Biomedica. 2024 Dec 23;44(Sp. 2):131-139. doi: 10.7705/biomedica.7558.

ABSTRACT

Introducción. Los errores innatos de la inmunidad se asocian frecuentemente con bronquiectasias. Actualmente, el diagnóstico de los errores innatos de la inmunidad ha mejorado porque se conoce con certeza la asociación de estas entidades con el daño progresivo de las vías respiratorias. Esto ha permitido el reconocimiento y la intervención adecuada, lo cual reduce el deterioro de la función pulmonar y mejora la calidad de vida. Objetivo. Describir un grupo de pacientes con bronquiectasias no relacionadas con la fibrosis quística y con diagnóstico de errores innatos de la inmunidad, estudiados en un centro de referencia de inmunología en Cali, Colombia. Materiales y métodos. Se desarrolló un estudio observacional, descriptivo y retrospectivo de pacientes menores de 18 años con diagnóstico de errores innatos de la inmunidad y bronquiectasias no relacionadas con fibrosis quística, entre diciembre de 2013 y diciembre de 2023 en la Fundación Valle del Lili, en Cali (Colombia). Resultados. Se incluyeron 17 pacientes con diagnóstico de bronquiectasias no relacionadas con fibrosis quística y errores innatos de la inmunidad, cuya edad media fue de nueve años. El inferior fue el lóbulo pulmonar más frecuentemente afectado y su compromiso fue unilateral en la mayoría de los casos. La inmunodeficiencia con predominio de defectos de los anticuerpos fue la más común, seguida de las inmunodeficiencias combinadas asociadas con síndromes. Trece pacientes presentaron compromiso de la inmunidad humoral y 4 pacientes, alteraciones en la inmunidad humoral y celular. En 12 pacientes se identificaron modificaciones genéticas relacionadas con su fenotipo. Trece pacientes recibieron suplemento de inmunoglobulina intravenosa y 3 fallecieron. Conclusión. La inmunodeficiencia con predominio de defectos de los anticuerpos, seguida de las inmunodeficiencias combinadas asociadas con características sindrómicas, fueron los errores innatos de la inmunidad que con mayor frecuencia se acompañaron de bronquiectasias no relacionadas con la fibrosis quística.

PMID:39836842 | DOI:10.7705/biomedica.7558

J Endocrinol. 2025 Jan 1:JOE-24-0190. doi: 10.1530/JOE-24-0190. Online ahead of print.

ABSTRACT

Endocrine dysfunction and diabetes can develop secondary to fibrotic diseases within the pancreas including cystic fibrosis (CF). Phenotypic shift within epithelial cells has been recognised in association with pro-fibrotic signalling. We sought evidence of endocrine cell epithelial-to-mesenchymal transition in CF and non-CF pancreas. Post mortem pancreatic sections from 24 people with CF and 10 organ donors without CF or diabetes were stained for insulin/glucagon/vimentin and Sirius Red Fast Green with collagen distribution assessed semi-quantitatively (CF) and quantitatively (non-CF). Analysis of existing single-cell RNA-sequencing data sets (three adult donors without diabetes and nine with chronic pancreatitis) for α-cell vimentin expression was performed. Cells co-expressing glucagon/vimentin were detected in a proportion (32(4,61)% (median(Q1,Q3)) of islets in all CF pancreata except donors dying perinatally. CF histopathology was characterised by peri-islet fibrosis and 60(45,80)% of islets were surrounded by collagen strands. A positive correlation between islet fibrosis and vimentin-expressing α-cells was seen in non-CF donors <31 years (r=0.972, p=0.006). A possible association with donor age was seen in all donors (r=0.343, p=0.047). Single-cell RNA-sequencing analysis of isolated islets from non-diabetic donors and donors with chronic pancreatitis confirmed presence of vimentin-positive and vimentin-negative α-cells. Differentiated α-cell function-associated gene expression was maintained. Differentially upregulated processes in co-expressing cells included pathways associated with extracellular matrix organisation, cell-cell adhesion, migratory capability and self-renewal. We have identified and characterised an intermediate epithelial/mesenchymal state in a sub-population of α-cells present throughout post-natal life which may play a role in their response to extrinsic stressors including fibrosis and ageing.

