J Vis Exp. 2021 Nov 10;(177). doi: 10.3791/63090.

ABSTRACT

Measurements of cilia function (beat frequency, pattern) have been established as diagnostic tools for respiratory diseases such as primary ciliary dyskinesia. However, the wider application of these techniques is limited by the extreme susceptibility of ciliary function to changes in environmental factors e.g., temperature, humidity, and pH. In the airway of patients with Cystic Fibrosis (CF), mucus accumulation impedes cilia beating. Cilia function has been investigated in primary airway cell models as an indicator of CF Transmembrane conductance Regulator (CFTR) channel activity. However, considerable patient-to-patient variability in cilia beating frequency has been found in response to CFTR-modulating drugs, even for patients with the same CFTR mutations. Furthermore, the impact of dysfunctional CFTR-regulated chloride secretion on ciliary function is poorly understood. There is currently no comprehensive protocol demonstrating sample preparation of in vitro airway models, image acquisition, and analysis of Cilia Beat Frequency (CBF). Standardized culture conditions and image acquisition performed in an environmentally controlled condition would enable consistent, reproducible quantification of CBF between individuals and in response to CFTR-modulating drugs. This protocol describes the quantification of CBF in three different airway epithelial cell model systems: 1) native epithelial sheets, 2) air-liquid interface models imaged on permeable support inserts, and 3) extracellular matrix-embedded three-dimensional organoids. The latter two replicate in vivo lung physiology, with beating cilia and production of mucus. The ciliary function is captured using a high-speed video camera in an environment-controlled chamber. Custom-built scripts are used for the analysis of CBF. Translation of CBF measurements to the clinic is envisioned to be an important clinical tool for predicting response to CFTR-modulating drugs on a per-patient basis.

PMID:34842237 | DOI:10.3791/63090

Tissue Eng Part A. 2021 Nov 27. doi: 10.1089/ten.TEA.2021.0071. Online ahead of print.

ABSTRACT

The nasal mucosa functions as a frontline biological defense against various foreign substances and pathogens. Maintaining homeostasis of the nasal epithelium is necessary to promote good health. Nasal epithelia are constantly replaced under normal conditions. However, hereditary diseases, including primary ciliary dyskinesia and cystic fibrosis, can result in intractable dysfunction of the nasal mucosa. Since there is no treatment for this underlying condition, extrinsic manipulation is necessary to recover and maintain nasal epithelia in cases of hereditary diseases. In this study, we explored the use of airway epithelial cells (AECs), including multi-ciliated airway cells (MCACs), derived from human induced pluripotent stem cells (hiPSCs) on porcine atelocollagen vitrigel membranes, as a candidate of a therapeutic method for irreversible nasal epithelial disorders. To confirm the regenerative capacity of iPSC-derived AECs, we transplanted them into nasal cavities of nude rats. Although the transplanted cells were found within cysts isolated from the recipient nasal respiratory epithelia, they survived in some rats. Furthermore, the surviving cells were composed of multiple cell types similar to the human airway epithelia. The results could contribute to the development of novel transplantation-related technologies for the treatment of severe irreversible nasal epithelial disorders.

PMID:34841888 | DOI:10.1089/ten.TEA.2021.0071

JAAD Case Rep. 2021 Oct 25;18:71-73. doi: 10.1016/j.jdcr.2021.10.018. eCollection 2021 Dec.

NO ABSTRACT

PMID:34841028 | PMC:PMC8606295 | DOI:10.1016/j.jdcr.2021.10.018

Curr Psychol. 2021 Nov 24:1-14. doi: 10.1007/s12144-021-02452-6. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a rare disease that severely compromises health and interferes with the lives of those who suffer from it and is especially challenging in adolescence. The use of tools such as MHealth may benefit the physical and psychological health of adolescents with CF. Therefore, this study aims to examine the benefits of MHealth in adolescents with CF through a systematic review. A search of the scientific literature following the PRISMA guidelines was conducted in the ProQuest Central, PubMed, Web Of Science, Embase and ínDICE databases, resulting in 186 studies, of which seven were selected (based on inclusion and exclusion criteria). Two blinded evaluators conducted the searches, the selection and data extraction process and the quality evaluation of the studies. The agreement between evaluators was excellent in all cases (Kappa ranged from .78 to .96). 214 pediatric CF patients (61.71% female) participated in the final analysis. The mean age was 12.76 years. The studies evaluated different types of mHealth tools, with greater homogeneity in the independent and dependent variables. The quality of the studies analyzed was poor, since these had small samples selected for convenience, conducted non-experimental and low-quality designs, recorded few variables, and their statistical analyses were not sufficiently robust. Further research is needed in this field, improving research designs and considering physical and psychological adjustment variables, as well as patients and family members in the process of health improvement.

