Improvement of Pulmonary Function in Cystic Fibrosis Patients following Endoscopic Sinus Surgery.

Laryngoscope. 2021 Feb 04;:

Authors: Kawai K, Dombrowski N, Sawicki GS, Adil EA

Abstract
OBJECTIVE/HYPOTHESIS: To compare pre-and post-operative pulmonary function relative to disease severity in cystic fibrosis (CF) patients following endoscopic sinus surgery (ESS).
STUDY DESIGN: Retrospective chart review.
METHODS: Patients with CF who underwent ESS between January 1996 and July 2018 were identified, with subsequent study exclusions based upon surgical indications or incomplete records. CF disease severity was based upon percentage predicted of forced expiratory volume in 1 second (%FEV1) with <40% considered severe disease, 40% to 70% as moderate disease, and >70% as mild disease. The changes in %FEV1 before and after ESS were examined using multivariable mixed-effects models controlling for age, gender, genotype, medications, nutritional status, diabetes status, microbiology results, extent of surgery, and number of surgeries.
RESULTS: A total of 427 surgeries were performed in 188 patients during the study period. Mean age at first ESS was 12.7 years (SD 6.0 years, range 4-38) and 54.8% were females. The effect of ESS varied by severity of lung disease. After surgery, %FEV1 increased by 8.1% (95% CI: 2.3, 13.9%) among patients with severe lung disease and by 3.0% (95% CI: 0.7, 5.2%) among patients with moderate disease. %FEV1 also increased by 7.3% (95% CI: 4.2, 10.5%) among patients with mild disease whose %FEV1 value was 70% to 80% at baseline. No improvement was observed in patients with a baseline %FEV1 >80%.
CONCLUSIONS: When controlling for important confounding factors, lung function improved following ESS among CF patients with severe and moderate disease and in select patients with mild disease. This improvement was sustained at 12 months following surgery.
LEVEL OF EVIDENCE: 4 Laryngoscope, 2021.

PMID: 33538334 [PubMed - as supplied by publisher]

Intestinal TMEM16A control luminal chloride secretion in a NHERF1 dependent manner.

Biochem Biophys Rep. 2021 Mar;25:100912

Authors: Saha T, Aoun J, Hayashi M, Ali SI, Sarkar P, Bag PK, Leblanc N, Ameen N, Woodward OM, Hoque KM

Abstract
TMEM16A (Transmembrane protein 16A or Anoctamin1) is a calcium-activated chloride channel. (CaCC),that exerts critical roles in epithelial secretion. However, its localization, function, and regulation in intestinal chloride (Cl-) secretion remain obscure. Here, we show that TMEM16A protein abundance correlates with Cl- secretion in different regions of native intestine activated by the Ca2+-elevating muscarinic agonist carbachol (CCH). Basal, as well as both cAMP- and CCH-stimulated Isc, was largely reduced in Ano1 ± mouse intestine. We found CCH was not able to increase Isc in the presence of apical to serosal Cl- gradient, strongly supporting TMEM16A as primarily a luminal Cl- channel. Immunostaining demonstrated apical localization of TMEM16A where it colocalized with NHERF1 in mouse colonic tissue. Cellular depletion of NHERF1 in human colonic T84 cells caused a significant reduction of both cAMP- and CCH-stimulated Isc. Immunoprecipitation experiments revealed that NHERF1 forms a complex with TMEM16A through a PDZ-based interaction. We conclude that TMEM16A is a luminal Cl- channel in the intestine that functionally interacts with CFTR via PDZ-based interaction of NHERF1 for efficient and specific cholinergic stimulation of intestinal Cl- secretion.

PMID: 33537462 [PubMed]

Gender-affirming hormone therapy in cystic fibrosis - A case of new Pseudomonas infection.

Respir Med Case Rep. 2021;32:101353

Authors: Shaffer L, Bozkanat K, Lau M, Sharma P, Sathe M, Lopez X, Jain R

Abstract
Background: Little is known about the impact of hormone therapy on transgender youth with Cystic Fibrosis (CF). This case report describes an 18-year-old affirmed female with CF who was treated with hormone therapy associated in timing with new growth of Pseudomonas aeruginosa in her sputum culture.
Discussion: We highlight important considerations, including the impact of gender-affirming hormone therapy on overall CF disease course. Evidence supports that females with CF have worse outcomes than males, which are partly attributed to estrogen effects. Pseudomonas aeruginosa is one of the most prevalent pathogens in people with CF. Here, we highlight a transfemale who grows Pseudomonas aeruginosa for the first time since her youth, nearly 1 year after starting estrogen therapy. This is consistent with previous literature of an association between high estrogen levels and Pseudomonas aeruginosa prevalence, but has never been evaluated in a transgender population.
Conclusion: Through this case, we demonstrate the need for additional research to understand the relationship between gender-affirmative hormone transition and CF care and management.

