Pharmaceutics. 2025 Apr 29;17(5):585. doi: 10.3390/pharmaceutics17050585.

ABSTRACT

Background: Childhood cancers represent a heterogeneous group of malignancies and remain one of the leading causes of mortality among children under 14 years of age, ranking second only to accidental injuries, and fourth among individuals aged 15 to 19 years. Despite notable improvements in cure rates, a substantial proportion of patients experience acute or long-term toxicities associated with treatment. Methotrexate (MTX), a chemotherapeutic agent, has been employed effectively for over six decades in the management of pediatric malignancies. High-dose methotrexate constitutes a cornerstone of pediatric cancer therapy; however, its clinical utility is frequently constrained by dose-limiting toxicities. Objectives: This study investigates the impact of genetic polymorphisms in genes involved in nucleotide metabolism, as well as methotrexate and folate metabolic pathways, on treatment-related toxicity in childhood cancer. Methods: Using real-time polymerase chain reaction, 14 polymorphisms across 12 genes were analyzed in a cohort of 107 patients. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v. 5.0. Results: Multivariate logistic regression analysis revealed that the male sex (p = 0.3) and the AA genotype of MTHFD1 rs2236225 were associated with grade III-IV gastrointestinal toxicity (p = 0.03), while the A allele of MTHFR rs1801133 and the AA genotype of GSTP1 rs1695 were associated with grade I-IV hematologic toxicity (p < 0.01 and p = 0.02, respectively). Conclusions: High-dose methotrexate (HDMTX) is a critical agent in the treatment of childhood cancers. Our findings suggest that genetic polymorphisms within methotrexate and folate metabolic pathways may serve as potential predictive biomarkers of treatment-related toxicity.

PMID:40430876 | DOI:10.3390/pharmaceutics17050585

Pharmaceutics. 2025 Apr 24;17(5):555. doi: 10.3390/pharmaceutics17050555.

ABSTRACT

Background: Advancements in pharmacogenomics, artificial intelligence (AI), and CRISPR gene-editing technology are revolutionizing precision medicine by enabling highly individualized therapeutic strategies. Artificial intelligence-driven computational techniques improve biomarker discovery and drug optimization while pharmacogenomics helps to identify genetic polymorphisms affecting medicine metabolism, efficacy, and toxicity. Genetically editing based on CRISPR presents a precise method for changing gene expression and repairing damaging mutations. This review explores the convergence of these three fields to enhance improved precision medicine. Method: A methodical study of the current literature was performed on the effects of pharmacogenomics on drug response variability, artificial intelligence, and CRISPR in predictive modeling and gene-editing applications. Results: Driven by artificial intelligence, pharmacogenomics allows clinicians to classify patients and select the appropriate medications depending on their DNA profiles. This reduces the side effect risk and increases the therapeutic efficacy. Precision genetic modifications made feasible by CRISPR technology improve therapy outcomes in oncology, metabolic illnesses, neurological diseases, and other fields. The integration of artificial intelligence streamlines genome-editing applications, lowers off-target effects, and increases CRISPR specificity. Notwithstanding these advances, issues including computational biases, moral dilemmas, and legal constraints still arise. Conclusions: The synergy of artificial intelligence, pharmacogenomics, and CRISPR alters precision medicine by letting customized therapeutic interventions. Clinically translating, however, hinges on resolving data privacy concerns, assuring equitable access, and strengthening legal systems. Future research should focus on refining CRISPR gene-editing technologies, enhancing AI-driven pharmacogenomics, and developing moral guidelines for applying these tools in individualized medicine going forward.

PMID:40430848 | DOI:10.3390/pharmaceutics17050555

Pharmaceutics. 2025 Apr 22;17(5):542. doi: 10.3390/pharmaceutics17050542.

