PLoS One. 2024 Jun 25;19(6):e0305975. doi: 10.1371/journal.pone.0305975. eCollection 2024.

ABSTRACT

OBJECTIVES: Periodontitis is a highly prevalent complication of diabetes. However, the association between cystic fibrosis-related diabetes (CFRD) and periodontitis has not yet been evaluated. The objective of this study was to assess if: 1) CFRD is associated with periodontitis among adults with CF, and 2) periodontitis prevalence differs by CF and diabetes status.

METHODS: This was a pilot cross-sectional study of the association between CFRD and periodontitis in adults with cystic fibrosis (CF) (N = 32). Historical non-CF controls (N = 57) from the U.S. National Health and Nutrition Examination Survey (NHANES) dataset were frequency matched to participants with CF on age, sex, diabetes status, and insulin use. We defined periodontitis using the U.S. Centers for Disease Control and Prevention and the American Academy of Periodontology (CDC/AAP) case definition, as the presence of two or more interproximal sites with CAL ≥3 mm and two or more interproximal sites with PD ≥4 mm (not on the same tooth) or one site with PD ≥5 mm. Because NHANES periodontal data were only available for adults ages ≥30 years, our analysis that included non-CF controls focused on this age group (CF N = 19, non-CF N = 57). Based on CF and diabetes status, we formed four groups: CFRD, CF and no diabetes, non-CF with diabetes, and non-CF and no diabetes (healthy). We used the Fisher's exact test for hypotheses testing.

RESULTS: There was no association between CFRD and periodontitis for participants with CF ages 22-63 years (CFRD 67% vs. CF no diabetes 53%, P = 0.49), this was also true for those ages ≥30 years (CFRD 78% vs. CF no diabetes 60%, P = 0.63). For the two CF groups, the prevalence of periodontitis was significantly higher than for healthy controls (CFRD 78% vs. healthy 7%, P<0.001; CF no diabetes 60% vs. healthy 7%, P = 0.001) and not significantly different than the prevalence for non-CF controls with diabetes (CFRD 78% vs. non-CF with diabetes 56%, P = 0.43; CF no diabetes 60% vs. non-CF with diabetes 56%, P = 0.99).

CONCLUSION: Among participants with CF, CFRD was not associated with periodontitis. However, regardless of diabetes status, participants with CF had increased prevalence of periodontitis compared to healthy controls.

PMID:38917148 | DOI:10.1371/journal.pone.0305975

PLoS One. 2024 Jun 25;19(6):e0294827. doi: 10.1371/journal.pone.0294827. eCollection 2024.

ABSTRACT

Neutrophil proteinase 3 (PR3) is an important drug target for inflammatory lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Drug discovery efforts targeting PR3 require active enzyme for in vitro characterization, such as inhibitor screening, enzymatic assays, and structural studies. Recombinant expression of active PR3 overcomes the need for enzyme supplies from human blood and in addition allows studies on the influence of mutations on enzyme activity and ligand binding. Here, we report the expression of recombinant PR3 (rPR3) using a baculovirus expression system. The purification and activation process described resulted in highly pure and active PR3. The activity of rPR3 in the presence of commercially available inhibitors was compared with human PR3 by using a fluorescence-based enzymatic assay. Purified rPR3 had comparable activity to the native human enzyme, thus being a suitable alternative for enzymatic studies in vitro. Further, we established a surface plasmon resonance-based assay to determine binding affinities and kinetics of PR3 ligands. These methods provide valuable tools for early drug discovery aiming towards treatment of lung inflammation.

PMID:38917138 | DOI:10.1371/journal.pone.0294827

JCI Insight. 2024 Jun 25:e174888. doi: 10.1172/jci.insight.174888. Online ahead of print.

