Nat Med. 2025 Feb;31(2):478-489. doi: 10.1038/s41591-024-03420-w. Epub 2025 Jan 17.

ABSTRACT

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.

PMID:39825153 | DOI:10.1038/s41591-024-03420-w

Prog Mol Biol Transl Sci. 2025;210:163-203. doi: 10.1016/bs.pmbts.2024.07.019. Epub 2024 Aug 31.

ABSTRACT

The groundbreaking CRISPR-Cas gene editing method permits exact genetic code alteration. The "CRISPR" DNA protects bacteria from viruses. CRISPR-Cas utilizes a guide RNA to steer the Cas enzyme to the genome's gene editing target. After attaching to a sequence, Cas enzymes cleave DNA to insert, delete, or modify genes. The influence of CRISPR-Cas technology on molecular biology and genetics is profound. It allows for gene function research, animal disease models, and patient genetic therapy. Gene editing has transformed biotechnology, agriculture, and customized medicine. CRISPR-Cas could revolutionize genetics and medicine. CRISPR-Cas may accurately correct genetic flaws that underlie rare diseases, improving their therapy. Gene mutations make CRISPR-Cas gene editing a viable cure for uncommon diseases. We can use CRISPR-Cas to correct genetic abnormalities at the molecular level. This strategy offers hope for remedies and disease understanding. CRISPR-Cas genome editing may enable more targeted and effective treatments for rare medical illnesses with few therapy options. By developing base- and prime-editing CRISPR technology, CRISPR-Cas allows for accurate and efficient genome editing and advanced DNA modification. This advanced method provides precise DNA alterations without double-strand breakage. These advances have improved gene editing safety and precision, reducing unfavorable effects. Lipid nanoparticles, which use viral vectors, improve therapeutic cell and tissue targeting. In rare disorders, gene therapy may be possible with CRISPR-Cas clinical trials. CRISPR-Cas research is improving gene editing, delivery, and rare disease treatment.

PMID:39824580 | DOI:10.1016/bs.pmbts.2024.07.019

Genome Med. 2025 Jan 17;17(1):5. doi: 10.1186/s13073-025-01432-w.

ABSTRACT

BACKGROUND: Despite extensive analysis, the dynamic changes in prostate epithelial cell states during tissue homeostasis as well as tumor initiation and progression have been poorly characterized. However, recent advances in single-cell RNA-sequencing (scRNA-seq) technology have greatly facilitated studies of cell states and plasticity in tissue maintenance and cancer, including in the prostate.

METHODS: We have performed meta-analyses of new and previously published scRNA-seq datasets for mouse and human prostate tissues to identify and compare cell populations across datasets in a uniform manner. Using random matrix theory to denoise datasets, we have established reference cell type classifications for the normal mouse and human prostate and have used optimal transport to compare the cross-species transcriptomic similarities of epithelial cell populations. In addition, we have integrated analyses of single-cell transcriptomic states with copy number variants to elucidate transcriptional programs in epithelial cells during human prostate cancer progression.

RESULTS: Our analyses demonstrate transcriptomic similarities between epithelial cell states in the normal prostate, in the regressed prostate after androgen-deprivation, and in primary prostate tumors. During regression in the mouse prostate, all epithelial cells shift their expression profiles toward a proximal periurethral (PrU) state, demonstrating an androgen-dependent plasticity that is restored to normal during androgen restoration and gland regeneration. In the human prostate, we find substantial rewiring of transcriptional programs across epithelial cell types in benign prostate hyperplasia and treatment-naïve prostate cancer. Notably, we detect copy number variants predominantly within luminal acinar cells in prostate tumors, suggesting a bias in their cell type of origin, as well as a larger field of transcriptomic alterations in non-tumor cells. Finally, we observe that luminal acinar tumor cells in treatment-naïve prostate cancer display heterogeneous androgen receptor (AR) signaling activity, including a split between AR-positive and AR-low profiles with similarity to PrU-like states.