PMID: 33537203 [PubMed]

Considerations for Phage Therapy Against Mycobacterium abscessus.

Front Microbiol. 2020;11:609017

Authors: Senhaji-Kacha A, Esteban J, Garcia-Quintanilla M

Abstract
There is a global increasing number of Mycobacterium abscessus infections, especially pulmonary infections. Reduced therapeutic options exist against this opportunistic pathogen due to its high intrinsic and acquired levels of antibiotic resistance. Phage therapy is a promising afresh therapy, which uses viruses to lyse bacteria responsible for the infection. Bacteriophages have been recently administered under compassionate use to a 15-year-old patient infected with M. abscessus in combination with antibiotics with excellent results. This mini review highlights different recommendations for future phage administrations such as where to look for new phages, the use of cocktail of mycobacteriophages to broaden phage specificity and to tackle resistance and phage insensitivity due to temperate phages present in bacterial genomes, the combined use of phages and antibiotics to obtain a synergistic effect, the liposomal administration to reach a prolonged effect, intracellular delivery and protection against neutralizing antibodies, and the convenience of using this strategy in patients suffering from cystic fibrosis (CF) since phages are believed to promote immunomodulatory actions and eliminate biofilms.

PMID: 33537013 [PubMed]

Interspecies Metabolic Complementation in Cystic Fibrosis Pathogens via Purine Exchange.

Pathogens. 2021 Feb 01;10(2):

Authors: Al Mahmud H, Baishya J, Wakeman CA

Abstract
Cystic fibrosis (CF) is a genetic disease frequently associated with chronic lung infections caused by a consortium of pathogens. It is common for auxotrophy (the inability to biosynthesize certain essential metabolites) to develop in clinical isolates of the dominant CF pathogen Pseudomonas aeruginosa, indicating that the CF lung environment is replete in various nutrients. Many of these nutrients are likely to come from the host tissues, but some may come from the surrounding polymicrobial community within the lungs of CF patients as well. To assess the feasibility of nutrient exchange within the polymicrobial community of the CF lung, we selected P. aeruginosa and Staphylococcus aureus, two of the most prevalent species found in the CF lung environment. By comparing the polymicrobial culture of wild-type strains relative to their purine auxotrophic counterparts, we were able to observe metabolic complementation occurring in both P. aeruginosa and S. aureus when grown with a purine-producing cross-species pair. While our data indicate that some of this complementation is likely derived from extracellular DNA freed by lysis of S. aureus by the highly competitive P. aeruginosa, the partial complementation of S. aureus purine deficiency by P. aeruginosa demonstrates that bidirectional nutrient exchange between these classic competitors is possible.

PMID: 33535659 [PubMed]

Serum N-Glycomics Stratifies Bacteremic Patients Infected with Different Pathogens.

J Clin Med. 2021 Feb 01;10(3):

Authors: Chatterjee S, Kawahara R, Tjondro HC, Shaw DR, Nenke MA, Torpy DJ, Thaysen-Andersen M

Abstract
Bacteremia-i.e., the presence of pathogens in the blood stream-is associated with long-term morbidity and is a potential precursor condition to life-threatening sepsis. Timely detection of bacteremia is therefore critical to reduce patient mortality, but existing methods lack precision, speed, and sensitivity to effectively stratify bacteremic patients. Herein, we tested the potential of quantitative serum N-glycomics performed using porous graphitized carbon liquid chromatography tandem mass spectrometry to stratify bacteremic patients infected with Escherichia coli (n = 11), Staphylococcus aureus (n = 11), Pseudomonas aeruginosa (n = 5), and Streptococcus viridans (n = 5) from healthy donors (n = 39). In total, 62 N-glycan isomers spanning 41 glycan compositions primarily comprising complex-type core fucosylated, bisecting N-acetylglucosamine (GlcNAc), and α2,3-/α2,6-sialylated structures were profiled across all samples using label-free quantitation. Excitingly, unsupervised hierarchical clustering and principal component analysis of the serum N-glycome data accurately separated the patient groups. P. aeruginosa-infected patients displayed prominent N-glycome aberrations involving elevated levels of fucosylation and bisecting GlcNAcylation and reduced sialylation relative to other bacteremic patients. Notably, receiver operating characteristic analyses demonstrated that a single N-glycan isomer could effectively stratify each of the four bacteremic patient groups from the healthy donors (area under the curve 0.93-1.00). Thus, the serum N-glycome represents a new hitherto unexplored class of potential diagnostic markers for bloodstream infections.

