BJPsych Open. 2022 Feb 3;8(2):e40. doi: 10.1192/bjo.2022.9.

ABSTRACT

BACKGROUND: Public support for the implementation of personalised medicine policies (PMPs) within routine care is important owing to the high financial costs involved and the potential for redirection of resources from other services.

AIMS: We aimed to determine the attributes of a PMP most likely to elicit public support for implementation. We also aimed to determine whether such support differed between a depression PMP and one for cystic fibrosis.

METHOD: In a discrete-choice experiment, paired vignettes illustrating both the current model of care (CMoC) and a hypothetical PMP for either depression or cystic fibrosis were presented to a representative sample of the UK public (n = 2804). Each vignette integrated varying attributes, including anticipated therapeutic benefit over CMoC, and the annual cost to the taxpayer. Respondents were invited to express their preference for either the PMP or CMoC within each pair.

RESULTS: The financial cost was the most important attribute influencing public support for PMPs. Respondents favoured PMP implementation where it benefited a higher proportion of patients or was anticipated to be more effective than CMoC. A reduction in services for non-eligible patients reduced the likelihood of support for PMPs. Respondents were more willing to fund PMPs for cystic fibrosis than for depression.

CONCLUSIONS: Cost is a significant factor in the public's support for PMPs, but essential caveats, such as protection for services available to PMP-ineligible patients, may also apply. Further research should explore the factors contributing to condition-specific nuances in public support for PMPs.

PMID:35109949 | DOI:10.1192/bjo.2022.9

ACS Appl Mater Interfaces. 2022 Feb 2. doi: 10.1021/acsami.1c14975. Online ahead of print.

ABSTRACT

Inhaled siRNA therapy has a unique potential for treatment of severe lung diseases, such as cystic fibrosis (CF). Nevertheless, a drug delivery system tackling lung barriers is mandatory to enhance gene silencing efficacy in the airway epithelium. We recently demonstrated that lipid-polymer hybrid nanoparticles (hNPs), comprising a poly(lactic-co-glycolic) acid (PLGA) core and a lipid shell of dipalmitoyl phosphatidylcholine (DPPC), may assist the transport of the nucleic acid cargo through mucus-covered human airway epithelium. To study in depth the potential of hNPs for siRNA delivery to the lungs and to investigate the hypothesized benefit of PEGylation, here, an siRNA pool against the nuclear factor-κB (siNFκB) was encapsulated inside hNPs, endowed with a non-PEGylated (DPPC) or a PEGylated (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) or DSPE-PEG) lipid shell. Resulting hNPs were tested for their stability profiles and transport properties in artificial CF mucus, mucus collected from CF cells, and sputum samples from a heterogeneous and representative set of CF patients. Initial information on hNP properties governing their interaction with airway mucus was acquired by small-angle X-ray scattering (SAXS) studies in artificial and cellular CF mucus. The diffusion profiles of hNPs through CF sputa suggested a crucial role of lung colonization of the corresponding donor patient, affecting the mucin type and content of the sample. Noteworthy, PEGylation did not boost mucus penetration in complex and sticky samples, such as CF sputa from patients with polymicrobial colonization. In parallel, in vitro cell uptake studies performed on mucus-lined Calu-3 cells grown at the air-liquid interface (ALI) confirmed the improved ability of non-PEGylated hNPs to overcome mucus and cellular lung barriers. Furthermore, effective in vitro NFκB gene silencing was achieved in LPS-stimulated 16HBE14o- cells. Overall, the results highlight the potential of non-PEGylated hNPs as carriers for pulmonary delivery of siRNA for local treatment of CF lung disease. Furthermore, this study provides a detailed understanding of how distinct models may provide different information on nanoparticle interaction with the mucus barrier.

PMID:35107987 | DOI:10.1021/acsami.1c14975

Microbiol Spectr. 2022 Feb 2:e0253521. doi: 10.1128/spectrum.02535-21. Online ahead of print.