ABSTRACT

The number of adults living with cystic fibrosis (CF) has already increased significantly due to drastic improvements in life expectancy attributable to advances in treatment including the development of highly effective modulator therapy. Chronic airway inflammation in cystic fibrosis (CF) contributes to morbidity and mortality and aging processes like 'inflammaging' and cell senescence impact CF pathology. Our results show that single cell RNA sequencing data, human primary bronchial epithelial cells from non-CF and CF donors, a CF bronchial epithelial cell line, and Cftr knockout (Cftr-/-) rats all demonstrated increased cell senescence markers in the CF bronchial epithelium. This was associated with upregulation of fibroblast growth factor receptors (FGFRs) and mitogen-activated protein kinase (MAPK) p38. Inhibition of FGFRs, specifically FGFR4 and to some extent FGFR1 attenuated cell senescence and improved mucociliary clearance, which was associated with MAPK p38 signaling. Mucociliary dysfunction could also be improved using a combination of senolytics in a CF ex vivo model. In summary, FGFR/MAPK p38 signaling contributes to cell senescence in CF airways, which is associated with impaired mucociliary clearance. Therefore, attenuation of cell senescence in the CF airways might be a future therapeutic strategy improving mucociliary dysfunction and lung disease in an aging CF population.

PMID:38916962 | DOI:10.1172/jci.insight.174888

Pediatr Nephrol. 2024 Jun 25. doi: 10.1007/s00467-024-06433-2. Online ahead of print.

ABSTRACT

A 6-month-old girl, previously diagnosed with cystic fibrosis (CF), was admitted to hospital for nephrolithiasis. Her parents were first-degree cousins. The patient underwent endoscopic stone management. Despite no family history of stones and medical treatment with potassium citrate, the patient developed recurrent renal stones and atypical urinary tract infections during follow-up. Basic investigations were all normal. Due to consanguinity and early presentation of nephrolithiasis, metabolic causes such as cystinuria and hyperoxaluria were considered. Cystinuria was excluded due to normal cystine levels. High urinary oxalate excretion was found as expected due to absorptive (secondary) hyperoxaluria in CF patients. An early stone burden in the patient with a history of medical treatment and consanguinity led us to perform a genetic testing. Genetic testing revealed a missense homozygous variant in exon 1 of the AGXT gene. The patient was diagnosed with primary hyperoxaluria type 1. Two rare life-threatening genetic diseases were found together in the same child.

PMID:38916781 | DOI:10.1007/s00467-024-06433-2

Int J Mycobacteriol. 2024 Apr 1;13(2):133-139. doi: 10.4103/ijmy.ijmy_70_24. Epub 2024 Jun 15.

ABSTRACT

BACKGROUND: Microbiological diagnosis of mycobacteriosis is often difficult, as it is necessary to differentiate between transient colonization and active infection.

METHODS: We studied the cultural properties of Mycobacterium abscessus complex (MABSc) strains obtained from cystic fibrosis patients, and also analyzed composite correlation index (CCI) values in patients with repeated MABSc inoculation and their correlation with the presence of clinical and radiological manifestations of mycobacteriosis.

RESULTS: As a result, MABSc more often grew in S-form colonies in patients without clinical manifestations of chronic infection, while R-form colonies were characteristic of patients with chronic infection and clinical symptoms. At the same time, in patients examined once, no growth of colonies in the R-form was recorded, and all strains produced growth in the form of either S-colonies or in the S- and R-forms simultaneously. Statistically significant results were obtained for the relationship of the CCI with the clinical and radiological picture. In addition, a heterogeneous MABSc population with low CCI score values correlated with the development of mycobacteriosis in patients. In patients with high CCI score values (homogeneity of isolated strains), on the contrary, there were no radiological or clinical signs of the disease.

CONCLUSION: These data make it possible to build a strategy for monitoring patients depending on changes in CCI score values. The use of CCI matrix to evaluate microorganisms' identification results is a potentially new method that expands the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

PMID:38916382 | DOI:10.4103/ijmy.ijmy_70_24

Microbiol Spectr. 2024 Jun 25:e0078724. doi: 10.1128/spectrum.00787-24. Online ahead of print.

