Microorganisms. 2022 Apr 27;10(5):919. doi: 10.3390/microorganisms10050919.

ABSTRACT

Multidrug-resistant pathogens represent a serious threat to human health. The inefficacy of traditional antibiotic drugs could be surmounted through the exploitation of natural bioactive compounds of which medicinal plants are a great reservoir. The finding that bacteria living inside plant tissues, (i.e., the endophytic bacterial microbiome) can influence the synthesis of the aforementioned compounds leads to the necessity of unraveling the mechanisms involved in the determination of this symbiotic relationship. Here, we report the genome sequence of four endophytic bacterial strains isolated from the medicinal plant Origanum vulgare L. and able to antagonize the growth of opportunistic pathogens of cystic fibrosis patients. The in silico analysis revealed the presence of gene clusters involved in the production of antimicrobial compounds, such as paeninodin, paenilarvins, polymyxin, and paenicidin A. Endophytes' adaptation to the plant microenvironment was evaluated through the analysis of the presence of antibiotic resistance genes in the four genomes. The diesel fuel degrading potential was also tested. Strains grew in minimum media supplemented with diesel fuel, but no n-alkanes degradation genes were found in their genomes, suggesting that diesel fuel degradation might occur through other steps involving enzymes catalyzing the oxidation of aromatic compounds.

PMID:35630363 | DOI:10.3390/microorganisms10050919

Microorganisms. 2022 Apr 24;10(5):887. doi: 10.3390/microorganisms10050887.

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa is often involved in airway infections of cystic fibrosis (CF) patients. It persists in the hostile CF lung environment, inducing chronic infections due to the production of several virulence factors. In this regard, the ability to form a biofilm plays a pivotal role in CF airway colonization by P. aeruginosa. Bacterial virulence mitigation and bacterial cell adhesion hampering and/or biofilm reduced formation could represent a major target for the development of new therapeutic treatments for infection control. Essential oils (EOs) are being considered as a potential alternative in clinical settings for the prevention, treatment, and control of infections sustained by microbial biofilms. EOs are complex mixtures of different classes of organic compounds, usually used for the treatment of upper respiratory tract infections in traditional medicine. Recently, a wide series of EOs were investigated for their ability to modulate biofilm production by different pathogens comprising S. aureus, S. epidermidis, and P. aeruginosa strains. Machine learning (ML) algorithms were applied to develop classification models in order to suggest a possible antibiofilm action for each chemical component of the studied EOs. In the present study, we assessed the biofilm growth modulation exerted by 61 commercial EOs on a selected number of P. aeruginosa strains isolated from CF patients. Furthermore, ML has been used to shed light on the EO chemical components likely responsible for the positive or negative modulation of bacterial biofilm formation.

PMID:35630332 | DOI:10.3390/microorganisms10050887

Life (Basel). 2022 May 19;12(5):756. doi: 10.3390/life12050756.

ABSTRACT

Cystic fibrosis (CF) airways are affected by a deranged repair of the damaged epithelium resulting in altered regeneration and differentiation. Previously, we showed that human amniotic mesenchymal stem cells (hAMSCs) corrected base defects of CF airway epithelial cells via connexin (CX)43-intercellular gap junction formation. In this scenario, it is unknown whether hAMSCs, or fibroblasts sharing some common characteristics with MSCs, can operate a faster repair of a damaged airway epithelium. A tip-based scratch assay was employed to study wound repair in monolayers of CFBE14o- cells (CFBE, homozygous for the F508del mutation). hAMSCs were either co-cultured with CFBE cells before the wound or added to the wounded monolayers. NIH-3T3 fibroblasts (CX43+) were added to wounded cells. HeLa cells (CX43-) were used as controls. γ-irradiation was optimized to block CFBE cell proliferation. A specific siRNA was employed to downregulate CX43 expression in CFBE cells. CFBE cells showed a delayed repair as compared with wt-CFTR cells (16HBE41o-). hAMSCs enhanced the wound repair rate of wounded CFBE cell monolayers, especially when added post wounding. hAMSCs and NIH-3T3 fibroblasts, but not HeLa cells, increased wound closure of irradiated CFBE monolayers. CX43 downregulation accelerated CFBE wound repair rate without affecting cell proliferation. We conclude that hAMSCs and fibroblasts enhance the repair of a wounded CF airway epithelium, likely through a CX43-mediated mechanism mainly involving cell migration.