PMID: 33535571 [PubMed]

Clinical Implications of Polymicrobial Synergism Effects on Antimicrobial Susceptibility.

Pathogens. 2021 Feb 01;10(2):

Authors: Little W, Black C, Smith AC

Abstract
With the development of next generation sequencing technologies in recent years, it has been demonstrated that many human infectious processes, including chronic wounds, cystic fibrosis, and otitis media, are associated with a polymicrobial burden. Research has also demonstrated that polymicrobial infections tend to be associated with treatment failure and worse patient prognoses. Despite the importance of the polymicrobial nature of many infection states, the current clinical standard for determining antimicrobial susceptibility in the clinical laboratory is exclusively performed on unimicrobial suspensions. There is a growing body of research demonstrating that microorganisms in a polymicrobial environment can synergize their activities associated with a variety of outcomes, including changes to their antimicrobial susceptibility through both resistance and tolerance mechanisms. This review highlights the current body of work describing polymicrobial synergism, both inter- and intra-kingdom, impacting antimicrobial susceptibility. Given the importance of polymicrobial synergism in the clinical environment, a new system of determining antimicrobial susceptibility from polymicrobial infections may significantly impact patient treatment and outcomes.

PMID: 33535562 [PubMed]

DNAJB12 and Hsp70 Triage Arrested Intermediates of N1303K-CFTR for ER Associated-Autophagy.

Mol Biol Cell. 2021 Feb 03;:mbcE20110688

Authors: He L, Kennedy AS, Houck S, Aleksandrov A, Quinney NL, Cyr-Scully A, Cholon DM, Gentzsch M, Randell SH, Ren HY, Cyr DM

Abstract
The transmembrane Hsp40 DNAJB12 and cytosolic Hsp70 cooperate on the ER's cytoplasmic face to facilitate the triage of nascent polytopic membrane proteins for folding versus degradation. N1303K is a common mutation that causes misfolding of the ion channel CFTR, but unlike F508del-CFTR, biogenic and functional defects in N1303K-CFTR are resistant to correction by folding modulators. N1303K is reported to arrest CFTR folding at a late stage after partial assembly of its N-terminal domains. N1303K-CFTR intermediates are clients of JB12-Hsp70 complexes, maintained in a detergent soluble-state, and have a relatively long 3-hour half-life. ERAD-resistant pools of N1303K-CFTR are concentrated in ER-tubules that associate with autophagy initiation sites containing WIPI1, FlP200, and LC3. Destabilization of N1303K-CFTR or depletion of JB12 prevents entry of N1303K-CFTR into the membranes of ER-connected phagophores and traffic to autolysosomes. In contrast, the stabilization of intermediates with the modulator VX-809 promotes the association of N1303K-CFTR with autophagy initiation machinery. N1303K-CFTR is excluded from the ER-exit sites, and its passage from the ER to autolysosomes does not require ER-phagy receptors. DNAJB12 operates in biosynthetically active ER-microdomains to triage membrane protein intermediates in a conformation-specific manner for secretion versus degradation via ERAD or selective-ER-associated autophagy.

PMID: 33534640 [PubMed - as supplied by publisher]

Large pH oscillations promote host defense against human airways infection.