ABSTRACT

Background/Objectives: Irinotecan is used in monotherapy or combined with other drugs for treating different cancer streams. SN-38, the active metabolite of irinotecan, is 70% inactivated by the uridine diphosphate (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1) enzyme. The UGT1A1*6 (rs4148323) and *28 (rs3064744) alleles in the gene encoding the enzyme lead to decreased enzyme expression and increased severe irinotecan toxicity. Carrying one or two copies of these alleles results in a UGT1A1 intermediate or poor metabolizer status (IM, PM). The Food and Drug Administration (FDA)-approved drug labels and European Medicines Agency (EMA) European Public Assessment Report (EPAR) for irinotecan recommend dose adjustments based on UGT1A1 genotypes, but only for UGT1A1 PM patients. However, available pharmacogenetic (PGx) dosing guidelines for the UGT1A1-irinotecan interaction lack a consensus about considered genetic variants, genotype-translated phenotypes, and therapeutic recommendations. We aimed to describe evidence regarding the impact of the UGT1A1 genotype in irinotecan toxicity to inform irinotecan-dosing recommendations based on possible UGT1A1 genotypes. Methods: A systematic review was performed to find all the Phase I clinical trials looking for the maximum tolerated dose (MTD) or dose-limiting toxicities (DLTs) of irinotecan depending on the UGT1A1 genotype. Results: Toxicity-related events and the MTD of irinotecan differ among UGT1A1 normal metabolizers (NM), IM, and PM patients considering the UGT1A1*28 and/or *6 variants. Conclusions: Dose adjustments might also be recommended for UGT1A1 IM patients (*1/*28 or *1/*6 genotypes), with a 15% dose reduction considered.

PMID:40430836 | DOI:10.3390/pharmaceutics17050542

Pharmaceuticals (Basel). 2025 May 15;18(5):727. doi: 10.3390/ph18050727.

ABSTRACT

Background/Objectives: Fluoropyrimidines are widely used chemotherapeutic agents in various solid tumors. Germline variants in the DPYD gene, which encodes the enzyme dihydropyrimidine dehydrogenase (DPD), are known to impair drug metabolism and increase the risk of severe toxicity. This umbrella review aims to synthesize the current evidence from systematic reviews on the association between DPYD variants and fluoropyrimidine-induced toxicity. Methods: A comprehensive search was conducted in PubMed, Web of Science, Scopus, and the Cochrane Library from inception to 2023, including gray literature. Systematic reviews assessing fluoropyrimidine toxicity in oncologic patients with DPYD variants were included. Study quality was assessed using the AMSTAR-2 tool. Registration number in PROSPERO: CRD42023401226. Results: Two independent investigators performed the study selection, quality assessment, and data collection. Eight systematic reviews met the inclusion criteria. Methodological confidence was rated as critically low in six, low in one, and medium in another one. The reviews included 125 primary studies, most of them focused on four key DPYD variants (DPYD2*A, DPYD*13, c.2846A>T, and HapB3), all of which showed consistent associations with an increased risk of severe toxicity. Rare variants such as DPYD*4, *5, and *6 were also examined, though evidence remains limited. Pharmacogenetics-guided dosing of fluoropyrimidines significantly reduced toxicity rates in several studies. The integration of DPYD genotyping with phenotyping approaches faces limitations; these tests should complement rather than replace genotyping information. Conclusions: This umbrella review confirms the clinical relevance of DPYD genotyping to predict and mitigate fluoropyrimidine toxicity. Incorporating genotyping into clinical practice, potentially alongside phenotyping and therapeutic drug monitoring, may enhance patient safety and treatment efficacy.

PMID:40430545 | DOI:10.3390/ph18050727

Pharmaceuticals (Basel). 2025 May 2;18(5):677. doi: 10.3390/ph18050677.

ABSTRACT

Background/Objective: Vancomycin, a hydrophilic glycopeptide antibiotic with bactericidal activity against Gram-positive microorganisms, is one of the most commonly used antibiotics un the intensive care unit (ICU). Different efforts have been made to achieve a therapeutically effective plasma concentration of vancomycin by using loading and subsequent maintenance doses on an individual basis, but this remains subject to debate. Our objective was to individualize a dosage regimen in a Chilean ICU to optimize the pharmacological treatment of vancomycin by using a population pharmacokinetic model. Methods: A quantitative descriptive study was carried out in 51 patients at the adult ICU, San Borja Arriarán Clinical Hospital in Santiago, Chile. The dose of vancomycin was calculated by using a population pharmacokinetic software, the Antibiotic Kinetics®, and was subsequently validated with plasma trough levels of the drug through a patient sample. Results: The most commonly prescribed loading dose was 1500 mg and the most commonly used maintenance dose was 1000 mg, three times a day. The measured blood plasma concentrations of each patient (16.98 ± 5.423 μg/mL) were compared with the concentrations calculated through the population pharmacokinetic model (14.33 ± 4.630 μg/mL, p < 0.05). In addition, a correlation was found between the software-calculated trough concentration versus the measured trough concentration for vancomycin, with a positive correlation between both variables established (R2 = 0.65; p < 0.0001). No renal side effects were observed in the treated patient group. Conclusions: In the present study, a vancomycin dosing model for critically ill patients, based on a population pharmacokinetic model, was successfully implemented for routine clinical practice.

