Plant Cell. 2025 May 14:koaf093. doi: 10.1093/plcell/koaf093. Online ahead of print.

ABSTRACT

Systems biology aims to uncover gene regulatory networks (GRNs) for agricultural traits, but validating them in crops is challenging. We addressed this challenge by learning and validating model-to-crop GRN regulons governing nitrogen use efficiency (NUE). First, a fine-scale time-course nitrogen (N) response transcriptome analysis revealed a conserved temporal N response cascade in maize (Zea mays) and Arabidopsis (Arabidopsis thaliana). This data was used to infer time-based causal transcription factor (TF) target edges in N-regulated GRNs (N-GRNs). By validating 23 maize TFs in a cell-based TF-perturbation assay (TARGET), precision/recall analysis enabled us to prune high-confidence edges between ∼200 TFs/700 maize target genes. We next learned gene-to-NUE trait scores using XGBoost machine learning models trained on conserved N-responsive genes across maize and Arabidopsis accessions. By integrating NUE gene scores within our N-GRN, we ranked maize TFs based on a cumulative NUE regulon score. Regulons for top-ranked TFs were validated using the cell-based TARGET assay in maize (e.g. ZmMYB34/R3→24 targets) and the Arabidopsis ZmMYB34/R3 ortholog (e.g. AtDIV1→23 targets). The genes in this NUE regulon significantly enhanced the ability of XGBoost models to predict NUE traits in both maize and Arabidopsis. Thus, our pipeline for identifying NUE regulons that combines GRN inference, machine learning, and orthologous network regulons offers a strategic framework for crop trait improvement.

PMID:40365911 | DOI:10.1093/plcell/koaf093

Adv Sci (Weinh). 2025 May 14:e2500290. doi: 10.1002/advs.202500290. Online ahead of print.

ABSTRACT

Enhancing the oil or protein content of soybean, a major crop for oil and protein production is highly desirable. GmSWEET10a encodes a sugar transporter that is strongly selected during domestication and breeding, increasing seed size and oil content. GmSWEET10b is functionally similar to GmSWEET10a, yet has not been artificially selected. Here, AlphaFold is used to find that C-terminal variants of GmSWEET10a can endow enhanced or reduced transport activity. Guided by AlphaFold, the functionality is improved for GmSWEET10a in terms of oil content through gene editing. Furthermore, novel GmSWEET10b haplotypes possessing strengthened or weakened sugar-transport capabilities that are absent in nature are engineered. Consequently, soybean oil content or protein content in independent GmSWEET10b gene-edited lines during multi-year and multi-site field trials is consistently increased, without negatively affecting yield. The study demonstrates that the combination of AlphaFold-guided protein design and gene editing has the potential to generate novel beneficial alleles, which can optimize protein function in the context of crop breeding.

PMID:40365797 | DOI:10.1002/advs.202500290

Dermatol Ther (Heidelb). 2025 May 14. doi: 10.1007/s13555-025-01424-z. Online ahead of print.

ABSTRACT

INTRODUCTION: Bullous pemphigoid (BP) is a chronic autoimmune blistering disorder that imposes a significant health-related quality of life burden on the lives of patients; however, there are limited data on patient experiences.

METHODS: We conducted qualitative open-ended interviews of patients from the USA, Spain, and France, to understand BP symptoms and impacts, and develop a conceptual model. Adults with a confirmed BP diagnosis were included. Patients with pemphigus or drug-induced BP were excluded.

RESULTS: Thirty participants were recruited. The mean (standard deviation) age was 63.6 (16.0) years. Eleven signs and symptoms and 24 impacts were reported; six signs and symptoms, and 13 impacts affected ≥ 50% of participants with an average disturbance rating of ≥ 5 out of 10 (scale of 0 to 10 [0, not disturbing; 10, extremely disturbing]). All participants reported typical signs and symptoms of classic and/or mucosal BP. Overall, five of six salient symptoms and four of 13 salient impacts had an average disturbance rating of ≥ 7.5/10, indicating that BP is highly burdensome. Regarding corticosteroids, participants expressed a strong desire to avoid taking them again, due to the associated unwanted side effects.

