Front Mol Neurosci. 2024 Dec 24;17:1509280. doi: 10.3389/fnmol.2024.1509280. eCollection 2024.

ABSTRACT

The 90 kDa Heat shock protein (Hsp90) is a family of ubiquitously expressed molecular chaperones responsible for the stabilization and maturation of >400 client proteins. Hsp90 exhibits dramatic conformational changes to accomplish this, which are regulated by partner proteins termed co-chaperones. One of these co-chaperones is called the activator or Hsp90 ATPase activity homolog 1 (Aha1) and is the most potent accelerator of Hsp90 ATPase activity. In conditions where Aha1 levels are dysregulated including cystic fibrosis, cancer and neurodegeneration, Hsp90 mediated client maturation is disrupted. Accumulating evidence has demonstrated that many disease states exhibit large hetero-protein complexes with Hsp90 as the center. Many of these include Aha1, where increased Aha1 levels drive disease states forward. One strategy to block these effects is to design small molecule disruptors of the Hsp90/Aha1 complex. Studies have demonstrated that current Hsp90/Aha1 small molecule disruptors are effective in both models for cancer and neurodegeration.

PMID:39776493 | PMC:PMC11703849 | DOI:10.3389/fnmol.2024.1509280

Pharmacoepidemiol Drug Saf. 2025 Jan;34(1):e70076. doi: 10.1002/pds.70076.

ABSTRACT

The German Cystic Fibrosis (CF) Registry (GCFR) is a national General Data Protection Regulation-compliant centralised database sponsored by the German Cystic Fibrosis Association (Mukoviszidose e.V.) and based on informed consent for each participating patient, ethical approval, and data protection votes. The aims of the GCFR are to optimise quality of care for CF at the centres, generate epidemiologic overviews, address research questions related to improved CF care, and inform caregivers, patients (aimed at patient empowerment), and health authorities and industry (aimed at care planning and pharmacovigilance). Established in 1995, the Registry has captured data on > 9600 individuals with a combined total of more than 140 000 annual assessments with an estimated coverage rate of > 90%. Patient data are collected after informed consent and confirmed diagnosis of CF, or a CFTR-related disorder, or a screening-positive inconclusive diagnosis of CF (i.e., CFSPID). The registry collects core, encounter, and annual health data. Data include demographics, anthropometrics, lung function, microbiology, CF-specific complications and chronic medications, hospitalisations, demand-oriented antibiotic therapies, and outcomes (death and transplants). Real world and pharmacovigilance studies have been published and additional research underway; there is a formal process for requesting access to the GCFR.

PMID:39775994 | DOI:10.1002/pds.70076

Nat Commun. 2025 Jan 7;16(1):456. doi: 10.1038/s41467-025-55843-9.

ABSTRACT

Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed in the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions and demonstrate immunogenicity and safety in preclinical and clinical development. Optimized srRNA vaccines generate protective immunity (according to the WHO defined thresholds) at doses up to 1,000,000-fold lower than mRNA in female mouse models of influenza and rabies. Clinically, safety and immunogenicity of RBI-4000, an srRNA vector encoding the rabies glycoprotein, was evaluated in a Phase I study (NCT06048770). RBI-4000 was able to elicit de novo protective immunity in the majority of healthy participants when administered at a dose of 0.1, 1, or 10 microgram (71%, 94%, 100%, respectively) in a prime-boost schedule. Similarly, we observe immunity above the WHO benchmark of protection following a single administration in most participants at both 1 and 10 microgram doses. There are no serious adverse events reported across all cohorts. These data establish the high therapeutic index of optimized srRNA vectors, demonstrating feasibility of both low dose and single dose approaches for vaccine applications.

PMID:39774967 | DOI:10.1038/s41467-025-55843-9

Genes Immun. 2025 Jan 7. doi: 10.1038/s41435-024-00318-y. Online ahead of print.