J Exp Med. 2021 Apr 05;218(4):

Authors: Kim D, Liao J, Scales NB, Martini C, Luan X, Abu-Arish A, Robert R, Luo Y, McKay GA, Nguyen D, Tewfik MA, Poirier CD, Matouk E, Ianowski JP, Frenkiel S, Hanrahan JW

Abstract
The airway mucosal microenvironment is crucial for host defense against inhaled pathogens but remains poorly understood. We report here that the airway surface normally undergoes surprisingly large excursions in pH during breathing that can reach pH 9.0 during inhalation, making it the most alkaline fluid in the body. Transient alkalinization requires luminal bicarbonate and membrane-bound carbonic anhydrase 12 (CA12) and is antimicrobial. Luminal bicarbonate concentration and CA12 expression are both reduced in cystic fibrosis (CF), and mucus accumulation both buffers the pH and obstructs airflow, further suppressing the oscillations and bacterial-killing efficacy. Defective pH oscillations may compromise airway host defense in other respiratory diseases and explain CF-like airway infections in people with CA12 mutations.

PMID: 33533914 [PubMed - as supplied by publisher]

Longitudinal non-cystic fibrosis trends of pulmonary Mycobacterium abscessus disease from 2010 to 2017: spread of the "globally successful clone" in Asia.

ERJ Open Res. 2021 Jan;7(1):

Authors: Cheng A, Sun HY, Tsai YT, Lu PL, Lee SS, Lee YT, Wang YC, Liu PY, Chien JY, Hsueh PR, Chang SY, Wu UI, Sheng WH, Chen YC, Chang SC

Abstract
Background: Mycobacterium abscessus (MAB) has emerged as the predominant pulmonary non-tuberculous mycobacterial pathogen in parts of Asia, including Taiwan. The reasons for the significant increase in MAB infections in the non-cystic fibrosis (CF) populations are poorly understood. The study aimed to elucidate whether this increase is related to the spread of the globally successful clone of MAB.
Methods: We performed multilocus sequence typing of 371 nonduplicated MAB pulmonary isolates from 371 patients sampled between 2010-2017 at seven hospitals across Taiwan.
Results: In total, 183 (49.3%) isolates were M. abscessus subsp. abscessus (MAB-a), 187 (50.4%) were M. abscessus subsp. massiliense (MAB-m), and 1 (0.3%) was M. abscessus subsp. bolletii (MAB-b). MAB-a sequence type (ST)1 (23.7%) and ST127 (3.8%), followed by MAB-m ST48 (16.2%), ST117 (15.1%), ST23 (8.6%) were most common overall. Of MAB-a strains, 50 (27.3%) belonged to novel STs and 38 (10.2%) were singleton strains, while of MAB-m strains, only 10 (5.3%) were novel and 8 (2.2%) were singletons. From 2010 to 2017, the frequency of the historically dominant ST1 declined from 28.6% to 22.5%, whereas the recently emerged globally successful clonal cluster 3, ST23 and ST48, increased from 14.3% to 40.0%.
Conclusions: The dominance of ST1 particularly in the last 2 years of this study appears to be declining, while ST23, reported in outbreaks among CF and post-surgical cohorts across the Americas and Europe, alongside the closely related ST48, is present among non-CF populations in Taiwan. These trends need to be confirmed with further ongoing studies to track the molecular epidemiology of clinical MAB isolates worldwide.

PMID: 33532483 [PubMed]

Sex disparities in cystic fibrosis: review on the effect of female sex hormones on lung pathophysiology and outcomes.

ERJ Open Res. 2021 Jan;7(1):

Authors: Lam GY, Goodwin J, Wilcox PG, Quon BS

Abstract
Sex differences in morbidity and mortality have been reported in the cystic fibrosis (CF) population worldwide. However, it is unclear why CF women have worse clinical outcomes than men. In this review, we focus on the influence of female sex hormones on CF pulmonary outcomes and summarise data from in vitro and in vivo experiments on how oestrogen and progesterone might modify mucociliary clearance, immunity and infection in the CF airways. The potential for novel sex hormone-related therapeutic interventions is also discussed.

PMID: 33532475 [PubMed]

Avatar acceptability: views from the Australian Cystic Fibrosis community on the use of personalised organoid technology to guide treatment decisions.

