for rare diseases, model systems play an even larger role. Here, we outline how model organisms are crucial for confirming causal associations, understanding functional mechanisms and developing therapies for disease. As diseases that have been studied extensively through genetics and molecular biology, cystic fibrosis and Rett syndrome are portrayed as primary examples of how genetic diagnosis, model organism development and therapies have led to improved patient health. Considering which model to use, yeast, worms, flies, fish, mice or larger animals requires a careful evaluation of experimental genetic tools and gene pathway conservation. Recent advances in genome editing will aid in confirming diagnoses and developing model systems for rare disease. Genetic or chemical screening for disease suppression may reveal functional pathway members and provide candidate entry points for developing therapies. Model organisms may also be used in drug discovery and as preclinical models as a prelude to testing treatments in patient populations. Now, model organisms will increasingly be used as platforms for understanding variation in rare disease severity and onset, thereby informing therapeutic intervention.
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Merk, Daniel, and Manfred Schubert-Zsilavecz. "Innovations in the treatment of cystic fibrosis: outriders for the treatment of diseases with other genetic defects?" Future Medicinal Chemistry 3, no. 16 (December 2011): 1969–70. http://dx.doi.org/10.4155/fmc.11.157.
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Phennicie, Ryan T., Matthew J. Sullivan, John T. Singer, Jeffrey A. Yoder, and Carol H. Kim. "Specific Resistance to Pseudomonas aeruginosa Infection in Zebrafish Is Mediated by the Cystic Fibrosis Transmembrane Conductance Regulator." Infection and Immunity 78, no. 11 (August 23, 2010): 4542–50. http://dx.doi.org/10.1128/iai.00302-10.
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ABSTRACT Cystic fibrosis (CF) is a genetic disease caused by recessive mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is associated with prevalent and chronic Pseudomonas aeruginosa lung infections. Despite numerous studies that have sought to elucidate the role of CFTR in the innate immune response, the links between CFTR, innate immunity, and P. aeruginosa infection remain unclear. The present work highlights the zebrafish as a powerful model organism for human infectious disease, particularly infection by P. aeruginosa. Zebrafish embryos with reduced expression of the cftr gene (Cftr morphants) exhibited reduced respiratory burst response and directed neutrophil migration, supporting a connection between cftr and the innate immune response. Cftr morphants were infected with P. aeruginosa or other bacterial species that are commonly associated with infections in CF patients, including Burkholderia cenocepacia, Haemophilus influenzae, and Staphylococcus aureus. Intriguingly, the bacterial burden of P. aeruginosa was found to be significantly higher in zebrafish Cftr morphants than in controls, but this phenomenon was not observed with the other bacterial species. Bacterial burden in Cftr morphants infected with a P. aeruginosa ΔLasR mutant, a quorum sensing-deficient strain, was comparable to that in control fish, indicating that the regulation of virulence factors through LasR is required for enhancement of infection in the absence of Cftr. The zebrafish system provides a multitude of advantages for studying the pathogenesis of P. aeruginosa and for understanding the role that innate immune cells, such as neutrophils, play in the host response to acute bacterial infections commonly associated with cystic fibrosis.
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Mettang, Thomas, and Markus Streit. "Hautveränderungen als Schlüssel zur Diagnose systemischer Erkrankungen." DMW - Deutsche Medizinische Wochenschrift 143, no. 23 (November 2018): 1690–99. http://dx.doi.org/10.1055/a-0569-3822.
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AbstractMany systemic diseases go along with dermal involvement. Only a few of systemic diseases show characteristic skin derangements directly leading to the diagnosis of the underlying disease. Ten of these entities are described within this article. Some of these are autoimmune diseases, such as systemic lupus erythematodes, dermatomyositis or the anti-synthetase-syndrome. Others are genetic diseases with benign or malignant neoplasias (Peutz-Jeghers-syndrome, neurofibromatosis, tuberous sclerosis, Birt-Hogg-Dubé-syndrome, Cowden-syndrome). Other genetically based diseases with typical skin manifestations are characterised by vascular malformations (Pseudoxanthoma elasticum and Osler-Weber-Rendu syndrome) or metabolic and structural organ defects (Morbus Fabry, cystic fibrosis). Being familiar with the typical skin-appearance of these diseases will allow physicians and general practitioners to make a timely diagnosis.