CONCLUSION: The conceptual model presented here can be the basis for endpoint selection in studies of new therapies for BP.

PMID:40366568 | DOI:10.1007/s13555-025-01424-z

Molecules. 2025 Apr 24;30(9):1897. doi: 10.3390/molecules30091897.

ABSTRACT

Crohn's disease is an inflammatory bowel disease (IBD) that currently lacks satisfactory treatment options. Therefore, new targets for new drugs are urgently needed to combat this disease. In the present study, we investigated the transcriptomics-based mRNA expression of intestinal biopsies from patients with Crohn's disease. We compared the mRNA expression profiles of the ileum and colon of patients with those of healthy individuals. A total of 72 genes in the ileum and 33 genes in the colon were differentially regulated. Among these, six genes were overexpressed in both tissues, including IL1B, TCL1A, HCAR3, IGHG1, S100AB, and OSM. We further focused on OSM/oncostatin M. To confirm the responsiveness of intestinal tissues from patients with Crohn's disease to oncostatin M inhibition, we examined the expression of the oncostatin M using immunohistochemistry in patient biopsies as well as in kindlin-1-/- and kindlin-2-/- knockout mice, which exhibit an inflammatory bowel disease (IBD) phenotype, and found strong oncostatin M expression in all samples examined. Next, we conducted a drug-repurposing study using the supercomputer MOGON and bioinformatic methods. A total of 13 candidate compounds out of 1577 FDA-approved drugs were identified by PyRx-based virtual drug screening and AutoDock-based molecular docking. Their lowest binding energies (LBEs) ranged from -10.46 (±0.08) to -8.77 (±0.08) kcal/mol, and their predicted inhibition constants (pKi) ranged from 21.62 (±2.97) to 373.78 (±36.78) nM. Ecamsule has an interesting stereostructure with two C2-symmetric enantiomers (1S,4R-1'S,4'R and 1R,4S-1'R,4'S) (1a and 1b) and one meso diastereomer (1S,4R-1'R,4'S) (1c). These three stereoisomers showed strong, albeit differing, binding affinities in molecular docking. As examined by nuclear magnetic resonance and polarimetry, the 1S,4R-1'S,4'R isomer was the stereoisomer present in our commercially available preparations used for microscale thermophoresis. Ecamsule (1a) was chosen for in vitro validation using recombinant oncostatin M and microscale thermophoresis. Considerable dissociation constants were obtained for ecamsule after three repetitions with a Kd value of 11.36 ± 2.83 µM. Subsequently, we evaluated, by qRT-PCR, the efficacy of ecamsule (1a) as a potential drug that could prevent oncostatin M activation by inhibiting downstream inflammatory marker genes (IL6, TNFA, and CXCL11). In conclusion, we have identified oncostatin M as a promising new drug target for Crohn's disease through transcriptomics and ecamsule as a potential new drug candidate for Crohn's disease through a drug-repurposing approach both in silico and in vitro.

PMID:40363705 | DOI:10.3390/molecules30091897

Int J Mol Sci. 2025 May 7;26(9):4453. doi: 10.3390/ijms26094453.

ABSTRACT

Parkinson's disease (PD) is a complex neurodegenerative disorder lacking effective disease-modifying treatments. In this study, we integrated large-scale protein-protein interaction networks with a multi-modal graph neural network (GNN) to identify and prioritize multi-target drug repurposing candidates for PD. Network analysis and advanced clustering methods delineated functional modules, and a novel Functional Centrality Index was employed to pinpoint key nodes within the PD interactome. The GNN model, incorporating molecular descriptors, network topology, and uncertainty quantification, predicted candidate drugs that simultaneously target critical proteins implicated in lysosomal dysfunction, mitochondrial impairment, synaptic disruption, and neuroinflammation. Among the top hits were compounds such as dithiazanine, ceftolozane, DL-α-tocopherol, bromisoval, imidurea, medronic acid, and modufolin. These findings provide mechanistic insights into PD pathology and demonstrate that a polypharmacology approach can reveal repurposing opportunities for existing drugs. Our results highlight the potential of network-based deep learning frameworks to accelerate the discovery of multi-target therapies for PD and other multifactorial neurodegenerative diseases.