PMID:35629422 | DOI:10.3390/life12050756

J Pers Med. 2022 May 17;12(5):809. doi: 10.3390/jpm12050809.

ABSTRACT

The airway epithelium of children with asthma is characterized by aberrant repair that may be therapeutically modifiable. The development of epithelial-targeting therapeutics that enhance airway repair could provide a novel treatment avenue for childhood asthma. Drug discovery efforts utilizing high-throughput live cell imaging of patient-derived airway epithelial culture-based wound repair assays can be used to identify compounds that modulate airway repair in childhood asthma. Manual cell tracking has been used to determine cell trajectories and wound closure rates, but is time consuming, subject to bias, and infeasible for high-throughput experiments. We therefore developed software, EPIC, that automatically tracks low-resolution low-framerate cells using artificial intelligence, analyzes high-throughput drug screening experiments and produces multiple wound repair metrics and publication-ready figures. Additionally, unlike available cell trackers that perform cell segmentation, EPIC tracks cells using bounding boxes and thus has simpler and faster training data generation requirements for researchers working with other cell types. EPIC outperformed publicly available software in our wound repair datasets by achieving human-level cell tracking accuracy in a fraction of the time. We also showed that EPIC is not limited to airway epithelial repair for children with asthma but can be applied in other cellular contexts by outperforming the same software in the Cell Tracking with Mitosis Detection Challenge (CTMC) dataset. The CTMC is the only established cell tracking benchmark dataset that is designed for cell trackers utilizing bounding boxes. We expect our open-source and easy-to-use software to enable high-throughput drug screening targeting airway epithelial repair for children with asthma.

PMID:35629232 | DOI:10.3390/jpm12050809

J Pers Med. 2022 Apr 26;12(5):691. doi: 10.3390/jpm12050691.

ABSTRACT

Smoking traditionally has not been considered as a cause of bronchiectasis. However, few studies have evaluated the association between smoking and bronchiectasis. This study aimed to investigate the association between smoking status and bronchiectasis development in young adults. This study included 6,861,282 adults aged 20-39 years from the Korean National Health Insurance Service database 2009-2012 who were followed-up until the date of development of bronchiectasis, death, or 31 December 2018. We evaluated the incidence of bronchiectasis according to smoking status. During a mean of 7.4 years of follow-up, 23,609 (0.3%) participants developed bronchiectasis. In multivariable Cox regression analysis, ex-smokers (adjusted hazard ratio (aHR) = 1.07, 95% confidence interval (CI) = 1.03-1.13) and current-smokers (aHR = 1.06, 95% CI = 1.02-1.10) were associated with incident bronchiectasis, with the highest HR in ≥ 10 pack-years current smokers (aHR = 1.12, 95% CI = 1.06-1.16). The association of smoking with bronchiectasis was more profound in females than in males (p for interaction < 0.001), in younger than in older participants (p for interaction = 0.036), and in the overweight and obese than in the normal weight or underweight (p for interaction = 0.023). In conclusion, our study shows that smoking is associated with incident bronchiectasis in young adults. The association of smoking with bronchiectasis development was stronger in females, 20-29 year-olds, and the overweight and obese than in males, 30-40-year-olds, and the normal weight or underweight, respectively.