CONCLUSIONS: Taken together, our analyses of cellular heterogeneity and plasticity provide important translational insights into the origin and treatment response of prostate cancer. In particular, the identification of AR-low tumor populations suggests that castration-resistance and predisposition to neuroendocrine differentiation may be pre-existing properties in treatment-naïve primary tumors that are selected for by androgen-deprivation therapies.

PMID:39825401 | DOI:10.1186/s13073-025-01432-w

Pharmacogenomics. 2025 Jan 17:1-9. doi: 10.1080/14622416.2025.2452834. Online ahead of print.

ABSTRACT

AIMS: To ascertain and describe pharmacogenomic concepts included in the intended curriculum of accredited Australian medical schools.

METHODS: Content analysis of curriculum learning objectives of Australian medical schools was conducted, focusing on keywords and phrases pertaining to pharmacogenomic education. Learning objectives related to pharmacogenomics were categorized using (1) undergraduate medical genomic competencies per the Association of Professors in Human and Medical Genetics (2) Bloom's Taxonomy for cognitive and knowledge dimensions and (3) knowledge translation (enabling science, translation science and clinical implementation).

RESULTS: The curricula of 19 accredited medical schools in Australia were analyzed. Two-thirds (68%) contained genomic/pharmacogenomic education. Eight schools had content relating to undergraduate medical genomic competencies. Of those which had pharmacogenomic-related learning objectives, the majority (65%) were categorized in Bloom's Taxonomy's lower levels (Remember and Understand) and 15% were deemed to be at the level of 'Clinical Implementation.'

CONCLUSION: The majority of Australian medical schools have incorporated pharmacogenomics in their current curriculum; however, learning objectives addressing application and clinical implementation are required. Doctors have a unique role to play in implementing pharmacogenomics into clinical practice. Comprehensiveness of course curricula across all learning domains would support uptake of pharmacogenomics into routine practice.

PMID:39824782 | DOI:10.1080/14622416.2025.2452834

Am J Hum Genet. 2025 Jan 10:S0002-9297(24)00461-0. doi: 10.1016/j.ajhg.2024.12.019. Online ahead of print.

ABSTRACT

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and ciliogenesis. Depletion of Kics2 in zebrafish resulted in ciliary dysfunction consistent with a role of mTORC1 in cilia biology. These in vitro and in vivo functional studies confirmed the pathogenicity of identified KICS2 variants. Our genetic and experimental data provide evidence that variants in KICS2 are a factor involved in intellectual disability due to its dysfunction impacting mTORC1 regulation and cilia biology.

PMID:39824192 | DOI:10.1016/j.ajhg.2024.12.019

Leuk Res. 2025 Jan 7;149:107644. doi: 10.1016/j.leukres.2025.107644. Online ahead of print.

ABSTRACT

Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 are highly successful in chronic myeloid leukemia (CML). However, extensive interpatient variability in therapeutic responses and resistance supports the need to find new prognostic biomarkers. We have previously reported that TP53 SNP215 variant affects CML risk and clinical outcome. We aimed to evaluate the role of MDM2 genetic variants in CML susceptibility and treatment response to TKIs. We genotyped five MDM2 promoter variants (del1518, SNP309, SNP285, SNP288 and SNP344) in 135 CML patients and 136 healthy individuals. Our study showed that MDM2 variants alone or in combination had no effect on CML susceptibility. The analysis of MDM2 genotypes in relation to patients' clinical parameters revealed that individuals with SNP309 G/G genotypes were at a significantly increased risk of undergoing molecular response failure (p = 0.044). Improved overall survival was also observed for non-responders with the alternative MDM2 del1518 del allele (p = 0.017) as well as for MDM2 del1518-SNP309 combinations with alternative genotypes (p = 0.014). In addition, combinatorial analysis demonstrated that alternative MDM2 SNP309 and TP53 SNP215 genotypes together are associated with faster achievement of MR2 (p = 0.029) and MMR (p = 0.042) in non-responders, suggesting a relationship with a favorable outcome. Overall, our study highlights the influence of MDM2 variants on clinical outcome, supporting that specific genotypes, alone or in combination, underlie the treatment-responsive phenotype.