PMID:40362692 | DOI:10.3390/ijms26094453

Int J Mol Sci. 2025 Apr 25;26(9):4079. doi: 10.3390/ijms26094079.

ABSTRACT

Thiol-containing drugs may interact with a region of tropomyosin receptor kinase A (TrkA), potentially inhibiting its activation by nerve growth factor (NGF). This action has been linked to potential analgesic activities. Here, we describe the ability of erdosteine, a thiolic compound classified as a mucolytic agent, to bind to the TrkA receptor sequence in silico and its in vitro effects on TrkA activation induced by NGF in cultured human neuroblastoma cells. Our results show that erdosteine and its metabolite, Met-1, bind to the TrkA receptor pocket, involving the primary TrkA residues Glu331, Arg347, His298, and His297. Furthermore, Met-1 has the ability to reduce the disulfide bridge between Cys300 and Cys345 of TrkA. In vitro measurement of TrkA autophosphorylation following NGF activation confirmed that erdosteine and Met-1 interfere with NGF-induced TrkA activation, leading to a consequent loss of the molecular recognition and spatial reorganization necessary for the induction of the autophosphorylation process. This effect was inhibited by low millimolar concentrations of the two compounds, reaching a maximal inhibition (around 40%) after 24 h of exposure to 1 mM erdosteine, and then plateauing. These findings suggest that erdosteine can act as a TrkA antagonist, thus indicating that this drug may have potential as an analgesic via a novel non-opioid mechanism of action operating through NGF signaling inhibition at the level of TrkA.

PMID:40362318 | DOI:10.3390/ijms26094079

Int J Mol Sci. 2025 Apr 22;26(9):3936. doi: 10.3390/ijms26093936.

ABSTRACT

The high heterogeneity between patients can complicate the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we explored the association of universally differentially expressed genes (UDEGs) with resistance to chemotherapy and immunotherapy in the context of pancreatic cancer. In this work, sixteen up-regulated and three down-regulated genes that were dysregulated in more than 85% of 102 paired and 5% of 521 unpaired PDAC samples were identified and defined as UDEGs. A single-cell level analysis further validated the high expression levels of the up-UDEGs and the low levels of the down-UDEGs in cancer-related ductal cells, which could represent the malignant changes seen in pancreatic cancer. Based on a drug sensitivity analysis, we found that ANLN, GPRC5A and SERPINB5 are closely related to the resistance mechanism of PDAC, and their high expression predicted worse survival for PDAC patients. This suggests that targeting these genes could be a potential way to reduce drug resistance and improve survival. Based on the immune infiltration analysis, the abnormal expression of the UDEGs was found to be related to the formation of an immunosuppressive tumor microenvironment. In conclusion, these UDEGs are common features of PDAC and could be involved in the resistance of pancreatic cancer and might serve as novel drug targets to guide research into drug repurposing.

PMID:40362181 | DOI:10.3390/ijms26093936

Cancers (Basel). 2025 Apr 27;17(9):1470. doi: 10.3390/cancers17091470.

ABSTRACT

BACKGROUND/OBJECTIVES: Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP).

METHODS: Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses.

RESULTS: The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with PIK3CA, B-RAF (V600E), and TP53 mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells.

CONCLUSIONS: These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with the B-RAF (V600E) mutation showed promising findings in this study.

PMID:40361395 | DOI:10.3390/cancers17091470

Cancers (Basel). 2025 Apr 24;17(9):1430. doi: 10.3390/cancers17091430.