PMID:34840486 | PMC:PMC8610788 | DOI:10.1007/s12144-021-02452-6

Nutr Hosp. 2021 Nov 29. doi: 10.20960/nh.03836. Online ahead of print.

ABSTRACT

INTRODUCTION: few studies have evaluated body composition (BC) through different techniques, and the degree of agreement between them in adults with cystic fibrosis (CF).

OBJECTIVES: to describe BC using techniques to assess nutritional status and to test their concordance in CF.

METHODS: a cross-sectional study in CF patients in a clinically stable situation. Nutritional assessment was performed using skinfold measurement (SM) and densitometry (DXA). Fat-free mass index (FFMI) was also determined. The diagnosis of malnutrition was established if body mass index (BMI) < 18.5 kg/m2. Fat-free mass (FFM) malnutrition was diagnosed when FFMI was < 17 kg/m2 in males and < 15 kg/m2 in females (FFMI: fat-free mass in kg/height in m2).

RESULTS: forty-one patients were studied (twenty-two females, 53.7 %); median age was 29.8 (interquartile range, 20.9-33.7); BMI was 21.6 (19.8-23.0). Only four (9.8 %) patients had a BMI < 18.5. By DXA, FFM (kg) results were: median, 52.8 (47.8-56.9) with FFMI of 17.9 (16.7-19.3) in males and 36.7 (33.1-38.9) in females, FFMI of 14.7 (14.2-15.8). Twenty (48.6 %) patients presented FFM malnutrition, with 16.7 % of males and 59.1 % of females being affected. By SM, the FFMI was 18.7 (17.2-20.0) in males and 14.9 (14.2-15.8) in females; moreover, sixteen (39.1 %) patients presented malnutrition of FFM, with 20.8 % of males and 61.8 % of females being affected. For FFM (kg), a high concordance was obtained between SM and DXA (intraclass correlation coefficient of 0.950); likewise when they were compared by applying the ESPEN criteria for FFM malnutrition. However, when the techniques were compared to classify malnutrition according to FFMI, the kappa coefficient was only moderate (k = 0.440). The mean difference between FFM by DXA and SM was +1.44 ± 0.62 kg in favor of SM, with greater dispersion as FFM increased.

CONCLUSIONS: the prevalence of FFM malnutrition is high in adult CF patients, despite a normal BMI, especially in females. Notwithstanding the good statistical agreement between SM and DXA, concordance was moderate. Therefore, DXA remains the technique of choice, and SM may be used when the former is not available.

PMID:34839671 | DOI:10.20960/nh.03836

Cell Calcium. 2021 Nov 8;101:102499. doi: 10.1016/j.ceca.2021.102499. Online ahead of print.

ABSTRACT

Bitter taste receptors (T2Rs) localize to airway motile cilia and initiate innate immune responses in retaliation to bacterial quorum sensing molecules. Activation of cilia T2Rs leads to calcium-driven NO production that increases cilia beating and directly kills bacteria. Several diseases, including chronic rhinosinusitis, COPD, and cystic fibrosis, are characterized by loss of motile cilia and/or squamous metaplasia. To understand T2R function within the altered landscape of airway disease, we studied T2Rs in non-ciliated airway cell lines and primary cells. Several T2Rs localize to the nucleus in de-differentiated cells that typically localize to cilia in differentiated cells. As cilia and nuclear import utilize shared proteins, some T2Rs may target to the nucleus in the absence of motile cilia. T2R agonists selectively elevated nuclear and mitochondrial calcium through a G-protein-coupled receptor phospholipase C mechanism. Additionally, T2R agonists decreased nuclear cAMP, increased nitric oxide, and increased cGMP, consistent with T2R signaling. Furthermore, exposure to T2R agonists led to nuclear calcium-induced mitochondrial depolarization and caspase activation. T2R agonists induced apoptosis in primary bronchial and nasal cells differentiated at air-liquid interface but then induced to a squamous phenotype by apical submersion. Air-exposed well-differentiated cells did not die. This may be a last-resort defense against bacterial infection. However, it may also increase susceptibility of de-differentiated or remodeled epithelia to damage by bacterial metabolites. Moreover, the T2R-activated apoptosis pathway occurs in airway cancer cells. T2Rs may thus contribute to microbiome-tumor cell crosstalk in airway cancers. Targeting T2Rs may be useful for activating cancer cell apoptosis while sparing surrounding tissue.

