Cystic Fibrosis
CONCERNS FOR PEOPLE WITH CYSTIC FIBROSIS (PWCF) WHEN TRAVELLING PRE COVID-19
A small molecule high throughput screening platform to profile conformational properties of nascent, ribosome-bound proteins
Sci Rep. 2022 Feb 15;12(1):2509. doi: 10.1038/s41598-022-06456-5.
ABSTRACT
Genetic mutations cause a wide spectrum of human disease by disrupting protein folding, both during and after synthesis. Transient de-novo folding intermediates therefore represent potential drug targets for pharmacological correction of protein folding disorders. Here we develop a FRET-based high-throughput screening (HTS) assay in 1,536-well format capable of identifying small molecules that interact with nascent polypeptides and correct genetic, cotranslational folding defects. Ribosome nascent chain complexes (RNCs) containing donor and acceptor fluorophores were isolated from cell free translation reactions, immobilized on Nickel-NTA/IDA beads, and imaged by high-content microscopy. Quantitative FRET measurements obtained from as little as 0.4 attomole of protein/bead enabled rapid assessment of conformational changes with a high degree of reproducibility. Using this assay, we performed a pilot screen of ~ 50,000 small molecules to identify compounds that interact with RNCs containing the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) harboring a disease-causing mutation (A455E). Screen results yielded 133 primary hits and 1 validated hit that normalized FRET values of the mutant nascent peptide. This system provides a scalable, tractable, structure-based discovery platform for screening small molecules that bind to or impact the folding of protein substrates that are not amenable to traditional biochemical analyses.
PMID:35169219 | DOI:10.1038/s41598-022-06456-5
Clinical outcomes in cystic fibrosis at 6 years of age with tricare insurance coverage
J Cyst Fibros. 2022 Feb 12:S1569-1993(22)00036-4. doi: 10.1016/j.jcf.2022.02.004. Online ahead of print.
ABSTRACT
Health insurance coverage is associated with outcomes in cystic fibrosis (CF). A fraction of individuals in the United States are covered through Tricare, a federally funded program for military members and their dependents. The role of Tricare on CF health outcomes is unknown. Using a retrospective CF Foundation Patient Registry cohort born 2000-2011, insurance status was defined as any Tricare (n = 328) with reference groups of always private (n = 3,455) and exclusively public (n = 2,669) during the first 6 years of life. Subjects with Tricare coverage attended more CF care centers and lived in more zip codes by age 6 than their counterparts. BMI did not differ between groups. Subjects with Tricare had a higher FEV1 at age 6 compared to those with always public insurance. Overall, outcomes for those with Tricare insurance appeared more similar to those with always private insurance. Future research should consider treating Tricare coverage similar to private insurance.
PMID:35168871 | DOI:10.1016/j.jcf.2022.02.004
CFTR modulator therapy alters plasma sphingolipid profiles in people with cystic fibrosis
J Cyst Fibros. 2022 Feb 12:S1569-1993(22)00037-6. doi: 10.1016/j.jcf.2022.02.005. Online ahead of print.
ABSTRACT
BACKGROUND: Sphingolipids, in particular ceramides, play an important role in the pathogenesis of cystic fibrosis (CF) lung disease. Ceramides seem to be dysregulated in people with CF (PWCF): An elevated ratio of ceramides C16Cer/ C24Cer has been linked to inflammation and disease severity. CFTR modulators might influence sphingolipid dysregulation in PWCF.
METHODS: Sphingolipid profiles were retrospectively analyzed in serum from 112 PWCF and 96 healthy controls as well as in plasma from 25 PWCF before and after treatment with the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lipid data were correlated with clinical parameters.
RESULTS: There were significantly higher levels of long-chain ceramides C18Cer and C20Cer and of the very long-chain ceramide C24:1Cer in PWCF versus healthy controls. Sphingosine levels were significantly reduced and accurately distinguished PWCF from healthy controls. Treatment with ELX/TEZ/IVA was associated with a decrease in levels of long-chain ceramides C16Cer, C18Cer and C20Cer and very long-chain ceramide C24:1Cer. Plasma levels of the most abundant very long-chain ceramide C24Cer as well as sphingosine-1-phosphate increased. Consequently, the ratio of ceramides C16Cer/ C24Cer decreased. Sphingolipid levels showed weak correlations with clinical parameters.