ABSTRACT

Patients with chronic respiratory diseases use home nebulizers that are often contaminated with pathogenic microbes to deliver aerosolized medications. The conditions under which these microbes leave the surface as bioaerosols during nebulization are not well characterized. The objectives of this study were to (i) determine whether different pathogens detach and disperse from the nebulizer surface during aerosolization and (ii) measure the effects of relative humidity and drying times on bacterial surface detachment and aerosolization. Bacteria were cultured from bioaerosols after Pari LC Plus albuterol nebulization using two different sources, as follows: (i) previously used nebulizers donated by anonymous patients with cystic fibrosis (CF) and (ii) nebulizers inoculated with bacteria isolated from the lungs of CF patients. Fractionated bioaerosols were collected with a Next-Generation Impactor. For a subset of bacteria, surface adherence during rewetting was measured with fluorescence microscopy. Bacteria dispersed from the surface of used CF patient nebulizers during albuterol nebulization. Eighty percent (16/20) of clinical isolates inoculated on the nebulizer in the laboratory formed bioaerosols. Detachment from the plastic surface into the chamber solution predicted bioaerosol production. Increased relative humidity and decreased drying times after inoculation favored bacterial dispersion on aerosols during nebulized therapy. Pathogenic bacteria contaminating nebulizer surfaces detached from the surface as bioaerosols during nebulized therapies, especially under environmental conditions when contaminated nebulizers were dried or stored at high relative humidity. This finding emphasizes the need for appropriate nebulizer cleaning, disinfection, and complete drying during storage and informs environmental conditions that favor bacterial surface detachment during nebulization. IMPORTANCE Studies from around the world have demonstrated that many patients use contaminated nebulizers to deliver medication into their lungs. While it is known that using contaminated medications in a nebulizer can lead to a lung infection, whether bacteria on the surface of a contaminated nebulizer detach as bioaerosols capable of reaching the lung has not been studied. This work demonstrates that a subset of clinical bacteria enter solution from the surface during nebulization and are aerosolized. Environmental conditions of high relative humidity during storage favor dispersion from the surface. We also provide results of an in vitro assay conducted to monitor bacterial surface detachment during multiple cycles of rewetting that correlate with the results of nebulizer/bacterial surface interactions. These studies demonstrate for the first time that pathogenic bacteria on the nebulizer surface pose a risk of bacterial inhalation to patients who use contaminated nebulizers.

PMID:35107362 | DOI:10.1128/spectrum.02535-21

J Clin Endocrinol Metab. 2022 Feb 2:dgac020. doi: 10.1210/clinem/dgac020. Online ahead of print.

ABSTRACT

CONTEXT: Cystic fibrosis related diabetes (CFRD) is the most common extra pulmonary complication of cystic fibrosis (CF). Around 40% of people with CF above age 20 have CFRD. Presence of CFRD is associated with poor health outcomes in people with CF.

OBJECTIVE: This review summarizes current knowledge on pathophysiology of CFRD.

METHODS: A PubMed review of the literature was conducted, and search terms included CFRD, cystic fibrosis, cystic fibrosis related diabetes, and cystic fibrosis transmembrane conductance regulator (CFTR). Additional sources were identified through manual searches of reference lists. The pathophysiology underlying development of glucose tolerance abnormalities in CF is complex and not fully understood. β-cell loss and functional impairment of the remaining β-cell function results in progressive insulin insufficiency. Factors that may contribute to development in CFRD include local islet and systemic inflammation, alterations in the incretion hormone axis, varying degrees of insulin resistance and genetic factors related to type 2 diabetes.

CONCLUSION: The prevalence of CFRD is expected to further increase with improving life expectancy of people with CF. Further research is needed to better understand the mechanisms underlying the development of CFRD and the impact of diabetes on clinical outcomes in CF.

PMID:35106591 | DOI:10.1210/clinem/dgac020

FEMS Microbiol Rev. 2022 Feb 1:fuac005. doi: 10.1093/femsre/fuac005. Online ahead of print.

ABSTRACT

Essential genes encode the processes that are necessary for life. Until recently, commonly applied binary classifications left no space between essential and non-essential genes. In this review, we frame bacterial gene essentiality in the context of genetic networks. We explore how the quantitative properties of gene essentiality are influenced by the nature of the encoded process, environmental conditions, and genetic background, including a strain's distinct evolutionary history. The covered topics have important consequences for antibacterials, which inhibit essential processes. We argue that the quantitative properties of essentiality can thus be used to prioritize antibacterial cellular targets and desired spectrum of activity in specific infection settings. We summarize our points with a case study on the core essential genome of the cystic fibrosis pathobiome and highlight avenues for targeted antibacterial development.