PMID:39836539 | DOI:10.1530/JOE-24-0190

BMC Med. 2025 Jan 21;23(1):22. doi: 10.1186/s12916-025-03848-y.

ABSTRACT

BACKGROUND: Current research underscores the need to better understand the pathogenic mechanisms and treatment strategies for idiopathic pulmonary fibrosis (IPF). This study aimed to identify key targets involved in the progression of IPF.

METHODS: We employed Mendelian randomization (MR) with three genome-wide association studies and four quantitative trait loci datasets to identify key driver genes for IPF. Prioritized targets were evaluated for respiratory insufficiency and transplant-free survival. The therapeutic efficacy of the core gene was validated in cellular and animal models. Additionally, we conducted a comprehensive evaluation of therapeutic value, pathogenic mechanisms, and safety through phenome-wide association study (PheWAS), mediation analysis, transcriptomic analyses, shared causal variant exploration, DNA methylation MR, and protein interactions.

RESULTS: Multiple MR results revealed that BRSK2 has a significant pathogenic impact on IPF at both transcriptional and translational levels, with a lung tissue-specific association (OR = 1.596; CI, 1.300-1.961; Pval = 8.290 × 10 - 6). BRSK2 was associated with IPF progression driven by high-risk factors, with mediation effects ranging from 34.452 to 69.665%. Elevated BRSK2 expression in peripheral blood mononuclear cells correlated with reduced pulmonary function, while increased circulating BRSK2 levels suggested respiratory failure and shorter transplant-free survival in IPF patients. BRSK2 silencing attenuated lung fibrosis progression in cellular and animal models. Transcriptomic integration identified PSMB1, CTSD, and CTSH as significant downstream effectors of BRSK2, with PSMB1 showing robust shared causal variant support (PPH4 = 0.800). Colocalization analysis and phenotype scan deepened the pathogenic association of BRSK2 with IPF, while methylation MR analysis highlighted the critical role of epigenetic regulation in BRSK2-driven IPF pathogenesis. PheWAS revealed no significant drug-related toxicities for BRSK2, and its therapeutic potential was further underscored by protein interaction analyses.

CONCLUSIONS: BRSK2 is identified as a critical pathogenic factor in IPF, with strong potential as a therapeutic target. Future studies should focus on its translational implications and the development of targeted therapies to improve patient outcomes.

PMID:39838395 | DOI:10.1186/s12916-025-03848-y

Sci Total Environ. 2025 Jan 20;964:178409. doi: 10.1016/j.scitotenv.2025.178409. Online ahead of print.

ABSTRACT

Air pollution has been associated with a higher incidence of idiopathic pulmonary fibrosis (IPF), yet this metabolic mechanism remains unclear. 185,865 participants were included in the UK Biobank. We estimated air pollution exposure using the bilinear interpolation approach, including fine particle matter with diameter < 2.5 μm (PM2.5), particle matter with diameter < 10 μm (PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx). We identified metabolites and established the metabolic signature with air pollutants using an elastic net regularized regression. Cox proportional hazards models combined with generalized propensity score (GPS) were conducted to evaluate the relationships between metabolic signatures and incident IPF, and mediation analysis was performed to evaluate potential mediators. During a median follow-up of 12.3 years, 1239 IPF cases were ascertained. We identified multi-metabolite profiles comprising 87 metabolites for PM2.5, 65 metabolites for PM10, 71 metabolites for NO2, and 76 metabolites for NOx. Metabolic signatures were associated with incident IPF, with HRs of 1.20 (95 % CI: 1.13, 1.27), 1.09 (95 % CI: 1.03, 1.15), 1.23 (95 % CI: 1.16, 1.31), and 1.24 (95 % CI: 1.17, 1.31) per standard deviation (SD) increase in metabolic profiles associated with PM2.5, PM10, NO2, and NOx, respectively. Furthermore, metabolic signatures of PM2.5, PM10, NO2 and NOx significantly mediated 5.71 %, 3.98 %, 4.21 %, and 4.58 % of air pollution on IPF. Long-term air pollution was associated with a higher risk of IPF, with metabolites potentially playing a mediating role. The findings emphasize the significance of improving metabolic status for the prevention of IPF.