ABSTRACT

Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has revolutionized the treatment of cystic fibrosis (CF) for most affected individuals but the effects of treatment on sinus microbiota are still unknown. Changes to the airway microbiota in CF are associated with disease state and alterations to the bacterial community after ETI initiation may require changes to clinical management regimens. We collected sinus swab samples from the middle meatus in an observational study of 38 adults with CF and chronic rhinosinusitis (CRS) from 2017 to 2021 and captured the initiation of ETI therapy. We performed 16S and custom amplicon sequencing to characterize the sinus microbiota pre- and post-ETI. Real-time quantitative PCR (RT-qPCR) was performed to estimate total bacterial abundance. Sinus samples from people with CF (pwCF) clustered into three community types, dependent on the dominant bacterial organism: a Pseudomonas-dominant, Staphylococcus-dominant, and mixed dominance cluster. Shannon's diversity index was low and not significantly altered post-ETI. Total bacterial load was not significantly lowered post-ETI. Pseudomonas spp. abundance was significantly reduced post-ETI, but eradication was not observed. Staphylococcus spp. became the dominant organism in most individuals post-ETI and we showed the presence of methicillin-resistant Staphylococcus aureus (MRSA) in the sinus both pre- and post-ETI. We also demonstrated that the sinus microbiome is predictive of the presence of Pseudomonas spp., Staphylococcus spp., and Serratia spp. in the sputum. Pseudomonas spp. and Staphylococcus spp., including MRSA, persist in the sinuses of pwCF after ETI therapy, indicating that these pathogens will continue to be important in CF airway disease management in the era of highly effective modulator therapies (HEMT).IMPORTANCEHighly effective modulator therapies (HEMT), such as elexacaftor/tezacaftor/ivacaftor (ETI), for cystic fibrosis (CF) have revolutionized patient care and quality of life for most affected individuals. The effects of these therapies on the microbiota of the airways are still unclear, though work has already been published on changes to microbiota in the sputum. Our study presents evidence for reduced relative abundance of Pseudomonas spp. in the sinuses following ETI therapy. We also show that Staphylococcus spp. becomes the dominant organism in the sinus communities of most individuals in this cohort after ETI therapy. We identified methicillin-resistant Staphylococcus aureus (MRSA) in the sinus microbiota both pre- and post-therapy. These findings demonstrate that pathogen monitoring and treatment will remain a vital part of airway disease management for people with cystic fibrosis (pwCF) in the era of HEMT.

PMID:38916354 | DOI:10.1128/spectrum.00787-24

Int J Behav Med. 2024 Jun 24. doi: 10.1007/s12529-024-10306-1. Online ahead of print.

ABSTRACT

BACKGROUND: Daily airway clearance therapy (ACT) is a critical aspect of treatment in cystic fibrosis (CF), but poor adherence is a prominent concern. Identifying factors that might enhance or diminish adherence is a priority for treatment centers. Gratitude, a generalized tendency to notice and appreciate positive facets of experience, is a psychosocial resource that has commanded growing research interest. This longitudinal study examined whether gratitude at baseline was associated with ongoing or persistent ACT adherence over the course of a year.

METHODS: Trait gratitude was evaluated at baseline using a validated measure, among adults receiving care at a regional CF treatment center. Self-reported adherence to ACT was assessed at baseline, 6 months, and 12 months using the Cystic Fibrosis Treatment Questionnaire. Average age of participants was 27.2 years, 45.5% were women, and 19.7% had severe disease.

RESULTS: In multivariable logistic regression models that accounted for disease severity (Forced Expiratory Volume1% predicted) and other clinical and demographic variables, individuals with higher baseline gratitude were significantly more likely to demonstrate persistent adherence over the course of the year. Gratitude remained predictive after additionally adjusting for other well-known psychosocial resource variables (social support and emotional well-being).

CONCLUSION: This is among the first demonstrations that gratitude is associated with persistent self-reported adherence to treatment over time. Findings suggest that gratitude may be important psychosocial resource for adults with CF, as they contend with complex, highly burdensome treatment regimens. Further research is warranted to examine these relationships and their impact on downstream health outcomes.

PMID:38914922 | DOI:10.1007/s12529-024-10306-1

BMJ Case Rep. 2024 Jun 24;17(6):e260221. doi: 10.1136/bcr-2024-260221.