PMID:35104846 | DOI:10.1093/femsre/fuac005

Pediatr Pulmonol. 2022 Jan 31. doi: 10.1002/ppul.25852. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) registries play an essential role in improving disease outcomes of people with CF. This study aimed to evaluate the association of newly established CF registry system in Turkey on follow-up, clinical, growth, treatment, and complications of people with this disease.

METHODS: Age at diagnosis, current age, sex, z-scores of weight, height and body mass index (BMI), neonatal screening results, pulmonary function tests, history of meconium ileus, medications, presence of microorganisms, and follow-up were evaluated and compared to data of people with CF represented in both 2017 and 2019 registry data.

RESULTS: There were 1170 people with CF in 2017 and 1637 in 2019 CF registry. 814 people were registered in both 2017 and 2019 of whom z-scores of heights and BMI were significantly higher in 2019 (p=0.002,p=0.039,respectively). Inhaled hypertonic saline, bronchodilator and azithromycin usages were significantly higher in 2019 (p=0.001,p=0.001,p=0.003,respectively). The percent predicted of FEV1 and FVC were similar in 2017 and 2019 (88% and 89.5%,p=0.248 and 84.5% and 87%,p=0.332,respectively). Liver diseases and osteoporosis were significantly higher, and pseudo-Bartter syndrome (PBS) was significantly lower in 2019 (p=0.011,p=0.001,p=0.001,respectively).

CONCLUSIONS: The z-scores of height and BMI were higher, the use of medications that protect and improve lung functions was higher and incidence of PBS was lower in 2019. It was predicted that registry system increased the care of people with CF regarding their follow-up. The widespread use of national CF registry system across the country may be beneficial for the follow-up of people with CF. This article is protected by copyright. All rights reserved.

PMID:35102722 | DOI:10.1002/ppul.25852

J Biol Chem. 2022 Jan 28:101659. doi: 10.1016/j.jbc.2022.101659. Online ahead of print.

ABSTRACT

Ion channels use charged amino-acid side-chains to attract oppositely-charged permeant ions into the channel pore. In the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel, a number of arginine and lysine side-chains have been shown to be important for Cl- permeation. Among these, two in close proximity in the pore - Lys95 and Arg134 - are indispensable for anion binding and high Cl- conductance, suggesting that high positive charge density is required for pore function. Here we used mutagenesis and functional characterization to show that a nearby pore-lining negatively charged side-chain (Glu92) plays a functionally additive role with these two positively charged side-chains. While neutralization of this negative charge had little effect on anion binding or Cl- conductance, such neutralization was able to reverse the detrimental effects of removing the positive charge at either Lys95 or Arg134, as well as the similar effects of introducing a negative charge at a neighboring residue (Ser1141). Furthermore, neutralization of Glu92 greatly increased the susceptibility of the channel to blockage by divalent S2O32- anions, mimicking the effect of introducing additional positive charge in this region; this effect was reversed by concurrent neutralization of either Lys95 or Arg134. Across a panel of mutant channels that introduced or removed fixed charges at these four positions, we found that many pore properties are dependent on the overall charge or charge density. We propose that the CFTR pore uses a combination of positively and negatively charged side-chains to optimize the anion binding and Cl- conductance properties of the channel.

PMID:35101441 | DOI:10.1016/j.jbc.2022.101659

J Cyst Fibros. 2022 Jan 28:S1569-1993(22)00027-3. doi: 10.1016/j.jcf.2022.01.007. Online ahead of print.

ABSTRACT

BACKGROUND: The CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) leads to significant improvement in the symptoms and spirometry of people with cystic fibrosis (pwCF), but little evidence exists to understand its effect on respiratory pump function. Dynamic chest radiography (DCR) is a novel cineradiographic tool that identifies and tracks the chest wall and diaphragm throughout the breathing cycle, alongside fluoroscopic images of the chest of diagnostic quality.