PMID:35629114 | DOI:10.3390/jpm12050691

J Clin Med. 2022 May 13;11(10):2756. doi: 10.3390/jcm11102756.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease that is caused by a defect in the gene coding for the transmembrane cystic fibrosis transmembrane conductance regulator (CFTR). Research papers published so far point out that despite the numerous dental treatment needs of CF patients, there are no oral care guidelines for this group of patients. The aim of the article is to propose standards of dental prophylactic and therapeutic procedures for CF patients in different age groups. Regardless of the CF patient's age, dental check-ups should be scheduled at least every 6 months. However, taking into account the actual condition of the individual CF patients, therapeutic visits may be scheduled for earlier dates, to provide well-fitting treatment, considering the level of risk of oral diseases. The described management standards may be helpful and may improve the quality of dental care provided to CF patients.

PMID:35628882 | DOI:10.3390/jcm11102756

Int J Mol Sci. 2022 May 19;23(10):5692. doi: 10.3390/ijms23105692.

ABSTRACT

The identification of markers of inflammatory activity at the early stages of pulmonary diseases which share common characteristics that prevent their clear differentiation is of great significance to avoid misdiagnosis, and to understand the intrinsic molecular mechanism of the disorder. The combination of electrophoretic/chromatographic methods with mass spectrometry is currently a promising approach for the identification of candidate biomarkers of a disease. Since the fluid phase of sputum is a rich source of proteins which could provide an early diagnosis of specific lung disorders, it is frequently used in these studies. This report focuses on the state-of-the-art of the application, over the last ten years (2011-2021), of sputum proteomics in the investigation of severe lung disorders such as COPD; asthma; cystic fibrosis; lung cancer and those caused by COVID-19 infection. Analysis of the complete set of proteins found in sputum of patients affected by these disorders has allowed the identification of proteins whose levels change in response to the organism's condition. Understanding proteome dynamism may help in associating these proteins with alterations in the physiology or progression of diseases investigated.

PMID:35628501 | DOI:10.3390/ijms23105692

Healthcare (Basel). 2022 May 6;10(5):858. doi: 10.3390/healthcare10050858.

ABSTRACT

People with cystic fibrosis (pwCF) face great challenges during the ongoing COVID-19 pandemic. Recent research found equal levels of distress in pwCF and healthy controls (HC). The current study aimed to investigate the mental health burden and safety behavior in pwCF. Sixty-nine adult pwCF and sixty-nine propensity-score-matched HC participated in this study. Participants completed an anonymous online questionnaire assessing distress, generalized anxiety, depressive symptoms, COVID-19-related variables, self-reported adherent safety behavior (ASB), and dysfunctional safety behavior (DSB). PwCF showed equal amounts of distress (W = 2481.0, p = 0.669), depressive symptoms (W = 2632.5, p = 0.268), and generalized anxiety symptoms (W = 2515.5, p = 0.565) compared to the HC. COVID-19-related fear (W = 1872.0, p = 0.028), ASB (W = 1630.0, p = 0.001), and DSB (W = 1498.5, p < 0.001) were significantly elevated in pwCF. The pwCF estimated that the probability of suffering from symptoms (W = 954.5, p < 0.001), experiencing a severe course (W = 806.5, p < 0.001), or dying (W = 1079.0, p < 0.001) from COVID-19 is significantly higher than that of the HC. ASB was associated with a CF diagnosis, COVID-19-related fear, and a subjective level of information (R2 = 0.414, F(13, 124) = 6.936, p ≤ 0.001). DSB was associated with a diagnosis of CF and COVID-19-related fear (R2 = 0.196, F(13, 124) = 3.169, p ≤ 0.001). The data suggest that pwCF show functional and adequate behaviors towards the risk caused by the pandemic. Therefore, functional coping behaviors may provide advantages in addressing pandemic challenges.

PMID:35627996 | DOI:10.3390/healthcare10050858

Healthcare (Basel). 2022 Apr 20;10(5):766. doi: 10.3390/healthcare10050766.

