17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2020/12/17

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The first report of Methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patients in Saudi Arabia.

Int J Pediatr Adolesc Med. 2020 Dec;7(4):186-190

Authors: Banjar H, Al-Qahtani H, Yasin W, Al-Wgait W, Al-Amer H, Raja R, Al-Nakhli A, Karkour K

Abstract
Introduction: Methicillin-resistant Staphylococcus aureus infections have been increasingly reported in patients with cystic fibrosis (CF) who have progressive deterioration in their pulmonary function.
Objectives: To determine the prevalence of MRSA infections in CF in a tertiary care center in Saudi Arabia.
Methodology: This is a retrospective chart review conducted as part of the CF registry data from 1 January 2002 to 1 June 2016. All patients with confirmed CF of all age groups who had a respiratory culture positive for MRSA were included in the study.
Results: Among 385 patients with CF who had respiratory samples, 43 (11%) were positive for MRSA at a mean age of 10.4 ± 7.2 years. Twenty-two patients out of the 43 (51%) were treated with different regimens: nasal Bactroban in 13/22 (59%); a combination of nasal Bactroban, oral vancomycin, and rifampicin for 2 weeks in 5 patients (23%); Bactroban and linezolid in one patient (5%); and oral vancomycin and rifampicin in 3 patients (14%). Eight out of the 22 treated patients (36%) achieved MRSA eradication. Six out of the 22 treated (27%) had experienced MRSA recurrence within 3-6 months, and another 5/22 (23%) continued to have MRSA colonization up to 2-4 years of follow-up despite using a proper eradication protocol. Twelve out of the 43 (28%) patients with MRSA infection died.
Conclusion: MRSA infection in our population with CF is common. Therefore, an eradication protocol should be instituted at an early stage to prevent chronic colonization. Children with persistent MRSA colonization have high morbidity and mortality rate.

PMID: 33319017 [PubMed]

Antimicrobial Susceptibility Testing in Pseudomonas aeruginosa Biofilms: One Step Closer to a Standardized Method.

Antibiotics (Basel). 2020 Dec 09;9(12):

Authors: Lozano C, López M, Rojo-Bezares B, Sáenz Y

Abstract
The ability of Pseudomonas aeruginosa to form biofilm during a long-term infection makes it difficult to treat patients correctly. The current clinical antimicrobial susceptibility testing methods are based on the study of planktonic strains. A standardized protocol to analyze the antimicrobial susceptibility in biofilms is necessary for routine laboratories. The aims of this study were to develop a simple biofilm model and to study the antimicrobial susceptibility of P. aeruginosa strains in biofilm growth. Different artificial sputum media, and aerobiosis and microaerobiosis conditions were analyzed using a microtiter plate method and P. aeruginosa PAO1 as reference strain. Planktonic and biofilm antimicrobial susceptibility to cefepime, imipenem, azithromycin, gentamicin, tobramycin, and ciprofloxacin were determined in clinical and non-clinical P. aeruginosa strains. The Synthetic Cystic Fibrosis Medium was proposed as a good medium. The biofilm greatly increased the resistance to tested antimicrobials, except for azithromycin. Cefepime and imipenem showed poor anti-biofilm effect while tobramycin, gentamicin, and ciprofloxacin showed good activity in some strains. Azithromycin showed a better activity in biofilm than in planktonic state when aerobic conditions were used. This study establishes useful information to test antimicrobial susceptibility in P. aeruginosa biofilms, and includes possible antimicrobial options to treat long-term infected patients.

PMID: 33316877 [PubMed]

Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia.