PMID:39837121 | DOI:10.1016/j.scitotenv.2025.178409

BMC Vet Res. 2025 Jan 21;21(1):31. doi: 10.1186/s12917-024-04465-2.

ABSTRACT

BACKGROUND: Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) are recognized for their therapeutic potential in immune modulation and tissue repair, especially in veterinary medicine. This study introduces an innovative sequential stimulation (IVES) technique, involving low-oxygen gas mixture preconditioning using in vitro fertilization gas (IVFG) and direct current electrical stimulation (ES20), to enhance the anti-inflammatory properties of sEVs from canine adipose-derived MSCs (cAD-MSCs). Initial steps involved isolation and comprehensive characterization of cAD-MSCs, including morphology, gene expression, and differentiation potentials, alongside validation of the electrical stimulation protocol. IVFG, ES20, and IVES were applied simultaneously with a control condition. Stimulated cAD-MSCs were evaluated for morphological changes, cell viability, and gene expressions. Conditioned media were collected and purified for sEV isolation on Day1, Day2, and Day3. To validate the efficacy of IVES for sEV production, various analyses were conducted, including microscopic examination, surface marker assessment, zeta-potential measurement, protein quantification, nanoparticle tracking analysis, and determination of anti-inflammatory activity.

RESULTS: We found that IVES demonstrated non-cytotoxicity and induced crucial genotypic changes associated with sEV production in cAD-MSCs. Interestingly, IVFG influenced cellular adaptation, while ES20 induced hypoxia activation. By merging these stimulations, IVES enhanced sEV stability and quality profiles. The cAD-MSC-derived sEVs exhibited anti-inflammatory activity in lipopolysaccharide-induced RAW264.7 macrophages, emphasizing their improved effectiveness without cytotoxicity or immunogenicity. These effects were consistent across day 3 collection, indicating the establishment of an effective protocol for sEV production.

CONCLUSIONS: This research established an innovative sequential stimulation method with positive impact on sEV characteristics including stability, quality, and anti-inflammatory activity. This study not only contributes to the enhancement of sEV production but also sheds light on their functional aspects for therapeutic interventions.

PMID:39838398 | DOI:10.1186/s12917-024-04465-2

Commun Biol. 2025 Jan 21;8(1):105. doi: 10.1038/s42003-025-07457-6.

ABSTRACT

Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.

PMID:39838082 | DOI:10.1038/s42003-025-07457-6

Cell Res. 2025 Jan 21. doi: 10.1038/s41422-025-01076-w. Online ahead of print.

NO ABSTRACT

PMID:39837997 | DOI:10.1038/s41422-025-01076-w

Sci Rep. 2025 Jan 21;15(1):2711. doi: 10.1038/s41598-025-85927-x.

ABSTRACT

Drug development is known to be a costly and time-consuming process, which is prone to high failure rates. Drug repurposing allows drug discovery by reusing already approved compounds. The outcomes of past clinical trials can be used to predict novel drug-disease associations by leveraging drug- and disease-related similarities. To tackle this classification problem, collaborative filtering with implicit feedback (and potentially additional data on drugs and diseases) has become popular. It can handle large imbalances between negative and positive known associations and known and unknown associations. However, properly evaluating the improvement over the state of the art is challenging, as there is no consensus approach to compare models. We propose a reproducible methodology for comparing collaborative filtering-based drug repurposing. We illustrate this method by comparing 11 models from the literature on eight diverse drug repurposing datasets. Based on this benchmark, we derive guidelines to ensure a fair and comprehensive evaluation of the performance of those models. In particular, an uncontrolled bias on unknown associations might lead to severe data leakage and a misestimation of the model's true performance. Moreover, in drug repurposing, the ability of a model to extrapolate beyond its training distribution is crucial and should also be assessed. Finally, we identified a subcategory of collaborative filtering that seems efficient and robust to distribution shifts. Benchmarks constitute an essential step towards increased reproducibility and more accessible development of competitive drug repurposing methods.