ABSTRACT

Cystic Fibrosis (CF) is an autosomal multisystem recessive genetic disease. Patients with Cystic Fibrosis, oral bacteria related to dental and periodontal diseases that can also inhabit the lungs, increases the risk for systemic complications. Our study aimed at assessing oral hygiene status of cystic fibrosis adult patients. The study was conducted on 40 patients diagnosed with CF and 40 healthy participants. The following indices were included: Simplified Oral Hygiene (OHI-S), Approximal Plaque Index (API), Community Periodontal Index of Treatment Needs (CPITN), and a questionnaire. Obtained results proved that the API was 44.63% in the study group, indicating sufficient hygiene, and 37% in the control group, indicating quite good hygiene. Significantly higher OHI-S was found in the study group. It was found based on the analysis of treatment needs that home care and professional instructions on proper oral hygiene were more often needed in the control group compared to CF patients. In conclusion, the obtained API and OHI-S values in adult CF patients were indicative of satisfactory oral hygiene. Periodontal treatment needs assessed based on the CPITN index in patients with CF indicated the need for professional preventive treatments. An interdisciplinary dental care to support oral health could be recommendable in individuals with chronic respiratory diseases such as Cystic Fibrosis.

PMID:35627903 | DOI:10.3390/healthcare10050766

Int J Environ Res Public Health. 2022 May 17;19(10):6114. doi: 10.3390/ijerph19106114.

ABSTRACT

BACKGROUND: Modulator therapy represents a significant step forward in CF care and is expected to have a significant impact on the health and mortality of many individuals with CF. Studies have predominantly explored the physiological effects of modulator therapy on clinical outcomes, with little consideration of the individual lived experience of modulator therapy among adults with Cystic Fibrosis.

METHODS: To explore this, semi-structured interviews were conducted with 12 individuals currently taking Kaftrio, which were subsequently thematically analysed.

RESULTS: Three overarching themes were identified: (i) positive perception of Kaftrio, (ii) negative perception of Kaftrio, and (iii) the relationships with the clinical team. The experience of modulator therapy should be recognised as being unique to the individual, with perceptions of illness, self-identity, and outcomes strongly dictating the lived experience.

CONCLUSIONS: There is a consensus that, while for many, the quality of life is evidently increased through the use of Kaftrio, this is not without its own challenges. This highlights the need for both individuals with CF and their clinical teams to learn to navigate this new disease landscape.

PMID:35627651 | DOI:10.3390/ijerph19106114

Genes (Basel). 2022 May 16;13(5):889. doi: 10.3390/genes13050889.

ABSTRACT

OBJECTIVE: The co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation.

PATIENTS AND METHODS: A 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, hypertrichosis, scoliosis, recurrent bronchitis, and pneumonia with bronchiectasis, colelithiasis, chronic severe constipation, and a family history suggestive of autosomal dominant recurrence of polycystic kidney disease was analyzed by WES to identify the genomic events underlying the condition.

RESULTS: Four co-occurring genomic events fully explaining the proband's clinical features were identified. A de novo truncating USP7 variant was disclosed as the cause of Hao-Fountain syndrome, a disorder characterized by syndromic ID and distinctive behavior. Compound heterozygosity for a major cystic fibrosis-causing variant and the modulator allele, IVS8-5T, in CFTR explained the recurrent upper and lower respiratory way infections, bronchiectasis, cholelithiasis, and chronic constipation. Finally, a truncating PKD2 variant co-segregating with polycystic kidney disease in the family allowed presymptomatic disease diagnosis.

CONCLUSIONS: The co-occurring variants in USP7 and CFTR variants explained the multisystem disorder of the patient. The comprehensive dissection of the phenotype and early diagnosis of autosomal dominant polycystic kidney disease allowed us to manage the CFTR-related disorder symptoms and monitor renal function and other complications associated with PKD2 haploinsufficiency, addressing proper care and surveillance.

PMID:35627274 | DOI:10.3390/genes13050889

Cells. 2022 May 22;11(10):1712. doi: 10.3390/cells11101712.