ABSTRACT

Pseudohypoaldosteronism type 1 is a rare congenital autosomal recessive disorder, characterised by failure of receptor response to aldosterone. It is caused by mutation in SCNN1A gene with clinical features like failure to thrive in infancy, hyponatraemia, hyperkalaemia and metabolic acidosis. We present a male infant with seizures, hyperkalaemia and with failure to thrive, diagnosed at day 6 of life. The baby required repeated correction for hyperkalaemia; hence, after ruling out treatable causes for hyperkalaemia, exonerated sequencing was done which showed pathogenic mutation for cystic fibrosis and recessive mutation for pseudohypoaldosteronism. But the child was clinically in favour of pseudohypoaldosteronism. Hence, features of pseudohypoaldosteronism predominate cystic fibrosis; they both may coexist.

PMID:38914525 | DOI:10.1136/bcr-2024-260221

Curr Opin Pulm Med. 2024 Jun 25. doi: 10.1097/MCP.0000000000001090. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To provide a comprehensive overview of the underlying genetic defects of pulmonary (vascular) diseases and novel treatment avenues.

RECENT FINDINGS: Pulmonary arterial hypertension (PAH) is the prime example of a pulmonary vascular disease, which can be caused by genetic mutations in some patients. Germline mutations in the BMPR2 gene and further genes lead to vessel remodelling, increase of pulmonary vascular resistance and onset of heritable PAH. The PAH genes with the highest evidence and strategies for genetic testing and counselling have been assessed and evaluated in 2023 by international expert consortia. Moreover, first treatment options have just arisen targeting the molecular basis of PAH.

SUMMARY: Apart from PAH, this review touches on the underlying genetic causes of further lung diseases including alpha 1 antitrypsin deficiency, cystic fibrosis, familial pulmonary fibrosis and lymphangioleiomyomatosis. We point out the main disease genes, the underlying pathomechanisms and novel therapies trying not only to relieve symptoms but to treat the molecular causes of the diseases.

PMID:38913028 | DOI:10.1097/MCP.0000000000001090

Pediatr Investig. 2024 Jun 12;8(2):83-90. doi: 10.1002/ped4.12436. eCollection 2024 Jun.

ABSTRACT

IMPORTANCE: The 3-min step test is a simple option to monitor submaximal exercise capacity, although its use via remote video monitoring has not been investigated in children with cystic fibrosis (CF).

OBJECTIVE: This study aimed to assess the feasibility and reproducibility of performing the 3-min step test with remote supervision.

METHODS: A cross-sectional study including CF patients (6-18 years) from two CF services were performed. Demographic, anthropometric, clinical, and lung function data were collected and two 3-min step tests were performed: (i) in-person supervision, and (ii) remotely supervised by video monitoring. Before and after the tests, heart rate (HR), oxygen saturation (SpO2), and the Borg score for dyspnea and lower limb fatigue were monitored.

RESULTS: Twenty-three patients (10.7 ± 3.7 years) with a mean FEV1 of 89.5% ± 23.2% were included. There were no significant differences between tests, with mean differences (95% confidence intervals) in final HR of -3.3 (-8.9, 2.4), change in HR of -1.9 (-6.1, 2.1), final SpO2 of 0.3 (-0.4, 1.0), and final dyspnea of 0.1 (-0.8, 0.9). The intraclass correlation coefficient was 0.852 (final HR), 0.762 (final SpO2), and 0.775 (final lower limb fatigue). Significant and moderate correlations were found between tests for final HR (r = 0.75), change in HR (r = 0.61), and final SpO2 (r = 0.61). The Bland-Altman analysis showed a mean difference in final SpO2 between tests of 0.3% (limit of agreement -3.0%, 3.5%).

INTERPRETATION: Physiological responses between tests were similar, indicating it was feasible to perform the 3-min step test with remote supervision in CF children.

PMID:38910852 | PMC:PMC11193376 | DOI:10.1002/ped4.12436

J Heart Lung Transplant. 2024 Jun 21:S1053-2498(24)01701-7. doi: 10.1016/j.healun.2024.06.009. Online ahead of print.