PMID:39823766 | DOI:10.1016/j.leukres.2025.107644

Adv Exp Med Biol. 2025 Jan 18. doi: 10.1007/5584_2024_829. Online ahead of print.

ABSTRACT

Despite advances in healthcare, bacterial pathogens remain a severe global health threat, exacerbated by rising antibiotic resistance. Lower respiratory tract infections, with their high death toll, are of particular concern. Accurately replicating host-pathogen interactions in laboratory models is crucial for understanding these diseases and evaluating new therapies. In this communication, we briefly present existing in vivo models for cystic fibrosis and their limitations in replicating human respiratory infections. We then present a novel, 3D-printed, cytocompatible microfluidic lung-on-a-chip device, designed to simulate the human lung environment, and with possible use in recapitulating general infectious diseases.Our device enables the colonisation of fully differentiated lung epithelia at an air-liquid interface with Pseudomonas aeruginosa, a key pathogen in many severe infections. By incorporating dynamic flow, we replicate the clearance of bacterial toxins and planktonic cells, simulating both acute and chronic infections. This platform supports real-time monitoring of therapeutic interventions, mimics repeated drug administrations as in clinical settings, and facilitates the analysis of colony-forming units and cytokine secretion over time. Our findings indicate that this lung-on-a-chip device has significant potential for advancing infectious disease research, in optimizing treatment strategies against infections and in developing novel treatments.

PMID:39825043 | DOI:10.1007/5584_2024_829

Sci Rep. 2025 Jan 17;15(1):2247. doi: 10.1038/s41598-025-86010-1.

ABSTRACT

Clinical trials demonstrate the short-term efficacy of dual CFTR modulators, but long-term real-world data is limited. We aimed to investigate the effects of 24-month lumacaftor/ivacaftor (LUM/IVA) therapy in pediatric CF patients (pwCF). This observational study included pwCF homozygous for F508del mutation treated between 2021 and 2023. We report data for the first 24 months from therapy initiation. Variables were analyzed separately for ages 2-5, 6-11, and over 12. Data from 49 pwCF (median age: 9.3 years (5.5-14.2)) showed that ppFEV1 values after a transient increase at 12 months, decreased from 102% (82-114) at baseline to 87% (74-96) at 24 months. The decrease was more pronounced with higher initial ppFEV1. Median sweat chloride concentration decreased from 75 mmol/L (69-82) to 57 mmol/L (43-70) without any association with respiratory function change. Median BMI z-score increased from - 0.81 (- 1.37-0.49) to - 0.39 (- 0.88 to - 0.04) (p = 0.288), and the proportion of underweight and overweight children decreased. Skeletal muscle mass remained stable, while fat mass significantly increased (p = 0.011). Fecal elastase levels improved, especially among younger patients. These findings underscore the potential benefits of early initiation of CFTR modulator therapy in pediatric CF patients, highlighting improvements in nutritional status and pancreatic function.

PMID:39824960 | DOI:10.1038/s41598-025-86010-1

Sci Rep. 2025 Jan 17;15(1):2222. doi: 10.1038/s41598-024-82500-w.