ERJ Open Res. 2021 Jan;7(1):

Authors: Fawcett LK, Wakefield CE, Sivam S, Middleton PG, Wark P, Widger J, Jaffe A, Waters SA

Abstract
Background: Patient-oriented research approaches that reflect the needs and priorities of those most affected by health research outcomes improves translation of research findings into practice. Targeted therapies for cystic fibrosis (CF) are now a viable treatment option for some eligible individuals despite the heterogeneous patient-specific therapeutic response. This has necessitated development of a clinical tool that predicts treatment response for individual patients. Patient-derived mini-organs (organoids) have been at the forefront of this development. However, little is known about their acceptability in CF patients and members of the public.
Methods: We used a cross-sectional observational design to conduct an online survey in people with CF, their carers and community comparisons. Acceptability was examined in five domains: 1) willingness to use organoids, 2) perceived advantages and disadvantages of organoids, 3) acceptable out-of-pocket costs, 4) turnaround time and 5) source of tissue.
Results: In total, 188 participants completed the questionnaire, including adults with CF and parents of children with CF (90 (48%)), and adults without CF and parents of children without CF (98 (52%)). Use of organoids to guide treatment decisions in CF was acceptable to 86 (95%) CF participants and 98 (100%) community participants. The most important advantage was that organoids may improve treatment selection, improving the patient's quality of life and life expectancy. The most important disadvantage was that the organoid recommended treatment might be unavailable or too expensive.
Conclusions: These findings indicate acceptance of patient-derived organoids as a tool to predict treatment response by the majority of people surveyed. This may indicate successful future implementation into healthcare systems.

PMID: 33532470 [PubMed]

Losartan reduces cigarette smoke-induced airway inflammation and mucus hypersecretion.

ERJ Open Res. 2021 Jan;7(1):

Authors: Kim MD, Baumlin N, Dennis JS, Yoshida M, Kis A, Aguiar C, Schmid A, Mendes E, Salathe M

Abstract
The aim was to determine whether losartan reduces cigarette smoke (CS)-induced airway inflammation and mucus hypersecretion in an in vitro model and a small clinical trial. Primary human bronchial epithelial cells (HBECs) were differentiated at the air-liquid interface (ALI) and exposed to CS. Expression of transforming growth factor (TGF)-β1 and the mucin MUC5AC, and expression or activity of matrix metalloproteinase (MMP)-9 were measured after CS exposure. Parameters of mucociliary clearance were evaluated by measuring airway surface liquid volumes, mucus concentrations, and conductance of cystic fibrosis transmembrane conductance regulator (CFTR) and large conductance, Ca2+-activated and voltage-dependent potassium (BK) channels. Nasal cells were collected from study participants and expression of MUC5AC, TGF-β1, and MMP-9 mRNAs was measured before and after losartan treatment. In vitro, CS exposure of HBECs caused a significant increase in mRNA expression of MUC5AC and TGF-β1 and MMP-9 activity and decreased CFTR and BK channel activities, thereby reducing airway surface liquid volumes and increasing mucus concentrations. Treatment of HBECs with losartan rescued CS-induced CFTR and BK dysfunction and caused a significant decrease in MUC5AC expression and mucus concentrations, partially by inhibiting TGF-β signalling. In a prospective clinical study, cigarette smokers showed significantly reduced mRNA expression levels of MUC5AC, TGF-β1, and MMP-9 in the upper airways after 2 months of losartan treatment. Our findings suggest that losartan may be an effective therapy to reduce inflammation and mucus hypersecretion in CS-induced chronic airway diseases.

PMID: 33532463 [PubMed]

Mesenchymal Stem Cell exosome delivered Zinc Finger Protein activation of cystic fibrosis transmembrane conductance regulator.

J Extracell Vesicles. 2021 Jan;10(3):e12053

Authors: Villamizar O, Waters SA, Scott T, Grepo N, Jaffe A, Morris KV

Abstract
Cystic fibrosis is a genetic disorder that results in a multi-organ disease with progressive respiratory decline which leads to premature death. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupts the capacity of the protein to function as a channel, transporting chloride ions and bicarbonate across epithelial cell membranes. Small molecule treatments targeted at potentiating or correcting CFTR have shown clinical benefits, but are only effective for a small percentage of individuals with specific CFTR mutations. To overcome this limitation, we engineered stromal-derived mesenchymal stem cells (MSC) and HEK293 cells to produce exosomes containing a novel CFTR Zinc Finger Protein fusion with transcriptional activation domains VP64, P65 and Rta to target the CFTR promoter (CFZF-VPR) and activate transcription. Treatment with CFZF-VPR results in robust activation of CFTR transcription in patient derived Human Bronchial Epithelial cells (HuBEC). We also find that CFZF-VPR can be packaged into MSC and HEK293 cell exosomes and delivered to HuBEC cells to potently activate CFTR expression. Connexin 43 appeared to be required for functional release of CFZF-VPR from exosomes. The observations presented here demonstrate that MSC derived exosomes can be used to deliver a packaged zinc finger activator to target cells and activate CFTR. The novel approach presented here offers a next-generation genetic therapy that may one day prove effective in treating patients afflicted with Cystic fibrosis.

