Anal Methods. 2025 Jan 21. doi: 10.1039/d4ay01599a. Online ahead of print.

ABSTRACT

The study aims to evaluate and compare two advanced proteomic techniques, nanoLC-MALDI-MS/MS and nanoLC-TIMS-MS/MS, in characterizing extracellular vesicles (EVs) from the bronchoalveolar lavage fluid (BALF) of patients with asthma and idiopathic pulmonary fibrosis (IPF). Pulmonary diseases, driven by pollutants and infections, often necessitate detailed analysis of BALF to identify diagnostic biomarkers and therapeutic targets. EVs, which include exosomes, microvesicles, and apoptotic bodies, are isolated using filtration and ultracentrifugation, and their morphology, concentration, and size distribution are assessed through transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The proteomic profiles of these EVs are then analyzed using the aforementioned techniques, highlighting their unique and common proteins. The study found that nanoLC-TIMS-MS/MS identified significantly more proteins compared to nanoLC-MALDI-MS/MS. Functional analysis via Gene Ontology revealed pathways related to inflammation and cell signaling, underscoring the role of EVs in disease pathophysiology. The findings suggest that EVs in BALF can serve as valuable biomarkers and therapeutic targets in respiratory diseases, providing a foundation for future research and clinical applications.

PMID:39835386 | DOI:10.1039/d4ay01599a

Front Med (Lausanne). 2025 Jan 6;11:1497530. doi: 10.3389/fmed.2024.1497530. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic inflammation and progressive fibrosis. The blood urea nitrogen-to-albumin ratio (BAR) is a comprehensive parameter associated with inflammation status; however, it is unknown whether the BAR can predict the prognosis of IPF.

METHODS: This retrospective study included 176 patients with IPF, and 1-year all-cause mortality of these patients was recorded. A receiver operating characteristic (ROC) curve was used to explore the diagnostic value of BAR for 1-year all-cause mortality in IPF patients, and the survival rate was further estimated using the Kaplan-Meier survival curve. Cox proportional hazards regression model and forest plot were used to assess the association between the BAR and 1-year all-cause mortality in IPF patients.

RESULTS: The BAR of IPF patients was significantly higher in the non-survivor group than in the survivor group [0.16 (0.13-0.23) vs. 0.12 (0.09-0.17) mmol/g, p = 0.002]. The area under the ROC curve for predicting 1-year all-cause mortality in IPF patients was 0.671, and the optimal cut-off value was 0.12 mmol/g. The Kaplan-Meier survival curve showed that the 1-year cumulative survival rate of IPF patients with a BAR ≥0.12 was significantly decreased compared with the patients with a BAR <0.12. The Cox regression model and forest plot showed that the BAR was an independent prognostic biomarker for 1-year all-cause mortality in IPF patients (HR = 2.778, 95% CI 1.020-7.563, p = 0.046).

CONCLUSION: The BAR is a significant predictor of 1-year all-cause mortality of IPF patients, and high BAR values may indicate poor clinical outcomes.

PMID:39835108 | PMC:PMC11743257 | DOI:10.3389/fmed.2024.1497530

Front Immunol. 2025 Jan 6;15:1488745. doi: 10.3389/fimmu.2024.1488745. eCollection 2024.

ABSTRACT

INTRODUCTION: Serum levels of interleukin-6 (IL-6) are increased in COVID-19 patients. IL-6 is an effective therapeutic target in inflammatory diseases and tocilizumab, a monoclonal antibody that blocks signaling via the IL-6 receptor (IL-6R), is used to treat patients with severe COVID-19. However, the IL-6R exists in membrane-bound and soluble forms (sIL-6R), and the sIL-6R in combination with soluble glycoprotein 130 (sgp130) forms an IL-6-neutralizing buffer system capable of neutralizing small amounts of IL-6.

METHODS: In this study, we analyzed serum levels of IL-6, sIL-6R and sgp130 in the serum of COVID-19 convalescent individuals with a history of mild COVID-19 disease and in acute severely ill COVID-19 patients compared to uninfected control subjects. Furthermore, we used single cell RNA sequencing data in order to determine which immune cell types are sources and targets of the individual cytokines and whether their expression is altered in severe COVID-19 patients.