ABSTRACT

Pseudomonas aeruginosa is a Gram-negative bacterium that is notorious for airway infections in cystic fibrosis (CF) subjects. Bacterial quorum sensing (QS) coordinates virulence factor expression and biofilm formation at population level. Better understanding of QS in the bacterium-host interaction is required. Here, we set up a new P. aeruginosa infection model, using 2D upper airway nasal organoids that were derived from 3D organoids. Using dual RNA-sequencing, we dissected the interaction between organoid epithelial cells and WT or QS-mutant P. aeruginosa strains. Since only a single healthy individual and a single CF subject were used as donors for the organoids, conclusions about CF-specific effects could not be deduced. However, P. aeruginosa induced epithelial inflammation, whereas QS signaling did not affect the epithelial airway cells. Conversely, the epithelium influenced infection-related processes of P. aeruginosa, including QS-mediated regulation. Comparison of our model with samples from the airways of CF subjects indicated that our model recapitulates important aspects of infection in vivo. Hence, the 2D airway organoid infection model is relevant and may help to reduce the future burden of P. aeruginosa infections in CF.

PMID:39824906 | DOI:10.1038/s41598-024-82500-w

J Cyst Fibros. 2025 Jan 16:S1569-1993(25)00008-6. doi: 10.1016/j.jcf.2025.01.006. Online ahead of print.

ABSTRACT

BACKGROUND: Highly effective modulator therapies (HEMT) including ivacaftor (IVA) and elexacaftor/tezacaftor/ivacaftor (ETI) have transformed treatment for people with cystic fibrosis (pwCF). However, non-HEMT-responsive mutations are more common in pwCF of non-White race/ethnicity; introduction of HEMT might have exacerbated racial/ethnic disparities in CF care.

METHODS: Using the Scientific Registry of Transplant Recipients, we identified all lung transplant candidates and recipients 05/2005-12/2022 and categorized them by diagnosis (CF/non-CF), race/ethnicity (non-Hispanic White/Black/Hispanic) and era [Pre-HEMT (2005-1/30/2012), IVA (1/31/2012-10/30/2019), ETI (10/31/2019-12/31/2022)]. We compared the percentage of patients listed, delisted/died, or transplanted by race/ethnicity and era.

RESULTS: 34,659 lung transplants were performed: 10,521 pre-HEMT, 15,944 in IVA era, and 7,888 in ETI era. Over the three eras, the percentage of lung recipients with CF of White race decreased (94.5 % to 92.4 % to 78.4 %) and of Black race (1.7 % to 2.4 % to 5.7 %) or Hispanic ethnicity increased (3.5 % to 4.6 % to 14.2 %; p < 0.001). Similarly, among candidates listed for CF over the three eras, the percentage that were of White race decreased (82.0 % vs. 78.6 % vs. 71.0 %) and of Black race (9.2 % vs. 10.0 % vs. 10.3 %) or Hispanic ethnicity increased (6.4 % vs. 8.6 % vs. 13.6 %; p < 0.001).

CONCLUSION: The introduction of HEMT appears to have benefitted CF lung transplant candidates and recipients of Black race or Hispanic ethnicity less than those of White race. This is likely due to the higher prevalence of HEMT-ineligible CFTR mutations among Black and Hispanic patients and underscores the need for therapies aimed at non-HEMT-responsive mutations prevalent in these racial/ethnic populations.

PMID:39824680 | DOI:10.1016/j.jcf.2025.01.006

J Glob Antimicrob Resist. 2025 Jan 15:S2213-7165(25)00007-4. doi: 10.1016/j.jgar.2025.01.002. Online ahead of print.

ABSTRACT

OBJECTIVES: Pandoraea apista is notable for its multidrug resistance and is frequently identified in patients with cystic fibrosis or other chronic lung diseases, where it contributes to persistent lung infections. In this study, we describe a strain of P. apista harboring the blaOXA-153, isolated from the bronchoalveolar lavage (BAL) fluid of an inpatient in China.

METHODS: The genomic DNA of P. apista strain PA167 was sequenced using the Illumina NovaSeq 6000 system and assembled with SPAdes v.3.13.0. Antimicrobial resistance genes (ARGs) were identified using ResFinder v.3.2 within the ABRicate v.0.9.0. Phylogenetic analysis was performed using the Snippy v.4.6.0.

