Front Pharmacol. 2022 Mar 22;13:868863. doi: 10.3389/fphar.2022.868863. eCollection 2022.

ABSTRACT

Introduction: Severity and disease progression in people with Cystic Fibrosis (CF) is typically dependent on their genotype. One potential therapeutic strategy for people with specific mutations is exon skipping with antisense oligonucleotides (AO). CFTR exon 9 is an in-frame exon and hence the exclusion of this exon would excise only 31 amino acids but not alter the reading frame of the remaining mRNA. Splice mutations 1209 + 1 G > C and 1209 + 2 T > G were documented to cause CFTR exon 9 skipping and these variants were reported to manifest as a milder CF disease, therefore exon 9 skipping could be beneficial for people with class I mutations that affect exon 9 such as p.Trp401X. While the impact of exon 9 skipping on gene expression and cellular pathways can be studied in cells in vitro, trace amount of full-length normal or mutated material could confound the evaluation. To overcome this limitation, the impact of CFTR exon 9 skipping on disease phenotype and severity is more effectively evaluated in a small animal model. It was hypothesised that antisense oligonucleotide-mediated skipping this particular exon could result in a "mild mouse CF phenotype". Methods: Cftr exon 9 deleted mice were generated using homologous recombination. Survival of homozygous (Cftr Δ9/Δ9 ) and heterozygous (Cftr Δ9/+ ) mice was compared to that of other CF mouse models, and lung and intestinal organ histology examined for any pathologies. Primary airway epithelial cells (pAECs) were harvested from Cftr Δ9/Δ9 mice and cultured at the Air Liquid Interface for CFTR functional assessment using Ussing Chamber analysis. Results: A Cftr Δ9/Δ9 mouse model presented with intestinal obstructions, and at time of weaning (21 days). Cftr Δ9/Δ9 mice had a survival rate of 83% that dropped to 38% by day 50. Histological sections of the small intestine from Cftr Δ9/Δ9 mice showed more goblet cells and mucus accumulation than samples from the Cftr Δ9/+ littermates. Airway epithelial cell cultures established from Cftr Δ9/Δ9 mice were not responsive to forskolin stimulation. Summary: The effect of Cftr exon 9 deletion on Cftr function was assessed and it was determined that the encoded Cftr isoform did not result in a milder "mouse CF disease phenotype," suggesting that Cftr exon 9 is not dispensable, although further investigation in human CF pAECs would be required to confirm this observation.

PMID:35392567 | PMC:PMC8981082 | DOI:10.3389/fphar.2022.868863

Front Immunol. 2022 Mar 22;13:824746. doi: 10.3389/fimmu.2022.824746. eCollection 2022.

ABSTRACT

The origin of the impaired CD4 T-cell response and immunodeficiency of HIV-infected patients is still only partially understood. We recently demonstrated that PLA2G1B phospholipase synergizes with the HIV gp41 envelope protein in HIV viremic plasma to induce large abnormal membrane microdomains (aMMDs) that trap and inactivate physiological receptors, such as those for IL-7. However, the mechanism of regulation of PLA2G1B activity by the cofactor gp41 is not known. Here, we developed an assay to directly follow PLA2G1B enzymatic activity on CD4 T-cell membranes. We demonstrated that gp41 directly binds to PLA2G1B and increases PLA2G1B enzymatic activity on CD4 membrane. Furthermore, we show that the conserved 3S sequence of gp41, known to bind to the innate sensor gC1qR, increases PLA2G1B activity in a gC1qR-dependent manner using gC1qR KO cells. The critical role of the 3S motif and gC1qR in the inhibition of CD4 T-cell function by the PLA2G1B/cofactor system in HIV-infected patients led us to screen additional microbial proteins for 3S-like motifs and to study other proteins known to bind to the gC1qR to further investigate the role of the PLA2G1B/cofactor system in other infectious diseases and carcinogenesis. We have thus extended the PLA2G1B/cofactor system to HCV and Staphylococcus aureus infections and additional pathologies where microbial proteins with 3S-like motifs also increase PLA2G1B enzymatic activity. Notably, the bacteria Porphyromonas gingivalis, which is associated with pancreatic ductal adenocarcinoma (PDAC), encodes such a cofactor protein and increased PLA2G1B activity in PDAC patient plasma inhibits the CD4 response to IL-7. Our findings identify PLA2G1B/cofactor system as a CD4 T-cell inhibitor. It involves the gC1qR and disease-specific cofactors which are gC1qR-binding proteins that can contain 3S-like motifs. This mechanism involved in HIV-1 immunodeficiency could play a role in pancreatic cancer and several other diseases. These observations suggest that the PLA2G1B/cofactor system is a general CD4 T-cell inhibitor and pave the way for further studies to better understand the role of CD4 T-cell anergy in infectious diseases and tumor escape.