Am J Respir Crit Care Med. 2020 Dec 15;:

Authors: Okuda K, Dang H, Kobayashi Y, Carraro G, Nakano S, Chen G, Kato T, Asakura T, Gilmore RC, Morton LC, Lee RE, Mascenik T, Yin WN, Barbosa Cardenas SM, O'Neal YK, Minnick CE, Chua M, Quinney NL, Gentzsch M, Anderson CW, Ghio A, Matsui H, Nagase T, Ostrowski LE, Grubb BR, Olsen JC, Randell SH, Stripp BR, Tata PR, O'Neal WK, Boucher RC

Abstract
RATIONALE: Identification of the specific cell types expressing CFTR is required for precision medicine therapies for cystic fibrosis (CF). However, a full characterization of CFTR expression in normal human airway epithelia is missing.
OBJECTIVES: To identify the cell types that contribute to CFTR expression and function within the proximal-distal axis of the normal human lung.
METHODS: Single cell RNA-seq (scRNA-seq) was performed on freshly isolated human large and small airway epithelial cells. Single cell-based RNA in situ hybridization (scRNA-ISH) and quantitative RT-PCR (scqRT-PCR) were performed for validation. In vitro culture systems correlated CFTR function to cell types. Lentiviruses were used for cell-type specific transduction of wild-type CFTR in CF cells.
MEASUREMENTS AND MAIN RESULTS: scRNA-seq identified secretory cells as dominating CFTR expression in normal human large and particularly small airway superficial epithelia, followed by basal cells. Ionocytes expressed the highest CFTR levels but were rare, while expression in ciliated cells was infrequent and low. scRNA-ISH, and scqRT-PCR confirmed the scRNA-seq findings. CF lungs exhibited distributions of CFTR and ionocytes similar to normal controls. CFTR-mediated Cl- secretion in culture tracked secretory cell, not ionocyte, densities. Further, the nucleotide-purinergic regulatory system that controls CFTR-mediated hydration was associated with secretory cells, and not ionocytes. Lentiviral transduction of wild-type CFTR produced CFTR-mediated Cl- secretion in CF airway secretory cells but not ciliated cells.
CONCLUSIONS: Secretory cells dominate CFTR expression and function in human airway superficial epithelia. CFTR therapies may need to restore CFTR function to multiple cell types, with a focus on secretory cells.

PMID: 33321047 [PubMed - as supplied by publisher]

The human respiratory tract microbial community structures in healthy and cystic fibrosis infants.

NPJ Biofilms Microbiomes. 2020 Dec 15;6(1):61

Authors: Pust MM, Wiehlmann L, Davenport C, Rudolf I, Dittrich AM, Tümmler B

Abstract
The metagenome development of the human respiratory tract was investigated by shotgun metagenome metagenomic sequencing of cough swabs from healthy children and children with cystic fibrosis (CF) between 3 weeks and 6 years of age. A healthy microbial community signature was associated with increased absolute abundances in terms of bacterial-human cell ratios of core and rare species across all age groups, with a higher diversity of rare species and a tightly interconnected species co-occurrence network, in which individual members were found in close proximity to each other and negative correlations were absent. Even without typical CF pathogens, the CF infant co-occurrence network was found to be less stable and prone to fragmentation due to fewer connections between species, a higher number of bridging species and the presence of negative species correlations. Detection of low-abundant DNA of the CF hallmark pathogen Pseudomonas aeruginosa was neither disease- nor age-associated in our cohort. Healthy and CF children come into contact with P. aeruginosa on a regular basis and from early on.

PMID: 33319812 [PubMed - in process]

Mrr1 regulation of methylglyoxal catabolism and methylglyoxal-induced fluconazole resistance in Candida lusitaniae.

Mol Microbiol. 2020 Dec 14;:

Authors: Biermann AR, Demers EG, Hogan DA

Abstract
Transcription factor Mrr1, best known for its regulation of Candida azole resistance genes such as MDR1, regulates other genes that are poorly characterized. Among the other Mrr1-regulated genes are putative methylglyoxal reductases. Methylglyoxal (MG) is a toxic metabolite that is elevated in diabetes, uremia, and sepsis, which are diseases that increase the risk for candidiasis, and MG serves as a regulatory signal in diverse organisms. Our studies in Clavispora lusitaniae, also known as Candida lusitaniae, showed that Mrr1 regulates expression of two paralogous MG reductases, MGD1 and MGD2, and that both participate in MG resistance and MG catabolism. Exogenous MG increased Mrr1-dependent expression of MGD1 and MGD2 as well as expression of MDR1, which encodes an efflux pump that exports fluconazole. MG improved growth in the presence of fluconazole and this was largely Mrr1-dependent with contributions from a secondary transcription factor, Cap1. Increased fluconazole resistance was also observed in mutants lacking Glo1, a Mrr1-independent MG catabolic enzyme. Isolates from other Candida species displayed heterogeneity in MG resistance and MG stimulation of azole resistance. We propose endogenous and host-derived MG can induce MDR1 and other Mrr1-regulated genes causing increased drug resistance, which may contribute to some instances of fungal treatment failure.