ABSTRACT

Immunoglobulin GM (γ marker) and KM (κ marker) allotypes-encoded by immunoglobulin heavy chain G (IGHG) and immunoglobulin κ constant (IGKC) genes-have been shown to be associated with immune responsiveness to a variety of self and nonself antigens. The aim of the present investigation was to determine whether allelic variation at the GM and KM loci was associated with antibody responsiveness to poly-N-acetyl-D-glucosamine (PNAG), a broadly-conserved surface polysaccharide expressed by many microbial pathogens. In addition, we wished to determine whether Fcγ receptor 2 A (FCGR2A) genotypes, which have been shown to be risk factors for some pathogens, also influenced antibody responses to PNAG. DNA from 257 patients with various pulmonary diseases (PD) was genotyped for several GM, KM, and FCGR2A alleles, and plasma were characterized for anti-PNAG IgG antibodies. The levels of IgG4 antibodies to PNAG were associated with FCGR2A genotypes (p = 0.01). Also, KM and FCGR2A alleles epistatically contributed to anti-PNAG IgG3 antibody responses: subjects with KM 1/1 or KM 1/3 and homozygous for the R allele of FCGR2A had the highest levels of anti-PNAG IgG3 antibodies compared to all other genotype combinations. If confirmed by larger studies, these results are potentially relevant to immunotherapy against many PNAG-expressing infectious pathogens.

PMID:39774260 | DOI:10.1038/s41435-024-00318-y

Sci Rep. 2025 Jan 7;15(1):1143. doi: 10.1038/s41598-024-84003-0.

ABSTRACT

Continuous glucose monitors (CGM) provide valuable insights about glycemic control that aid in diabetes management. However, interpreting metrics and charts and synthesizing them into linguistic summaries is often non-trivial for patients and providers. The advent of large language models (LLMs) has enabled real-time text generation and summarization of medical data. The objective of this study was to assess the strengths and limitations of using an LLM to analyze raw CGM data and produce summaries of 14 days of data for patients with type 1 diabetes. We first evaluated the ability of GPT-4 to compute quantitative metrics specific to diabetes found in an Ambulatory Glucose Profile (AGP). Then, using two independent clinician graders, we evaluated the accuracy, completeness, safety, and suitability of qualitative descriptions produced by GPT-4 across five different CGM analysis tasks. GPT-4 performed 9 out of the 10 quantitative metrics tasks with perfect accuracy across all 10 cases. The clinician-evaluated CGM analysis tasks had good performance across measures of accuracy [lowest task mean score 8/10, highest task mean score 10/10], completeness [lowest task mean score 7.5/10, highest task mean score 10/10], and safety [lowest task mean score 9.5/10, highest task mean score 10/10]. Our work serves as a preliminary study on how generative language models can be integrated into diabetes care through data summarization and, more broadly, the potential to leverage LLMs for streamlined medical time series analysis.

PMID:39774031 | DOI:10.1038/s41598-024-84003-0

Cell Commun Signal. 2025 Jan 7;23(1):12. doi: 10.1186/s12964-024-02024-8.

ABSTRACT

BACKGROUND: Neutrophils are the most abundant leukocytes in human blood, and their recruitment is essential for innate immunity and inflammatory responses. The initial and critical step of neutrophil recruitment is their adhesion to vascular endothelium, which depends on G protein-coupled receptor (GPCR) triggered integrin inside-out signaling that induces β2 integrin activation and clustering on neutrophils. Kindlin-3 and talin-1 are essential regulators for the inside-out signaling induced β2 integrin activation. However, their contribution in the inside-out signaling induced β2 integrin clustering is unclear because conventional assays on integrin clustering are usually performed on adhered cells, where integrin-ligand binding concomitantly induces integrin outside-in signaling.

METHODS: We used flow cytometry and quantitative super-resolution stochastic optical reconstruction microscopy (STORM) to quantify β2 integrin activation and clustering, respectively, in kindlin-3 and talin-1 knockout leukocytes. We also tested whether wildtype or Pleckstrin homology (PH) domain deleted kindlin-3 can rescue the kindlin-3 knockout phenotypes.

RESULTS: GPCR-triggered inside-out signaling alone can induce β2 integrin clustering. As expected, both kindlin-3 and talin-1 knockout decreases integrin activation. Interestingly, only kindlin-3 but not talin-1 contributes to integrin clustering in the scenario of inside-out-signaling, wherein a critical role of the PH domain of kindlin-3 was highlighted.

CONCLUSIONS: Since talin was known to facilitate integrin clustering in outside-in-signaling-involved cells, our finding provides a paradigm shift by suggesting that the molecular mechanisms of integrin clustering upon inside-out signaling and outside-in signaling are different. Our data also contradict the conventional assumption that integrin activation and clustering are tightly inter-connected by showing separated regulation of the two during inside-out signaling. Our study provides a new mechanism that shows kindlin-3 regulates β2 integrin clustering and suggests that integrin clustering should be assessed independently, aside from integrin activation, when studying leukocyte adhesion in inflammatory diseases.