PMID:35392090 | PMC:PMC8981723 | DOI:10.3389/fimmu.2022.824746

Front Med (Lausanne). 2022 Mar 22;9:834354. doi: 10.3389/fmed.2022.834354. eCollection 2022.

ABSTRACT

OBJECTIVE: Our knowledge on the long-term consequences of COVID-19 is still scarce despite the clinical relevance of persisting syndrome. The aim of this study was to analyze patient-reported outcomes, including assessment by specific questionnaires of health impairment and symptoms.

METHODS: This is a prospective, observational and multicenter cohort study coordinated by Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico di Milano and Istituto di Ricerche Farmacologiche Mario Negri IRCCS including eight hospitals located in North and Central Italy. A telephone interview to assess rehospitalization, access to health care resources, general health status subjective evaluation, and symptoms was performed at 12 months after the discharge in patients admitted to hospital because of COVID-19 from February 2020 to the end of May 2020.

RESULTS: Among the 776 patients discharged alive, 44 (5.7%) died, 456 subjects (58.8%) completed the questionnaire and 276 (35.6%) were not reachable or refused to join the telephone interview. The mean age of the study population was 59.4 years (SD 14.1), 69.8% of individuals needed oxygen support during hospitalization and 10.4% were admitted to ICU. Overall, 91.7% of participants reported at least one symptom/sequela at 12 months. Exertional dyspnea (71.7%), fatigue (54.6%), and gastrointestinal symptoms (32.8%) were the most reported ones. Health issues after discharge including hospitalization or access to emergency room were described by 19.4% of subjects. Female and presence of comorbidities were independent predictors of whealth impairment and presence of ≥2 symptoms/sequelae after 12 months from hospitalization for COVID-19.

CONCLUSIONS: Patient-reported symptoms and sequelae, principally dyspnea and fatigue, are found in most individuals even 12 months from COVID-19 hospitalization. Long-term follow-up based on patient-centered outcome can contribute to plan tailored interventions.

PMID:35391879 | PMC:PMC8981315 | DOI:10.3389/fmed.2022.834354

Cochrane Database Syst Rev. 2022 Apr 7;4:CD012979. doi: 10.1002/14651858.CD012979.pub3.

ABSTRACT

BACKGROUND: Chronic rhinosinusitis frequently occurs in people with cystic fibrosis. Several medical interventions are available for treating chronic rhinosinusitis in people with cystic fibrosis; for example, different concentrations of nasal saline irrigations, topical or oral corticosteroids, antibiotics - including nebulized antibiotics - dornase alfa and modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) (such as lumacaftor, ivacaftor or tezacaftor). However, the efficacy of these interventions is unclear. This is an update of a previously published review.

OBJECTIVES: The objective of this review is to compare the effects of different medical interventions in people diagnosed with cystic fibrosis and chronic rhinosinusitis.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search of trials register: 09 September 2021. We also searched ongoing trials databases, other medical databases and the reference lists of relevant articles and reviews. Date of latest additional searches: 22 November 2021.

SELECTION CRITERIA: Randomized and quasi-randomized trials of different medical interventions compared to each other or to no intervention or to placebo.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials identified for potential inclusion in the review. We planned to conduct data collection and analysis in accordance with Cochrane methods and to independently rate the quality of the evidence for each outcome using the GRADE guidelines.

MAIN RESULTS: We identified no trials that met the pre-defined inclusion criteria. The most recent searches identified 44 new references, none of which were eligible for inclusion in the current version of this review; 12 studies are listed as excluded and one as ongoing.