PMID: 33319423 [PubMed - as supplied by publisher]

Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease.

Sci Rep. 2020 Dec 14;10(1):21900

Authors: Verstegen MMA, Roos FJM, Burka K, Gehart H, Jager M, de Wolf M, Bijvelds MJC, de Jonge HR, Ardisasmita AI, van Huizen NA, Roest HP, de Jonge J, Koch M, Pampaloni F, Fuchs SA, Schene IF, Luider TM, van der Doef HPJ, Bodewes FAJA, de Kleine RHJ, Spee B, Kremers GJ, Clevers H, IJzermans JNM, Cuppen E, van der Laan LJW

Abstract
The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.

PMID: 33318612 [PubMed - in process]

In vitro antibacterial activity and in vivo efficacy of sulbactam-durlobactam against pathogenic Burkholderia species.

Antimicrob Agents Chemother. 2020 Dec 14;:

Authors: Papp-Wallace KM, Shapiro AB, Becka SA, Zeiser ET, LiPuma JJ, Lane DJ, Panchal RG, Mueller JP, O'Donnell JP, Miller AA

Abstract
The Gram-negative bacterial genus Burkholderia includes several hard-to-treat human pathogens: two biothreat species, B. mallei (causing glanders) and B. pseudomallei (causing melioidosis), and the B. cepacia complex (BCC) and B. gladioli, which cause chronic lung infections in persons with cystic fibrosis. All Burkholderia spp possess an Ambler class A Pen β-lactamase, which confers resistance to β-lactams. The β-lactam-β-lactamase inhibitor combination sulbactam-durlobactam (SUL-DUR) is in clinical development for the treatment of Acinetobacter infections. Herein, we evaluated SUL-DUR for in vitro and in vivo activity against Burkholderia clinical isolates. We measured minimal inhibitory concentrations (MICs) of SUL-DUR against BCC and B. gladioli (N = 150), B. mallei (N = 30) and B. pseudomallei (N = 28); studied the kinetics of inhibition of the PenA1 β-lactamase from B. multivorans and the PenI β-lactamase from B pseudomallei by durlobactam; tested for bla PenA1 induction by SUL-DUR; and evaluated in vivo efficacy in a mouse model of melioidosis. SUL-DUR inhibited growth of 87.3% of the BCC and B. gladioli strains and 100% of the B. mallei and B. pseudomallei strains at 4/4 μg/mL. Durlobactam potently inhibited PenA1 and PenI with k2/K values of 3.9 x 106 M-1s-1 and 2.6 x 103 M-1s-1 and Ki app of 15 nM and 241 nM, respectively, by forming highly stable covalent complexes. Neither sulbactam, durlobactam, nor SUL-DUR increased production of PenA1. SUL-DUR demonstrated activity in vivo in a murine melioidosis model. Taken together, these data suggest SUL-DUR may be useful as a treatment for Burkholderia infections.

PMID: 33318017 [PubMed - as supplied by publisher]

Burkholderia ubonensis high-level tetracycline resistance is due to efflux pump synergy involving a novel TetA(64) resistance determinant.