PMID:39837888 | DOI:10.1038/s41598-025-85927-x

J Neurosci. 2025 Jan 21:e1337242025. doi: 10.1523/JNEUROSCI.1337-24.2025. Online ahead of print.

ABSTRACT

Microglia respond to cytotoxic protein aggregates associated with the progression of neurodegenerative disease. Pathological protein aggregates activate the microglial NLRP3 inflammasome resulting in proinflammatory signaling, secretion, and potentially pyroptotic cell death. We characterized mixed sex primary mouse microglia exposed to microbial stressors and alpha synuclein preformed fibrils (αsyn PFFs) to identify cellular mechanisms related to Parkinson's disease. Microglia package and release the endosome fate regulator Coronin1A (Coro1A) in EVs in an Nlrp3-dependent manner in widely used experimental activation conditions. We were surprised to find that Coro1A packaging and release was not Nlrp3-dependent in αsyn PFF exposure conditions. Coro1A-/- microglia exposed to αsyn PFFs trafficked more αsyn to lysosomal compartment increasing lysosomal membrane permeabilization. This corresponds to a decrease in αsyn released in EVs suggesting that Coro1A functions to shunt pathological proteins to a secretory pathway to attenuate lysosomal stress. αsyn PFF driven lysosomal stress resulting from Coro1a loss was associated with enhanced cytotoxicity. Intrinsic apoptosis signaling was unaffected, but we observed elevated cytosolic cathepsin B and the presence of a cathepsin associated 55kD PARP cleavage product. Post-mortem analysis of the PD mesencephalon supported a role for Coro1a in microglia, revealing elevated levels of Coro1A protein in human PD brains compared to those of healthy donors. Findings are relevant to the distribution of pathological αsyn and indicate that Coro1a protects microglia from lysosomal overload, inflammasome activation, and pyroptotic demise.Significance Statement Microglia are responsible for clearing toxic protein aggregates such as alpha synuclein (αsyn) in Parkinson's Disease (PD). PD is slowly progressive, implying that microglia are under proteinaceous stress for an extended time, maintaining some level of homeostasis while attempting to clear pathologically aggregated proteins. Pathological proteins can overload the lysosomes resulting in rupture, decreasing the ability of microglia to clear protein aggregates, and contributing to a hyperreactive inflammatory state. We determined that the protein Coronin1A functions in microglia to attenuate αsyn-induced lysosomal stress, preventing Nlrp3-inflammasome activation, and cell death. These findings identify a protective cellular mechanism operating in microglia that may contribute to the distribution of pathological proteins into the microenvironment.

PMID:39837661 | DOI:10.1523/JNEUROSCI.1337-24.2025

Proc Biol Sci. 2025 Jan;292(2039):20241559. doi: 10.1098/rspb.2024.1559. Epub 2025 Jan 22.