AUTHORS' CONCLUSIONS: We identified no eligible trials assessing the medical interventions in people with cystic fibrosis and chronic rhinosinusitis. High-quality trials are needed which should assess the efficacy of different treatment options detailed above for managing chronic rhinosinusitis, preventing pulmonary exacerbations and improving quality of life in people with cystic fibrosis.

PMID:35390177 | DOI:10.1002/14651858.CD012979.pub3

Mol Biol Cell. 2022 Apr 7:mbcE21110578. doi: 10.1091/mbc.E21-11-0578. Online ahead of print.

ABSTRACT

Pharmacological chaperones represent a class of therapeutic compounds for treating protein misfolding diseases. One of the most prominent examples is the FDA-approved pharmacological chaperone lumacaftor (VX-809), which has transformed cystic fibrosis (CF) therapy. CF is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). VX-809 corrects folding of F508del CFTR, the most common patient mutation, yet F508del exhibits only mild VX-809 response. In contrast, rarer mutations P67L and L206W are hyper-responsive to VX-809, while G85E is non-responsive. Despite the clinical success of VX-809, the mechanistic origin for the distinct susceptibility of mutants remains unclear. Here, we use interactomics to characterize the impact of VX-809 on proteostasis interactions of P67L and L206W and compare these to F508del and G85E. We determine hyper-responsive mutations P67L and L206W exhibit decreased interactions with proteasomal, and autophagy degradation machinery compared to F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response. Our data suggests a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.

PMID:35389766 | DOI:10.1091/mbc.E21-11-0578

Ir J Med Sci. 2022 Apr 7. doi: 10.1007/s11845-022-02994-z. Online ahead of print.

ABSTRACT

OBJECTIVE: Bronchiectasis is usually caused by recurrent bacterial infections and is characterized by irreversible dilation of the bronchi. In this study, we aimed to give an overview of the genetic backgrounds of patients with non-cystic fibrosis bronchiectasis (NCFB) that have been suspected to an underlying ciliary dysfunction or inborn error of immunity (IEI).

METHOD: This is a retrospective cross-sectional study. Seventy-one NCFB patients who were referred to the Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran, from 1996 to 2020 were included. These patients were referred to this center for immunological and genetic evaluation. Genetic analysis with whole-exome sequencing and Sanger sequencing was confirmed in 30 patients. However, the genetic evaluations of 41 patients were either still under evaluation or the patients had refused to be genetically evaluated.

RESULT: Thirty-eight of our 71 patients (53.52%) were diagnosed with ciliary dysfunction and the detected mutations included mutations in the CCDC65, DNAH11, RSPH1, CCDC40, and GAS8 genes as well as a novel mutation. Thirty-three patients (46.47%) had an IEI and the detected mutations included mutations of the following genes: TNFRSF13B, PTPN2, ZNF341 BTK, TCF3, CD79a, PIK3CD, JAGN1, WAS, RFXANK, STK4, GSDMD, and NEMO.

CONCLUSION: This study presents an overview of the underlying ciliary and immune dysfunctions and their genetic mutations in NCFB in a highly consanguine population. This would give us a better understanding of the etiologies and the known and novel genetic mutations in NCFB in Iran and, in turn, in the Middle East and North Africa (MENA) region.

PMID:35389161 | DOI:10.1007/s11845-022-02994-z

Sci Rep. 2022 Apr 6;12(1):5746. doi: 10.1038/s41598-022-09463-8.