Antimicrob Agents Chemother. 2020 Dec 14;:

Authors: Somprasong N, Hall CM, Webb JR, Sahl JW, Wagner DM, Keim P, Currie BJ, Schweizer HP

Abstract
Burkholderia ubonensis, a non-pathogenic soil bacterium belonging to the Burkholderia cepacia complex (Bcc), is highly resistant to some clinically significant antibiotics. The concern is that B. ubonensis may serve as a resistance reservoir for Bcc or B. pseudomallei complex (Bpc) organisms that are opportunistic human pathogens. Using a B. ubonensis strain highly resistant to tetracycline (MIC ≥256 μg/ml), we identified and characterized tetA(64) that encodes a novel tetracycline-specific efflux pump of the major facilitator superfamily. TetA(64) and associated TetR(64) regulator expression is induced by tetracyclines. Although TetA(64) is the primary tetracycline and doxycycline resistance determinant, maximum tetracycline and doxycycline resistance requires synergy between TetA(64) and the non-specific AmrAB-OprA resistance nodulation cell division efflux pump. TetA(64) does not efflux minocycline, tigecycline and eravacycline. Comprehensive screening of genome sequences showed that TetA(64) is unequally distributed in the Bcc and absent from the Bpc. It is present in some major cystic fibrosis pathogens, like B. cenocepacia, but absent from others like B. multivorans The tetR(64)-tetA(64) genes are located in a region of chromosome 1 that is highly conserved in Burkholderia Because there is no evidence for transposition, the tetR(64)-tetA(64) genes may have been acquired by homologous recombination after horizontal gene transfer. Although Burkholderia species contain a resident multi-component efflux pump that allows them to respond to tetracyclines up to a certain concentration, the acquisition of the single-component TetA(64) by some species likely provides the synergy that these bacteria need to defend against high tetracycline concentrations in niche environments.

PMID: 33318011 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa Susceptibility Patterns and Associated Clinical Outcomes in People with Cystic Fibrosis following Approval of Aztreonam Lysine for Inhalation.

Antimicrob Agents Chemother. 2020 Dec 14;:

Authors: Keating CL, Zuckerman JB, Singh PK, McKevitt M, Gurtovaya O, Bresnik M, Marshall BC, Saiman L, CFFPR-AZLI Study Group

Abstract
Rationale: Approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect susceptibility profiles of Pseudomonas aeruginosa (PA) isolates from cystic fibrosis (CF) patients.Objective: This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic PA infection.Methods: Sputum cultures were collected annually (2011-2016). The primary study endpoint was the proportion of subjects whose least susceptible PA isolate had an aztreonam minimum inhibitory concentration (MIC) that was >8 μg/mL (parenteral breakpoint) and increased ≥4-fold compared with the least susceptible isolate from the previous year. Annualized data for pulmonary exacerbations, hospitalizations, and FEV1% predicted were obtained from the CF Foundation Patient Registry and compared between subjects meeting/not meeting the primary endpoint.Results: 510 subjects were enrolled; 334 (65%) completed the study. A consistent proportion of evaluable subjects (13-22%) met the primary endpoint each year; and AZLI use during the previous 12 months was not associated with meeting the primary endpoint. While the annual decline in lung function was comparable for subjects meeting/not meeting the primary endpoint, more pulmonary exacerbations and hospitalizations were experienced by those who met it.Conclusions: Aztreonam susceptibility of PA remained consistent during the 5-year study. The relationship between PA isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with accelerated decline in lung function, but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure.

PMID: 33318007 [PubMed - as supplied by publisher]

33 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2020/12/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

27 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2020/12/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Inhaled tobramycin for chronic infection with pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis: A systematic review and meta-analysis.