ABSTRACT

The two main extensions of rain forest in South America are the Amazon (Amazônia) and the Atlantic rain forest (Mata Atlântica), which are separated by a wide 'dry diagonal' of seasonal vegetation. We used the species-rich tree genus Inga to test if Amazônia-Mata Atlântica dispersals have been clustered during specific time periods corresponding to past, humid climates. We performed hybrid capture DNA sequencing of 810 nuclear loci for 453 accessions representing 164 species that included 62% of Mata Atlântica species and estimated a dated phylogeny for all accessions using maximum likelihood, and a species-level tree using coalescent methods. There have been 16-20 dispersal events to the Mata Atlântica from Amazônia with only one or two dispersals in the reverse direction. These events have occurred over the evolutionary history of Inga, with no evidence for temporal clustering, and model comparisons of alternative biogeographic histories and null simulations showing the timing of dispersal events matches a random expectation. Time-specific biogeographic corridors are not required to explain dispersal between Amazônia and the Mata Atlântica for rain forest trees such as Inga, which are likely to have used a dendritic net of gallery forests to cross the dry diagonal.

PMID:39837505 | DOI:10.1098/rspb.2024.1559

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jan 19:111258. doi: 10.1016/j.pnpbp.2025.111258. Online ahead of print.

ABSTRACT

BACKGROUND: Type 2 diabetes (T2D) is a chronic metabolic disorder that has high comorbidity with mental disorders. The genetic relationships between T2D and depression are far from being well understood.

METHODS: We performed genetic correlation, polygenic overlap, Mendelian randomization (MR) analyses, cross-trait meta-analysis, and Bayesian colocalization analysis to assess genetic relationships between T2D and depression, in the forms of major depressive disorder (MDD) and depressed affect (DAF). Then, the summary data-based MR (SMR) analysis was performed to prioritize genes contributing to MDD and to T2D from functional perspective. MDD-driven signaling pathways were constructed to understand the influence of MDD on T2D at the molecular level.

RESULTS: T2D has positive genetic correlations both with MDD (rg = 0.14) and with DAF (rg = 0.19). The polygenic overlap analysis showed that about 60 % of causal variants for T2D are shared with MDD and DAF. The MR analysis indicated that genetic liabilities to both MDD (OR: 1.24, 95 % CI: 1.11-1.38) and DAF (OR: 1.48, 95 % CI: 1.23-1.78) are associated with an increased risk for T2D, while genetic liability to T2D is not associated with the risk for MDD (OR: 1.00, 95 % CI: 0.99-1.01) or DAF (OR: 1.01, 95 % CI: 1.00-1.02). The cross-trait meta-analysis identified 271 genomic loci, of which 29 were novel. Genetic predisposition to MDD and T2D shares six overlapping loci, involving some well-characterized genes, such as TCF4 and NEGR1. Colocalization analysis revealed three shared chromosome regions between MDD and T2D, which covers mediator genes including SCYL1, DENND1A, and MAD1L1. Molecular pathway analysis suggests mechanisms that promote the development of T2D through inflammatory pathways overactive in patients with MDD. The SMR analysis and the meta-analysis highlighted seven genes with functional implications for both MDD and T2D, including TNKS2, CCDC92, FADS1, ERI1, THUMPD3, NUCKS1, and PM20D1.

CONCLUSIONS: Our study points out that depression, in the forms of MDD and DAF, may increase the risk of T2D. Analysis of underlying genetic variation and the molecular pathways, connecting depression and T2D, indicate that the pathophysiological foundations of these two conditions have a notable overlap.

PMID:39837361 | DOI:10.1016/j.pnpbp.2025.111258

Neuron. 2025 Jan 16:S0896-6273(24)00926-7. doi: 10.1016/j.neuron.2024.12.026. Online ahead of print.

ABSTRACT

Gliomas are aggressive neoplasms that diffusely infiltrate the brain and cause neurological symptoms, including cognitive deficits and seizures. Increased mTOR signaling has been implicated in glioma-induced neuronal hyperexcitability, but the molecular and functional consequences have not been identified. Here, we show three types of changes in tumor-associated neurons: (1) downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development and upregulation of cytoskeletal transcripts via neuron-specific profiling of ribosome-bound mRNA, (2) marked decreases in dendritic spine density via light and electron microscopy, and (3) progressive functional alterations leading to neuronal hyperexcitability via in vivo calcium imaging. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed these tumor-induced changes. These findings reveal mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma and suggest new strategies for treating glioma-associated neurological symptoms.