ABSTRACT

Diagnosis of chronic disease in a child can result in unresolved grief (UG) in parents. This study aimed to evaluate the efficacy of psychological insight-oriented therapy (IOT) as a treatment for UG compared to disease related education in parents of children with cystic fibrosis (CF). Sequence of delivery, first IOT then disease related education (or vice versa) was also examined, to let all participants experience both interventions. Parents were screened for UG. Parents with UG were randomised to either five 1-h sessions of IOT or five 1-h sessions of education. Measures were assessed pre-intervention, after the first intervention period (primary efficacy assessment), and after the second intervention period (swapping intervention). Forty-seven parents were screened of which 46.8% (22/47) had UG. Median duration of UG was 5 years (range: 6 months-14 years). Anxiety (50% vs. 20%, p = 0.03) and stress (59% vs. 28%, p = 0.03) were significantly more prevalent in parents with UG. There was no difference between arms in the odds of UG resolving either following the first intervention period (OR 0.88; 95% CI 0.5, 1.5) or the second intervention period (OR 0.91; 95% CI 0.5, 1.6). While not statistically significant, adjusted mean values for seven of the eight mental health measures were lower in the IOT (first) arm compared to the ED (first) arm, following the first intervention period. UG is a significant burden for families affected by CF. Provision of disease related education and psychological support, regardless of sequence, can result in resolution of grief.Trial registration number: ACTRN12621000796886, date of registration 24/06/2021, retrospectively registered.

PMID:35388038 | DOI:10.1038/s41598-022-09463-8

Endocr J. 2022 Apr 7. doi: 10.1507/endocrj.EJ22-0024. Online ahead of print.

ABSTRACT

Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m2, and blood samples under fibrate medication showed triglyceride 451 mg/dL and HbA1c 7.2%. Type V dyslipidemia became more apparent at postprandial state. The WES analysis showed that the patients had two heterozygous variants in Apolipoprotein A5 (APOA5) gene (p.G185C and p.V153M), a heterozygous variant in Apolipoprotein E (APOE) gene (p.R176C), three heterozygous variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (p.T1220I, p.R1453W and p.V470M). On the other hand, her mother, who had moderate hypertriglyceridemia without acute pancreatitis, had a heterozygous variant in APOA5 gene (p.G185C) and two heterozygous variants in CFTR gene (p.T1220I and p.V470M). These results suggest that the more severe pathology of the patient than her mother might be due to the possible compound heterozygous APOA5 variants, the heterozygous APOE variant, and the possible compound heterozygous CFTR variants. In this case, WES analyses were useful to evaluate not only the causative genes of hypertriglyceridemia (APOA5 and APOE) but also the genes involved in the development of acute pancreatitis (CFTR) simultaneously.

PMID:35387941 | DOI:10.1507/endocrj.EJ22-0024

ERJ Open Res. 2022 Apr 4;8(2):00582-2021. doi: 10.1183/23120541.00582-2021. eCollection 2022 Apr.

ABSTRACT

Curvilinearity, as calculated from multiple-breath washout, is abnormal in a small number of children with cystic fibrosis when other tests are still normal https://bit.ly/3p9QAV4.

PMID:35386828 | PMC:PMC8977591 | DOI:10.1183/23120541.00582-2021

Front Allergy. 2022 Mar 9;3:852546. doi: 10.3389/falgy.2022.852546. eCollection 2022.

ABSTRACT

Chronic upper airway inflammation is amongst the most prevalent chronic disease entities in the Western world with prevalence around 30% (rhinitis) and 11% (rhinosinusitis). Chronic rhinitis and rhinosinusitis may severely impair the quality of life, leading to a significant socio-economic burden. It becomes more and more clear that the respiratory mucosa which forms a physiological as well as chemical barrier for inhaled particles, plays a key role in maintaining homeostasis and driving disease. In a healthy state, the mucosal immune system provides protection against pathogens as well as maintains a tolerance toward non-harmful commensal microbes and benign environmental substances such as allergens. One of the most important players of the mucosal immune system is immunoglobulin (Ig) A, which is well-studied in gut research where it has emerged as a key factor in creating tolerance to potential food allergens and maintaining a healthy microbiome. Although, it is very likely that IgA plays a similar role at the level of the respiratory epithelium, very little research has been performed on the role of this protein in the airways, especially in chronic upper airway diseases. This review summarizes what is known about IgA in upper airway homeostasis, as well as in rhinitis and rhinosinusitis, including current and possible new treatments that may interfere with the IgA system. By doing so, we identify unmet needs in exploring the different roles of IgA in the upper airways required to find new biomarkers or therapeutic options for treating chronic rhinitis and rhinosinusitis.