PMID:34839223 | DOI:10.1016/j.ceca.2021.102499

Chest. 2021 Nov 24:S0012-3692(21)04412-3. doi: 10.1016/j.chest.2021.11.014. Online ahead of print.

ABSTRACT

BACKGROUND: Non-tuberculous mycobacterial (NTM) infections are difficult to diagnose and treat. Biomarkers to identify patients with active infection or at risk of disease progression would have clinical utility. Sputum is the most frequently used matrix for diagnosis of NTM lung disease.

RESEARCH QUESTION: Can sputum proteomics be used to identify NTM associated inflammatory profiles in sputum?

STUDY DESIGN AND METHODS: Patients with NTM lung disease and a matched cohort of patients with chronic obstructive pulmonary disease (COPD), bronchiectasis (BE) and cystic fibrosis (CF) without NTM lung disease were enrolled from two hospitals in the UK. Liquid chromatography-tandem mass spectrometry was used to identify proteomic biomarkers associated with underlying diagnosis (COPD, BE, CF), the presence of NTM lung disease defined by ATS/IDSA criteria and severity of NTM. A subset of patients receiving guideline concordant NTM treatment were studied to identify protein changes associated with treatment response.

RESULTS: We analysed 95 sputum samples from 55 subjects (21 BE, 19 COPD, 15 CF). Underlying disease and infection with Pseudomonas aeruginosa were the strongest drivers of sputum protein profiles. Comparing protein abundance in COPD, BE and CF showed 12 proteins were upregulated in CF including MPO, AZU1, CTSG, CAT and RNASE3 with 21 proteins downregulated including SCGB1A1, IGFBP2, SFTPB, GC and CFD. Across CF, BE and COPD, NTM infection (n=15) was not associated with statistically significant differences in sputum protein profiles compared to those without NTM. 2 proteins associated with iron chelation were significantly downregulated in severe NTM disease. NTM treatment was associated with heterogeneous changes in sputum protein profile. NTM patients with a decrease in immune response proteins had a subjective symptomatic improvement.

INTERPRETATION: Sputum proteomics identified candidate biomarkers of NTM severity and treatment response, however underlying lung disease and typical bacterial pathogens such as P. aeruginosa are also key determinants of sputum proteome profile.

PMID:34838525 | DOI:10.1016/j.chest.2021.11.014

J Cardiothorac Surg. 2021 Nov 27;16(1):341. doi: 10.1186/s13019-021-01719-0.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease, cystic fibrosis and usual interstitial pneumonia are three most common indications for lung transplantation (LuTx) in Poland. As a result of irreversible destruction of pulmonary parenchyma and extended respiratory insufficiency that appear afterwards, it is crucial to estimate the reserve of gas exchange in each lung before and during surgery. Altering conditions of gas exchange require adaptation in circulatory system as well. In some of the cases the use of extracorporeal life support appears to be necessary to undergo the transplantation successfully. Cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) used during operation allow to replace the function of heart and lung, but they are also related to complications in the form of acute kidney failure, bleeding, heart arrhythmias or thromboembolic complications.

METHODS: We reviewed 77 LuTx from 2009 to 2020 performed at the Department of Thoracic Surgery and Transplantation. 40/77 (51%) patients required intraoperative extracorporeal assistance: 8 required CBP and 32 required ECMO. In the ECMO group 14/32 (44%) patients had peripheral cannulation and 18/32 (56%) had central one. We have calculated the survival rates and reviewed postoperative complications after lung transplantations. Cumulative Kaplan-Meier survival curves were calculated. Differences between the groups were evaluated by the Chi- square analysis for discontinuous variables and t-test for continuous variables.