PMID:39837324 | DOI:10.1016/j.neuron.2024.12.026

Eur J Cell Biol. 2025 Jan 15;104(2):151476. doi: 10.1016/j.ejcb.2025.151476. Online ahead of print.

ABSTRACT

Since the development of the three-dimensional (3D) "mini-gut" culture system, adult stem cell-derived organoid technology has rapidly advanced, providing in vitro models that replicate key cellular, molecular, and physiological properties of multiple organs. The 3D intestinal organoid system has resolved many long-standing challenges associated with immortalized or cancer cell cultures, offering unparalleled capabilities for modeling gastrointestinal development and diseases. However, significant limitations remain, including restricted accessibility to the epithelial apical surface for studying host-microbe interactions, interruptions in modeling chronic gastrointestinal diseases due to frequent passaging and dissociation, and the absence of mechanical cues such as peristalsis and luminal flow, which are critical for organ development and function. To address these challenges, recent advancements have introduced Transwell-based monolayer cultures and microfluidic device-based technologies including "organ-on-a-chip" and scaffold-guided 'mini-gut' system. This review highlights these innovations, with a focus on adult stem cell-derived intestinal organoid models that feature an open apical surface and discusses their prospects and challenges for advancing basic research and clinical applications.

PMID:39837176 | DOI:10.1016/j.ejcb.2025.151476

PLoS Biol. 2025 Jan 21;23(1):e3002982. doi: 10.1371/journal.pbio.3002982. Online ahead of print.

ABSTRACT

Coronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5' genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon searching for emergence of this motif in the global SARS-CoV-2 sequences, we find that it evolves frequently, especially in the 3' end of the genome. We show well-supported examples upstream of the Spike gene-within the nsp16 coding region of ORF1b-which is expressed during human infection, and upstream of the canonical Envelope gene TRS, both of which have evolved convergently in multiple lineages. The most frequent neo-TRS is within the coding region of the Nucleocapsid gene, and is present in virtually all viruses from the B.1.1 lineage, including the variants of concern Alpha, Gamma, Omicron and descendants thereof. Here, we demonstrate that this TRS leads to the expression of a novel subgenomic mRNA encoding a truncated C-terminal portion of Nucleocapsid, which is an antagonist of type I interferon production and contributes to viral fitness during infection. We observe distinct phenotypes when the Nucleocapsid coding sequence is mutated compared to when the TRS alone is ablated. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level.

PMID:39836705 | DOI:10.1371/journal.pbio.3002982

Mini Rev Med Chem. 2025 Jan 17. doi: 10.2174/0113895575339660250106093738. Online ahead of print.

ABSTRACT

Metabolic reprogramming is a hallmark of cancer. Distinct and unusual metabolic aberrations occur during tumor development that lead to the growth and development of tumors. Oncogenic signaling pathways eventually converge to regulate three major metabolic pathways in tumor cells i.e., glucose, lipid, and amino acid metabolism. Therefore, identifying and targeting the metabolic nodes of cancer cells can be a promising intervention and therapeutic strategy for patients with malignancies. The long road of new drug discovery for cancer therapy has necessitated relooking alternative strategies such as drug repurposing. Advanced genomic and proteomic technologies for the assessment of cancer-specific biological pathways have led to the discovery of new drug targets, which provide excellent opportunities for drug repurposing. The development of effective, safe, cheaper, and readily available anticancer agents is the need of the hour, and drug repurposing has the potential to break the current drug shortage bottleneck. This review will accordingly cover various metabolic pathways that are aberrant in cancer, and strategies for targeting metabolic reprogramming by using repurposed drugs.

PMID:39835565 | DOI:10.2174/0113895575339660250106093738

Expert Opin Drug Metab Toxicol. 2025 Jan 21:1-28. doi: 10.1080/17425255.2024.2433626. Online ahead of print.