CONCLUSIONS: These findings highlight the existence of a distinctive sphingolipid profile in blood from PWCF, which appears to be altered by ELX/TEZ/IVA therapy. Thus, strategies for sphingolipid remodeling need to be reassessed and adjusted in the light of highly effective CFTR modulator therapies.
PMID:35168870 | DOI:10.1016/j.jcf.2022.02.005
Men's sexual and reproductive health in cystic fibrosis in the era of highly effective modulator therapies-A qualitative study
J Cyst Fibros. 2022 Feb 12:S1569-1993(22)00034-0. doi: 10.1016/j.jcf.2022.02.002. Online ahead of print.
ABSTRACT
BACKGROUND: As people with cystic fibrosis (CF) are living longer, men with CF increasingly face both general and disease-specific sexual and reproductive health (SRH) concerns. This study explored the SRH experiences and preferences of men with CF in health care in the era of widespread use of highly effective CF modulator therapies.
METHODS: We recruited men with CF aged 18 years and older to participate in a qualitative descriptive study using semi-structured telephone interviews to explore experiences and preferences related to CF SRH care. Two independent researchers coded interview transcripts and conducted content and thematic analysis using an inductive approach.
FINDINGS: We interviewed 24 participants (mean age 33.7 ± 11.8 years, range 19-60) and identified five major themes: 1) CF SRH concerns, specifically infertility, can have negative impacts on men's perceptions of masculinity, relationships, and mental health; 2) As life expectancy increases, addressing male SRH is increasingly important in CF care; 3) Men with CF experience lack of SRH counseling and care; 4) Conversations about SRH should begin in early adolescence and be addressed regularly by CF providers in a stepwise fashion; 5) Men with CF value peer support and SRH information featuring the experiences of other men with CF.
CONCLUSIONS: Men with CF acknowledge the need for comprehensive CF care that includes SRH and value early, stepwise, provider-initiated SRH conversations. Future work should seek a broader understanding of the impact of SRH on the mental health of men with CF as these concerns can have significant effects on the lives and self-identities of men with CF.
PMID:35168869 | DOI:10.1016/j.jcf.2022.02.002
Managing Pulmonary Infection in Adults With Cystic Fibrosis: Adult Cystic Fibrosis Series
Chest. 2022 Feb 12:S0012-3692(22)00251-3. doi: 10.1016/j.chest.2022.02.007. Online ahead of print.
ABSTRACT
Cystic fibrosis (CF) is characterised by chronic airway infection and progressive respiratory decline. Historically, a narrow spectrum of bacterial pathogens was believed to comprise the bulk of respiratory infections in CF, with Haemophilus influenzae and Staphylococcus aureus dominating childhood infections and Pseudomonas aeruginosa or, less commonly, a member of the Burkholderia cepacia complex (Bcc) becoming the dominant infecting organism in adulthood .1 Today, the landscape is changing for airway infection in CF. Prevalence of "less typical" Gram-negative bacterial infections are rising due to a number of factors: the CF population is ageing; new therapies are being introduced; antibiotic usage is increasing; diagnostic tests are evolving and taxonomic changes are being made as new bacterial species are being discovered. Less is known about the clinical relevance and evidence for treatment strategies for many of the other lower prevalence organisms that are encountered in CF. This article aims to discuss the current evidence and recommended strategies for treating airway infection in CF, focusing on bacterial infections.
PMID:35167860 | DOI:10.1016/j.chest.2022.02.007
Advancing bacteriophages as a treatment of antibiotic-resistant bacterial pulmonary infections
Curr Opin Pulm Med. 2022 Feb 14. doi: 10.1097/MCP.0000000000000864. Online ahead of print.
ABSTRACT
PURPOSE OF REVIEW: The current article summarizes the recent advances in the use of bacteriophages to treat pulmonary infections, particularly those caused by Gram-negative drug-resistant bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Burkholderia species. It provides an updated overview of the current available evidence, with a summary of published clinical cases, case series and clinical trials currently underway.