ABSTRACT

Colonic epithelial cells are responsible for maintaining a delicate balance between luminal secretion and the absorption of fluids and ions. This review aims to discuss and update the model of colonic electrolyte secretion and absorption via the cystic fibrosis transmembrane regulator (CFTR), epithelial sodium channel (ENaC), Na-K-Cl cotransporters (NKCC1 and 2), Na-H exchangers (NHE1-4), colonic H,KATPase, and several other key components involved in multi-level transepithelial ion transport. Developments in our understanding of the activity, regulation, localization, and relationships of these ion transporters and their interactions have helped forge a more robust understanding of colonic ion movement that accounts for the colonic epithelium's role in mucosal pH modulation, the setting of osmotic gradients pivotal for fluid retention and secretion, and cell death regulation. Deviations from homeostatic ion transport cause diarrhea, constipation, and epithelial cell death and contribute to cystic fibrosis, irritable bowel syndrome (IBS), ulcerative colitis, and cancer pathologies. Signal transduction pathways that regulate electrolyte movement and the regulatory relationships between various sensors and transporters (CFTR as a target of CaSR regulation and as a regulator of ENaC and DRA, for example) are imperative aspects of a dynamic and comprehensive model of colonic ion homeostasis.

PMID:35626748 | DOI:10.3390/cells11101712

Biomedicines. 2022 May 2;10(5):1050. doi: 10.3390/biomedicines10051050.

ABSTRACT

(1) Background: Ciprofloxacin (CPF) is widely used for the treatment of cystic fibrosis, including pediatric patients, but its pharmacokinetics is poorly studied in this population. Optimal CPF dosing in pediatric patients may be affected by gene polymorphism of the enzymes involved in its biotransformation. (2) Materials and Methods: a two-center prospective non-randomized study of CPF pharmacokinetics with sequential enrollment of patients (n-33, mean age 9.03 years, male-33.36%), over a period from 2016 to 2021. All patients received tablets of the original CPF drug Cyprobay® at a dose of 16.5 mg/kg to 28.80 mg/kg. Blood sampling schedule: 0 (before taking the drug), 1.5 h; 3.0 h; 4.5 h; 6.0 h; 7.5 h after the first dosing. CPF serum concentrations were analyzed by high performance liquid chromatography mass spectrometry. The genotype of biotransformation enzymes was studied using total DNA isolated from whole blood leukocytes by the standard method. (4) Results: a possible relationship between the CA genotype of the CYP2C9 gene (c.1075A > C), the GG genotype of the CYP2D6*4 gene (1846G > A), the AG genotype of the GSTP1 gene (c.313A > G), the GCLC* genotype 7/7 and the CPF concentration in plasma (increased value of the area under the concentration-time curve) was established. Conclusions: Gene polymorphism of biotransformation enzymes may affect ciprofloxacin pharmacokinetics in children.

PMID:35625789 | DOI:10.3390/biomedicines10051050

Biomolecules. 2022 Apr 21;12(5):618. doi: 10.3390/biom12050618.

ABSTRACT

Pancreatic exocrine and endocrine dysfunctions often come together in the course of pancreatic diseases as interdependent manifestations of the same organ. However, the mechanisms underlying the bidirectional connection of the exocrine and endocrine pancreas are not fully understood. In this review, we aimed to synthetize the current knowledge regarding the effects of several exocrine pancreatic pathologies on the homeostasis of β-cells, with a special interest in the predisposition toward diabetes mellitus (DM). We focused on the following pancreatic exocrine diseases: chronic pancreatitis, acute pancreatitis, cystic fibrosis, pancreatic cancer, pancreatic resections, and autoimmune pancreatitis. We discuss the pathophysiologic mechanisms behind the impact on β-cell function and evolution into DM, as well as the associated risk factors in progression to DM, and we describe the most relevant and statistically significant findings in the literature. An early and correct diagnosis of DM in the setting of pancreatic exocrine disorders is of paramount importance for anticipating the disease's course and its therapeutical needs.

PMID:35625546 | DOI:10.3390/biom12050618

Antibiotics (Basel). 2022 May 17;11(5):674. doi: 10.3390/antibiotics11050674.