ABSTRACT

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) has no currently available specific treatment. Benefits of lung transplantation (LT) for PPFE are poorly documented.

METHODS: We conducted a nation-wide multicentric retrospective study in patients who underwent lung or heart-lung transplantation for chronic end-stage lung disease secondary to PPFE between 2012 and 2022 in France.

RESULTS: Thirty-one patients were included. At transplantation, median age was 48 years [IQR 35 - 55]. 64.5% were women. Twenty-one (67.7%) had idiopathic PFFE. Sixteen (52%) had bilateral LT, 10 (32%) had single LT, 4 (13%) had lobar transplantation and one (3%) had heart-lung transplantation. Operative mortality was 3.2%. Early mortality (< 90 days or during the first hospitalization) was 32%. Eleven patients (35.5%) underwent reoperation for hemostasis. Eight (30.8%) experienced bronchial complications. Mechanical ventilation time was 10 days [IQR 2-55]. Length of stay in intensive care unit and hospital were 34 [IQR 18-73] and 64 [IQR 36-103] days, respectively. Median survival was 21 months. Post-transplant survival rates after 1, 2, and 5 years were 57.9%, 42.6% and 38.3% respectively. Low albuminemia (p=0.046), FVC (p=0.021), FEV1 (p=0.009) and high emergency lung transplantation (p=0.04) were associated with increased early mortality. Oversized graft tended to be correlated to a higher mortality (p=0.07).

CONCLUSION: LT for PPFE is associated with high post-operative morbi-mortality rates. Patients requiring high emergency lung transplantation with advanced disease, malnutrition, or critical clinical status experienced worse outcomes.

GOV IDENTIFIER: NCT05044390.

PMID:38909712 | DOI:10.1016/j.healun.2024.06.009

Cell Commun Signal. 2024 Jun 21;22(1):341. doi: 10.1186/s12964-024-01609-7.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa (PA) is an opportunistic pathogen that can cause sight threatening infections in the eye and fatal infections in the cystic fibrosis airway. Extracellular vesicles (EVs) are released by host cells during infection and by the bacteria themselves; however, there are no studies on the composition and functional role of host-derived EVs during PA infection of the eye or lung. Here we investigated the composition and capacity of EVs released by PA infected epithelial cells to modulate innate immune responses in host cells.

METHODS: Human telomerase immortalized corneal epithelial cells (hTCEpi) cells and human telomerase immortalized bronchial epithelial cells (HBECs) were treated with a standard invasive test strain of Pseudomonas aeruginosa, PAO1, for 6 h. Host derived EVs were isolated by qEV size exclusion chromatography. EV proteomic profiles during infection were compared using mass spectrometry and functional studies were carried out using hTCEpi cells, HBECs, differentiated neutrophil-like HL-60 cells, and primary human neutrophils isolated from peripheral blood.

RESULTS: EVs released from PA infected corneal epithelial cells increased pro-inflammatory cytokine production in naïve corneal epithelial cells and induced neutrophil chemotaxis independent of cytokine production. The EVs released from PA infected bronchial epithelial cells were also chemotactic although they failed to induce cytokine secretion from naïve HBECs. At the proteomic level, EVs derived from PA infected corneal epithelial cells exhibited lower complexity compared to bronchial epithelial cells, with the latter having reduced protein expression compared to the non-infected control.

CONCLUSIONS: This is the first study to comprehensively profile EVs released by corneal and bronchial epithelial cells during Pseudomonas infection. Together, these findings show that EVs released by PA infected corneal and bronchial epithelial cells function as potent mediators of neutrophil migration, contributing to the exuberant neutrophil response that occurs during infection in these tissues.

PMID:38907250 | DOI:10.1186/s12964-024-01609-7

Immunol Lett. 2024 Jun 19:106886. doi: 10.1016/j.imlet.2024.106886. Online ahead of print.

ABSTRACT

OBJECTIVE: Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2 protecting individuals, especially the immunocompromised, from COVID-19. Still, it remains largely unknown how solid organ transplant and different immunosuppressive medications affect development of vaccine-induced immunity.