RESULTS: The use of intraoperative central extracorporeal membrane oxygenator was associated with increased survival rates comparing to patients without external support (30-days, 1-year, 3-years, 5-years rates: 78%, 66%, 66%, 66% vs 83%, 65%, 59%, 44% respectively). Furthermore, survival was enhanced comparing to peripheral ECMO or cardiopulmonary bypass as well (50%, 41%, 41%, 33%; 75%, 50%, 50%, 38% respectively). Acute kidney injury and thromboembolic complications occurred statistically more often in case of patients that underwent lung transplantation with support devices (p = 0.005, p = 0.02 respectively). Frequency of other complications was comparable among groups.

CONCLUSIONS: The use of central extracorporeal membrane oxygenation should be favorized over peripheral cannulation or cardiopulmonary bypass. CPB should be no longer used during LuTx. Trial registration Not applicable.

PMID:34838067 | DOI:10.1186/s13019-021-01719-0

Methods Mol Biol. 2022;2393:733-750. doi: 10.1007/978-1-0716-1803-5_39.

ABSTRACT

Electrical impedance tomography (EIT) is a medical imaging technique in which low frequency, low amplitude electromagnetic fields applied through electrodes on the skin are used to compute the conductivity and/or permittivity inside the body and form functional images from the reconstructed values. This work describes methods of computing EIT-derived surrogate measures of pulmonary function and identifying regions of air trapping and consolidation from functional EIT images. These methods were developed for pediatric patients with cystic fibrosis, for whom a real-time non-ionizing imaging modality can be of great benefit for monitoring disease progression or a pulmonary exacerbation.

PMID:34837209 | DOI:10.1007/978-1-0716-1803-5_39

Adv Microb Physiol. 2021;79:25-88. doi: 10.1016/bs.ampbs.2021.07.001. Epub 2021 Nov 16.

ABSTRACT

Toward the end of August 2000, the 6.3 Mbp whole genome sequence of Pseudomonas aeruginosa strain PAO1 was published. With 5570 open reading frames (ORFs), PAO1 had the largest microbial genome sequenced up to that point in time-including a large proportion of metabolic, transport and antimicrobial resistance genes supporting its ability to colonize diverse environments. A remarkable 9% of its ORFs were predicted to encode proteins with regulatory functions, providing new insight into bacterial network complexity as a function of network size. In this celebratory article, we fast forward 20 years, and examine how access to this resource has transformed our understanding of P. aeruginosa. What follows is more than a simple review or commentary; we have specifically asked some of the leaders in the field to provide personal reflections on how the PAO1 genome sequence, along with the Pseudomonas Community Annotation Project (PseudoCAP) and Pseudomonas Genome Database (pseudomonas.com), have contributed to the many exciting discoveries in this field. In addition to bringing us all up to date with the latest developments, we also ask our contributors to speculate on how the next 20 years of Pseudomonas research might pan out.

PMID:34836612 | DOI:10.1016/bs.ampbs.2021.07.001

Nutrients. 2021 Nov 16;13(11):4107. doi: 10.3390/nu13114107.

ABSTRACT

BACKGROUND: Loss of fat-free mass (FFM) is associated with an increase in morbidity and mortality in cystic fibrosis (CF) patients. Handgrip strength (HGS) measures muscle function and may be associated with clinical parameters with prognostic value. Our objectives were to evaluate muscle strength through HGS in CF patients and to determine if there are any associations with respiratory clinical variables, FFM, and bone mineral density (BMD).

METHODS: A cross-sectional study conducted in clinically stable patients. We evaluated muscle function through HGS, respiratory function-forced expiratory volume in 1 s (FEV1) (%), forced vital capacity (FVC) (%), bronchorrhea, annual exacerbations, and body composition (FFM and FFM index, FFMI: fat-free mass in kg/height in m2) and Bone Mineral Density (BMD) through densitometry (DXA).

RESULTS: The study included 53 CF patients (58.5% females, mean age 28.3 ± 8.1, body mass index (BMI) 21.7 ± 3.4). The mean values for dynamometry were 40.2 ± 8.1 kg in males and 23.1 ± 7.0 kg in women, being 20.8% below the 10th percentile. Patients with lower muscle strength showed significantly more exacerbations and lower FEV1% and FVC%, as well as lower BMI, worse BMD (g/cm2), T-score, and Z-score. A significant and positive correlation was found between the mean and maximum dynamometry values and age, FVC%, BMI, FFMI, FFM (kg), and BMD.

CONCLUSIONS: For adults with CF, HGS is a practical tool for assessment of health status. Low values reflect poor nutritional status and are associated with poor respiratory function, low fat-free mass and low bone mineral density.