ABSTRACT

INTRODUCTION: Genetic load influences the therapeutic response to conventional drugs in Alzheimer's disease (AD). Pharmacogenetics (PGx) is the best option to reduce drug-drug interactions and adverse drug reactions in patients undergoing polypharmacy regimens. However, there are important limitations that make it difficult to incorporate pharmacogenetics into routine clinical practice.

AREAS COVERED: This article analyzes the pharmacogenetic apparatus made up of pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes responsible for the efficacy and safety of pharmacological treatment, the impact of genetic load on the outcome of multifactorial treatments, and practical aspects for the effective use of PGx.

EXPERT OPINION: Over 120 genes are closely associated with AD. There is an accumulation of cerebrovascular (CVn) and neurodegenerative (ADn) genes in AD. APOE-4 carriers accumulate more deleterious genetic load related to other CVn and ADn genes, develop the disease earlier, and are at a biological disadvantage compared to APOE-4 non-carriers. CYP2D6-PMs and APOE-4 carriers are the worst responders to anti-dementia drugs. Some limitations hinder the implementation of PGx in clinical practice, including lack of pharmacogenetic information for many drugs, low number of genes in PGx screening protocols, and educational deficiencies in the medical community regarding PGx and genomic medicine.

PMID:39835706 | DOI:10.1080/17425255.2024.2433626

Am J Physiol Lung Cell Mol Physiol. 2025 Jan 21. doi: 10.1152/ajplung.00328.2024. Online ahead of print.

ABSTRACT

Background: Secondhand smoke exposure (SHSe) is a public health threat for people with cystic fibrosis (CF) and other lung diseases. Primary smoking reduces CFTR channel function, the causative defect in CF. We reported that SHSe worsens respiratory and nutritional outcomes in CF by disrupting immune responses and metabolic signaling. Recently, electronic cigarette (e-cigs) usage by caregivers and peers has increased rapidly, causing new secondhand e-cig vape exposures. Primary vaping is associated with immunologic deficits in healthy people, but it is unknown if e-cigs similarly impacts CF immune function or how it differs from SHSe. Methods: Human CF and non-CF blood monocyte derived macrophages (MDMs) and bronchial epithelial cells (HBECs) were exposed to flavored and unflavored e-cigs. The effect of e-cigs on CFTR expression and function, bacterial killing, cytokine signaling, lipid mediators, and metabolism was measured during treatment with CFTR modulators. Results: E-cigs decreased CFTR expression and function in CF and non-CF MDMs and negated CFTR functional restoration by elexacaftor/tezacaftor/ivacaftor (ETI). E-cigs also negated the restoration of anti-inflammatory PGD2 expression in CF MDMs treated with ETI compared to controls. Flavored but not unflavored e-cigs increased pro-inflammatory cytokine expression in CF MDMs and e-cigs promoted glycolytic metabolism. E-cigs did not impact bacterial killing. Overall, HBECs were less impacted by e-cigs compared to MDMs. Conclusion: E-cigs reduced macrophage CFTR expression and hindered functional CFTR restoration by CFTR modulators, promoting a glycolytic, pro-inflammatory state. E-cigs are an emerging public health threat that may limit the efficacy of CFTR modulators in people with CF.

PMID:39836014 | DOI:10.1152/ajplung.00328.2024

Pediatr Pulmonol. 2025 Jan;60(1):e27487. doi: 10.1002/ppul.27487.

ABSTRACT

OBJECTIVE: Although studies have examined changes in C-reactive protein (CRP) during pulmonary exacerbations (PEX) in people with cystic fibrosis (PwCF), few have evaluated CRP profiles across age groups. Here, we characterize age-related CRP responses to PEX treatment.

METHODS: We measured CRP concentrations at the beginning and end of intravenous (IV) antibiotic therapy for PEX in 100 pediatric and 147 adult PwCF at 10 US CF Centers. We examined relationships between CRP and age, lung function, severity of PEX symptoms, and time to next PEX.