RECENT FINDING: Personalized treatment with bacteriophages is still in its infancy in Europe and the USA, despite extensive experience in Eastern countries. However, more patients are expected to be treated with clinical trials in progress and others planned.
SUMMARY: Despite very promising initial results and the confirmation of phage safety, there are still many ethical and practical implications to be considered, from the necessary regulatory approval to optimization of dose and route of administration, to developing strategies to tackle bacterial resistance. Patients with cystic fibrosis are a group where phage therapy, if successful, could have a major impact.
PMID:35165237 | DOI:10.1097/MCP.0000000000000864
How can the transition of adolescents from a children's to an adult CF center be improved? Analysis of adolescents' and parents' needs during the post-transfer period
Rev Mal Respir. 2022 Feb 11:S0761-8425(22)00027-4. doi: 10.1016/j.rmr.2022.01.006. Online ahead of print.
ABSTRACT
INTRODUCTION: In 2018, 55.4% of the 7180 French cystic fibrosis (CF) patients were adults. Our study was aimed at identifying young adult patients' needs and those of their parents when the young adults arrived in an adult CF center.
METHODOLOGY: Semi-structured interviews, conducted between July 2018 and December 2019and involving all the concerned teenagers and their parents, took place at least 6 months after their transfer. The interview guide dwelt on the aspects having had an impact on their experience of the transition. The interviews were recorded, transcribed and analyzed exhaustively. The results were classified by categorizing the contents according to respondent profile.
RESULTS: Thirty-eight young adult patients and 16 parents were interviewed. As regards the young adults, analysis of their needs underlined the importance of their continuing to develop their skills in adaptation, communication and self-care. As regards their parents, they needed support in view of defining their role in their children's new care pathway.
CONCLUSION: During and also following the transfer, therapeutic education for the parents as well as the young adults requires reinforcement.
PMID:35165013 | DOI:10.1016/j.rmr.2022.01.006
Unprecedented Epimerization of an Azithromycin Analogue: Synthesis, Structure and Biological Activity of 2'-Dehydroxy-5″-Epi-Azithromycin
Molecules. 2022 Feb 3;27(3):1034. doi: 10.3390/molecules27031034.
ABSTRACT
Certain macrolide antibiotics, azithromycin included, possess anti-inflammatory properties that are considered fundamental for their efficacy in the treatment of chronic inflammatory diseases, such as diffuse pan-bronchiolitis and cystic fibrosis. In this study, we disclose a novel azithromycin analog obtained via Barton-McCombie oxidation during which an unprecedented epimerization on the cladinose sugar occurs. Its structure was thoroughly investigated using NMR spectroscopy and compared to the natural epimer, revealing how the change in configuration of one single stereocenter (out of 16) profoundly diminished the antimicrobial activity through spatial manipulation of ribosome binding epitopes. At the same time, the anti-inflammatory properties of parent macrolide were retained, as demonstrated by inhibition of LPS- and cigarette-smoke-induced pulmonary inflammation. Not surprisingly, the compound has promising developable properties including good oral bioavailability and a half-life that supports once-daily dosing. This novel anti-inflammatory candidate has significant potential to fill the gap in existing anti-inflammatory agents and broaden treatment possibilities.
PMID:35164298 | DOI:10.3390/molecules27031034
Genistein-Opportunities Related to an Interesting Molecule of Natural Origin
Molecules. 2022 Jan 26;27(3):815. doi: 10.3390/molecules27030815.
ABSTRACT
Nowadays, increasingly more attention is being paid to a holistic approach to health, in which diet contributes to disease prevention. There is growing interest in functional food that not only provides basic nutrition but has also been demonstrated to be an opportunity for the prevention of disorders. A promising functional food is soybean, which is the richest source of the isoflavone, genistein. Genistein may be useful in the prevention and treatment of such disorders as psoriasis, cataracts, cystic fibrosis, non-alcoholic fatty liver disease and type 2 diabetes. However, achievable concentrations of genistein in humans are low, and the use of soybean as a functional food is not devoid of concerns, which are related to genistein's potential side effects resulting from its estrogenic and goitrogenic effects.