PMID:39773732 | DOI:10.1186/s12964-024-02024-8

Orphanet J Rare Dis. 2025 Jan 7;20(1):6. doi: 10.1186/s13023-024-03522-1.

ABSTRACT

BACKGROUND: Patients with cystic fibrosis (CF) are rare in China and differ significantly from the Caucasian populations in terms of clinical and genetic characteristics. However, the progression and mortality of Chinese patients with CF have not been well described.

RESULTS: This study included all 67 patients from the Peking Union Medical College Hospital CF cohort, with a median followed up time of 5.2 years. Compared to patients diagnosed with CF in childhood, adult-diagnosed patients exhibit a lower proportion of pancreatic exocrine insufficiency (25.0% vs. 77.8%, P = 0.001) and a higher body mass index (19.6 vs. 17.7 kg/m2, P = 0.045). According to the mixed-effects model, for patients ≤ 30 years of age at diagnosis, FEV1% predicted decreased 1.17% per year. The generalized linear regression model showed that higher baseline FEV1% predicted and occurrence of pulmonary exacerbations were associated with the progression of patients with CF. The survival rates at 5 years and 10 years after the diagnosis were 96.7% and 80.6%, respectively. The log-rank test showed baseline FEV1% predicted < 50%, and high CF-ABLE and 3-year prognostic scores were associated with mortality in patients with CF in China.

CONCLUSIONS: We reported the progression and mortality of patients with CF in China, which was a rare and relatively unknown population in the past. Baseline FEV1% predicted is associated with progression and mortality. Pulmonary exacerbations can accelerate the decline in lung function. The CF-ABLE and 3-year prognostic scores are applicable for predicting poor prognosis in patients with CF in China.

PMID:39773272 | DOI:10.1186/s13023-024-03522-1

Am J Respir Cell Mol Biol. 2025 Jan 7. doi: 10.1165/rcmb.2024-0130OC. Online ahead of print.

ABSTRACT

In asthma, tissue factor (TF) levels are elevated in the lung. In our previous studies using mechanically compressed human bronchial epithelial (HBE) cells, which are a well-defined in vitro model of bronchoconstriction during asthma exacerbations, we detected TF within extracellular vesicles (EVs) released from compressed HBE cells. Here, to better characterize the potential role of this mechanism in asthma, we tested the extent to which the transcriptional regulation of epithelial cell-derived TF varied between donors with and without asthma. Using RNA in situ hybridization, we detected epithelial expression of F3, the TF protein-encoding gene, in human airways. Next, to determine the role of TGF-β receptor (TGF-βR) in the regulation of TF, we exposed well-differentiated HBE cells to mechanical compression in the presence or absence of a pharmacological inhibitor of TGF-β receptor. Furthermore, to identify the protein cargo of EVs released from HBE cells, we used Tandem Mass Tag mass spectrometry. Our findings revealed significantly higher F3 expression in the airways of patients with asthma compared to healthy controls. However, we observed no differences in F3 expression or TF release between asthmatic and non-asthmatic HBE cells, both at baseline and after compression. Mechanistically, compression-induced F3 expression in HBE cells depended on TGF-βR. Our proteomic analysis identified 22 differentially released proteins in EVs, with higher levels in compressed cells compared to controls. Gene ontology analysis indicates these proteins are involved in diverse biological processes, highlighting a potential role for epithelial cell-derived EVs during asthma exacerbations.

PMID:39773168 | DOI:10.1165/rcmb.2024-0130OC

Am J Physiol Lung Cell Mol Physiol. 2025 Jan 8. doi: 10.1152/ajplung.00289.2024. Online ahead of print.

ABSTRACT

Lung infection is one of the leading causes of morbidity and mortality worldwide. Even with appropriate antibiotic and antiviral treatment, mortality in hospitalized patients often exceeds 10%, highlighting the need for the development of new therapeutic strategies. Of late, cystic fibrosis transmembrane conductance regulator (CFTR) is - in addition to its well-established roles in the lung airway and extrapulmonary organs - increasingly recognized as a key regulator of alveolar homeostasis and defense. In the alveolar epithelium, CFTR mediates alveolar fluid secretion and liquid homeostasis; in the microvascular endothelium, CFTR maintains vascular barrier function. CFTR also contributes to alveolar immunity. Yet, in lung infection, diverse molecular mechanisms reduce CFTR abundance and otherwise impair its function, promoting alveolar inflammation, edema, and cell death. Preservation or restoration of CFTR function by CFTR modulator drugs thus presents a promising avenue to combat lung infection in a pathogen-independent manner.