RESULTS: The genome sequence of P. apista strain PA167 comprises 5,580,873 bp, with 4,926 protein-coding sequences, 4 ncRNAs, 59 tRNAs, and 3 rRNA operons. Only one ARG was identified: blaOXA-153. PA167 exhibited resistance to multiple antibiotics, including cephalosporins and carbapenems, and was susceptible only to sulfamethoxazole/trimethoprim. Twenty-four P. apista strains, including PA167, could be retrieved from the NCBI database, all carrying the blaOXA-153. Complete genomic sequencing of five strains confirmed the chromosomal presence of blaOXA-153. The isolation sources of these 24 strains were predominantly clinical samples, mainly respiratory specimens, with some strains isolated from environmental sources.

CONCLUSION: Here, we present the genome sequence of a P. apista strain carrying the blaOXA-153, marking the first isolation of this strain from a clinical setting in China. The potential for future epidemic spread highlights the necessity for targeted antimicrobial strategies.

PMID:39824284 | DOI:10.1016/j.jgar.2025.01.002

BMC Med Educ. 2025 Jan 17;25(1):83. doi: 10.1186/s12909-024-06537-1.

ABSTRACT

BACKGROUND: Educational innovation in health professional education is needed to keep up with rapidly changing healthcare systems and societal needs. This study evaluates the implementation of PACE, an innovative curriculum designed by the physiotherapy department of the HAN University of Applied Sciences in The Netherlands. The PACE concept features an integrated approach to learning and assessment based on pre-set learning outcomes, personalized learning goals, flexible learning routes, and programmatic assessment. PACE distinguishes itself from traditional education because of the flexible learning routes, vertical organization in learning communities, absence of pre-defined learning activities and class schedules, and a culture of continuous learning and development. PACE is based on three guiding principles: 1) flexible and varied, 2) self-directed and collaborative, 3) future-oriented. PACE was implemented in 2021 for first-year students. This study evaluates the implementation to inform future curriculum development.

METHODS: A sequential explanatory mixed methods design was used to evaluate the implementation of PACE using a questionnaire, focus groups, in-depth interviews, and a national progress test allowing for benchmarking results. Participants were undergraduate physiotherapy students of cohort 2021-2022, the first group who experienced PACE and teachers involved with this cohort. Questionnaire data were analyzed using descriptive statistics. To compare mean total scores of the national progress test between four different universities a one-way ANOVA was conducted including a post-hoc analysis. Reflexive thematic analysis guidelines were applied to analyze the interview data.

RESULTS: In total 82 first year students (44,6%) of cohort 2021-2022 and 36 teachers (60%) completed the questionnaire. Results show that the guiding principles were implemented as intended. Results of the national progress test on knowledge and clinical reasoning showed that students of the HAN University performed well compared to other universities. Thematic analysis of interviews and focus groups resulted in three themes and nine subthemes: 1) navigating a personalized curriculum, 2) caring and sharing, and 3) shaping professional identity. PACE contributed positively to students' intrinsic motivation, learning joy, identity development, and life-long learning skills. Areas for improvement were self-directed learning support, and teaching strategies to prompt deep learning.

CONCLUSION: The evaluation showed that the guiding principles of PACE were implemented as intended and that the innovation positively contributed to student learning.

PMID:39825299 | DOI:10.1186/s12909-024-06537-1

BMC Bioinformatics. 2025 Jan 17;26(1):20. doi: 10.1186/s12859-024-06031-x.

NO ABSTRACT

PMID:39825265 | DOI:10.1186/s12859-024-06031-x

Nat Microbiol. 2025 Jan 17. doi: 10.1038/s41564-024-01907-3. Online ahead of print.