ABSTRACT

Tebipenem-pivoxil hydrobromide, an orally bioavailable carbapenem, is currently in clinical development for the treatment of extended-spectrum β-lactamase- and AmpC-producing Enterobacterales. Previously, tebipenem was found to possess antimicrobial activity against the biothreat pathogens, Burkholderia pseudomallei and Burkholderia mallei. Thus, herein, tebipenem was evaluated against a panel of 150 curated strains of Burkholderia cepacia complex (Bcc) and Burkholderia gladioli, pathogens that infect people who are immunocompromised or have cystic fibrosis. Using the provisional susceptibility breakpoint of 0.12 mg/L for tebipenem, 100% of the Bcc and B. gladioli tested as being provisionally resistant to tebipenem. Bcc and B. gladioli possess two inducible chromosomal β-lactamases, PenA and AmpC. Using purified PenA1 and AmpC1, model β-lactamases expressed in Burkholderia multivorans ATCC 17616, PenA1 was found to slowly hydrolyze tebipenem, while AmpC1 was inhibited by tebipenem with a k2/K value of 1.9 ± 0.1 × 103 M-1s-1. In addition, tebipenem was found to be a weak inducer of blaPenA1 expression. The combination of the slow hydrolysis by PenA1 and weak induction of blaPenA1 likely compromises the potency of tebipenem against Bcc and B. gladioli.

PMID:35625319 | DOI:10.3390/antibiotics11050674

Antibiotics (Basel). 2022 Apr 19;11(5):545. doi: 10.3390/antibiotics11050545.

ABSTRACT

Multidrug resistance is an emerging healthcare issue, especially concerning Pseudomonas aeruginosa. In this multicenter study, P. aeruginosa isolates with resistance against meropenem detected by routine methods were collected and tested for carbapenemase production and susceptibility against ceftazidime-avibactam. Meropenem-resistant isolates of P. aeruginosa from various clinical materials were collected at 11 tertiary care hospitals in Germany from 2017-2019. Minimum inhibitory concentrations (MICs) were determined via microdilution plates (MICRONAUT-S) of ceftazidime-avibactam and meropenem at each center. Detection of the presence of carbapenemases was performed by PCR or immunochromatography. For meropenem-resistant isolates (n = 448), the MIC range of ceftazidime-avibactam was 0.25-128 mg/L, MIC90 was 128 mg/L and MIC50 was 16 mg/L. According to EUCAST clinical breakpoints, 213 of all meropenem-resistant P. aeruginosa isolates were categorized as susceptible (47.5%) to ceftazidime-avibactam. Metallo-β-lactamases (MBL) could be detected in 122 isolates (27.3%). The MIC range of ceftazidime-avibactam in MBL-positive isolates was 4-128 mg/L, MIC90 was >128 mg/L and MIC50 was 32 mg/L. There was strong variation in the prevalence of MBL-positive isolates among centers. Our in vitro results support ceftazidime-avibactam as a treatment option against infections caused by meropenem-resistant, MBL-negative P. aeruginosa.

PMID:35625189 | DOI:10.3390/antibiotics11050545

Antioxidants (Basel). 2022 Apr 29;11(5):887. doi: 10.3390/antiox11050887.