PMID:35164079 | DOI:10.3390/molecules27030815
Expression of a Truncated Form of <em>ODAD1</em> Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype
Int J Mol Sci. 2022 Feb 3;23(3):1753. doi: 10.3390/ijms23031753.
ABSTRACT
Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in > 50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of ODAD1 (CCDC114), a component of the outer dynein arm docking complex, results in a failure to assemble outer dynein arms (ODAs), mostly immotile cilia, and a typical PCD phenotype. We identified a female (now 34 years old) with an unusually mild clinical phenotype who has a homozygous non-canonical splice mutation (c.1502+5G>A) in ODAD1. To investigate the mechanism for the unusual phenotype, we performed molecular and functional studies of cultured nasal epithelial cells. We demonstrate that this splice mutation results in the expression of a truncated protein that is attached to the axoneme, indicating that the mutant protein retains partial function. This allows for the assembly of some ODAs and a significant level of ciliary activity that may result in the atypically mild clinical phenotype. The results also suggest that partial restoration of ciliary function by therapeutic agents could lead to significant improvement of disease symptoms.
PMID:35163670 | DOI:10.3390/ijms23031753
Assays of CFTR Function In Vitro, Ex Vivo and In Vivo
Int J Mol Sci. 2022 Jan 27;23(3):1437. doi: 10.3390/ijms23031437.
ABSTRACT
Cystic fibrosis, a multi-organ genetic disease, is characterized by abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel at the apical membrane of several epithelia. In recent years, therapeutic strategies have been developed to correct the CFTR defect. To evaluate CFTR function at baseline for diagnosis, or the efficacy of CFTR-restoring therapy, reliable tests are needed to measure CFTR function, in vitro, ex vivo and in vivo. In vitro techniques either directly or indirectly measure ion fluxes; direct measurement of ion fluxes and quenching of fluorescence in cell-based assays, change in transmembrane voltage or current in patch clamp or Ussing chamber, swelling of CFTR-containing organoids by secondary water influx upon CFTR activation. Several cell or tissue types can be used. Ex vivo and in vivo assays similarly evaluate current (intestinal current measurement) and membrane potential differences (nasal potential difference), on tissues from individual patients. In the sweat test, the most frequently used in vivo evaluation of CFTR function, chloride concentration or stimulated sweat rate can be directly measured. Here, we will describe the currently available bio-assays for quantitative evaluation of CFTR function, their indications, advantages and disadvantages, and correlation with clinical outcome measures.
PMID:35163362 | DOI:10.3390/ijms23031437
Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease
Int J Mol Sci. 2022 Jan 19;23(3):1085. doi: 10.3390/ijms23031085.
ABSTRACT
Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl- currents and intracellular Ca2+ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca2+ activated Cl- channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca2+ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application.
PMID:35163010 | DOI:10.3390/ijms23031085
Factors Associated with the Willingness to Become a Living Kidney Donor: A National Cross-Sectional Study
Int J Environ Res Public Health. 2022 Jan 25;19(3):1313. doi: 10.3390/ijerph19031313.
ABSTRACT
INTRODUCTION: Living donor kidney transplantation is the preferred method of treating kidney failure. The donor agrees to undergo an elective procedure for the benefit of the recipient.
AIM: To assess the attitude toward living kidney donation and to investigate the factors that contribute to kidney donation willingness.
METHODS: A cross-sectional study was carried out between December 2020 and February 2021. The study covered a representative group of 953 Poles aged 18-77, living in all Polish voivodships. The relationship between sociodemographic factors, personal values (Personal Values List), the total score of life satisfaction (Satisfaction with Life Scale) and the willingness to donate a kidney to another human was assessed using a logistic regression model.