PMID:35386640 | PMC:PMC8974816 | DOI:10.3389/falgy.2022.852546

Respirol Case Rep. 2022 Mar 31;10(5):e0941. doi: 10.1002/rcr2.941. eCollection 2022 May.

ABSTRACT

We describe a 6-year-old girl with homozygous p.Phe508del cystic fibrosis with severe multi-lobar bronchiectasis and obstructive lung disease who was found to have prominent parenchymal calcifications in the right middle lobe on a computed tomography scan of the chest. Histopathology from the calcified area of lung biopsy showed fibrous tissue with chronic inflammation with CD3+ T-lymphocytes and macrophages with no granulomas. Dystrophic calcification was seen within this necrotic debris.

PMID:35386578 | PMC:PMC8968259 | DOI:10.1002/rcr2.941

PLoS One. 2022 Apr 6;17(4):e0266218. doi: 10.1371/journal.pone.0266218. eCollection 2022.

ABSTRACT

BACKGROUND: Advances in Molecular Therapy have made gene editing through systemic or topical administration of reagents a feasible strategy to treat genetic diseases in a rational manner. Encapsulation of therapeutic agents in nanoparticles can improve intracellular delivery of therapeutic agents, provided that the nanoparticles are efficiently taken up within the target cells. In prior work we had established proof-of-principle that nanoparticles carrying gene editing reagents can mediate site-specific gene editing in fetal and adult animals in vivo that results in functional disease improvement in rodent models of β-thalassemia and cystic fibrosis. Modification of the surface of nanoparticles to include targeting molecules (e.g. antibodies) holds the promise of improving cellular uptake and specific cellular binding.

METHODS AND FINDINGS: To improve particle uptake for diseases of the airway, like cystic fibrosis, our group tested the impact of nanoparticle surface modification with cell surface marker antibodies on uptake in human bronchial epithelial cells in vitro. Binding kinetics of antibodies (Podoplanin, Muc 1, Surfactant Protein C, and Intracellular Adhesion Molecule-1 (ICAM)) were determined to select appropriate antibodies for cellular targeting. The best target-specific antibody among those screened was ICAM antibody. Surface conjugation of nanoparticles with antibodies against ICAM improved cellular uptake in bronchial epithelial cells up to 24-fold.

CONCLUSIONS: This is a first demonstration of improved nanoparticle uptake in epithelial cells using conjugation of target specific antibodies. Improved binding, uptake or specificity of particles delivered systemically or to the luminal surface of the airway would potentially improve efficacy, reduce the necessary dose and thus safety of administered therapeutic agents. Incremental improvement in the efficacy and safety of particle-based therapeutic strategies may allow genetic diseases such as cystic fibrosis to be cured on a fundamental genetic level before birth or shortly after birth.

PMID:35385514 | DOI:10.1371/journal.pone.0266218

Phys Ther. 2022 Apr 6:pzac037. doi: 10.1093/ptj/pzac037. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to follow the developmental functioning of infants, 3 to 5 months of age, with cystic fibrosis (CF), according to recent published results based on Prechtl General Movement Assessment (GMA).

METHODS: Motor repertoire was evaluated using Prechtl GMA, and developmental function was assessed using Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) in infants with CF and their peers who were neurotypical.

RESULTS: Twelve infants with CF clinically stable and 12 infants who were neurotypical, with respective median postterm ages of 14 and 13 weeks, were assessed using GMA. At 24 to 36 months, the Bayley-III was applied to the CF group (median postterm age = 27.5 months) and the control group (median post-term age = 27.0 months). Fidgety movements (FMs) were absent in 5 infants with CF, whereas all infants who were neurotypical had normal FMs. The Motor Optimality Score (MOS) was significantly lower in the CF group (median = 18.5) compared with the control group (median = 26). The CF group had significantly lower composite scores in the Bayley-III cognition, language, and motor domains compared to the control group.

CONCLUSIONS: Cognitive, language, and motor development was delayed in infants with CF. Developmental functioning of infants with CF should be assessed as early as possible and monitored, and age-specific early intervention programs should be considered when necessary.