ABSTRACT

Cystic fibrosis (CF) is one of the most common, yet fatal genetic diseases in Caucasians. The presence of a defective CF transmembrane conductance regulator and the massive neutrophils influx into the airways contribute to an imbalance in epithelial cell processes and extracellular fluids and lead to excessive production of reactive oxygen species and intensification of oxidative stress. The study included 16 controls and 42 participants with CF aged 10 to 38. The products of protein oxidation, total antioxidant capacity (TAC) and markers of lipid peroxidation were estimated in the serum of the subjects. Furthermore, we compared the level of oxidative stress in patients with CF according to the severity of disease and type of bacterial infection. Thiol groups and serum TAC decreased significantly in patients with CF (p < 0.05). Elevated levels of 3-nitrotyrosine, malondialdehyde and 8-isoprostane were observed in CF subjects (p < 0.05). Furthermore, as the severity of the disease increased, there was a decrease in the thiol groups and TAC levels, as well as an increase in the concentration of 3-nitrotyrosine and 8-isoprostane. CF participants infected with Pseudomonas aeruginosa had elevated 3-nitrotyrosine concentration levels (p < 0.05), while those infected with Staphylococcus aureus noted a decrease in thiol groups (p < 0.05). Elevated levels of oxidative stress markers were found in the serum of CF patients. Furthermore, oxidative stress progressively increased over the years and along with the severity of the disease. The presence of bacterial infection with P. aeruginosa or S. aureus had a slight effect on oxidative stress, while co-infection by two species did not affect the level of oxidative stress.

PMID:35624751 | DOI:10.3390/antiox11050887

Br J Cancer. 2022 May 27. doi: 10.1038/s41416-022-01857-9. Online ahead of print.

ABSTRACT

BACKGROUND: The causal pathway between high education and reduced risk of gastric cancer (GC) has not been explained. The study aimed at evaluating the mediating role of lifestyle factors on the relationship between education and GC METHODS: Ten studies with complete data on education and five lifestyle factors (smoking, alcohol drinking, fruit and vegetable intake, processed meat intake and salt consumption) were selected from a consortium of studies on GC including 4349 GC cases and 8441 controls. We created an a priori score based on the five lifestyle factors, and we carried out a counterfactual-based mediation analysis to decompose the total effect of education on GC into natural direct effect and natural indirect effect mediated by the combined lifestyle factors. Effects were expressed as odds ratios (ORs) with a low level of education as the reference category.

RESULTS: The natural direct and indirect effects of high versus low education were 0.69 (95% CI: 0.62-0.77) and 0.96 (95% CI: 0.95-0.97), respectively, corresponding to a mediated percentage of 10.1% (95% CI: 7.1-15.4%). The mediation effect was limited to men.

CONCLUSIONS: The mediation effect of the combined lifestyle factors on the relationship between education and GC is modest. Other potential pathways explaining that relationship warrants further investigation.

PMID:35624300 | DOI:10.1038/s41416-022-01857-9

Nat Commun. 2022 May 27;13(1):2978. doi: 10.1038/s41467-022-30668-y.

ABSTRACT

Low CFTR mRNA expression due to nonsense-mediated mRNA decay (NMD) is a major hurdle in developing a therapy for cystic fibrosis (CF) caused by the W1282X mutation in the CFTR gene. CFTR-W1282X truncated protein retains partial function, so increasing its levels by inhibiting NMD of its mRNA will likely be beneficial. Because NMD regulates the normal expression of many genes, gene-specific stabilization of CFTR-W1282X mRNA expression is more desirable than general NMD inhibition. Synthetic antisense oligonucleotides (ASOs) designed to prevent binding of exon junction complexes (EJC) downstream of premature termination codons (PTCs) attenuate NMD in a gene-specific manner. We describe cocktails of three ASOs that specifically increase the expression of CFTR-W1282X mRNA and CFTR protein upon delivery into human bronchial epithelial cells. This treatment increases the CFTR-mediated chloride current. These results set the stage for clinical development of an allele-specific therapy for CF caused by the W1282X mutation.

PMID:35624092 | DOI:10.1038/s41467-022-30668-y

Cell. 2022 May 26;185(11):1807-1808. doi: 10.1016/j.cell.2022.04.037.

ABSTRACT

People with cystic fibrosis (CF) are commonly infected with difficult to treat organisms, including non-tuberculous mycobacteria. Bacteriophage are viruses that lyse specific bacteria. Nick and colleagues describe the first successful treatment of a Mycobacterium abscessus lung infection with bacteriophage in an immune competent individual. This report provides important information regarding the efficacy of phage therapy and timeline of treatment response.

PMID:35623325 | DOI:10.1016/j.cell.2022.04.037