PMID:40430496 | DOI:10.3390/ph18050677

Pharmaceuticals (Basel). 2025 Apr 25;18(5):623. doi: 10.3390/ph18050623.

ABSTRACT

Background/Objectives: Methadone maintenance treatment (MMT) is widely used in opioid use disorder (OUD). Its efficacy is influenced by its metabolism, primarily mediated by Cytochrome P450 (CYP450) enzymes in the liver. Genetic polymorphisms in CYP450 genes and other factors, such as age, sex, and concomitant treatments, contribute to interindividual variability in methadone response. This article addresses the relevance of pharmacokinetic biomarkers in methadone metabolism and its impact on treatment outcomes in European populations over the past 25 years. Methods: A systematic review was conducted using four databases (PsycINFO, PubMed, Scopus, and Web of Science) for studies published between 2000 and 2024 following the PRISMA 2020 guidelines (CRD42025641373 in PROSPERO). Two independent reviewers screened and assessed the study quality using NHLBI tools. Discrepancies were solved through consensus. Relevant data including sample size, genetic biomarkers, and key findings were extracted for each study. Data were synthesized and described in detail. Results: Fourteen studies on pharmacogenetic biomarkers influencing methadone metabolism in European populations were analyzed, encompassing a total of 3180 subjects. CYP2B6*6 was identified as a key variant associated with increased (S)-methadone plasma levels, potentially leading to cardiac complications, while the role of other pharmacokinetic genes, including ABCB1 and CYP2D6, was inconclusive. Conclusions: Genetic polymorphisms significantly influence methadone metabolism, with the CYP2B6*6 allele playing a key role in (S)-methadone metabolism and associated with cardiac risks. Pharmacogenetic studies integrating co-mediation-the principal cause of phenoconversion-as a potential variable alongside gender differences and encompassing adequate sample sizes could improve outcomes and establish the basis for personalized medicine of MMT.

PMID:40430443 | DOI:10.3390/ph18050623

J Clin Med. 2025 May 14;14(10):3432. doi: 10.3390/jcm14103432.

ABSTRACT

Porcine peripheral blood mononuclear cells (pPBMCs) are increasingly recognized as a valuable model in biomedical and translational research, particularly in contexts directly related to human health and disease. Their immunological features, such as the presence of CD4+CD8+ double-positive T cells and cytokine expression patterns, exhibit a notable degree of similarity to human immune cells, making them an attractive tool for studying human-relevant immune responses. This review outlines current methodologies for isolating and cryopreserving pPBMCs, with a focus on maintaining high cell viability and functionality. Key technical considerations, including the optimal use of gradient media, appropriate anticoagulants, and standardized freezing/thawing protocols, are discussed in detail. Furthermore, the article highlights the applications of pPBMCs in various research contexts, including vaccine development, inflammation studies, infection models, and xenotransplantation. A comparative perspective is provided to identify similarities and differences between porcine and human PBMCs, supporting the validity of swine as a translational model. Evidence from pPBMC-based studies has shown predictive value for human outcomes, reinforcing their role as a surrogate system for preclinical investigations. Given their anatomical, physiological, and immunogenetic similarities to humans, porcine PBMCs represent a valuable bridge between basic science and clinical application, playing an increasingly important role in translational medicine.

PMID:40429425 | DOI:10.3390/jcm14103432

Genes (Basel). 2025 May 17;16(5):592. doi: 10.3390/genes16050592.

ABSTRACT

BACKGROUND/OBJECTIVES: Pharmacogenomic screening plays a crucial role in optimizing chemotherapy outcomes and minimizing toxicity. Characterizing the baseline distribution of genetic variants in specific populations is essential to inform the prioritization of drug-gene combinations for clinical implementation. The objective of this study was to investigate the distribution of pharmacogenetic variants in 36 genes related to the fluoropyrimidine (FP) pathway among healthy Omani individuals, forming a foundation for future studies in cancer patients receiving FP-based chemotherapy.