METHODS: In this work, we monitored humoral and cellular memory responses after mRNA SARS-CoV-2 two-doses and booster doses vaccination in cystic fibrosis lung transplanted patients (CFT) and compared them with both cystic fibrosis patients without lung transplant (CF) and with kidney transplant recipients (KT). In particular, we investigated the effects of immunosuppressive regimens on immune memory to SARS-CoV-2 after mRNA SARS-CoV-2 vaccine in transplanted patients.

RESULTS: Our results showed that immunocompromised transplanted patients displayed a weak cellular and humoral memory to SARS-CoV-2 mRNA vaccination. In addition, obtained data clearly demonstrate that immunosuppressive therapy regimen including antimetabolites, further reduces patients' ability to respond to vaccination at both humoral and cell-mediated level. Notably, patient treated with antimetabolites showed a lower humoral and cellular response also after a booster dose vaccination.

CONCLUSION: These results, even if obtained on a small patient's cohort, question whether immunocompromised patients need interventions to improve vaccine SARS-CoV-2 mRNA vaccine response such as additional jab or modulation of immunosuppressive therapy.

PMID:38906482 | DOI:10.1016/j.imlet.2024.106886

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241253990. doi: 10.1177/17534666241253990.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disease caused by the inheritance of two mutant cystic fibrosis transmembrane conductance regulator (CFTR) alleles, one from each parent. Autosomal recessive disorders are rarely associated with germline mutations or mosaicism. Here, we propose a case of paternal germline mutation causing CF. The subject also had an identifiable maternal mutant allele. We identified the compound heterozygous variants in the proband through Sanger sequencing, and in silico studies predicted functional effects on the protein. Also, short tandem repeat markers revealed the de novo nature of the mutation. The maternal mutation in the CFTR gene was c.1000C > T. The de novo mutation was c.178G > A, p.Glu60Lys. This mutation is located in the lasso motif of the CFTR protein and, according to in silico structural analysis, disrupts the interaction of the lasso motif and R-domain, thus influencing protein function. This first reported case of de novo mutation in Asia has notable implications for molecular diagnostics, genetic counseling, and understanding the genetic etiology of recessive disorders in the Iranian population.

PMID:38904297 | DOI:10.1177/17534666241253990

Front Med (Lausanne). 2024 Jun 5;11:1349466. doi: 10.3389/fmed.2024.1349466. eCollection 2024.

ABSTRACT

BACKGROUND: Previous studies showed that contrast-enhanced (CE) morpho-functional magnetic resonance imaging (MRI) detects abnormalities in lung morphology and perfusion in patients with cystic fibrosis (CF). Novel matrix pencil decomposition MRI (MP-MRI) enables quantification of lung perfusion and ventilation without intravenous contrast agent administration.

OBJECTIVES: To compare MP-MRI with established morpho-functional MRI and spirometry in patients with CF.

METHODS: Thirty-nine clinically stable patients with CF (mean age 21.6 ± 10.7 years, range 8-45 years) prospectively underwent morpho-functional MRI including CE perfusion MRI, MP-MRI and spirometry. Two blinded chest radiologists assessed morpho-functional MRI and MP-MRI employing the validated chest MRI score. In addition, MP-MRI data were processed by automated software calculating perfusion defect percentage (QDP) and ventilation defect percentage (VDP).

RESULTS: MP perfusion score and QDP correlated strongly with the CE perfusion score (both r = 0.81; p < 0.01). MP ventilation score and VDP showed strong inverse correlations with percent predicted FEV1 (r = -0.75 and r = -0.83; p < 0.01). The comparison of visual and automated parameters showed that both MP perfusion score and QDP, and MP ventilation score and VDP were strongly correlated (r = 0.74 and r = 0.78; both p < 0.01). Further, the MP perfusion score and MP ventilation score, as well as QDP and VDP were strongly correlated (r = 0.88 and r = 0.86; both p < 0.01).

CONCLUSION: MP-MRI detects abnormalities in lung perfusion and ventilation in patients with CF without intravenous or inhaled contrast agent application, and correlates strongly with the well-established CE perfusion MRI score and spirometry. Automated analysis of MP-MRI may serve as quantitative noninvasive outcome measure for diagnostic monitoring and clinical trials.