PMID:39772994 | DOI:10.1152/ajplung.00289.2024

J Asthma. 2025 Jan 8:1-11. doi: 10.1080/02770903.2024.2448317. Online ahead of print.

ABSTRACT

ObjectivesPatient perception of treatment effectiveness is key to optimizing adherence. This is potentially impacted by color, yet no such studies have been conducted in asthma. This study assessed the influence of pink vs. white pressurized metered-dose inhaler (pMDI) actuators on asthma symptoms perception.MethodsIn this double-blind, randomized, multicenter, crossover study, adults with moderate-to-severe asthma received extrafine formulation beclomethasone dipropionate/formoterol furoate (BDP/FF) pMDI for a two-week run-in. During two, two-week treatment periods they received BDP/FF pMDI, white in one, pink in the other, using an 'authorized deception' approach (patients were told the inhalers contained the same active ingredients, but device characteristics differed). Endpoints included patient-reported asthma symptoms and psychopharmacological aspects (prior to use: did patients expect an improvement; after use: did they think there had been an improvement; both on 100-point visual analog scales [VAS]).ResultsOf 74 patients analyzed, 72 completed the study. There were no statistically significant differences between inhalers for asthma symptoms, with minimal changes from baseline. Patients were numerically more likely to expect symptoms improvement with the white than pink inhaler (mean VAS 64.5 vs. 60.8). Perceived improvements were lower than expected with both, numerically favoring the pink inhaler (mean VAS 41.1 vs. 44.6); 46.6% believed a change had been made, 51.9% of whom believed this impacted symptoms.ConclusionsChanging inhaler color had no impact on asthma symptoms, but did have a numerical impact on patients' expectations of subsequent treatment effect. This emphasizes the importance of communication between patients and healthcare practitioners when changing inhalers.

PMID:39772981 | DOI:10.1080/02770903.2024.2448317

Nutrients. 2024 Dec 14;16(24):4319. doi: 10.3390/nu16244319.

ABSTRACT

The gut microbiome is essential for children's normal growth and development, with its formation aligning closely with key stages of growth. Factors like birth method, feeding practices, and antibiotic exposure significantly shape the composition and functionality of the infant gut microbiome. Small intestinal bacterial overgrowth (SIBO) involves an abnormal increase in bacteria within the small intestine. This overgrowth can interfere with digestion, impair nutrient absorption, and lead to both local and systemic inflammation, potentially contributing to malnutrition. In this review, we provide a comprehensive overview of the current understanding of the relationship between SIBO and malnutrition, with a particular focus on the pediatric population. SIBO seems to play an important role in nutrient malabsorption through the gut microbiome imbalance, local inflammation, and disruption of the mucosal intestinal barrier. Additionally, SIBO is more prevalent in digestive disorders linked to malabsorption and malnutrition. Different therapeutic strategies for addressing malnutrition-related SIBO have been proposed. While antibiotics are the primary treatment for SIBO, their effectiveness in promoting weight gain among malnourished children remains uncertain. Hence, future research directed at the impact of microbiome imbalance on nutrient intake and absorption could bring to light new strategies for the effective prevention and treatment of malnutrition.

PMID:39770940 | DOI:10.3390/nu16244319

Microorganisms. 2024 Dec 9;12(12):2538. doi: 10.3390/microorganisms12122538.

ABSTRACT

Pseudomonas aeruginosa is a major cause of chronic respiratory infections in patients with cystic fibrosis (CF), with biofilm formation contributing to its persistence and antibiotic resistance. This study aimed to gain insights into the mechanistic action of succinic acid as a ciprofloxacin adjuvant against clinically relevant CF isolates, including small colony variants and mucoid strains, and a ciprofloxacin-resistant strain grown within CF dense mucus. Time-kill assays in artificial CF mucus, along with planktonic and surface-attached biofilm experiments, were used to assess the activity of succinic acid alone and in combination with sublethal ciprofloxacin concentrations. Succinic acid demonstrated an adjuvant effect of ciprofloxacin against P. aeruginosa grown within CF mucus at pH levels below pKa1 during the early bacterial growth stages. In examining planktonic growth and biofilms under these conditions, we found that succinic acid demonstrated strong antibacterial and antibiofilm properties. Conversely, succinic acid activity decreased at later growth stages, though it enhanced the ciprofloxacin effect, especially against mucoid biofilms. Moreover, we noted that, in dense CF mucus, succinic acid activity was attenuated compared to a non-CF environment, indicating diffusion challenges. These findings underscore the potential of succinic acid as a therapeutic adjuvant for improving antibiotic treatment outcomes and overcoming biofilm-associated resistance in CF.