PMID: 33532041 [PubMed]

Challenges in the use of highly effective modulator treatment for cystic fibrosis.

J Cyst Fibros. 2021 Jan 30;:

Authors: Ramos KJ, Pilewski JM, Taylor-Cousar JL

Abstract
The last decade has seen development of oral, small molecule therapies that address the basic cystic fibrosis transmembrane conductance regulator (CFTR) protein defect. Highly effective modulator treatment (HEMT) that is efficacious for a large majority of people living with cystic fibrosis (CF) promises to change the landscape of this chronic life-limiting disease. Some people living with CF have a CFTR genotype that renders them eligible for HEMT, but also have comorbidities that excluded them from the original Phase III clinical trials that led to US Food and Drug Administration approval. The purpose of this review is to address the use of HEMT in challenging situations, including initiation for those with advanced CF lung disease, and use after solid organ transplant, during pregnancy, and for individuals with CFTR-related disorders without a definitive diagnosis of CF.

PMID: 33531206 [PubMed - as supplied by publisher]

Primary care during the transition to adult care for adolescents involved with pediatric specialty services: a scoping review protocol.

Syst Rev. 2021 Feb 02;10(1):46

Authors: Schraeder K, Allemang B, Scott C, McBrien K, Dimitropoulos G, Felske A, Samuel S

Abstract
BACKGROUND: Of the 15-20% of youth in North America affected by a chronic health condition (e.g., type 1 diabetes, cystic fibrosis) and/or mental health or neurodevelopmental disorder (e.g., depression, eating disorder, Attention Deficit-Hyperactivity Disorder), many often require lifelong specialist healthcare services. Ongoing primary care during childhood and into young adulthood is recommended by best practice guidelines. To date, it is largely unknown if, how, and when primary care physicians (PCPs; such as family physicians) collaborate with specialists as AYAs leave pediatric-oriented services. The proposed scoping review will synthesize the available literature on the roles of PCPs for AYAs with chronic conditions leaving pediatric specialty care and identify potential benefits and challenges of maintaining PCP involvement during transition.
METHODS: Arksey and O'Malley's original scoping review framework will be utilized with guidance from Levac and colleagues and the Joanna Briggs Institute. A search of databases including MEDLINE (OVID), EMBASE, PsycINFO, and CINAHL will be conducted following the development of a strategic search strategy. Eligible studies will (i) be published in English from January 2004 onwards, (ii) focus on AYAs (ages 12-25) with a chronic condition(s) who have received specialist services during childhood, and (iii) include relevant findings about the roles of PCPs during transition to adult services. A data extraction tool will be developed and piloted on a subset of studies. Both quantitative and qualitative data will be synthesized.
DISCUSSION: Key themes about the roles of PCPs for AYAs involved with specialist services will be identified through this review. Findings will inform the development and evaluation of a primary-care based intervention to improve transition care for AYAs with chronic conditions.

PMID: 33531077 [PubMed - in process]

Reflections on the Importance of Cost of Illness Analysis in Rare Diseases: A Proposal.

Int J Environ Res Public Health. 2021 Jan 26;18(3):

Authors: Armeni P, Cavazza M, Xoxi E, Taruscio D, Kodra Y

Abstract
In the field of rare diseases (RDs), the evidence standard is often lower than that required by health technology assessment (HTA) and payer authorities. In this commentary, we propose that appropriate economic evaluation for rare disease treatments should be initially informed by cost-of-illness (COI) studies conducted using a societal perspective. Such an approach contributes to improving countries' understanding of RDs in their entirety as societal and not merely clinical, or product-specific issues. In order to exemplify how the disease burden's distribution has changed over the last fifteen years, key COI studies for Hemophilia, Fragile X Syndrome, Cystic Fibrosis, and Juvenile Idiopathic Arthritis are examined. Evidence shows that, besides methodological variability and cross-country differences, the disease burden's share represented by direct costs generally grows over time as novel treatments become available. Hence, to support effective decision-making processes, it seems necessary to assess the re-allocation of the burden produced by new medicinal products, and this approach requires identifying cost drivers through COI studies with robust design and standardized methodology.