PMID:38903825 | PMC:PMC11188455 | DOI:10.3389/fmed.2024.1349466

Front Med (Lausanne). 2024 Jun 6;11:1388959. doi: 10.3389/fmed.2024.1388959. eCollection 2024.

ABSTRACT

Phenotypic drug discovery (PDD) involves screening compounds for their effects on cells, tissues, or whole organisms without necessarily understanding the underlying molecular targets. PDD differs from target-based strategies as it does not require knowledge of a specific drug target or its role in the disease. This approach can lead to the discovery of drugs with unexpected therapeutic effects or applications and allows for the identification of drugs based on their functional effects, rather than through a predefined target-based approach. Ultimately, disease definitions are mostly symptom-based rather than mechanism-based, and the therapeutics should be likewise. In recent years, there has been a renewed interest in PDD due to its potential to address the complexity of human diseases, including the holistic picture of multiple metabolites engaging with multiple targets constituting the central hub of the metabolic host-microbe interactions. Although PDD presents challenges such as hit validation and target deconvolution, significant achievements have been reached in the era of big data. This article explores the experiences of researchers testing the effect of a thymic peptide hormone, thymosin alpha-1, in preclinical and clinical settings and discuss how its therapeutic utility in the precision medicine era can be accommodated within the PDD framework.

PMID:38903817 | PMC:PMC11187271 | DOI:10.3389/fmed.2024.1388959

Eur Respir J. 2024 Jun 20:2400004. doi: 10.1183/13993003.00004-2024. Online ahead of print.

ABSTRACT

BACKGROUND: We recently demonstrated that elexacaftor/tezacaftor/ivacaftor (ETI) improves the lung clearance index (LCI) and abnormalities in lung morphology detected by magnetic resonance imaging (MRI) in adolescent and adult patients with cystic fibrosis (CF). However, real-world data on the effect of ETI on these sensitive outcomes of lung structure and function in school-age children with CF have not been reported. The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children with CF and one or two F508del alleles aged 6 to 11 years.

METHODS: This prospective, observational, multicenter, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and three months after initiation of ETI.

RESULTS: A total of 107 children with CF including 40 heterozygous for F508del and a minimal function mutation (F/MF) and 67 homozygous for F508del (F/F) were enrolled in this study. Treatment with ETI improved the LCI in F/MF children (-1.0; IQR, -2.0 to -0.1; p<0.01) and F/F children (-0.8; IQR, -1.9 to -0.2; p<0.001) from 3 months onwards. Further, ETI improved the MRI global score in F/MF (-4.0; IQR, -9.0 to 0.0; p<0.01) and F/F children (-3.5; IQR, -7.3 to -0.8; p<0.001).

CONCLUSIONS: ETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least one F508del alleles in a real-world setting. Our results support early initiation of ETI to reduce or even prevent lung disease progression in school-age children with CF.

PMID:38901883 | DOI:10.1183/13993003.00004-2024

Biochem Biophys Res Commun. 2024 Jun 11;725:150254. doi: 10.1016/j.bbrc.2024.150254. Online ahead of print.

ABSTRACT

Decreased pancreatic β-cell volume is a serious problem in patients with type 2 diabetes mellitus, and there is a need to establish appropriate treatments. Increasingly, sodium/glucose cotransporter 2 (SGLT2) inhibitors, which have a protective effect on pancreatic β-cells, are being prescribed to treat diabetes; however, the underlying mechanism is not well understood. We previously administered SGLT2 inhibitor dapagliflozin to a mouse model of type 2 diabetes and found significant changes in gene expression in the early-treated group, which led us to hypothesize that epigenetic regulation was a possible mechanism of these changes. Therefore, we performed comprehensive DNA methylation analysis by methylated DNA immunoprecipitation using isolated pancreatic islets after dapagliflozin administration to diabetic model mice. As a result, we identified 31 genes with changes in expression due to DNA methylation changes. Upon immunostaining, cystic fibrosis transmembrane conductance regulator and cadherin 24 were found to be upregulated in islets in the dapagliflozin-treated group. These molecules may contribute to the maintenance of islet morphology and insulin secretory capacity, suggesting that SGLT2 inhibitors' protective effect on pancreatic β-cells is accompanied by DNA methylation changes, and that the effect is long-term and not temporary. In future diabetes care, SGLT2 inhibitors may be expected to have positive therapeutic effects, including pancreatic β-cell protection.