IMPACT: Children with CF may have motor, cognitive, and language developmental delays compared with peers who are neurotypical during early childhood, and hospitalization was negatively correlated with motor development at 24 to 36 months of age. This study highlights the importance of early assessment of developmental functioning and age-specific, early intervention programs when necessary in infants with CF.

PMID:35385120 | DOI:10.1093/ptj/pzac037

Inflamm Bowel Dis. 2022 Apr 6:izac064. doi: 10.1093/ibd/izac064. Online ahead of print.

ABSTRACT

BACKGROUND: Data from the first wave of the coronavirus disease 2019 (COVID-19) pandemic suggested that patients with inflammatory bowel disease (IBD) are not at higher risk of being infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than the general population and that a worse prognosis is not associated with immunomodulatory drugs, with the possible exception of systemic steroids.

METHODS: This retrospective, observational study included consecutive IBD patients from the Sicilian Network for Inflammatory Bowel Disease (SN-IBD) cohort who had a SARS-CoV-2 infection diagnosis (polymerase chain reaction-confirmed presence of the viral genome in a nasopharyngeal swab) during the second COVID-19 pandemic wave (September 2020 to December 2020). Data regarding demographics, IBD features and treatments, and comorbidities were analyzed in correlation with COVID-19 clinical outcomes.

RESULTS: Data on 122 patients (mean age, 43.9 ± 16.7 years; males, 50.0%; Crohn's disease, 62.3%; ulcerative colitis, 37.7%) were reported. Twelve patients developed COVID-19-related pneumonia (9.8%), 4 (3.3%) required respiratory assistance (nonmechanical ventilation or orotracheal intubation), and 4 died (case fatality rate, 3.3%). In a multivariable analysis, age (odds ratio [OR], 1.034; 95% CI, 1.006-1.147; P = .032) and severe IBD activity (OR, 13.465; 95% CI, 1.104-164.182; P = .042) were independent predictors of COVID-19-related pneumonia, while severe IBD activity (OR, 15.359; 95% CI, 1.320-178.677; P = .030) was the only independent predictor of severe COVID-19, a composite endpoint defined as the need for respiratory assistance or death. A trend towards a protective role of tumor necrosis factor α inhibitors on pneumonia development was reported (P = .076).

CONCLUSIONS: In this cohort of patients with IBD and SARS-CoV-2 infection, severe IBD activity was the only independent risk factor for severe COVID-19.

PMID:35385102 | DOI:10.1093/ibd/izac064

Einstein (Sao Paulo). 2022 Apr 1;20:eRW5686. doi: 10.31744/einstein_journal/2022RW5686. eCollection 2022.

ABSTRACT

OBJECTIVE: To develop a scientific consensus on nutrition in cystic fibrosis.

METHODS: Sixteen coordinators elaborated relevant questions on nutritional therapy in cystic fibrosis, which were divided into six sections: nutritional assessment, nutritional recommendations, nutritional intervention, dietary counseling, special situations and enzyme replacement, and gastrointestinal manifestations. Two to three specialists in the field were responsible for each section and obtaining answers formulated based on standardized bibliographic searches. The available literature was searched in the PubMed®/MEDLINE database, after training and standardization of search strategies, to write the best level of evidence for the questions elaborated. Issues related to disagreement were discussed until a consensus was reached among specialists, based on the current scientific literature.

RESULTS: Forty-two questions were prepared and objectively answered, resulting in a consensus of nutritional therapy in cystic fibrosis.

CONCLUSION: This work enabled establishing a scientific consensus for nutritional treatment of cystic fibrosis patients.

PMID:35384985 | DOI:10.31744/einstein_journal/2022RW5686

Turk Arch Pediatr. 2022 Mar;57(2):247-248. doi: 10.5152/TurkArchPediatr.2022.21305.

NO ABSTRACT

PMID:35383026 | DOI:10.5152/TurkArchPediatr.2022.21305

J Pediatr Hematol Oncol. 2022 Mar 30. doi: 10.1097/MPH.0000000000002459. Online ahead of print.