PMID:34836360 | DOI:10.3390/nu13114107

Nutrients. 2021 Nov 12;13(11):4048. doi: 10.3390/nu13114048.

ABSTRACT

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) affects up to half of the people with cystic fibrosis (CF) by adulthood. CFRD is primarily caused by pancreatic dysfunction that leads to insufficient insulin release and/or insulin resistance. Exocrine pancreatic insufficiency in people with CF is associated with fat-soluble vitamin malabsorption, including vitamins A, D, E, and K. This study examined the relationship between vitamin D status, assessed by serum 25-hydroxyvitamin D (25(OH)D), and the development of CF-related diabetes (CFRD) in adults with CF.

METHODS: This was a retrospective cohort study of adults seen at a single CF center. The data were extracted from the electronic medical records and the Emory Clinical Data Warehouse, a data repository of health information from patients seen at Emory Healthcare. We collected age, race, the first recorded serum 25-hydroxyvitamin D (25(OH)D) concentration, body mass index (BMI), and onset of diabetes diagnosis. Log-rank (Mantel-Cox) tests were used to compare the relative risk of CFRD onset in the subjects with stratified vitamin D status and weight status. A sub-group analysis using chi-square tests assessed the independence between vitamin D deficiency and CFRD risk factors, including gender and CF mutation types (homozygous or heterozygous for F508del, or others). Unpaired t-tests were also used to compare the BMI values and serum 25(OH)D between the CF adults based on the CFRD development.

RESULTS: This study included 253 subjects with a mean age of 27.1 years (±9.0), a mean follow-up time period of 1917.1 (±1394.5) days, and a mean serum 25(OH)D concentration of 31.8 ng/mL (±14.0). The majority (52.6%) of the subjects developed CFRD during the study period. Vitamin D deficiency (defined as 25(OH)D < 20 ng/mL) was present in 25.3% of the subjects. Close to two thirds (64.1%) of the subjects with vitamin D deficiency developed CFRD during the study. Vitamin D deficiency increased the risk of developing CFRD (chi-square, p = 0.03) during the course of the study. The time to the onset of CFRD stratified by vitamin D status was also significant (25(OH)D < 20 ng/mL vs. 25(OH)D ≥ 20 ng/mL) (95% CI: 1.2, 2.7, p < 0.0078).

CONCLUSION: Our findings support the hypothesis that adults with CF and vitamin D deficiency are at a higher risk of developing CFRD and are at risk for earlier CFRD onset. The maintenance of a serum 25(OH)D concentration above 20 ng/mL may decrease the risk of progression to CFRD.

PMID:34836301 | DOI:10.3390/nu13114048

Nutrients. 2021 Nov 10;13(11):3996. doi: 10.3390/nu13113996.

ABSTRACT

Food insecurity (FI) is defined as "the limited or uncertain access to adequate food." One root cause of FI is living in a food desert. FI rates among people with cystic fibrosis (CF) are higher than the general United States (US) population. There is limited data on the association between food deserts and CF health outcomes. We conducted a retrospective review of people with CF under 18 years of age at a single pediatric CF center from January to December 2019 using demographic information and CF health parameters. Using a Geographic Information System, we conducted a spatial overlay analysis at the census tract level using the 2015 Food Access Research Atlas to assess the association between food deserts and CF health outcomes. We used multivariate logistic regression analysis and adjusted for clinical covariates and demographic covariates, using the Child Opportunity Index (COI) to calculate odds ratios (OR) with confidence intervals (CI) for each health outcome. People with CF living in food deserts and the surrounding regions had lower body mass index/weight-for-length (OR 3.18, 95% CI: 1.01, 9.40, p&nbsp;≤ 0.05 (food desert); OR 4.41, 95% CI: 1.60, 12.14, p ≤ 0.05 (600 ft buffer zone); OR 2.83, 95% CI: 1.18, 6.76, p ≤ 0.05 (1200 ft buffer zone)). Food deserts and their surrounding regions impact pediatric CF outcomes independent of COI. Providers should routinely screen for FI and proximity to food deserts. Interventions are essential to increase access to healthy and affordable food.