METHODS: In this observational work, we examined the spirometry and DCR of 24 pwCF before and after starting ELX/TEZ/IVA. DCR automatically tracked the hemidiaphragm midpoints and projected lung area (PLA) during tidal and deep breathing manoeuvres.

RESULTS: ppFEV1 (61±18 to 73±22, P<0.001) and ppFVC (77±16 to 88±15, P<0.001) improved significantly. DCR demonstrated a significant increase in hemidiaphragm excursion on both the right (18±11 to 26±9 mm, P<0.001) and left (21±11 to 31±11 mm, P<0.001) sides, as well as maximum hemidiaphragm speed during inspiration (right 22±14 to 31±11 mm/s, P=0.03; left 28±11 to 37±16 mm/s, P=0.02). PLA at end-expiration was significantly reduced (334±71 to 290±72cm2, P<0.001), with a significant increase in ΔPLA (83±40 to 117±36cm2, P<0.001).

CONCLUSIONS: DCR demonstrated significant improvements in hemidiaphragm excursion and ΔPLA in pwCF started on ELX/TEZ/IVA. These changes likely reflect a reduction in air trapping and improved elastic recoil of the chest, and are consistent with improvements seen in spirometry. The changes seen with DCR are physiologically plausible and correlate well with spirometry. DCR warrants further investigation as a tool for assessing the impact of CFTR-modulating therapies.

PMID:35101365 | DOI:10.1016/j.jcf.2022.01.007

Klin Padiatr. 2022 Jan 28. doi: 10.1055/a-1700-5105. Online ahead of print.

ABSTRACT

BACKGROUND: Newborn screening (NBS) has been shown to improve cystic fibrosis (CF) disease course and has been widely implemented worldwide. This monocentric study compared children diagnosed by NBS vs. a cohort preceding the implementation of NBS in Germany in 2016 to evaluate ascribed benefits of NBS.

METHODS: We compared all children with confirmed CF diagnosis (n=19, "NBS group") out of all children presenting with positive NBS at our center after implementation of NBS (n=100) to children diagnosed with CF at our center within 4 years before NBS implementation (n=29, "pre-NBS group") for outcomes of anthropometry, gastrointestinal and pulmonary disease manifestations and respiratory microbiology.

RESULTS: Children diagnosed by NBS had a lower incidence of initial difficulty to thrive (15 vs. 41%) and showed higher mean z-scores for Body-Mass-Index (BMI), weight and length at diagnosis and during study period. Children in the pre-NBS group displayed higher proportions of oxygen-dependent pulmonary exacerbations (10 vs. 0%). They show a significantly lower amount of normal bacterial flora (p=0.005) along with a significantly higher number of throat swab cultures positive for Pseudomonas aeruginosa (p=0.0154) in the first year of life. Yet, pulmonary imaging did not reveal less pulmonary morbidity in the NBS group.

CONCLUSIONS: Our results confirm that NBS for CF leads to earlier diagnosis and improves nutritional outcomes in early childhood. Although trajectories of structural lung damage at early age were unaffected by NBS, NBS positive CF patients at preschool age displayed less pulmonary exacerbations and pathological bacteria in throat swabs.

PMID:35098497 | DOI:10.1055/a-1700-5105

J Membr Biol. 2022 Jan 30. doi: 10.1007/s00232-022-00216-2. Online ahead of print.