ABSTRACT

Background: Chronic nicotine exposure drives head and neck cancer (HNC) progression, yet its molecular mechanisms remain underexplored. This study examines nicotine-induced transcriptomic changes and potential therapies via drug repurposing. Methods: HNC cell lines (OECM1, SAS, and CGHNC9) were exposed to an IC30 nicotine dose for three months to model chronic exposure in habitual smokers. Transcriptomic profiling of these sublines was integrated with TCGA-HNSC patient data. Differentially expressed genes (DEGs) underwent functional pathway enrichment analysis. Drug repurposing was conducted using gene-drug correlation analysis across GDSC, CTRP, and PRISM databases. Results: Transcriptomic analysis identified 1223 DEGs in nicotine-exposed HNC cells, and integration with TCGA-HNSC data defined a Nic-HNC gene set of 168 genes: 149 oncogenes and 19 tumor suppressors, with 36 oncogenes overexpressed in heavy smokers. Pathway analysis revealed the upregulation of oncogenic signaling, such as PI3K-AKT, alongside the suppression of immune regulation and metabolic reprogramming. Drug repurposing identified five compounds-AZD1332, JAK-8517, NU7441, BRD-K30748066, and neopeltolide-with the first two exhibiting the strongest inverse correlations with nicotine-induced oncogenes in heavy smokers, highlighting their potential as targeted therapies for tobacco-associated HNC. Conclusions: This study comprehensively characterizes nicotine-driven molecular dysregulation in HNC and proposes AZD1332 and JAK-8517 as promising therapeutic candidates through drug repurposing. These insights advance our understanding of nicotine's oncogenic role and provide a foundation for translational research to develop targeted interventions for tobacco-associated HNC.

PMID:40361356 | DOI:10.3390/cancers17091430

Int J Mol Sci. 2025 May 4;26(9):4367. doi: 10.3390/ijms26094367.

ABSTRACT

The scarcity of robust models and therapeutic options for rare diseases continues to hamper their preclinical investigation. Traditional animal models and two-dimensional cell cultures are limited in their ability to replicate human heredity-associated traits and complex pathological features. Organoids-on-a-chip approaches open up new frontiers in rare-disease research via the integration of organ chips and organoid technology. This integrative strategy offers immense opportunities for the mimicry of disease-related traits, the clarification of the mechanisms underlying disease, and the prediction of treatment responses in a highly human-related manner. This forward-looking perspective suggests organoids on chips are transformative tools for parsing rare-disease pathogenesis, accelerating therapeutic discovery, and bridging the gap between basic research and precision medicine.

PMID:40362604 | DOI:10.3390/ijms26094367

J Clin Med. 2025 Apr 29;14(9):3063. doi: 10.3390/jcm14093063.

ABSTRACT

Background: Primary progressive aphasia (PPA) is a neurodegenerative disorder that worsens over time without appropriate treatment. Although referral to a speech and language pathologist is essential for diagnosing language deficits and developing effective treatment plans, there is no scientific consensus regarding the most effective treatment. Thus, our study aims to assess the efficacy and safety of various therapeutic interventions for PPA. Methods: Google Scholar, PubMed, Web of Science, and the Cochrane Library databases were systematically searched to identify articles assessing different therapeutic interventions for PPA. To ensure comprehensive coverage, the search strategy employed specific medical subject headings. The primary outcome measure was language gain; the secondary outcome assessed overall therapeutic effects. Data on study characteristics, patient demographics, PPA subtypes, therapeutic modalities, and treatment patterns were collected. Results: Fifty-seven studies with 655 patients were included. For naming and word finding, errorless learning therapy, lexical retrieval cascade (LRC), semantic feature training, smartphone-based cognitive therapy, picture-naming therapy, and repetitive transcranial magnetic stimulation (rTMS) maintained effects for up to six months. Repetitive rTMS, video-implemented script training for aphasia (VISTA), and structured oral reading therapy improved speech fluency. Sole transcranial treatments enhanced auditory verbal comprehension, whereas transcranial direct current stimulation (tDCS) combined with language or cognitive therapy improved repetition abilities. Phonological and orthographic treatments improved reading accuracy across PPA subtypes. tDCS combined with speech therapy enhanced mini-mental state examination (MMSE) scores and cognitive function. Several therapies, including smartphone-based cognitive therapy and VISTA therapy, demonstrated sustained language improvements over six months. Conclusions: Various therapeutic interventions offer potential benefits for individuals with PPA. However, due to the heterogeneity in study designs, administration methods, small sample sizes, and lack of standardized measurement methods, drawing a firm conclusion is difficult. Further studies are warranted to establish evidence-based treatment protocols.

PMID:40364094 | DOI:10.3390/jcm14093063

Int J Mol Sci. 2025 May 3;26(9):4356. doi: 10.3390/ijms26094356.