RESULTS: The most frequently chosen personal values were: good health; physical and mental fitness; love and friendship; knowledge and wisdom. The most frequently chosen symbols of happiness were: good health, successful family life, being needed by others. The median satisfaction with life for the entire group was 20 [16; 24]. Voluntary donation of a kidney to another human being i.e., family, friends, strangers were more often declared by women (OR = 1.21; Cl95%: 1.03-1.42), for whom the most important symbol of happiness was a life full of adventures, travels (OR = 1.39; Cl95%: 1.06-1.82) and the most important personal value was goodness and tenderness (OR = 1.21; Cl95%: 1.05-1.40). Total scores of The Satisfaction with Life Scale correlated positively with the willingness to voluntarily donate a kidney (OR = 1.03; Cl95%: 1.003-1.06), while age correlated negatively (OR = 0.99; Cl95%: 0.98-0.99).
CONCLUSIONS: Respondents who declare their willingness to be a living kidney donor are mainly female, for which the most important symbol of happiness is a life full of adventures and travel, and the most important values are personal goodness and tenderness. The desire to donate a kidney to another person decreases with age and grows with life satisfaction.
TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT04789122).
PMID:35162337 | DOI:10.3390/ijerph19031313
A Systematic Literature Review of Indoor Air Disinfection Techniques for Airborne Bacterial Respiratory Pathogens
Int J Environ Res Public Health. 2022 Jan 21;19(3):1197. doi: 10.3390/ijerph19031197.
ABSTRACT
Interrupting the transmission of airborne (<≈5 µm) respiratory pathogens indoors is not a new challenge, but it has attracted unprecedented interest due to the COVID-19 pandemic during 2020-2021. However, bacterial respiratory pathogens with known or potential airborne transmission account for an appreciable proportion of the communicable disease burden globally. We aimed to systematically review quantitative, laboratory-based studies of air disinfection techniques for airborne respiratory bacteria. Three databases (PubMed, Web of Science, Scopus) were searched, following PRISMA guidelines. A total of 9596 articles were identified, of which 517 were assessed in detail and of which 26 met the inclusion and quality assessment criteria. Seven air disinfection techniques, including UV-C light, filtration, and face masks, among others, were applied to 13 different bacterial pathogens. More than 80% of studies suggested that air disinfection techniques were more effective at inactivating or killing bacteria than the comparator or baseline condition. However, it was not possible to compare these techniques because of methodological heterogeneity and the relatively small number of the studies. Laboratory studies are useful for demonstrating proof-of-concept and performance under controlled conditions. However, the generalisability of their findings to person-to-person transmission in real-world settings is unclear for most of the pathogens and techniques we assessed.
PMID:35162224 | DOI:10.3390/ijerph19031197
Intestinal Inflammation and Alterations in the Gut Microbiota in Cystic Fibrosis: A Review of the Current Evidence, Pathophysiology and Future Directions
J Clin Med. 2022 Jan 27;11(3):649. doi: 10.3390/jcm11030649.
ABSTRACT
Cystic fibrosis (CF) is a life-limiting autosomal recessive multisystem disease. While its burden of morbidity and mortality is classically associated with pulmonary disease, CF also profoundly affects the gastrointestinal (GI) tract. Chronic low-grade inflammation and alterations to the gut microbiota are hallmarks of the CF intestine. The etiology of these manifestations is likely multifactorial, resulting from cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, a high-fat CF diet, and the use of antibiotics. There may also be a bidirectional pathophysiological link between intestinal inflammation and changes to the gut microbiome. Additionally, a growing body of evidence suggests that these GI manifestations may have significant clinical associations with growth and nutrition, quality of life, and respiratory function in CF. As such, the potential utility of GI therapies and long-term GI outcomes are areas of interest in CF. Further research involving microbial modulation and multi-omics techniques may reveal novel insights. This article provides an overview of the current evidence, pathophysiology, and future research and therapeutic considerations pertaining to intestinal inflammation and alterations in the gut microbiota in CF.
PMID:35160099 | DOI:10.3390/jcm11030649
Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges
Cancers (Basel). 2022 Jan 22;14(3):552. doi: 10.3390/cancers14030552.