ABSTRACT

The volume-activated chloride channel (VACC) serves vital cellular functions in secretion and cell volume regulation via regulatory volume decrease (RVD) in various epithelia. Previously, we have shown that RVD in primary CF mouse cholangiocytes is impaired. Thus, the effect of CFTR defect on VACC and RVD in CF human immortalized cholangiocyte cell (HBDC) was examined in comparison with those in normal HBDC by using cell volume measurement and whole-cell patch clamp techniques, respectively. The CF HBDC had an impaired RVD, which was not further inhibited by removing the extracellular calcium or administering BAPTA-AM, NPPB, or DIDS. When exposed to a hypotonic solution, CF HBDC exhibited large, outwardly rectified currents with time-dependent inactivation at a positive potential. The amplitude of the outward currents was about three times that of the inward currents. The amplitude and reversal potential of VACC was dependent on chloride concentration. The VACC was significantly inhibited by replacing chloride with gluconate, glutamate, sucrose, or acetate in the hypotonic solution as well as by an administration of NPPB or tamoxifen, classical VACC inhibitors. Surprisingly, the VACC amplitude is greater in CF HBDC than in normal HBDC, suggesting that the channel density or open probability of VACC is increased, thus CFTR may have inhibitory effects on VACC. On the contrary, the amplitude of the volume-activated potassium current is lower in CF HBDC, suggesting the potassium channel density or open probability is decreased in CF cholangiocytes and/or CFTR may have regulatory effects on volume-activated potassium current. In conclusion, RVD is impaired in CF human cholangiocytes. The VACC of CF human cholangiocytes has similar electrophysiological characteristics as that of normal cholangiocytes but its activity is augmented in CF cholangiocytes, while volume-activated potassium current is decreased in CF human cholangiocytes, providing a fundamental underlying pathophysiologic mechanism for the impaired RVD in CF cholangiocytes.

PMID:35098342 | DOI:10.1007/s00232-022-00216-2

Biomed Res Int. 2022 Jan 19;2022:5818840. doi: 10.1155/2022/5818840. eCollection 2022.

ABSTRACT

BACKGROUND: Saliva biomarkers could be easily used as a noninvasive alternative tool for diagnosing cystic fibrosis (CF) disease. In this study, the significance of changes in salivary compositions in patients with CF was systematically reviewed.

METHODS: An electronic search was utilized to include studies published in English, with case-control, cohort, or cross-sectional design. The evaluated salivary components were extracted and summarized. The included studies were assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist.

RESULTS: Out of 498 identified studies, nine met the eligibility criteria. Salivary electrolytes showed a substantial alteration in the CF group, especially with chloride and sodium. Total protein concentration was higher in patients with CF. However, SCN- concentration was lower in patients with CF. In addition, a reduction in the salivary flow rate and amylase levels was found in patients with CF.

CONCLUSION: Alterations in salivary biomarkers among patients with CF could be used as a promising diagnostic tool for cystic fibrosis.

PMID:35097122 | PMC:PMC8791744 | DOI:10.1155/2022/5818840

Front Med (Lausanne). 2022 Jan 12;8:757739. doi: 10.3389/fmed.2021.757739. eCollection 2021.

ABSTRACT

Background: This systematic review evaluates the oral health-related quality of life (OHRQoL) of patients with chronic respiratory diseases. Methods: A systematic literature search was performed based on the PubMed, Medline, Web of Science, and Scopus, using the search terms: "oral health-related quality of life" and "respiratory disease" or "lung" and "oral health-related quality of life." Full-text articles published until June 30, 2021 and reporting any OHRQoL measurement in children or adults with a chronic respiratory disease or condition were included and analyzed qualitatively. Results: A total of seven out of 44 studies were included, of which four studies examined adults and three studies investigated children. The respective diseases were chronic obstructive pulmonary disease (COPD) (n = 2), sleep apnea (n = 2), severe asthma (n = 1), cystic fibrosis (n = 1), and lung transplantation (n = 1). Four studies confirmed a worse OHRQoL in the respiratory diseased group compared to healthy controls. The overall OHRQoL was reduced in the included studies. Oral health, health-related quality of life, and disease-related parameters were rarely examined with regard to OHRQoL. Conclusion: Patients with chronic respiratory diseases show a reduced OHRQoL. Oral health should be fostered in these individuals to support their OHRQoL.

PMID:35096862 | PMC:PMC8790480 | DOI:10.3389/fmed.2021.757739

Front Pediatr. 2022 Jan 13;9:734292. doi: 10.3389/fped.2021.734292. eCollection 2021.