Respir Med. 2020 Dec 05;176:106283

Authors: Sangiovanni S, Morales EI, Fernández-Trujillo L

Abstract
INTRODUCTION: Non-cystic fibrosis bronchiectasis (NCFBE) is a chronic and progressive disease characterized by the permanent destruction of small and mid-sized airways. Many patients are chronically colonized by Pseudomona aueruginosa, for which oral antibiotics are given. Evidence to support the use of inhaled antibiotics is contradictory.
OBJECTIVE: To describe the clinical effects of inhaled Tobramycin in P. aeruginosa density in sputum and eradication, lung function, bacterial resistance, and exacerbations requiring hospital admission, in the context of patients with NCFBE colonized by P. aeruginosa.
METHODS: We included RCTs comparing inhaled tobramycin to other antibiotics and placebo in patients with NCFBE.
MAIN FINDINGS: 5 studies with 211 participants were included. 2 studies reported a significant but transitory decrease in P. aeruginosa density in sputum as compared to placebo. There was a small difference in the eradication of P. aeruginosa among groups, although with very wide confidence intervals. Tobramycin reduced the rate of hospital admissions but no frequency of exacerbations. There was no evidence of an increased rate of bacterial resistance but was associated to respiratory adverse effects.
CONCLUSIONS: Evidence is not robust enough to confirm a benefit of inhaled Tobramycin in reducing P. aeruginosa sputum density or eradication. There was a high attrition rate, in part due to respiratory adverse events after drug administration, which affects interpretation of the data and raises concerns about the tolerability of the drug. Further network meta-analysis should be done to compare the efficacy and safety of different inhaled antibiotics.

PMID: 33307314 [PubMed - as supplied by publisher]

Romantic Relationships in Young People with Long-Term Health Conditions: A Scoping Review.

J Pediatr Psychol. 2020 Dec 11;:

Authors: Jordan A, Carter B, Forgeron P, Fournier K, Sanders K

Abstract
OBJECTIVE: Forming and maintaining romantic relationships is an important developmental task in adolescence and young adulthood. This scoping review seeks to explore how young people with long-term physical health conditions understand and experience romantic relationships.
METHODS: Using Arksey and O'Malley's scoping review framework, a systematic search of five databases was conducted (PsychINFO, Cinahl, MEDLINE, Embase, and Web of Science). Studies were eligible for inclusion in the review if they were published in peer-reviewed journals, used primary data collection methods, and adopted quantitative, qualitative, or mixed-methods approaches to study romantic relationships in 11-25 year olds with long-term physical health conditions. Using a data extraction form, data pertaining to demographic characteristics of young people with long-term physical health conditions and relationship engagement were extracted from eligible papers.
RESULTS: Searches returned 4645 papers after duplicate removal, with a two-stage screening process resulting in 111 full-text papers being reviewed. Thirty-three eligible papers were included across a range of long-term physical health conditions. Findings identified that living with a long-term physical health condition impacted young people's perceptions and experiences of romantic relationships across the relationship lifespan, from envisaging future relationships, to forming relationships, and sustaining relationships. Issues around body confidence and self-esteem were identified as challenging in terms of perceptions and experiences of romantic relationships.
CONCLUSIONS: Findings demonstrate that young people wish to engage with romantic relationships, yet many report particular challenges associated with forming and sustaining relationships due to the constraints of their condition and treatment. Future research should consider nonheterosexual relationships.

PMID: 33306805 [PubMed - as supplied by publisher]

Reciprocal Links Between Physical Health and Coping Among Adolescents With Cystic Fibrosis.

J Pediatr Psychol. 2020 Dec 11;:

Authors: D'Angelo CM, Mrug S, Grossoehme D, Leon K, Thomas L, Troxler B

Abstract
OBJECTIVE: Adolescents with cystic fibrosis (CF) often face a unique set of difficulties and challenges as they transition to adulthood and autonomy while also managing a progressive illness with a heavy treatment burden. Coping styles have been related to changes in physical health among youth with chronic illness more generally, but the directionality of these links has not been fully elucidated. Therefore, the objective of this study was to evaluate bidirectional links between coping styles and physical health indicators among adolescents with CF over time.
METHODS: Adolescents (N = 79, 54% female) recruited from inpatient and outpatient CF clinics at two sites completed questionnaires assessing secular and religious/spiritual coping styles at two time points (18 months apart, on average). Health indicators including pulmonary functioning, nutritional status, and days hospitalized were obtained from medical records.
RESULTS: More frequent hospitalizations predicted lower levels of adaptive secular coping over time. However, poorer pulmonary functioning predicted higher levels of positive religious/spiritual coping. The number of days hospitalized was related to adaptive secular coping and negative religious/spiritual coping.
CONCLUSIONS: Among youth with CF, physical health functioning is more consistent in predicting coping strategies than the reverse. Poorer pulmonary functioning appears to enhance adaptive coping over time, suggesting resilience of adolescents with CF, while more frequent hospitalizations may inhibit the use of adaptive coping strategies. Findings support the use of interventions aimed at promoting healthy coping among hospitalized adolescents with CF.