ABSTRACT

Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor of DβH, nepicastat, particularly in the aspect of cocaine-seeking behavior. Hence, the objective of this study was to verify whether or not nepicastat reproduces disulfiram activity in pain reduction. Moreover, determination of its likely biological effects resulting from interactions with targets other than DβH has been given, in particular acetylcholinesterase. As was found, nepicastat was characterized by the absence of desired antinociceptive activity, though its co-administration with morphine resulted in a dose- and time-dependent enhancement of morphine-induced analgesic effect and attenuation of tolerance. Similarly, nepicastat was found to manifest antimicrobial potency against selected bacterial strains, although the effect was found to be weak. Intriguingly, this compound interacted with acetylcholinesterase through inhibition of its activity. These results clearly indicate nepicastat as a potent molecule that exhibits various biological effects. This, in turn, suggests its possible application in pathological conditions that still require effective treatment.

PMID:40362592 | DOI:10.3390/ijms26094356

Int J Mol Sci. 2025 May 1;26(9):4285. doi: 10.3390/ijms26094285.

ABSTRACT

In this review, we explore the biomarkers of different psychiatric disorders, such as major depressive disorder, generalized anxiety disorder, schizophrenia, and bipolar disorder. Moreover, we show the interplay between genetic and environmental factors. Novel techniques such as genome-wide association studies (GWASs) have identified numerous risk loci and single-nucleotide polymorphisms (SNPs) implicated in these conditions, contributing to a better understanding of their mechanisms. Moreover, the impact of genetic variations on drug metabolisms, particularly through cytochrome P450 (CYP450) enzymes, highlights the importance of pharmacogenomics in optimizing psychiatric treatment. This review also explores the role of neurotransmitter regulation, immune system interactions, and metabolic pathways in psychiatric disorders. As the technology advances, integrating genetic markers into clinical practice will be crucial in advancing precision psychiatry, improving diagnostic accuracy and therapeutic interventions for individual patients.

PMID:40362522 | DOI:10.3390/ijms26094285

Int J Mol Sci. 2025 Apr 29;26(9):4245. doi: 10.3390/ijms26094245.

ABSTRACT

The cornerstone of first-line treatment in extensive-stage small cell lung cancer (ES-SCLC) is platinum- and etoposide-based chemotherapy. Platinum compounds could immunomodulate the tumor microenvironment in addition to their cytotoxic effect. Genetic variation in immune checkpoint (IC) pathways may predict chemotherapy efficacy. Polymorphisms in the IC genes were determined, and their association with survival was analyzed in 78 patients with ES-SCLC treated with chemotherapy. PD-L1 protein expression in tumor tissue was determined. Three variants in CD274 were associated with better median progression-free survival (mPFS): rs2297136 (hazard ratio [HR] 0.52, 95% CI 0.29-0.93; p = 0.03), rs2282055 (HR 0.23, 95% CI 0.09-0.64; p = 0.005), and rs822336 (HR 0.41, 95% CI 0.23-0.73; p = 0.002). CTLA4 rs231775 was also associated with mPFS (HR 0.30, 95% CI 0.14-0.63; p = 0.002). The variants CD274 rs2297136 and CD274 rs822336 were associated with platinum sensitivity (odds ratio [OR] 0.13, 95% CI 0.02-0.70; p = 0.02, and OR 0.08, 95% CI 0.01-0.46; p = 0.005, respectively). CD274 rs2297136 was also associated with better overall survival (p = 0.02), but not after adjustment for covariates. No association was found between CD274 germline variants and PD-L1 tumor expression. Our results suggest that CD274 and CTLA4 variants may be predictive biomarkers for platinum plus etoposide treatment in ES-SCLC.

PMID:40362483 | DOI:10.3390/ijms26094245

Int J Mol Sci. 2025 Apr 25;26(9):4106. doi: 10.3390/ijms26094106.