METHODS: Ninety-eight healthy Omani participants aged ≥18 years were recruited at the Sultan Qaboos Comprehensive Cancer Care and Research Center. Whole-blood samples were collected, and genomic DNA was extracted. Targeted next-generation sequencing was performed using a custom Ion AmpliSeq panel covering coding exons and splice-site regions of 36 genes involved in FP metabolism and response.

RESULTS: A total of 999 variants were detected across the 36 genes, with 63.3% being heterozygous. The ABCC4 gene had the highest mutation frequency (76 mutations), while DHFR and SMUG1 had the lowest (<10 mutations). In DPYD, four functionally significant variants were found at frequencies ranging from 1 to 8.2% of the population. Missense mutations were also observed in MTHFR and UGT1A1. Three actionable variants in DPYD and MTHFR, associated with 5-fluorouracil and/or capecitabine response, were identified. Additionally, 27 novel single-nucleotide polymorphisms of unknown clinical significance were detected.

CONCLUSIONS: This study reveals key pharmacogenetic variants in the Omani population, underscoring the importance of integrating pharmacogenomic testing into routine care to support safer, more personalized chemotherapy in the region.

PMID:40428413 | DOI:10.3390/genes16050592

Genes (Basel). 2025 Apr 30;16(5):540. doi: 10.3390/genes16050540.

ABSTRACT

A variable number tandem repeat polymorphism has been described in the CYP2C9 promoter (pVNTR) with three types of fragments: short (pVNTR-S), medium (pVNTR-M), and long (pVNTR-L). The pVNTR-S allele appears in strong linkage disequilibrium (LD) with the non-functional CYP2C9*3 allele in populations of European ancestry, but independently of this, it also appears to reduce the level of CYP2C9 expression in human liver by up to 34%.

OBJECTIVES: This study, in a Dominican population with varying amounts of Western European, African, and Native American ancestry, aims primarily to determine the frequency of CYP2C9 pVNTR, and the degree of LD of pVNTR-S with CYP2C9*3. Secondarily, it explores if the frequency of the pVNTR-S allele is over- or under-represented in those with a greater component of African ancestry.

METHODS: A total of 193 healthy volunteers from the Dominican Republic participated in the study. The promoter region of CYP2C9 was amplified and analyzed by capillary electrophoresis. Analyses of CYP2C9 genotypes (*2, *3, *5, *6, and *8) and genetic ancestry, estimated in 176 Dominican individuals by genotyping 90 ancestry informative markers, were previously performed in this population.

RESULTS: The frequencies of CYP2C9 pVNTR-L, M, and S variants are 0.065, 0.896, and 0.039, respectively. LD between pVNTR-S and CYP2C9*3 was found (D' = 0.756, r2 = 0.702) to be weaker than in European populations.

CONCLUSIONS: Populations with a greater African ancestry component appear to present a lower-than-expected frequency of pVNTR-S, as well as a lower tendency for this and CYP2C9*3 alleles to be inherited together, as is common in Europeans. The present exploratory results warrant further research in vivo about the effects of pVNTR-S in predicting CYP2C9 activity. Its inclusion in CYP2C9 testing panels for personalized drug therapy could be relevant in populations such as the Dominican, where the LD between pVNTR-S and CYP2C9*3 is low.

PMID:40428362 | DOI:10.3390/genes16050540

Bioengineering (Basel). 2025 Apr 27;12(5):463. doi: 10.3390/bioengineering12050463.