RESULTS: We find that sIL-6R levels are not only increased in acute severely ill patients, but also in convalescents after a mild COVID-19 infection. We show that this increase in sIL-6R results in an enhanced capacity of the sIL-6R/sgp130 buffer system, but that significantly enhanced free IL-6 is still present due to an overload of the buffer. Further, we identify IL-6 serum levels, age and the number of known pre-existing medical conditions as crucial determinants of disease outcome for the patients. We also show that IL-11 has no major systemic role in COVID-19 patients and that sCD25 is only increased in acute severely ill COVID-19 patients, but not in mild convalescent individuals.

DISCUSSION: In conclusion, our study shows long-lasting alterations of the IL-6 system after COVID-19 disease, which might be relevant when applying anti-IL-6 or anti-IL-6R therapy.

PMID:39835136 | PMC:PMC11743636 | DOI:10.3389/fimmu.2024.1488745

Front Immunol. 2025 Jan 6;15:1468969. doi: 10.3389/fimmu.2024.1468969. eCollection 2024.

ABSTRACT

INTRODUCTION: Extracellular vesicles (EVs) can potently inhibit inflammation yet there is a lack of understanding about the impact of donor characteristics on the efficacy of EVs. The goal of this study was to determine whether the sex and age of donor platelet-derived EVs (PEV) affected their ability to inhibit viral myocarditis.

METHODS: PEV, isolated from men and women of all ages, was compared to PEV obtained from women under 50 years of age, which we termed premenopausal PEV (pmPEV). Because of the protective effect of estrogen against myocardial inflammation, we hypothesized that pmPEV would be more effective than PEV at inhibiting myocarditis. We injected PEV, pmPEV, or vehicle control in a mouse model of viral myocarditis and examined histology, gene expression, protein profiles, and performed proteome and microRNA (miR) sequencing of EVs.

RESULTS: We found that both PEV and pmPEV significantly inhibited myocarditis; however, PEV was more effective, which was confirmed by a greater reduction of inflammatory cells and proinflammatory and profibrotic markers determined using gene expression and immunohistochemistry. Proteome and miR sequencing of EVs revealed that PEV miRs specifically targeted antiviral, Toll-like receptor (TLR)4, and inflammasome pathways known to contribute to myocarditis while pmPEV contained general immunoregulatory miRs.

DISCUSSION: These differences in EV content corresponded to the differing anti-inflammatory effects of the two types of EVs on viral myocarditis.

PMID:39835120 | PMC:PMC11743460 | DOI:10.3389/fimmu.2024.1468969

iScience. 2024 Dec 5;28(1):111546. doi: 10.1016/j.isci.2024.111546. eCollection 2025 Jan 17.

ABSTRACT

The genome of Methanocaldococcus (Methanococcus) jannaschii DSM 2661 was the first Archaeal genome to be sequenced in 1996. Subsequent sequence-based annotation cycles led to its first metabolic reconstruction in 2005. Leveraging new experimental results and function assignments, we have now re-annotated M. jannaschii, creating an updated resource with novel information and testable predictions in a pathway-genome database available at BioCyc.org. This reannotation effort has resulted in 652 function assignments with enzyme roles, accounting for a third of the total protein-coding entries for this genome. The updated resource includes 883 reactions, 540 enzymes, and 142 individual pathways. Despite notable progress in computational genomics, more than a third of the genome remains functionally uncharacterized. The publicly available MjCyc pathway-genome database holds great potential for the wider community to conduct research on the biology of methanogenic Archaea.

PMID:39834858 | PMC:PMC11742838 | DOI:10.1016/j.isci.2024.111546

iScience. 2024 Dec 15;28(1):111603. doi: 10.1016/j.isci.2024.111603. eCollection 2025 Jan 17.