ABSTRACT

Children with cystic fibrosis (CF) (cwCF) suffer from inadequate weight gain, failure to thrive, and muscle weakness. The latter may be secondary to disuse atrophy (muscle wasting or reduction in muscle size associated with reduced physical activity and inflammation). Handgrip strength (HGS) is a reliable surrogate for muscle strength and lean body mass. Data from our CF center have shown an association between low HGS and forced expiratory volume in 1 s (FEV1) in cwCF. High-intensity interval training (HIIT) improves physical strength. Therefore, we devised a project to assess implementing a HIIT exercise program in the home setting, in order to improve physical strength in cwCF with HGS ≤ 50th percentile. Patients were instructed to complete 3-5 sessions of HIIT exercises per week. Wilcoxon matched-pairs signed-rank tests were used to compare HGS, FEV1, and body mass index (BMI) percentile at baseline and at a follow-up clinic visit. Follow-up was limited due to the COVID pandemic. Adherence to the HIIT regimen was poor. A total of twenty-nine cwCF participated in the program. However, a total of 13 individuals reported some form of moderate activity at follow-up and therefore constituted our final study population. There was a statistically significant increase in absolute grip strength (AGS) and FEV1 for these individuals. Even though the home HIIT protocol was not followed, the project demonstrated that moderate physical activity in cwCF can lead to significant improvement in HGS and overall physical strength.

PMID:35096701 | PMC:PMC8793844 | DOI:10.3389/fped.2021.734292

Front Pediatr. 2022 Jan 14;9:692949. doi: 10.3389/fped.2021.692949. eCollection 2021.

ABSTRACT

INTRODUCTION: In cystic fibrosis (CF), pathological lung changes begin early in life. The technological progress currently gives many diagnostic possibilities. However, pulmonary function testing in children remains problematic.

OBJECTIVES: Our study aimed to correlate the results of impulse oscillometry (IOS) with those of multiple breath nitrogen washout (MBNW) in our pediatric CF population. We also compared those parameters between the groups with and without spirometric features of obturation.

METHODS: We collected 150 pulmonary function test sets, including spirometry, IOS, and MBNW in patients with CF aged 12.08 ± 3.85 years [6-18]. The study group was divided into two subgroups: IA (without obturation) and IB (with obturation). We also compared Sacin, Scond, and oscillometry parameters of 20 patients aged 14-18 years who reached the appropriate tidal volume (VT) during MBNW.

RESULTS: Statistical analysis showed a negative correlation between lung clearance index (LCI) and spimoetric parameters. Comparison of subgroups IA (n = 102) and IB (n = 48) indicated a statistically significant difference in LCI (p < 0.001) and FEV1z-score (p < 0.001), FEV1% pred (p < 0.001), MEF25z-score (p < 0.001), MEF50 z-score (p < 0.001), MEF75 z-score (p < 0.001), R5% pred (p < 0.05), and R20% pred (p < 0.01). LCI higher than 7.91 was found in 75.33% of the study group, in subgroup IB-91.67%, and IA-67.6%.

CONCLUSIONS: LCI derived from MBNW may be a better tool than IOS for assessing pulmonary function in patients with CF, particularly those who cannot perform spirometry.

PMID:35096700 | PMC:PMC8795905 | DOI:10.3389/fped.2021.692949

Front Cell Infect Microbiol. 2022 Jan 12;11:773665. doi: 10.3389/fcimb.2021.773665. eCollection 2021.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that causes life-threatening infections in cystic fibrosis patients and immunocompromised individuals. A tightly regulated immune response possessed by healthy individuals can effectively control P. aeruginosa infections, whereas the patients with dysregulated immune response are susceptible to this bacterial pathogen. Early growth response 1 (Egr-1) is a zinc-finger transcription factor involved in regulation of various cellular functions, including immune responses. We previously identified that Egr-1 was deleterious to host in a mouse model of acute P. aeruginosa pneumonia by promoting systemic inflammation and impairing bacterial clearance in lung, which associated with reduced phagocytosis and bactericidal ability of leucocytes, including macrophages and neutrophils. However, the molecular mechanisms underlying the Egr-1-suppressed phagocytosis of P. aeruginosa are incompletely understood. Herein, we investigated whether the Egr-1-regulated autophagy play a role in macrophage phagocytosis during P. aeruginosa infection by overexpression or knockdown of Egr-1. We found that overexpression of Egr-1 inhibited the phagocytic activity of macrophages, and the autophagy activator rapamycin and inhibitor chloroquine could reverse the effects of Egr-1 knockdown and Egr-1 overexpression on phagocytosis of P. aeruginosa, respectively. Furthermore, the Egr-1-overexpressing macrophages displayed upregulated expression of autophagy-related proteins LC3A, LC3B and Atg5, and decreased levels of p62 in macrophages. Further studies revealed that the macrophages with Egr-1 knockdown displayed enhanced activation of transcription factor NRF2 and expression of scavenger receptors MACRO and MSR1. Altogether, these findings suggest that Egr-1 suppresses the phagocytosis of P. aeruginosa by macrophages through upregulation of autophagy and inhibition of NRF2 signaling.