ABSTRACT

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The precursor of CRC is a colorectal polyp, of which adenoma is the most common histological type. The initial step in CRC development is the gradual accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium. Genetic alterations play a major role in a subset of CRCs, but the pathophysiological contribution of epigenetic aberrations has recently attracted attention. Epigenetic marks occur early in cancer pathogenesis and are therefore important molecular hallmarks of cancer. This makes some epigenetic alterations clinically relevant for early detection not only of CRC but also of precancerous polyps. In this review we focus on three types of non-coding RNAs as epigenetic regulators: miRNA, lncRNA, and lncRNAs, highlighting their biomarker potential.

PMID:40362348 | DOI:10.3390/ijms26094106

J Clin Med. 2025 May 5;14(9):3187. doi: 10.3390/jcm14093187.

ABSTRACT

Cystic fibrosis (CF) is a multisystemic disease caused by a genetic defect, namely a mutation in the CFTR gene, that results in the production of an abnormal protein that regulates the flow of chloride ions through epithelial cells, leading to the dehydration of secreted mucus and changes in its biological properties. Chronic inflammation and recurrent respiratory infections progressively damage lung tissue, leading to respiratory and cardiorespiratory failure. This study aims to present a clinical case and explore the clinical changes in CF that may influence the provision of pre-hospital first aid. The study presents a case report of a 23-year-old CF patient undergoing evaluation for lung transplantation, infected with Pseudomonas aeruginosa and Staphylococcus aureus with the MSSA phenotype, and in a severe condition due to infectious exacerbation. Despite antibiotic treatment, the patient's condition deteriorated, leading to respiratory failure and cardiac arrest. Emergency measures were taken to maintain airway patency-the patient was sedated, intubated, and connected to a ventilator. CF involves systemic complications that, during exacerbations, may require urgent interventions. Cystic fibrosis is associated with multiple systemic complications, some of which may, during exacerbations, require emergency medical interventions. Providing care to this patient group involves specific procedures addressing the consequences of the underlying disease. Due to increasing survival rates and the emergence of new phenotypes, there is a need for the continuous education of medical personnel, including emergency responders, regarding the management of genetically determined diseases. This study underscores the importance of recognizing CF's complex nature and adapting emergency care accordingly to ensure timely and effective intervention in life-threatening situations.

PMID:40364218 | DOI:10.3390/jcm14093187

J Clin Med. 2025 Apr 30;14(9):3118. doi: 10.3390/jcm14093118.

ABSTRACT

Background: The global health burden of chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS) affects billions of people and is associated with high levels of healthcare expenditure. Conventional therapies (bronchodilators and corticosteroids) provide symptomatic benefit but take no effect on disease progression, demonstrating the need to develop new therapies. Emerging therapies treat the underlying mechanisms of these chronic diseases, which provide symptomatic relief and benefit the underlying disease. Methods: This review assesses the evolution of therapeutic interventions for chronic lung diseases from a series of established inhaled combination therapies to biologics, gene therapy, and even AI-based stratification of therapies for patients. In addressing these issues, we review the mechanisms of action, evidence of efficacy, and clinical trial evidence, while discussing access issues affecting the implementation of these therapies and ethical issues in relation to their use. Results: The review highlights recent developments in treatment approaches, such as gene therapies aimed at cystic fibrosis mutations, advanced drug delivery pathways for more accurate targeting, and stem cell-based therapies designed to replace damaged lung tissue. These developments have the potential to improve outcomes for chronic lung diseases, but the challenges, including a lack of access, adequate patient selection, and long-term safety, need to be addressed. Conclusions: New therapies offer tremendous potential, but their transition from laboratory to clinic still face numerous barriers including access, regulation, and a need for personalized therapy approaches. The review indicates that future research should develop strategies to reduce barriers to access, improve distribution, and improve clinical guidelines to successfully implement these new therapies.

PMID:40364149 | DOI:10.3390/jcm14093118

J Clin Med. 2025 Apr 25;14(9):2979. doi: 10.3390/jcm14092979.