PMID:38901223 | DOI:10.1016/j.bbrc.2024.150254

Ital J Pediatr. 2024 Jun 21;50(1):119. doi: 10.1186/s13052-024-01688-9.

ABSTRACT

BACKGROUND: Respiratory syncytial virus (RSV) affects 60-80% of children below 1 year and it's the first cause of acute bronchiolitis. The aim of this study was to assess the trend and characteristics of hospitalizations for RSV infections in Italy.

METHODS: This is a retrospective study based on the Italian Hospital Discharge Record (HDR) database. We analysed HDRs from June 2015 to May 2019, considering two groups of infants: Group 1 had a confirmed diagnosis of RSV; Group 2 had a diagnosis of acute bronchiolitis not RSV-coded.

RESULTS: There were 67,746 overall hospitalizations (40.1% Group 1, and 59.9% Group 2). Hospitalization rate increased for Group 1 from 125 to 178 per 10,000 infants (+ 42.4%), and for Group 2 from 210 to 234 per 10,000 (+ 11.4%). The mean hospitalization length was 6.3 days in Group 1, longer than Group 2 (+ 1.0 day). A further analysis revealed that infants with heart disease or born premature had longer mean hospital stay compared to infants without risk factors (10.7 days versus 6.1 days, p < 0.0001; 34.0 days versus 6.1 days, p < 0.0001, respectively). Group 1 required more critical care (oxygen therapy and/or mechanical ventilation) than Group 2. We found that, in proportion to hospital admissions in pediatric and general hospitals, RSV was more frequently diagnosed in the first ones. The mean hospitalization cost increased for Group 1 (from € 2,483 to € 2,617) and Group 2 (from € 2,007 to € 2,180).

CONCLUSIONS: Our results confirmed that RSV pulmonary disease in infants is seasonal and often requires hospitalization. Our study suggested that RSV is responsible for an increasing hospitalization rate and related costs during the study period.

PMID:38902751 | DOI:10.1186/s13052-024-01688-9

Hepatology. 2024 Jun 20. doi: 10.1097/HEP.0000000000000973. Online ahead of print.

ABSTRACT

Porto-sinusoidal vascular disorder is a rare liver disease. The pathophysiological mechanisms underlying the development of porto-sinusoidal vascular disorder are unknown. Isolated cases of porto-sinusoidal vascular disorder associated with gene mutations have been reported, but no overview is available. Therefore, we performed an extensive literature search to provide a comprehensive overview of gene mutations associated with porto-sinusoidal vascular disorder. We identified 34 genes and one chromosomal abnormality associated with porto-sinusoidal vascular disorder in the literature, and we describe here one additional gene mutation (TBL1XR1 mutation, leading to Pierpont syndrome). These gene mutations are associated either with extrahepatic organ involvement as part of syndromes (Adams Oliver, telomere biology disorders, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, immune deficiencies, cystic fibrosis, cystinosis, Williams Beuren, Turner, Pierpont) or with isolated porto-sinusoidal vascular disorder (KCNN3, DGUOK, FOPV, GIMAP5, FCHSD1, TRMT5, HRG gene mutations). Most of the cases were revealed by signs or complications of portal hypertension. When analysing the cell types in which these genes are expressed, we found that these genes are predominantly expressed in immune cells, suggesting that these cells may play a more important role in the development of porto-sinusoidal vascular disorder than previously thought. In addition, pathway analyses suggested that there may be 2 types of porto-sinusoidal vascular disorder associated with gene mutations: those resulting directly from morphogenetic abnormalities and those secondary to immune changes.

PMID:38900412 | DOI:10.1097/HEP.0000000000000973