PMID:39770741 | DOI:10.3390/microorganisms12122538

Pathogens. 2024 Nov 22;13(12):1030. doi: 10.3390/pathogens13121030.

ABSTRACT

The poor prognosis of infections associated with multidrug-resistant Pseudomonas aeruginosa can be attributed to several conditions of the patient and virulence factors of the pathogen, such as the type III secretion system (T3SS), which presents the ability to inject four effectors into the host cell: ExoS, ExoT, ExoU and ExoY. The aim of this study was to analyze the distribution of exo genes through multiplex polymerase chain reaction in P. aeruginosa strains isolated from patients at a third-level pediatric hospital and their relationships with clinical variables, e.g., the origin of the sample, susceptibility profile and outcome, through a multinomial logistic regression model. A total of 336 bacterial strains were obtained from cystic fibrosis (CF; n = 55) and bloodstream infection (BSI; n = 281) samples, and eleven presence (+)/absence (-) exo virulotype patterns were identified. The virulotype V3 (exoU-/exoS+/exoT+/exoY+) was observed in 64.28%, followed by V1 (exoU+/exoS-/exoT+/exoY+) with 11.60%. Additionally, V2 (exoU+/exoS-/exoT+/exoY-) was present in 11.60%, and V7 (exoU-/exoS+/exoT+/exoY-) was present in 4.17%. The remaining virulotypes (8.33%) identified were clustered in the other virulotype (OV) group (V4, V5, V6, V8, V9, V10 and V11). The clinical records of 100 patients and their outcomes were reviewed. Fifteen patients died (CF = 4; BSI = 11). V2 and V1 were the virulotypes most related to pandrug resistance (PDR), whereas the V1 relative risk of death was determined to be almost four-fold greater than that of V3, followed by V2 and OV. In summary, the virulotypes V1, V2 and CF are related to death. This study highlights the association of T3SS virulotypes with the susceptibility profile, clinical origin and their potential for predicting a poor prognosis.

PMID:39770290 | DOI:10.3390/pathogens13121030

Int J Mol Sci. 2024 Dec 11;25(24):13313. doi: 10.3390/ijms252413313.

ABSTRACT

Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is a rare disease that currently has no cure. It is caused by defects in the SGCB gene, mainly missense mutations, which cause the impairment of the sarcoglycan complex, membrane fragility, and progressive muscle degeneration. Here, we studied the fate of some β-sarcoglycan (β-SG) missense mutants, confirming that, like α-SG missense mutants, they are targeted for degradation through the ubiquitin-proteasome system. These data, collected using HEK-293 cells expressing either the I119F- or Y184C mutants of β-SG, were subsequently confirmed in primary myotubes derived from an LGMD2E/R4 patient carrying a homozygous I92T mutation. The knowledge that β-SG with an amino acid substitution shares a pathway of degradation with α-SG mutants, allowed us to explore the pharmacological approach successfully tested in LGMD2D/R3. Several CFTR correctors, particularly corrector C17, preserved β-SG mutants from degradation and promoted localization at the sarcolemma of the entire SG complex. The presence of the complex, despite containing a mutated subunit, improved sarcolemma integrity, as evidenced by the reduced creatine kinase release from myotubes under hypoosmotic stress. These results suggest that β-SG missense mutants undergo proteasomal degradation as α-SG mutants, and that CFTR correctors, particularly C17, may be used as a potential therapeutic option for recovering and stabilizing the SG complex in patients with sarcoglycanopathies.

PMID:39769077 | DOI:10.3390/ijms252413313

Life (Basel). 2024 Dec 18;14(12):1676. doi: 10.3390/life14121676.