PMID: 33306793 [PubMed - as supplied by publisher]

The impact of liver disease on mortality in cystic fibrosis - a systematic review protocol.

HRB Open Res. 2020;3:44

Authors: Sasame A, Connolly L, Fitzpatrick E, Stokes D, Bourke B, Rowland M

Abstract
Background Cystic fibrosis (CF) is a multiorgan disease affecting the lungs pancreas and gastrointestinal tract. Pulmonary complications are the most common clinical manifestation of the disease. Recent advances in the treatment of pulmonary complications have resulted in substantial improvement in life expectancy. Less than 10% of persons with CF (PWCF) develop liver disease (CFLD). There is conflicting evidence as to the impact of liver disease on mortality in CF, with evidence suggesting that CFLD contributes to increased mortality in CF, while other studies suggest that the impact on mortality is limited. Understanding the contribution of liver disease to mortality in CF is essential if further improvements in life expectancy are to be achieved. Objective: To document the impact of liver disease on life expectancy for PWCF. Methods: This systematic review will be conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P 2015). PubMed, Medline and Embase will be searched for English language publications between 1949 and 2020 reporting liver related and all-cause mortality in CF. Observational studies that use an unambiguous definition of liver disease in well-defined CF populations will be included. Studies with and without a comparator will be evaluated. Clinical trials of ursodeoxycholic acid will be excluded as well as organ transplantation outcome studies. The ROBINS-1 risk of bias tool for non-randomised studies will be used to evaluate the quality of the studies. We will provide a narrative synthesis of our findings using tabular formats to highlight any impact of liver disease on mortality in CF. Conclusion: It is anticipated that this review will bring clarity to the question of whether CFLD shortens life expectancy in PWCF and stimulate new approaches to the management of CFLD. Registration: This protocol has been submitted for registration on PROSPERO and is awaiting review.

PMID: 33305166 [PubMed]

Small interfering RNA for cancer treatment: overcoming hurdles in delivery.

Acta Pharm Sin B. 2020 Nov;10(11):2075-2109

Authors: Charbe NB, Amnerkar ND, Ramesh B, Tambuwala MM, Bakshi HA, Aljabali AAA, Khadse SC, Satheeshkumar R, Satija S, Metha M, Chellappan DK, Shrivastava G, Gupta G, Negi P, Dua K, Zacconi FC

Abstract
In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies.

PMID: 33304780 [PubMed]

Mepolizumab use in cystic fibrosis-associated allergic bronchopulmonary aspergillosis.

Respirol Case Rep. 2021 Jan;9(1):e00696

Authors: Boyle M, Mulrennan S, Morey S, Vekaria S, Popowicz N, Tai A

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) is common in cystic fibrosis (CF). Treatment is challenging and the relapse rate is high. Standard therapy is oral steroids and antifungals. However, long-term systemic steroid often results in adverse effects and drug interactions between azoles and CFTR modulators are a potential concern. Mepolizumab, an anti-interleukin (IL)-5 monoclonal antibody, can benefit patients with severe eosinophilic asthma and there are reports of mepolizumab use in ABPA but not in ABPA complicating CF. We present the case of an adult with CF who had recurrent ABPA and intolerable treatment side effects with steroid, azole, and omalizumab. Mepolizumab was well tolerated and led to significantly improved clinical stability and symptomatic improvement. To our knowledge, this is the first report of successful mepolizumab treatment for ABPA in CF. Mepolizumab may be an important adjunctive treatment for difficult to control ABPA in CF.

PMID: 33304594 [PubMed]

(R)-Roscovitine and CFTR modulators enhance killing of multi-drug resistant Burkholderia cenocepacia by cystic fibrosis macrophages.