PMID: 33530652 [PubMed - in process]

A Peptide-Nucleic Acid Targeting miR-335-5p Enhances Expression of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene with the Possible Involvement of the CFTR Scaffolding Protein NHERF1.

Biomedicines. 2021 Jan 26;9(2):

Authors: Tamanini A, Fabbri E, Jakova T, Gasparello J, Manicardi A, Corradini R, Finotti A, Borgatti M, Lampronti I, Munari S, Dechecchi MC, Cabrini G, Gambari R

Abstract
(1) Background: Up-regulation of the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) might be of great relevance for the development of therapeutic protocols for cystic fibrosis (CF). MicroRNAs are deeply involved in the regulation of CFTR and scaffolding proteins (such as NHERF1, NHERF2 and Ezrin). (2) Methods: Content of miRNAs and mRNAs was analyzed by RT-qPCR, while the CFTR and NHERF1 production was analyzed by Western blotting. (3) Results: The results here described show that the CFTR scaffolding protein NHERF1 can be up-regulated in bronchial epithelial Calu-3 cells by a peptide-nucleic acid (PNA) targeting miR-335-5p, predicted to bind to the 3'-UTR sequence of the NHERF1 mRNA. Treatment of Calu-3 cells with this PNA (R8-PNA-a335) causes also up-regulation of CFTR. (4) Conclusions: We propose miR-335-5p targeting as a strategy to increase CFTR. While the efficiency of PNA-based targeting of miR-335-5p should be verified as a therapeutic strategy in CF caused by stop-codon mutation of the CFTR gene, this approach might give appreciable results in CF cells carrying other mutations impairing the processing or stability of CFTR protein, supporting its application in personalized therapy for precision medicine.

PMID: 33530577 [PubMed]

Interactions between ABCC4/MRP4 and ABCC7/CFTR in Human Airway Epithelial Cells in Lung Health and Disease.

Int J Biochem Cell Biol. 2021 Jan 30;:105936

Authors: Nguyen JP, Kim Y, Cao Q, Hirota JA

Abstract
ATP binding cassette (ABC) transporters are present in all three domains of life - Archaea, Bacteria, and Eukarya. The conserved nature is a testament to the importance of these transporters in regulating endogenous and exogenous substrates required for life to exist. In humans, 49 ABC transporters have been identified to date with broad expression in different lung cell types with multiple transporter family members contributing to lung health and disease. The ABC transporter most commonly known to be linked to lung pathology is ABCC7, also known as cystic fibrosis transmembrane conductance regulator - CFTR. Closely related to the CFTR genomic sequence is ABCC4/multi-drug resistance protein-4. Genomic proximity is shared with physical proximity, with ABCC4 and CFTR physically coupled in cell membrane microenvironments of epithelial cells to orchestrate functional consequences of cyclic-adenosine monophosphate (cAMP)-dependent second messenger signaling and extracellular transport of endogenous and exogenous substrates. The present concise review summarizes the emerging data defining a role of the (ABCC7/CFTR)-ABCC4 macromolecular complex in human airway epithelial cells as a physiologically important pathway capable of impacting endogenous and exogenous mediator transport and ion transport in both lung health and disease.

PMID: 33529712 [PubMed - as supplied by publisher]

From genotype to phenotype: adaptations of Pseudomonas aeruginosa to the cystic fibrosis environment.

Microb Genom. 2021 Feb 02;:

Authors: Camus L, Vandenesch F, Moreau K

Abstract
Pseudomonas aeruginosa is one of the main microbial species colonizing the lungs of cystic fibrosis patients and is responsible for the decline in respiratory function. Despite the hostile pulmonary environment, P. aeruginosa is able to establish chronic infections thanks to its strong adaptive capacity. Various longitudinal studies have attempted to compare the strains of early infection with the adapted strains of chronic infection. Thanks to new '-omics' techniques, convergent genetic mutations, as well as transcriptomic and proteomic dysregulations have been identified. As a consequence of this evolution, the adapted strains of P. aeruginosa have particular phenotypes that promote persistent infection.

PMID: 33529147 [PubMed - as supplied by publisher]