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Pehote, Garrett, and Neeraj Vij. "Autophagy Augmentation to Alleviate Immune Response Dysfunction, and Resolve Respiratory and COVID-19 Exacerbations." Cells 9, no. 9 (August 24, 2020): 1952. http://dx.doi.org/10.3390/cells9091952.
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The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris. This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy–lysosome pathway. These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19). Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease. Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases. In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease. Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.
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Tan, Marsha, Felisa Reyes-Ortega, and Elena K. Schneider-Futschik. "Successes and Challenges: Inhaled Treatment Approaches Using Magnetic Nanoparticles in Cystic Fibrosis." Magnetochemistry 6, no. 2 (June 4, 2020): 25. http://dx.doi.org/10.3390/magnetochemistry6020025.
Full textAbstract:
Magnetic nanoparticles have been largely applied to increase the efficacy of antibiotics due to passive accumulation provided by enhancing permeability and retention, which is essential for the treatment of lung infections. Recurring lung infections such as in the life-shortening genetic disease cystic fibrosis (CF) are a major problem. The recent advent of the CF modulator drug ivacaftor, alone or in combination with lumacaftor or tezacaftor, has enabled systemic treatment of the majority of patients. Magnetic nanoparticles (MNPs) show unique properties such as biocompatibility and biodegradability as well as magnetic and heat-medicated characteristics. These properties make them suitable to be used as drug carriers and hyperthermia-based agents. Hyperthermia is a promising approach for the thermal activation therapy of several diseases, including pulmonary diseases. The benefits of delivering CF drugs via inhalation using MNPs as drug carriers afford application of sufficient therapeutic dosages directly to the primary target site, while avoiding potential suboptimal pharmacokinetics/pharmacodynamics and minimizing the risks of systemic toxicity. This review explores the multidisciplinary approach of using MNPs as vehicles of drug delivery. Additionally, we highlight advantages such as increased drug concentration at disease site, minimized drug loss and the possibility of specific cell targeting, while addressing major challenges for this emerging field.
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Mention, Karen, Lúcia Santos, and Patrick T. Harrison. "Gene and Base Editing as a Therapeutic Option for Cystic Fibrosis—Learning from Other Diseases." Genes 10, no. 5 (May 21, 2019): 387. http://dx.doi.org/10.3390/genes10050387.
Full textAbstract:
Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the CFTR gene. There are at least 346 disease-causing variants in the CFTR gene, but effective small-molecule therapies exist for only ~10% of them. One option to treat all mutations is CFTR cDNA-based therapy, but clinical trials to date have only been able to stabilise rather than improve lung function disease in patients. While cDNA-based therapy is already a clinical reality for a number of diseases, some animal studies have clearly established that precision genome editing can be significantly more effective than cDNA addition. These observations have led to a number of gene-editing clinical trials for a small number of such genetic disorders. To date, gene-editing strategies to correct CFTR mutations have been conducted exclusively in cell models, with no in vivo gene-editing studies yet described. Here, we highlight some of the key breakthroughs in in vivo and ex vivo gene and base editing in animal models for other diseases and discuss what might be learned from these studies in the development of editing strategies that may be applied to cystic fibrosis as a potential therapeutic approach. There are many hurdles that need to be overcome, including the in vivo delivery of editing machinery or successful engraftment of ex vivo-edited cells, as well as minimising potential off-target effects. However, a successful proof-of-concept study for gene or base editing in one or more of the available CF animal models could pave the way towards a long-term therapeutic strategy for this disease.