PMID:35096638 | PMC:PMC8790152 | DOI:10.3389/fcimb.2021.773665

Front Oncol. 2022 Jan 14;11:821785. doi: 10.3389/fonc.2021.821785. eCollection 2021.

ABSTRACT

Local anesthetics are frequently employed during surgery in order to control peri- and postoperative pain. Retrospective studies have revealed an unexpected correlation between increased long-term survival and the use of local anesthetics during oncological surgery. This effect of local anesthetics might rely on direct cytotoxic effects on malignant cells or on indirect, immune-mediated effects. It is tempting to speculate, yet needs to be formally proven, that the combination of local anesthetics with oncological surgery and conventional anticancer therapy would offer an opportunity to control residual cancer cells. This review summarizes findings from fundamental research together with clinical data on the use of local anesthetics as anticancer standalone drugs or their combination with conventional treatments. We suggest that a better comprehension of the anticancer effects of local anesthetics at the preclinical and clinical levels may broadly improve the surgical treatment of cancer.

PMID:35096626 | PMC:PMC8796204 | DOI:10.3389/fonc.2021.821785

Oncoimmunology. 2022 Jan 25;11(1):2031500. doi: 10.1080/2162402X.2022.2031500. eCollection 2022.

ABSTRACT

Vitamin B5 (panthotenic acid), the precursor of coenzyme A (CoA), is contained in most food items and is produced by the intestinal microbiota. A recent study published in Cell Metabolism reports that vitamin B5 and CoA favor the differentiation of CD8+ cytotoxic T cells into interleukin-22 (IL-22)-producing Tc22 cells, likely through fueling mitochondrial metabolism. Importantly, in a small cohort of melanoma patients, the plasma levels of vitamin B5 positively correlate with responses to PD-1-targeted immunotherapy. Moreover, in mice, supplementation with vitamin B5 increases the efficacy of PD-L1-targeted cancer immunotherapy, and in vitro culture of T cells with CoA enhances their antitumor activity upon adoptive transfer into mice. These finding suggest that vitamin B5 is yet another B vitamin that stimulates anti-cancer immunosurveillance.

PMID:35096488 | PMC:PMC8794238 | DOI:10.1080/2162402X.2022.2031500

Virulence. 2022 Dec;13(1):215-224. doi: 10.1080/21505594.2022.2028484.

ABSTRACT

Cystic fibrosis (CF) disease is characterized by an intense airway inflammatory response mediated by neutrophils and chronic respiratory infections caused by P. aeruginosa. High levels of the complement component C5a, the strongest neutrophil chemoattractant molecule, are commonly found in the CF lung and have been associated with a worsening of the disease. In this study, we investigated how the isolates from CF patients modulate the levels of C5a and identified the bacterial factors involved. We demonstrated that most isolates from airway chronic infections induce the production and accumulation of C5a, an effect attributable to the loss of C5a cleavage by the exoproteases alkaline protease (AprA) and elastase B (LasB). Furthermore, we found that lack of the bacterial protease-dependent C5a degradation is due to mutations in the master regulator LasR. Thus, complementation of a non-C5a-cleaving CF isolate with a functional wild-type LasR restored its ability to express both proteases, cleave C5a and reduce neutrophil recruitment in vitro. These findings suggest that the non-cleaving C5a phenotype acquired by the LasR variants frequently isolated in CF patients may account for the strong neutrophilia and general neutrophil dysfunction predisposing toward increased inflammation and reduced bacterial clearance described in CF patients.