ABSTRACT

Artificial intelligence (AI) is a promising approach to identify new antimicrobial compounds in diverse microbial species. Here we developed an AI-based, explainable deep learning model, EvoGradient, that predicts the potency of antimicrobial peptides (AMPs) and virtually modifies peptide sequences to produce more potent AMPs, akin to in silico directed evolution. We applied this model to peptides encoded in low-abundance human oral bacteria, resulting in the virtual evolution of 32 peptides into potent AMPs. Of these, the 6 most effective were synthesized and tested against multidrug-resistant pathogens and demonstrated activity against carbapenem-resistant species Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii, and vancomycin-resistant Enterococcus faecium. The most potent AMP, pep-19-mod, was validated in vivo, achieving over 95% reduction in bacterial loads in mouse models of thigh infection through both systemic and local administration. Our approach advances the automatic identification and optimization of AMPs.

PMID:39825096 | DOI:10.1038/s41564-024-01907-3

Sci Rep. 2025 Jan 17;15(1):2341. doi: 10.1038/s41598-025-86327-x.

ABSTRACT

Complex structures can be understood as compositions of smaller, more basic elements. The characterization of these structures requires an analysis of their constituents and their spatial configuration. Examples can be found in systems as diverse as galaxies, alloys, living tissues, cells, and even nanoparticles. In the latter field, the most challenging examples are those of subdivided particles and particle-based materials, due to the close proximity of their constituents. The characterization of such nanostructured materials is typically conducted through the utilization of micrographs. Despite the importance of micrograph analysis, the extraction of quantitative data is often constrained. The presented effort demonstrates the morphological characterization of subdivided particles utilizing a pre-trained artificial intelligence model. The results are validated using three types of nanoparticles: nanospheres, dumbbells, and trimers. The automated segmentation of whole particles, as well as their individual subdivisions, is investigated using the Segment Anything Model, which is based on a pre-trained neural network. The subdivisions of the particles are organized into sets, which presents a novel approach in this field. These sets collate data derived from a large ensemble of specific particle domains indicating to which particle each subdomain belongs. The arrangement of subdivisions into sets to characterize complex nanoparticles expands the information gathered from microscopy analysis. The presented method, which employs a pre-trained deep learning model, outperforms traditional techniques by circumventing systemic errors and human bias. It can effectively automate the analysis of particles, thereby providing more accurate and efficient results.

PMID:39825089 | DOI:10.1038/s41598-025-86327-x

Int J Cardiovasc Imaging. 2025 Jan 18. doi: 10.1007/s10554-024-03307-4. Online ahead of print.

ABSTRACT

Computed tomography (CT)-derived Epicardial Adipose Tissue (EAT) is linked to cardiovascular disease outcomes. However, its role in patients undergoing Transcatheter Aortic Valve Replacement (TAVR) and the interplay with aortic stenosis (AS) cardiac damage (CD) remains unexplored. We aim to investigate the relationship between EAT characteristics, AS CD, and all-cause mortality. We retrospectively included consecutive patients who underwent CT-TAVR followed by TAVR. EAT volume and density were estimated using a deep-learning platform and CD was assessed using echocardiography. Patients were classified according to low/high EAT volume and density. All-cause mortality at 4 years was compared using Kaplan-Meier and Cox regression analyses. A total of 666 patients (median age 81 [74-86] years; 54% female) were included. After a median follow-up of 1.28 (IQR 0.53-2.57) years, 11.7% (n = 77) of patients died. The EAT volume (p = 0.017) decreased, and density increased (p < 0.001) with worsening AS CD. Patients with low EAT volume (< 49cm3) and high density (≥-86 HU) had higher all-cause mortality (log-rank p = 0.02 and p = 0.01, respectively), even when adjusted for age, sex, and clinical characteristics (HR 1.71, p = 0.02 and HR 1.73, p = 0.03, respectively). When CD was added to the model, low EAT volume (HR 1.67 p = 0.03) and CD stages 3 and 4 (HR 3.14, p = 0.03) remained associated with all-cause mortality. In patients with AS undergoing TAVR, CT-derived low EAT volume, and high density were independently associated with increased 4-year mortality and worse CD stage. Only EAT volume remained associated when adjusted for CD.