PMID:34836250 | DOI:10.3390/nu13113996

Microorganisms. 2021 Oct 29;9(11):2257. doi: 10.3390/microorganisms9112257.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen responsible for nosocomial infections, and is often involved in airway infections of cystic fibrosis (CF) patients. P. aeruginosa virulence is related to its ability to form biofilm, trigger different types of motilities, and produce toxins (for example, bacterial pigments). In this scenario, essential oils (EOs) have gained notoriety for their role in phenotype modulation, including virulence modulation. Among different EOs previously analyzed, herein we investigated the activity of Coridothymus capitatus EO (CCEO) against specific virulence factors produced by P. aeruginosa isolated from CF patients. CCEO showed inhibition of new biofilm formation and reduction in mature biofilm in about half of the tested strains. On selected strains, SEM analysis provided interesting information regarding CCEO action in a pre-adhesion assay. CCEO treatment showed a dramatic modification of the extracellular matrix (ECM) structure. Our results clearly showed a drastic reduction in pyocyanin production (between 84% and 100%) for all tested strains in the presence of CCEO. Finally, CCEO was also able to strongly affect P. aeruginosa swarming and swimming motility for almost all tested strains. In consideration of the novel results obtained on clinical strains isolated from CF patients, CCEO may be a potential candidate to limit P. aeruginosa virulence.

PMID:34835383 | DOI:10.3390/microorganisms9112257

Vaccines (Basel). 2021 Nov 11;9(11):1311. doi: 10.3390/vaccines9111311.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disorder that affects multiple organs, although a decline in respiratory function represents the major cause of morbidity and mortality. The airways of CF patients are characterized by a chronic inflammatory state to which the receptor for advanced glycation end-products greatly contributes. Glyoxalase 1 (GLO1) is the major enzyme metabolizing methylglyoxal, a potent precursor of advanced glycation end-products. Its role in CF has never been investigated. We herein resorted to murine and human preclinical models of CF to define the contribution of GLO1 to inflammatory pathology. We found that the expression and activity of GLO1, measured by real-time PCR and Western blot or a specific spectrophotometric assay, respectively, are defective in mice and human bronchial cells from CF patients exposed to Aspergillus fumigatus, a common pathogen in CF, but could be restored upon blockade of interleukin-1 receptor signaling by anakinra in mice. This study suggests that GLO1 contributes to pathology in CF and may be potentially targeted to mitigate inflammation.

PMID:34835243 | DOI:10.3390/vaccines9111311

Vaccines (Basel). 2021 Oct 22;9(11):1232. doi: 10.3390/vaccines9111232.

ABSTRACT

Immunization through vaccination is a milestone achievement that has made a tremendous contribution to public health. Historically, immunization programs aimed firstly to protect children, who were disproportionally affected by infectious diseases. However, vaccine-preventable diseases can have significant impacts on adult mortality, health, and quality of life. Despite this, adult vaccinations have historically been overlooked in favor of other health priorities, because their benefits to society were not well recognized. As the general population is aging, the issue of vaccination in older adults is gaining importance. In high-income countries, recommendations for the routine vaccination of older adults have been gradually introduced. The Italian National Immunization Plan is considered to be among the most advanced adult vaccination plans in Europe. However, available data indicate there is low adherence to vaccination recommendations in Italy. The COVID-19 pandemic has exposed the damage that can be caused by an infectious disease, especially among adults and individuals with comorbidities. The aim of this "Manifesto", therefore, is to provide an overview of the existing evidence on the value of adult vaccination, in the Italian context, with a call to action to healthcare providers and health authorities.

PMID:34835163 | DOI:10.3390/vaccines9111232

J Pers Med. 2021 Oct 24;11(11):1072. doi: 10.3390/jpm11111072.

ABSTRACT

The MINERVA platform is currently the most widely used platform for visualizing and providing access to disease maps. Disease maps are systems biological maps of molecular interactions relevant in a certain disease context, where they can be used to support drug discovery. For this purpose, we extended MINERVA's own drug and chemical search using the MINERVA plugin starter kit. We developed a plugin to provide a linkage between disease maps in MINERVA and application-specific databases of candidate therapeutics. The plugin has three main functionalities; one shows all the targets of all the compounds in the database, the second is a compound-based search to highlight targets of specific compounds, and the third can be used to find compounds that affect a certain target. As a use case, we applied the plugin to link a disease map and compound database we previously established in the context of cystic fibrosis and, herein, point out possible issues and difficulties. The plugin is publicly available on GitLab; the use-case application to cystic fibrosis, connecting disease maps and the compound database CandActCFTR, is available online.