ABSTRACT

The presence of bile acids in the cystic fibrosis patient's lungs contributes to an increase in the inflammatory response, in the dominance of pathogens, as well as in the decline in lung function, increasing morbidity. The aim of this study is to determine the effects of exposure of Pseudomonas aeruginosa to primary and secondary bile acids on the production of several virulence factors which are involved in its pathogenic power. The presence of bile acids in the bacterial culture medium had no effect on growth up to a concentration of 1 mM. However, a slight decrease in the adhesion index as well as a reduction in the virulence of the bacteria on the HT29 cell line could be observed. In this model, exposure of P. aeruginosa to bile acids showed a significant decrease in the production of LasB and AprA proteases due to the reduction in the expression of their genes. A decrease in pyocyanin production was also observed in relation to the effects of bile acids on the quorum sensing regulators. In order to have an effect on gene expression, it is necessary for bile acids to enter the bacteria. P. aeruginosa harbors two potential homologs of the eukaryotic genes encoding the bile acid transporters NTCP1 and NTCP2 that are expressed in hepatocytes and enterocytes, respectively. By carrying out a comparative BLAST-P between the amino acid sequences of the PAO1 proteins and those of NTCP1 and NTCP2, we identified the products of the PA1650 and PA3264 genes as the unique homologs of the two eukaryotic genes. Exposure of the mutant in the PA1650 gene to chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) showed a less significant effect on pyocyanin production than with the isogenic PAO1 strain. Also, no effect of CDCA on the PA3264 gene mutant was observed. This result indicated that CDCA should enter the bacteria by the transporter produced by this gene. The entry of LCA into bacteria seemed more complex and rather responded to a multifactorial system involving the product of the PA1650 gene but also the products of other genes encoding potential transporters.

PMID:39768382 | DOI:10.3390/life14121676

Diagnostics (Basel). 2024 Dec 19;14(24):2859. doi: 10.3390/diagnostics14242859.

ABSTRACT

BACKGROUND/OBJECTIVES: Recent studies indicate that sleep and sleep disorders differ between men and women, but corresponding data in people with chronic lung diseases are lacking. This study aims to answer the question of what the sex-specific differences in sleep profiles and responses to elexacaftor/tezacaftor/ivacaftor (ETI) therapy in people with cystic fibrosis (pwCF) are.

METHODS: Adult pwCF and a matched control group (adults with suspected sleep-disordered breathing undergoing in-laboratory polysomnography (PSG)) were included. PSG data at baseline and after 6 months' ETI therapy were compared between men (mwCF) and women (wwCF) with cystic fibrosis. PSG data at baseline and 6-month follow-up for mwCF/wwCF were compared with baseline PSG data for men/women in the control group. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS). Correlations between change in percentage predicted forced expiratory volume in 1 s from baseline to 6 months were correlated with corresponding changes in key sleep parameters. Changes in transferrin during ETI therapy were also documented.

RESULTS: Twenty-eight pwCF (12 wwCF, 16 mwCF) and 28 matched controls were included. Both mwCF (4 ± 5 vs. 9 ± 20 events/h, p = 0.028) and wwCF (3 ± 3 vs. 8 ± 9 events/h, p = 0.004) had fewer respiratory events during sleep versus male and female controls, but worse sleep efficiency (75 ± 11% vs. 84 ± 11%; p = 0.004 and 76 ± 10% vs. 83 ± 11%; p = 0.011. The baseline ESS score was significantly higher in wwCF versus female controls (8 ± 4 vs. 14 ± 8; p = 0.040). Although some sleep parameters normalized during ETI therapy in pwCF, sleep quality remained poor. The transferrin levels at baseline (2.7 ± 0.4 vs. 2.2 ± 0.5; p = 0.049) and 6 months (3.8 ± 0.4 vs. 2.6 ± 0.5; p < 0.001) were significantly higher in the wwCF versus the mwCF, and the change from baseline during ETI therapy was significantly greater in women versus men (1.1 ± 0.6 vs. 0.4 ± 0.4; p < 0.001).

CONCLUSIONS: These data suggest that wwCF and mwCF should be managed differently with respect to their sleep.

PMID:39767222 | DOI:10.3390/diagnostics14242859

Genes (Basel). 2024 Dec 5;15(12):1573. doi: 10.3390/genes15121573.