ABSTRACT

The term "big data analytics (BDA)" defines the computational techniques to study complex datasets that are too large for common data processing software, encompassing techniques such as data mining (DM), machine learning (ML), and predictive analytics (PA) to find patterns, correlations, and insights in massive datasets. Cardiovascular diseases (CVDs) are attributed to a combination of various risk factors, including sedentary lifestyle, obesity, diabetes, dyslipidaemia, and hypertension. We searched PubMed and published research using the Google and Cochrane search engines to evaluate existing models of BDA that have been used for CVD prediction models. We critically analyse the pitfalls and advantages of various BDA models using artificial intelligence (AI), machine learning (ML), and artificial neural networks (ANN). BDA with the integration of wide-ranging data sources, such as genomic, proteomic, and lifestyle data, could help understand the complex biological mechanisms behind CVD, including risk stratification in risk-exposed individuals. Predictive modelling is proposed to help in the development of personalized medicines, particularly in pharmacogenomics; understanding genetic variation might help to guide drug selection and dosing, with the consequent improvement in patient outcomes. To summarize, incorporating BDA into cardiovascular research and treatment represents a paradigm shift in our approach to CVD prevention, diagnosis, and management. By leveraging the power of big data, researchers and clinicians can gain deeper insights into disease mechanisms, improve patient care, and ultimately reduce the burden of cardiovascular disease on individuals and healthcare systems.

PMID:40428082 | DOI:10.3390/bioengineering12050463

Cancers (Basel). 2025 May 20;17(10):1705. doi: 10.3390/cancers17101705.

ABSTRACT

BACKGROUND: Approximately 25.0% of metastatic prostate cancer patients harbour DNA damage repair mutations, including BRCA1 and BRCA2, which are actionable targets for poly(ADP-ribose) polymerase (PARP) inhibitors. Accurate detection of BRCA1/2 mutations is critical for guiding targeted therapies, but crucial pre-analytical factors, such as tissue storage duration and DNA fragmentation, drastically affect the reliability of next-generation sequencing (NGS) using real-world diagnostic specimens.

METHODS: This multicentre study analysed 954 formalin-fixed paraffin-embedded tissue samples from 11 centres, including 559 biopsies and 395 surgical specimens. This study examined the impact of storage duration (<1 year, 1-2 years, and >2 years) and DNA parameters (concentration and fragmentation index) on NGS success rates. Logistic regression and Cox regression analyses were used to assess correlations between these factors and sequencing outcomes.

RESULTS: NGS success rates decreased significantly with longer storage, from 87.8% (<1 year) to 69.1% (>2 years). Samples with higher DNA concentrations and fragmentation indexes had higher success rates (p < 0.001). Surgical specimens had superior success rates (83.3%) compared with biopsies (72.8%) due to better DNA quality. The DNA degradation rate was more pronounced in older samples, underscoring the negative impact of extended storage.

CONCLUSIONS: Timely testing of BRCA1/2 mutations is critical for optimizing the identification of prostate cancer patients eligible for PARP inhibitors. Surgical specimens provide more reliable results than biopsies and minimizing the storage duration significantly enhances testing outcomes. Standardizing pre-analytical and laboratory procedures across centres is essential to ensure personalized treatments and improve patient outcomes.

PMID:40427202 | DOI:10.3390/cancers17101705

Biomedicines. 2025 Apr 28;13(5):1071. doi: 10.3390/biomedicines13051071.

ABSTRACT

Background: The implantation process is complex and involves numerous factors that can affect its success. In artificial reproductive treatments (ARTs), chronic inflammation seems to be associated with implantation failure, largely contributing to reproductive dysfunction. Pentraxin 3 (PTX3) is overexpressed in several pathological conditions by exerting a pivotal role both as a regulator and indicator of inflammatory response. Some literature data have shown that PTX3 could have an impact on follicle growth and development, influencing women's fertility. This study aimed to detect PTX3 in follicular fluids collected during an ART protocol in relation to implantation outcomes. Methods: The PTX3/NF-kB/TLR4 pathway and other cytokines were assessed in the follicular fluid of 169 subjects, under the age of 40 years, undergoing IVF cycles, including females without achieved implantation (n = 98) and those with implantation (n = 71). Furthermore, subgroup analyses were performed to evaluate PTX3 values according to age difference. Results: From our data, PTX3 emerged as a strong predictor, more than TNFα and IL-1β, of implantation failure and related inflammatory follicular state. Overall, the results point to PTX3 as a potential biomarker for ART success, and their testing may be helpful in women whose successful implantation remains unexplained. Conclusions: Therefore, PTX3 could constitute a reliable biomarker and a valuable target to improve ART outcomes.

PMID:40426899 | DOI:10.3390/biomedicines13051071

Brain Sci. 2025 Apr 23;15(5):430. doi: 10.3390/brainsci15050430.