ABSTRACT
Uncontrolled inflammation is a salient factor in multiple chronic inflammatory diseases and cancers. In this review, we provided an in-depth analysis of the relationships and distinctions between uncontrolled inflammation, fibrosis and cancers, while emphasizing the challenges and opportunities of developing novel therapies for the treatment and/or management of these diseases. We described how drug delivery systems, combination therapy and the integration of tissue-targeted and/or pathways selective strategies could overcome the challenges of current agents for managing and/or treating chronic inflammatory diseases and cancers. We also recognized the value of the re-evaluation of the disease-specific roles of multiple pathways implicated in the pathophysiology of chronic inflammatory diseases and cancers-as well as the application of data from single-cell RNA sequencing in the success of future drug discovery endeavors.
PMID:35158821 | DOI:10.3390/cancers14030552
Guanylin and uroguanylin: a promising nexus in intestinal electrolyte and fluid homeostasis
J Physiol Pharmacol. 2021 Oct;72(5). doi: 10.26402/jpp.2021.5.02. Epub 2021 Feb 12.
ABSTRACT
Intestinal guanyl peptides like guanylin and uroguanylin are the potent regulators of fluid-ion homeostasis. They are secreted from various cells of the intestinal mucosa, including enterochromaffin cells, epithelial cells, goblet cells, Paneth cells and others. These peptide hormones serve as ligands for receptor guanylyl cyclase-C (GC-C), which produces intracellular cyclic guanosine monophosphate (cGMP) and activates protein kinase G II (PKGII). cGMP/PKGII activates cystic fibrosis transmembrane conductance regulator for anion transport to the intestinal lumen, inhibits Na+/H+ exchanger that restricts H+ secretion and Na+ absorption, resulting in the retention of luminal fluid. These functions maintain intestinal pH, prevents hypernatremia and unwanted hypervolemic shock. Additionally, fluid balance in the intestine preserves the hydrated state of the colonic mucus that influences the growth of the commensal microorganisms and bowel clearance. Moreover, GC-C/cGMP signaling is involved in the regulation of intestinal barrier integrity, epithelial cell renewal, cell cycle, DNA damage repair, inflammatory responses, epithelial-mesenchymal transition and cancer progression. Impairment of GC-C activation causes functional gastrointestinal disorders, inflammatory bowel disease, visceral pain and colorectal cancer, suggesting that oral supplementation of guanyl peptide analogs (linaclotide, plecanatide) may prove useful for the treatment of these diseases.
PMID:35158329 | DOI:10.26402/jpp.2021.5.02
CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system
Mol Syst Biol. 2022 Feb;18(2):e10629. doi: 10.15252/msb.202110629.
ABSTRACT
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a chloride and bicarbonate channel in secretory epithelia with a critical role in maintaining fluid homeostasis. Mutations in CFTR are associated with Cystic Fibrosis (CF), the most common lethal autosomal recessive disorder in Caucasians. While remarkable treatment advances have been made recently in the form of modulator drugs directly rescuing CFTR dysfunction, there is still considerable scope for improvement of therapeutic effectiveness. Here, we report the application of a high-throughput screening variant of the Mammalian Membrane Two-Hybrid (MaMTH-HTS) to map the protein-protein interactions of wild-type (wt) and mutant CFTR (F508del), in an effort to better understand CF cellular effects and identify new drug targets for patient-specific treatments. Combined with functional validation in multiple disease models, we have uncovered candidate proteins with potential roles in CFTR function/CF pathophysiology, including Fibrinogen Like 2 (FGL2), which we demonstrate in patient-derived intestinal organoids has a significant effect on CFTR functional expression.
PMID:35156780 | DOI:10.15252/msb.202110629
REAL-world clinical effectiveness of ivacaftor therapy in the first 24 months in two infants with cystic fibrosis and different gating mutations-A case report
Clin Case Rep. 2022 Feb 10;10(2):e05364. doi: 10.1002/ccr3.5364. eCollection 2022 Feb.
ABSTRACT
This study summarizes efficacy of ivacaftor treatment in 2 infants in a real-world setting. A distinct decline of sweat chloride and lung clearance index plus increase in fecal elastase was seen. The results underline the early and sustainable effect and give cause for discussing whether a reduction in standard cystic fibrosis therapy is possible.
PMID:35154718 | PMC:PMC8829656 | DOI:10.1002/ccr3.5364