ABSTRACT

Background/Objectives: The FARSA gene encodes for the catalytic α subunit of Cytoplasmic phenylalanine-tRNA synthetase (FARS1), an essential enzyme for protein biosynthesis in transferring its amino acid component to tRNAs. Biallelic pathogenic variants have been associated with a multisystemic condition, characterized by variable expressivity and incomplete penetrance. Here, we report the case of an 11 year-old girl presenting interstitial lung disease, supratentorial leukoencephalopathy with brain cysts, hepatic dysfunction, hypoalbuminemia, skin and joint hyperlaxity, growth retardation, and dysmorphic features. In addition, our patient also developed two clinical features never reported before: hypergammaglobulinemia and myopic chorioretinitis. Methods: NGS analysis of the patient's skin-derived DNA revealed two novel biallelic variants in FARSA gene (NM_004461.3) never described before: the maternal nonsense variant, c.799C>T [p.(Gln267Ter)], and the paternal missense variant, c.737T>C [p.(Met246Thr)], both predicted as deleterious. Results: From a therapeutic perspective, this young girl has been enrolled in a clinical trial with Nintedanib, in order to treat the severe pulmonary fibrosis, with interesting initial results. Conclusions: Our findings expand the clinical and molecular spectrum of the FARSA-related phenotype and introduce new cues on lung fibrosis treatment in pediatric age.

PMID:39766840 | DOI:10.3390/genes15121573

Biology (Basel). 2024 Dec 16;13(12):1052. doi: 10.3390/biology13121052.

ABSTRACT

Adenoviral vectors (AdVs) are effective vectors for gene therapy due to their broad tropism, high capacity, and high transduction efficiency, which makes them actively used as oncolytic vectors and for creating vector vaccines. However, despite their numerous advantages, AdVs have not yet found their place in gene therapy for hereditary diseases. This review provides an overview of AdVs, their features, and clinical trials using them for gene replacement therapy in monogenic diseases and analyzes the reasons for the failures of these studies. Additionally, current research on the modification of AdVs to reduce immune responses and target delivery is discussed.

PMID:39765719 | DOI:10.3390/biology13121052

J Health Psychol. 2025 Jan 7:13591053241307874. doi: 10.1177/13591053241307874. Online ahead of print.

ABSTRACT

Because of the lengthening of their life-expectancy, more people with cystic fibrosis (CF) now pursue parenthood. To explore the experience of parenting while having CF, 18 French parents with CF were interviewed (including 12 mothers and 9 participants with a lung transplant). A thematic analysis of the interview transcripts was conducted. Within the domain of parenthood, seven themes were found: Journey to Parenthood; Experience of Parenthood; Daily Life; Administrative and Financial Aspects; Interaction of CF with Children's Lives; The Spouse; The Children. This paper documents the positive aspects of parenthood, and the logistical and emotional challenges faced by participants and how they adjust to them. Notably, this paper highlights the struggle of most participants to become parents, the sensitive period of lung transplant surgery for the family, what children are told about CF, and how children's lives are coloured by a sense of normality and worries for their sick parent.

PMID:39764735 | DOI:10.1177/13591053241307874

J Clin Transl Endocrinol. 2024 Nov 7;38:100375. doi: 10.1016/j.jcte.2024.100375. eCollection 2024 Dec.

ABSTRACT

Cystic fibrosis-related diabetes (CFRD) is the most common non-pulmonary comorbidity in people with cystic fibrosis (CF). Current guidelines recommend insulin therapy as the treatment of choice for people with CFRD. In the past, obesity and overweight were uncommon in individuals with CF. However, in recent years, advancements in CF therapies have led to a significant increase in the prevalence of overweight and obesity within this population. Glucagon-like peptide1 receptor agonist (GLP-1 RA) therapies could potentially improve glycemic control in people with CF by increasing insulin secretion, slowing gastric emptying, and promoting weight loss through central appetite suppression, which in turn can enhance insulin sensitivity. We report, for the first time, five cases of individuals with CFRD complicated by obesity treated with GLP 1-RA for at least two years. With GLP 1-RA therapy, 4 out of 5 individuals exhibited weight reduction ranging from 7% to 19% over two years, while forced expiratory volume in 1 s (FEV1)/predicted FEV1 % remained stable or improved in all cases. The impact on glycemic control was variable. Insulin requirements either reduced or remained stable in all five cases. Overall, GLP-1 RA was well tolerated in this case series; one individual discontinued the medication after two years of therapy due to poor appetite and nausea.

PMID:39764279 | PMC:PMC11702000 | DOI:10.1016/j.jcte.2024.100375