PMID:39825067 | DOI:10.1007/s10554-024-03307-4

Sci Rep. 2025 Jan 17;15(1):2293. doi: 10.1038/s41598-025-85338-y.

ABSTRACT

Interstitial lung disease (ILD) has shown limited treatment advancements, with minimal exploration of circulating protein biomarkers causally linked to ILD and its subtypes beyond idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify potential drug targets and circulating protein biomarkers for ILD and its subtypes. We utilized the most recent large-scale plasma protein quantitative trait loci (pQTL) data detected from the antibody-based method and ILD and its subtypes' GWAS data from the updated FinnGen database for Mendelian randomization analysis. To enhance the reliability of causal associations, we conducted external validation and sensitivity analyses, including Bayesian colocalization and bidirectional Mendelian randomization analysis. Our study identified eight plasma proteins genetically associated with ILD or its subtypes. Among these, three proteins-CDH15 (Cadherin-15), LTBR (Lymphotoxin-beta receptor), and ADAM15 (A disintegrin and metalloproteinase 15)-emerged as priority biomarkers and potential therapeutic targets, demonstrating more reliable associations by passing a series of sensitivity analyses compared to the others. Based on these findings, we propose for the first time that CDH15, ADAM15, and LTBR hold promise as novel potential circulating protein biomarkers and therapeutic targets for the diagnosis and treatment of ILD, IPF, and sarcoidosis, respectively, especially ADAM15, and these findings have the potential to provide new perspectives for advancing the research on the heterogeneity of ILD.

PMID:39824903 | DOI:10.1038/s41598-025-85338-y

Genome Med. 2025 Jan 17;17(1):5. doi: 10.1186/s13073-025-01432-w.

ABSTRACT

BACKGROUND: Despite extensive analysis, the dynamic changes in prostate epithelial cell states during tissue homeostasis as well as tumor initiation and progression have been poorly characterized. However, recent advances in single-cell RNA-sequencing (scRNA-seq) technology have greatly facilitated studies of cell states and plasticity in tissue maintenance and cancer, including in the prostate.

METHODS: We have performed meta-analyses of new and previously published scRNA-seq datasets for mouse and human prostate tissues to identify and compare cell populations across datasets in a uniform manner. Using random matrix theory to denoise datasets, we have established reference cell type classifications for the normal mouse and human prostate and have used optimal transport to compare the cross-species transcriptomic similarities of epithelial cell populations. In addition, we have integrated analyses of single-cell transcriptomic states with copy number variants to elucidate transcriptional programs in epithelial cells during human prostate cancer progression.

RESULTS: Our analyses demonstrate transcriptomic similarities between epithelial cell states in the normal prostate, in the regressed prostate after androgen-deprivation, and in primary prostate tumors. During regression in the mouse prostate, all epithelial cells shift their expression profiles toward a proximal periurethral (PrU) state, demonstrating an androgen-dependent plasticity that is restored to normal during androgen restoration and gland regeneration. In the human prostate, we find substantial rewiring of transcriptional programs across epithelial cell types in benign prostate hyperplasia and treatment-naïve prostate cancer. Notably, we detect copy number variants predominantly within luminal acinar cells in prostate tumors, suggesting a bias in their cell type of origin, as well as a larger field of transcriptomic alterations in non-tumor cells. Finally, we observe that luminal acinar tumor cells in treatment-naïve prostate cancer display heterogeneous androgen receptor (AR) signaling activity, including a split between AR-positive and AR-low profiles with similarity to PrU-like states.

CONCLUSIONS: Taken together, our analyses of cellular heterogeneity and plasticity provide important translational insights into the origin and treatment response of prostate cancer. In particular, the identification of AR-low tumor populations suggests that castration-resistance and predisposition to neuroendocrine differentiation may be pre-existing properties in treatment-naïve primary tumors that are selected for by androgen-deprivation therapies.

PMID:39825401 | DOI:10.1186/s13073-025-01432-w