PMID:34834423 | DOI:10.3390/jpm11111072

Pharmaceutics. 2021 Nov 12;13(11):1914. doi: 10.3390/pharmaceutics13111914.

ABSTRACT

Messenger RNA (mRNA) has generated great attention due to its broad potential therapeutic applications, including vaccines, protein replacement therapy, and immunotherapy. Compared to other nucleic acids (e.g., siRNA and pDNA), there are more opportunities to improve the delivery efficacy of mRNA through systematic optimization. In this report, we studied a high-throughput library of 1200 functional polyesters for systemic mRNA delivery. We focused on the chemical investigation of hydrophobic optimization as a method to adjust mRNA polyplex stability, diameter, pKa, and efficacy. Focusing on a region of the library heatmap (PE4K-A17), we further explored the delivery of luciferase mRNA to IGROV1 ovarian cancer cells in vitro and to C57BL/6 mice in vivo following intravenous administration. PE4K-A17-0.2C8 was identified as an efficacious carrier for delivering mRNA to mouse lungs. The delivery selectivity between organs (lungs versus spleen) was found to be tunable through chemical modification of polyesters (both alkyl chain length and molar ratio in the formulation). Cre recombinase mRNA was delivered to the Lox-stop-lox tdTomato mouse model to study potential application in gene editing. Overall, we identified a series of polymer-mRNA polyplexes stabilized with Pluronic F-127 for safe and effective delivery to mouse lungs and spleens. Structure-activity relationships between alkyl side chains and in vivo delivery were elucidated, which may be informative for the continued development of polymer-based mRNA delivery.

PMID:34834329 | DOI:10.3390/pharmaceutics13111914

Sensors (Basel). 2021 Nov 13;21(22):7554. doi: 10.3390/s21227554.

ABSTRACT

This paper presents sensor nanotechnologies that can be used for the skin-based gas "smelling" of disease. Skin testing may provide rapid and reliable results, using specific "fingerprints" or unique patterns for a variety of diseases and conditions. These can include metabolic diseases, such as diabetes and cholesterol-induced heart disease; neurological diseases, such as Alzheimer's and Parkinson's; quality of life conditions, such as obesity and sleep apnea; pulmonary diseases, such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease; gastrointestinal tract diseases, such as irritable bowel syndrome and colitis; cancers, such as breast, lung, pancreatic, and colon cancers; infectious diseases, such as the flu and COVID-19; as well as diseases commonly found in ICU patients, such as urinary tract infections, pneumonia, and infections of the blood stream. Focusing on the most common gaseous biomarkers in breath and skin, which is nitric oxide and carbon monoxide, and certain abundant volatile organic compounds (acetone, isoprene, ammonia, alcohols, sulfides), it is argued here that effective discrimination between the diseases mentioned above is possible, by capturing the relative sensor output signals from the detection of each of these biomarkers and identifying the distinct breath print for each disease.

PMID:34833630 | DOI:10.3390/s21227554

Pharmaceuticals (Basel). 2021 Nov 15;14(11):1162. doi: 10.3390/ph14111162.

ABSTRACT

Phage therapy is a century-old technique employing viruses (phages) to treat bacterial infections, and in the clinic it is often used in combination with antibiotics. Antibiotics, however, interfere with critical bacterial metabolic activities that can be required by phages. Explicit testing of antibiotic antagonism of phage infection activities, though, is not a common feature of phage therapy studies. Here we use optical density-based 'lysis-profile' assays to assess the impact of two antibiotics, colistin and ciprofloxacin, on the bactericidal, bacteriolytic, and new-virion-production activities of three Pseudomonas aeruginosa phages. Though phages and antibiotics in combination are more potent in killing P. aeruginosa than either acting alone, colistin nevertheless substantially interferes with phage bacteriolytic and virion-production activities even at its minimum inhibitory concentration (1× MIC). Ciprofloxacin, by contrast, has little anti-phage impact at 1× or 3× MIC. We corroborate these results with more traditional measures, particularly colony-forming units, plaque-forming units, and one-step growth experiments. Our results suggest that ciprofloxacin could be useful as a concurrent phage therapy co-treatment especially when phage replication is required for treatment success. Lysis-profile assays also appear to be useful, fast, and high-throughput means of assessing antibiotic antagonism of phage infection activities.

PMID:34832944 | DOI:10.3390/ph14111162