ABSTRACT

BACKGROUND/OBJECTIVES: Precision medicine is not just hype. Instead, it represents a high bar for developing more effective, safer, and better-tolerated therapies in medicine, without exception in psychiatry, including bipolar disorder (BD). A burgeoning body of narrative reviews and perspective papers has already appraised the boundaries of precision medicine in BD.

METHODS: This brief perspective follows a narrative, critical approach focusing explicitly on the antipsychotic management of BD using precision approaches.

RESULTS: While most controversies align with those previously appraised in BD's overall precision medicine approach, specific insights are provided herein.

CONCLUSIONS: Beyond other implications and the strengthened call for valid diagnostic coding systems, the implementation of shared decision-making tools and pharmacogenomics studies focusing on persons with BD are particularly warranted.

PMID:40426603 | DOI:10.3390/brainsci15050430

Front Pediatr. 2025 May 13;13:1574919. doi: 10.3389/fped.2025.1574919. eCollection 2025.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is caused by CFTR gene mutations. Its diagnosis mainly depends on genetic and sweat chloride tests, but the complexity of these mutations challenges diagnosis.

METHODS: This paper reports a new case of a Chinese child with cough and wheezing, suspected of having CF. Trio whole-exome sequencing for the pedigree was carried out to detect CFTR gene mutations. Five tools, namely Mutation Taster, PolyPhen-2, SIFT, FATHMM, and PROVEAN, were used to predict the impacts of mutations on protein function. AlphaFold was employed to predict protein structures, and GROMACS software was used to conduct stability analysis through molecular dynamics simulations.

RESULTS: The child was diagnosed with severe pneumonia, plastic bronchitis, and acute asthmatic bronchitis, with a high suspicion of CF. Whole-exome sequencing revealed compound missense mutations in the CFTR gene: c.1408 (exon 11) G>A (p.V470M) and c.650 (exon 6) A>G (p.E217G), both of which were homozygous mutations. Parental genetic tests showed that the father was heterozygous for the mutations, and the mother was heterozygous at the c.650 (exon 6) A>G locus and homozygous at the c.1408 (exon 11) G>A locus. The results obtained by different prediction tools varied, and molecular dynamics simulations indicated that these mutations significantly affected the stability of the CFTR protein.

CONCLUSION: Analysis of this new case using multiple tools and computational chemistry simulations helps to further understand the impacts of mutations on CFTR protein function and the disease, offering novel insights into the diagnosis, treatment, and genetic counseling of CF caused by the complex and diverse mutations of the CFTR gene.

PMID:40433478 | PMC:PMC12106003 | DOI:10.3389/fped.2025.1574919

Exp Ther Med. 2025 May 13;30(1):134. doi: 10.3892/etm.2025.12884. eCollection 2025 Jul.

ABSTRACT

In the present review, simple approaches for the screening and characterization of natural compound agents that alter pro-inflammatory gene expression are described, with a particular focus on aged garlic extract (AGE), which has been the subject of several investigations that have supported its potential application as an anti-inflammatory agent. Additionally, evidence regarding the possible effects and mechanisms of action of two major AGE components, S-allyl cysteine (SAC) and S-1-propenyl-l-cysteine (S1PC), is reviewed. The proposed molecular targets of SAC and S1PC are IKKβ kinase, the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 complex, peroxisome proliferator-activated receptor-γ, histone deacetylase and toll-like receptor 4 (TLR4). Targeting these molecules causes a marked reduction in NF-κB activity accompanied by a notable decrease in the transcription of NF-κB-regulated genes. Another main objective of the present review was to discuss the possibility that AGE and its bioactive components could be employed in the treatment of several human pathologies that are characterized by a hyperinflammatory state resulting from dysregulation of the TLR4 and NF-κB pathways. SAC is of interest in the treatment of lung pathologies, neurological diseases, osteoarthritis, muscular atrophy, cardiovascular diseases, diabetes and cancer. Additionally, the anti-oxidative activities of AGE, SAC and S1PC are compatible with their employment in the treatment of diseases characterized by oxidative stress, such as sickle cell disease and β-thalassemia.