Sci Rep. 2020 Dec 10;10(1):21700

Authors: Shrestha CL, Zhang S, Wisniewski B, Häfner S, Elie J, Meijer L, Kopp BT

Abstract
Cystic fibrosis (CF) is characterized by chronic bacterial infections and heightened inflammation. Widespread ineffective antibiotic use has led to increased isolation of drug resistant bacterial strains from respiratory samples. (R)-roscovitine (Seliciclib) is a unique drug that has many benefits in CF studies. We sought to determine roscovitine's impact on macrophage function and killing of multi-drug resistant bacteria. Human blood monocytes were isolated from CF (F508del/F508del) and non-CF persons and derived into macrophages (MDMs). MDMs were infected with CF clinical isolates of B. cenocepacia and P. aeruginosa. MDMs were treated with (R)-roscovitine or its main hepatic metabolite (M3). Macrophage responses to infection and subsequent treatment were determined. (R)-roscovitine and M3 significantly increased killing of B. cenocepacia and P. aeruginosa in CF MDMs in a dose-dependent manner. (R)-roscovitine-mediated effects were partially dependent on CFTR and the TRPC6 channel. (R)-roscovitine-mediated killing of B. cenocepacia was enhanced by combination with the CFTR modulator tezacaftor/ivacaftor and/or the alternative CFTR modulator cysteamine. (R)-roscovitine also increased MDM CFTR function compared to tezacaftor/ivacaftor treatment alone. (R)-roscovitine increases CF macrophage-mediated killing of antibiotic-resistant bacteria. (R)-roscovitine also enhances other macrophage functions including CFTR-mediated ion efflux. Effects of (R)-roscovitine are greatest when combined with CFTR modulators or cysteamine, justifying further clinical testing of (R)-roscovitine or optimized derivatives.

PMID: 33303916 [PubMed - in process]

IL-17A from innate and adaptive lymphocytes contributes to inflammation and damage in cystic fibrosis lung disease.

Eur Respir J. 2020 Dec 10;:

Authors: Hagner M, Albrecht M, Guerra M, Braubach P, Halle O, Zhou-Suckow Z, Butz S, Jonigk D, Hansen G, Schultz C, Dittrich AM, Mall MA

Abstract
BACKGROUND: Elevated levels of IL-17A were detected in the airways of patients with cystic fibrosis (CF), but its cellular sources and role in the pathogenesis of CF lung disease remain poorly understood. The aim of this study was to determine the sources of IL-17A and its role in airway inflammation and lung damage in CF.
METHODS: We performed flow cytometry to identify IL-17A-producing cells in lungs and peripheral blood from CF patients and β-epithelial Na+ channel transgenic (Scnn1b-Tg) mice with CF-like lung disease and determined effects of genetic deletion of Il17a and Rag1 on the pulmonary phenotype of Scnn1b-Tg mice.
RESULTS: T helper (Th)17 cells, CD3+CD8+, γδ T cells, invariant natural killer T cells (iNKT) and innate lymphoid cells (ILCs) contribute to IL-17A secretion in lung tissue, lymph nodes and peripheral blood of patients with CF. Scnn1b-Tg mice displayed increased pulmonary expression of Il17a and elevated IL-17A-producing innate and adaptive lymphocytes with a major contribution by γδ T cells. Lack of IL-17A, but not RAG1 reduced neutrophilic airway inflammation in Scnn1b-Tg mice. Genetic deletion of Il17a or Rag1 had no effect on mucus obstruction, but reduced structural lung damage and revealed an IL-17A-dependent macrophage activation in Scnn1b-Tg mice.
CONCLUSION: We identify innate and adaptive sources of IL-17A in CF lung disease. Our data demonstrate that IL-17A contributes to airway neutrophilia, macrophage activation and structural lung damage in CF-like lung disease in mice. These results suggest IL-17A as a novel target for anti-inflammatory therapy of CF lung disease.

PMID: 33303549 [PubMed - as supplied by publisher]