ABSTRACT

Human Rhinovirus (HRV) is one of the most common pathogens causing acute respiratory tract infections in infants and children. Several reports suggest that HRV has the potential to cause chronic infection after an acute viral infection in an immunosuppressed patient. Although chronic HRV infection has been reported in lung transplant recipients, patients with hypogammaglobulinemia and cystic fibrosis, the duration and severity of HRV infection remain unclear. In this study, we present a case of persistent HRV infection in a stem cell transplanted leukemia patient. This report raises several questions regarding the risk factors, duration, and severity of persistent HRV infection in acute leukemia patients, which warrants prospective and longitudinal studies.

PMID:35380551 | DOI:10.1097/MPH.0000000000002459

J Bacteriol. 2022 Apr 5:e0004622. doi: 10.1128/jb.00046-22. Online ahead of print.

ABSTRACT

Mycobacteroides abscessus (Mab; also known as Mycobacterium abscessus) is an emerging opportunistic pathogen. Patients with structural lung conditions such as bronchiectasis, cystic fibrosis, and chronic obstructive pulmonary disease are at high risk of developing pulmonary Mab disease. This disease is often chronic as the current treatment regimens are sub-efficacious. Here, we characterize the phenotype of a Mab strain lacking the MAB_3167c locus, which encodes a protein hereafter referred to as Glby. We demonstrate that the loss of Glby impairs normal planktonic growth in liquid broth, results in longer average cell length, and a melding of surfaces between cells. Glby also exhibits a mild β-lactamase activity. We also present evidence that amino acid substitutions that potentially alter Glby function are not favored. Lastly, we demonstrate that, in a mouse model of pulmonary Mab infection, the mutant lacking Glby was unable to proliferate, gradually cleared, and was undetectable after 3 weeks. These data suggest that an agent that inhibits Glby in vivo may be an efficacious treatment against Mab disease. IMPORTANCE Mycobacteroides abscessus can cause chronic pulmonary infections requiring administration of multiple antibiotics, still resulting in a low cure rate. The incidence of M. abscessus disease is increasing in the United States and the developed regions of the world. We show for the first time that a protein, Glby, affects growth of this bacterium. Using a mouse model of lung M. abscessus disease, we demonstrate that Glby is required for this bacterium to cause disease.

PMID:35380462 | DOI:10.1128/jb.00046-22

Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2201937119. doi: 10.1073/pnas.2201937119. Epub 2022 Apr 4.

ABSTRACT

Significance The awareness of the individuals' biological status is critical for creating interactive environments. Accordingly, we devised a multimodal cryptographic bio-human-machine interface (CB-HMI), which seamlessly translates touch-based entries into encrypted biochemical, biophysical, and biometric indices (i.e., circulating biomarkers levels, heart rate, oxygen saturation level, and fingerprint pattern). As its central component, the CB-HMI features thin hydrogel-coated chemical sensors and a signal interpretation framework to access/interpret biochemical indices, bypassing the challenge of circulating analyte accessibility and the confounding effect of pressing force variability. Upgrading the surrounding objects with CB-HMI, we demonstrated new interactive solutions for driving safety and medication use, where the integrated CB-HMI uniquely enabled one-touch bioauthentication (based on the user's biological state/identity), prior to rendering the intended services.

PMID:35377784 | DOI:10.1073/pnas.2201937119

J Med Chem. 2022 Apr 4. doi: 10.1021/acs.jmedchem.1c01897. Online ahead of print.

ABSTRACT

In cystic fibrosis (CF), the deletion of phenylalanine 508 (F508del) in the CF transmembrane conductance regulator (CFTR) leads to misfolding and premature degradation of the mutant protein. These defects can be targeted with pharmacological agents named potentiators and correctors. During the past years, several efforts have been devoted to develop and approve new effective molecules. However, their clinical use remains limited, as they fail to fully restore F508del-CFTR biological function. Indeed, the search for CFTR correctors with different and additive mechanisms has recently increased. Among them, drugs that modulate the CFTR proteostasis environment are particularly attractive to enhance therapy effectiveness further. This Perspective focuses on reviewing the recent progress in discovering CFTR proteostasis regulators, mainly describing the design, chemical structure, and structure-activity relationships. The opportunities, challenges, and future directions in this emerging and promising field of research are discussed, as well.

PMID:35377645 | DOI:10.1021/acs.jmedchem.1c01897