RESULTS: CRP measured at initiation of IV antibiotic treatment for PEX was higher in adults than children, median 8 mg/L (IQR 4, 32) versus 5 mg/L (IQR 2, 10), respectively (p < 0.001). There was a significant correlation between the initial CRP and drop in lung from baseline to the beginning of IV antibiotics in adults and children. Adjusted CRP dropped in response to PEX treatment more commonly in adults than in children (70% vs. 48%, respectively). The range of treatment responses was greater in adults, in those with higher symptom scores, and in those with more advanced lung disease. In adults elevated CRP at the end of treatment was also associated with incomplete recovery of lung function. CRP at the start of IV antibiotics was inversely related to time until the next PEX.

CONCLUSION: In children and adults with CF, CRP is increased at the initiation of IV antibiotic therapy for PEX and declines with treatment. The response is more pronounced in highly symptomatic adults with advanced lung disease.

PMID:39835779 | DOI:10.1002/ppul.27487

Pediatr Pulmonol. 2025 Jan;60(1):e27488. doi: 10.1002/ppul.27488.

ABSTRACT

INTRODUCTION: Cellular characteristics of induced sputum (IS) are not investigated in cystic fibrosis (CF) patients.

OBJECTIVES: This pilot study, conducted on 17 expectorating CF adolescents, compared sputa obtained the same day, in a stable period, by autogenic drainage (expectorating sputum, ES) and 4 h later after inhaling hypertonic saline (IS).

RESULTS: No difference was noted concerning weight, volume, and percentage of dead cells between the two collection methods. Sample quality (< 50% of dead cells and < 20% squamous cells) was higher in the case of IS than ES (94.1% vs. 58.8%, p = 0.03), with a doubled cell count (p = 0.01), a higher proportion of alveolar macrophages (p = 0.03), and a lower proportion of squamous cells (p = 0.004). The detection of germs increased by 44% in IS samples, possibly modifying therapeutic management in 17.6% of the patients.

CONCLUSION: IS improves the quality and the microbiological detection of the sample, even among CF patients who spontaneously expectorate.

PMID:39835741 | DOI:10.1002/ppul.27488

Int J Comput Assist Radiol Surg. 2025 Jan 21. doi: 10.1007/s11548-025-03321-4. Online ahead of print.

ABSTRACT

PURPOSE: Identifying muscles linked to postoperative physical function can guide protocols to enhance early recovery following total hip arthroplasty (THA). This study aimed to evaluate the association of preoperative pelvic and thigh muscle volume and quality with early physical function after THA in patients with unilateral hip osteoarthritis (HOA).

METHODS: Preoperative Computed tomography (CT) images of 61 patients (eight males and 53 females) with HOA were analyzed. Six muscle groups were segmented from CT images, and muscle volume and quality were calculated on the healthy and affected sides. Muscle quality was quantified using the mean CT values (Hounsfield units [HU]). Early postoperative physical function was evaluated using the Timed Up & Go test (TUG) at three weeks after THA. The effect of preoperative muscle volume and quality of both sides on early postoperative physical function was assessed.

RESULTS: On the healthy and affected sides, mean muscle mass was 9.7 cm3/kg and 8.1 cm3/kg, and mean muscle HU values were 46.0 HU and 39.1 HU, respectively. Significant differences in muscle volume and quality were observed between the affected and healthy sides. On analyzing the function of various muscle groups, the TUG score showed a significant association with the gluteus maximum volume and the gluteus medius/minimus quality on the affected side.

CONCLUSION: Patients with HOA showed significant muscle atrophy and fatty degeneration in the affected pelvic and thigh regions. The gluteus maximum volume and gluteus medius/minimus quality were associated with early postoperative physical function. Preoperative rehabilitation targeting the gluteal muscles on the affected side could potentially enhance recovery of physical function in the early postoperative period.

PMID:39836355 | DOI:10.1007/s11548-025-03321-4