PMID:40432842 | PMC:PMC12107228 | DOI:10.3892/etm.2025.12884

ERJ Open Res. 2025 May 27;11(3):00970-2024. doi: 10.1183/23120541.00970-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: The triple cystic fibrosis transmembrane conductance regulator (CFTR) modulators combination elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with cystic fibrosis (pwCF) bearing at least one F508del allele. Despite the development of CFTR modulators having dramatically improved respiratory outcomes in pwCF, clinical studies have showed variable responses to this drug formulation. Of note, airway inflammation and bacterial colonisation persist in the upper and lower respiratory tract even in ETI-treated patients.

METHODS: We first tested the clinical exoproducts (EXO) of Pseudomonas aeruginosa isolated from 15 CF patients in wild-type (WT) and F508del-CFTR CF bronchial epithelial (CFBE) cells. We were then prompted to evaluate the effects of EXO in ex-vivo patient-derived tissues. Therefore, we cultured primary nasal epithelial cells (HNECs) with EXO isolated from the corresponding pwCF to mimic the native status of CF airway.

RESULTS: We found that EXO variably decreased WT-, F508del- and ETI-dependent F508del-CFTR function and increased proinflammatory cytokines and reactive oxygen species (ROS) levels in a clinical strain-specific manner. Similarly, we observed a variable reduction of F508del-CFTR function in presence or absence of ETI and upregulation of proinflammatory cytokines and ROS levels. Interestingly, HNECs treated with EXO isolated from the corresponding donor and three different pwCF showed a variable reduction of ETI-dependent F508del-CFTR function mainly due to clinical strains with limited effect of patient background. Furthermore, we demonstrated that ETI pretreatment decreased the cytokines and ROS levels down to the levels of uninfected cells.

CONCLUSION: These preclinical studies suggest that in vitro screening of patient-specific response to CFTR modulators under infection/inflammation conditions could prove to be a valuable tool to enhance the prediction of clinical response.

PMID:40432819 | PMC:PMC12107384 | DOI:10.1183/23120541.00970-2024

Cureus. 2025 Apr 26;17(4):e83047. doi: 10.7759/cureus.83047. eCollection 2025 Apr.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by impaired mucociliary clearance, leading to recurrent respiratory tract infections, chronic rhinosinusitis, and progressive bronchiectasis. Pseudomonas aeruginosa is a common pathogen associated with poorer clinical outcomes in patients with PCD. While environmental sources of P. aeruginosa are well-documented in cystic fibrosis (CF) patients, to our knowledge, this is the first reported case implicating toothbrush colonization as a likely source of recurrent P. aeruginosa infections in a patient with PCD. We present a case of a 53-year-old Puerto Rican male with a history of sinusitis, bronchiectasis, hearing loss, and chronic cough, diagnosed with PCD, having a positive genetic testing for RSPH4A (c.921+3_921+6del (intronic)) founder mutation. Despite aggressive treatment, the patient continued to experience recurrent P. aeruginosa infections. Investigation into potential environmental sources revealed that the patient's toothbrush was colonized with P. aeruginosa, making it a likely source of reinfection. After modifying his oral hygiene practices, the patient showed significant clinical improvement with no subsequent hospitalizations. This case highlights the novel identification of a toothbrush as a source of recurrent P. aeruginosa infections in a patient with PCD. It underscores the importance of considering environmental factors in the management of chronic respiratory infections in patients with PCD. These findings suggest that routine evaluation and disinfection of hygiene tools, such as toothbrushes, may be critical in preventing recurrent infections and their long-term consequences in patients with PCD. Future research should aim to establish clinical guidelines for preventing bacterial transmission from the built environment in this vulnerable population.

PMID:40432624 | PMC:PMC12106793 | DOI:10.7759/cureus.83047

Nutrients. 2025 May 9;17(10):1632. doi: 10.3390/nu17101632.