PMID:35094639 | DOI:10.1080/21505594.2022.2028484

Biochem Biophys Res Commun. 2022 Jan 15;595:14-21. doi: 10.1016/j.bbrc.2021.12.021. Online ahead of print.

ABSTRACT

Organoid cryopreservation method is one of key step in the organoid culture. We aimed to establish a simple and efficient cryopreservation method for mouse small intestinal organoids (MIOs) and colon organoids (MCOs) using various concentrations of cryoprotectant. Based on the theoretical simulation, we optimized the dimethyl sulfoxide (DMSO) concentration by pretreating the organoids with 5, 7.5, and 10% DMSO for 30 min at 4 °C to allow penetration into the organoids and evaluated their viability, proliferation, and function after cryopreservation. Gene expression in the MIOs and staining of lineage markers were examined real-time PCR. The organoids in the DMSO-treated groups as well as the control, expressed ChrgA, Ecad, Muc2, Lyz, villin, and Lgr5, and there are no significant. A forskolin-induced swelling assay for MIOs was performed to confirm normal cystic fibrosis transmembrane conductance regulator (CFTR) activity. Similar forskolin-induced swelling was observed in the DMSO-treated groups and the control. In addition, MCOs were transplanted into mouse colon for confirmation of regeneration therapy efficacy. Thawing organoids were cultured for two and four sequential passages after cryopreservation with 5% DMSO to confirm any changes in the gene expression of lineage markers after subculture. We developed a simple and efficient organoid freezing method using 5% DMSO with low potential toxicity and validated our findings with theoretical simulation.

PMID:35093635 | DOI:10.1016/j.bbrc.2021.12.021

BMC Pediatr. 2022 Jan 29;22(1):69. doi: 10.1186/s12887-022-03134-3.

ABSTRACT

BACKGROUND: Adolescents and young adults (AYA) with a chronic medical condition show an increased risk for developing mental comorbidities compared to their healthy peers. Internet- and mobile-based cognitive behavioral therapy (iCBT) might be a low-threshold treatment to support affected AYA. In this randomized controlled pilot trial, the feasibility and potential efficacy of youthCOACHCD, an iCBT targeting symptoms of anxiety and depression in AYA with chronic medical conditions, was evaluated.

METHODS: A total of 30 AYA (Mage 16.13; SD= 2.34; 73% female), aged 12-21 years either suffering from cystic fibrosis, juvenile idiopathic arthritis or type 1 diabetes, were randomly assigned to either a guided version of the iCBT youthCOACHCD (IG, n=15) or to a waitlist control group (CG, n=15), receiving an unguided version of the iCBT six months post-randomization. Participants of the IG and the CG were assessed before (t0), twelve weeks after (t1) and six months after (t2) randomization. Primary outcome was the feasibility of the iCBT. Different parameters of feasibility e.g. acceptance, client satisfaction or potential side effects were evaluated. First indications of the possible efficacy with regard to the primary efficacy outcome, the Patient Health Questionnaire Anxiety and Depression Scale, and further outcome variables were evaluated using linear regression models, adjusting for baseline values.

RESULTS: Regarding feasibility, intervention completion was 60%; intervention satisfaction (M = 25.42, SD = 5.85) and perceived therapeutic alliance (M = 2.83, SD = 1.25) were moderate and comparable to other iCBTs. No patterns emerged regarding subjective and objective negative side effects due to participation in youthCOACHCD. Estimates of potential efficacy showed between group differences, with a potential medium-term benefit of youthCOACHCD (β = -0.55, 95%CI: -1.17; 0.07), but probably not short-term (β = 0.20, 95%CI: -0.47; 0.88).

CONCLUSIONS: Our results point to the feasibility of youthCOACHCD and the implementation of a future definitive randomized controlled trial addressing its effectiveness and cost-effectiveness. Due to the small sample size, conclusions are premature, however, further strategies to foster treatment adherence should be considered.

TRIAL REGISTRATION: The trial was registered at the WHO International Clinical Trials Registry Platform via the German Clinical Trials Register (ID: DRKS00016714 , 25/03/2019).

PMID:35093047 | DOI:10.1186/s12887-022-03134-3