ABSTRACT

Background/Objectives: Patients with chronic lung diseases, such as cystic fibrosis, were considered a risk group for a severe course of coronavirus disease 2019 at the beginning of the pandemic. However, mounting evidence suggests that this group may not face an elevated risk for a severe SARS-CoV-2 infection. Methods: Here, we present data on the incidence and clinical course of SARS-CoV-2 infections in a single pediatric CF centre in Austria. Clinical variables were analyzed for their potential impact on disease acquisition and severity. A total of 135 young people with CF were assessed from February 2020 until December 2022. Results: Eighty-four patients were infected with SARS-CoV-2, out of which nine patients reported re-infection, resulting in 93 SARS-CoV-2 infections. Most infections, 76/93 (82%), occurred during the period of omicron variant predominance. Higher body mass index and respiratory colonization with Haemophilus influenzae before the beginning of the pandemic were significantly associated with the risk of acquiring SARS-CoV-2 infection. All patients had an uncomplicated COVID-19 course, regardless of the SARS-CoV-2 variant and COVID-19 vaccine status at infection. The most frequent symptoms were rhinitis (53%), fatigue (49%), cephalea (43%), and fever (38%). Neither oxygen therapy nor hospitalization were needed for any of the patients. Lung function parameters (FEV1, FVC, FEF50, LCI), both in the early post-viral as well as late post-viral stages, were not significantly impacted by SARS-CoV-2 infections. No long-term post-COVID-19 effects were reported. Conclusions: Our single-centre experience suggests that the course of SARS-CoV-2 infections in children and adolescents with CF is primarily mild and uncomplicated.

PMID:40364010 | DOI:10.3390/jcm14092979

J Clin Med. 2025 Apr 25;14(9):2977. doi: 10.3390/jcm14092977.

ABSTRACT

Objectives: In this retrospective study, we performed a volumetric analysis of paranasal cavity pneumatization in a population of adult patients with cystic fibrosis compared to healthy controls, providing parcel evaluation of each sinus, and analyzing the prevalence of major anatomical sinonasal variants in the two groups. Methods: We compared paranasal sinus volumes of 89 adult patients with cystic fibrosis and 144 healthy controls who underwent paranasal sinus computed tomography. Volumes were segmented and extracted on tomographic images using the freely available software MRIcron 2019, then compared using a t-test; the z-score test was used to determine whether the two groups differ significantly in terms of major anatomical variants prevalence. Results: Overall sinus volumes in patients with cystic fibrosis patients differ significantly as compared to the healthy population (p < 0.00001). Furthermore, with the only exception of ethmoid sinus pneumatization, which was similar in both populations, all the other sinuses were statistically different. No significant difference emerged concerning anatomical variants' prevalence. Conclusions: Our results further stress the impact of cystic fibrosis on sinus structure in adult patients, better revealing the consequences of the disease on upper airways and in optimizing the management of patients with sinonasal manifestations.

PMID:40364008 | DOI:10.3390/jcm14092977

Molecules. 2025 Apr 22;30(9):1866. doi: 10.3390/molecules30091866.

ABSTRACT

Cystic fibrosis (CF) is a life-threatening disorder caused by mutations in the CFTR gene, leading to defective chloride ion transport and thickened mucus in the respiratory and gastrointestinal systems. CFTR modulators, including ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have improved patient outcomes, but interindividual pharmacokinetic variability and potential drug-drug interactions require therapeutic drug monitoring (TDM) for optimal efficacy and safety. In this context, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous quantification of CFTR modulators and their major active metabolites in human plasma to support pharmacokinetic studies and routine TDM. The multiplex LC-MS/MS assay was established using plasma protein precipitation, followed by chromatographic separation on an Xselect HSS T3 (Waters®) column and positive electrospray ionization mode detection. The method was validated based on FDA and EMA guidelines for specificity, linearity, accuracy (89.8-107.8%), repeatability (1.1-8.1%), intermediate fidelity (1.3-10.9%), matrix effects, and stability, demonstrating a robust performance with excellent precision and accuracy. International interlaboratory comparisons confirmed the reliability of the assay. The developed method can be applied for the clinical monitoring of caftors' plasma concentrations and preliminary data suggest that it can also be applied to alternative matrices, such as breast milk. This method will serve to characterize caftors' pharmacokinetic variability and monitor drug-drug interactions to further refine personalized dosing strategies and enhance precision medicine treatments for patients with CF.

PMID:40363673 | DOI:10.3390/molecules30091866