ABSTRACT

Background: Sufficient choline supply is essential for tissue functions via phosphatidylcholine and sphingomyelin within membranes and secretions like bile, lipoproteins and surfactant, and in one-carbon metabolism via betaine. Choline requirements are linked to age and genetics, folate and cobalamin via betaine, and arachidonic (ARA) and docosahexaenoic (DHA) acid transport via the phosphatidylcholine moiety of lipoproteins. Groups at risk of choline deficiency include preterm infants, children with cystic fibrosis (CF) and patients dependent on parenteral nutrition. Fortifiers, formula and supplements may differently impact their choline supply. Objective: To evaluate added amounts of choline, folate, cobalamin, ARA and DHA in fortifiers, supplements and formula used in pediatric care from product files. Methods: Nutrient contents from commonly used products, categorized by age and patient groups, were obtained from public sources. Data are shown as medians and interquartile ranges. Results: 105 nutritional products including fortifiers, formula and products for special indications were analyzed. Choline concentrations were comparable in preterm and term infant formulas (≤6 months) (31.9 [27.6-33.3] vs. 33.3 [30.8-35.2] mg/100 kcal). Products for toddlers, and patients with CF, kidney or Crohn's disease showed Choline levels from 0 to 39 mg/100 kcal. Several products contain milk components and lecithin-based emulsifiers potentially increasing choline content beyond indicated amounts. Conclusions: Choline addition is standardized in formula for term and preterm infants up to 6 months, but not in other products. Choline content may be higher in several products due to non-declared sources. The potential impact of insufficient choline supply in patients at risk for choline deficiency suggests the need for biochemical analysis of products.

PMID:40431372 | DOI:10.3390/nu17101632

Pharmaceuticals (Basel). 2025 May 15;18(5):729. doi: 10.3390/ph18050729.

ABSTRACT

This article profiles 27 innovative advancements in small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) in 2024. These drugs target various therapeutic areas including non-small cell lung cancer, advanced or metastatic breast cancer, glioma, relapsed or refractory acute leukemia, urinary tract infection, Staphylococcus aureus bloodstream infections, nonalcoholic steatohepatitis, primary biliary cholangitis, Duchenne muscular dystrophy, hypertension, anemia due to chronic kidney disease, extravascular hemolysis, primary axillary hyperhidrosis, chronic obstructive pulmonary disease, severe alopecia areata, WHIM syndrome, Niemann-Pick disease type C, schizophrenia, supraventricular tachycardia, congenital adrenal hyperplasia, and cystic fibrosis. Among these approved small-molecule drugs, those with unique mechanisms of action and designated as breakthrough therapies by the FDA represent a significant proportion, highlighting ongoing innovation. Notably, eight of these drugs (including Rezdiffra®, Voydeya®, Iqirvo®, Voranigo®, Livdelzi®, Miplyffa®, Revuforj®, and Crenessity®) are classified as "first-in-class" and have received breakthrough therapy designation. These agents not only exhibit distinct mechanisms of action but also offer substantial improvements in efficacy for patients compared to prior therapeutic options. This article offers a comprehensive analysis of the mechanisms of action, clinical trials, drug design, and synthetic methodologies related to representative drugs, aiming to provide crucial insights for future pharmaceutical development.

PMID:40430547 | DOI:10.3390/ph18050729

Life (Basel). 2025 May 20;15(5):815. doi: 10.3390/life15050815.

ABSTRACT

This study investigated the prevalence of cystic fibrosis-related diabetes (CFRD) in the Croatian cystic fibrosis (CF) population, the age at diagnosis, insulin requirements, and the relationship between age at diagnosis and other clinical parameters. Medical records from 152 patients with genetically and laboratory-confirmed CF were reviewed through to 2025. The American Diabetes Association criteria were used to diagnose CFRD. Anthropometric and clinical data were collected from the latest medical records. A total of 17 out of 152 patients had CFRD, with a prevalence of 4.8% in the paediatric population (4/84) and 19.1% in adults (13/68). The median age of CFRD diagnosis was 14 years (range 9-22 years, SD = 3.95). Thirteen patients used insulin: one used bolus only, seven used basal-bolus multiple daily injections, and five used insulin pumps. The average total daily insulin (TDI) per kilogram (kg) body weight was 0.447 U/kg (SD = 0.429). The age at CFRD diagnosis was positively correlated with the body mass index (BMI) (p = 0.029). Patients requiring insulin by age 15 had higher TDI and were more likely to have CF liver disease (p = 0.027, p = 0.037, respectively). The prevalence of CFRD and age at diagnosis aligned with previous studies. Patients diagnosed at a younger age and requiring insulin earlier had lower BMIs, likely due to a faster decline in beta cell function and earlier onset of insulinopenia.

PMID:40430241 | DOI:10.3390/life15050815