ABSTRACT

Cdc25C undergoes a sudden and substantial gel mobility shift at M-phase onset, correlating with abrupt activation of both Cdc25C and Cdk1 activities. A positive feedback loop between Cdk1 and Cdc25C has been used to explain this hallmark phenomenon. Here, we demonstrate that the M-phase supershift and robust activation of Cdc25C are due to the site-comprehensive phosphorylation of its long intrinsically disordered regulatory domain without requiring Cdk1 or other major mitotic kinase activities. The phosphorylation process involves substrate-mediated assembly of phosphorylation machinery that catalyzes multisite phosphorylation continuously without substrate dissociation. In contrast to the site-comprehensive phosphorylation of Cdc25C occurring at M-phase onset, the site-specific phosphorylation of Cdc25C by Cdk1 or other major mitotic kinases generates slight gel mobility shifts and modest activation of Cdc25C prior to M-phase onset. These findings suggest a two-stage framework consisting of site-specific phosphorylation followed by site-comprehensive phosphorylation for Cdc25C regulation during M-phase induction.

PMID:39834856 | PMC:PMC11743101 | DOI:10.1016/j.isci.2024.111603

Front Pharmacol. 2025 Jan 6;15:1543291. doi: 10.3389/fphar.2024.1543291. eCollection 2024.

NO ABSTRACT

PMID:39834828 | PMC:PMC11743618 | DOI:10.3389/fphar.2024.1543291

Infect Drug Resist. 2025 Jan 16;18:307-311. doi: 10.2147/IDR.S501604. eCollection 2025.

ABSTRACT

The Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI) patients infected with methicillin-resistant Staphylococcus aureus (MRSA) urgently require safe and effective treatment options due to their compromised hepatic and renal functions, as well as thrombocytopenia resulting from hypersplenism. In our case, an HRS-AKI patient who underwent continuous renal replacement therapy for fluid overload developed fever with chills. His blood tests indicated elevated C-reactive protein and neutrophils, low platelet count, and bilateral lung infiltrates. Subsequently, his blood culture and catheter culture confirmed a catheter-related MRSA bloodstream infection. To address this complex clinical challenge, a novel oxazolidinone antibiotic, contezolid (800mg orally every 12 hours), was introduced into the patient's anti-infection regimen. Notably, the patient exhibited remarkable improvements and responded favorably to this treatment. During subsequent follow-up, no recurrence of the infection or drug-related adverse events was observed. The successful utilization of contezolid in this case underscores its potential as a novel therapeutic option for treating MRSA infections in patients with HRS-AKI.

PMID:39835163 | PMC:PMC11745060 | DOI:10.2147/IDR.S501604

Cureus. 2024 Dec 19;16(12):e76007. doi: 10.7759/cureus.76007. eCollection 2024 Dec.

ABSTRACT

Glucagon-like peptide-1 (GLP-1) receptor agonists, including tirzepatide (Mounjaro), are widely used to manage type 2 diabetes mellitus (T2DM) and obesity. While gastrointestinal side effects are common, acute pancreatitis remains a rare but significant complication. Limited evidence exists on the risks associated with switching between GLP-1 agonists, emphasizing the need for clinical awareness. We present a 59-year-old male with T2DM, hyperlipidemia, and hypertension, who was recently transitioned from semaglutide (Ozempic) to tirzepatide (Mounjaro). He presented with acute epigastric pain, nausea, and vomiting two days after initiating tirzepatide. Laboratory findings revealed elevated lipase levels (847 U/L), leukocytosis, and diagnostic imaging confirming acute pancreatitis with other causes ruled out. Supportive care improved symptoms initially, but the clinical course was complicated by fevers prompting repeat imaging, revealing worsening pancreatitis with colonic involvement and pleural effusion. The patient was treated with empiric antibiotics and supportive measures, resulting in resolution of symptoms. Tirzepatide was discontinued, with a follow-up arranged for glycemic management. Acute pancreatitis is a rare but documented adverse effect of GLP-1 agonists, with limited cases reported in the literature. Switching between GLP-1 agonists may increase the risk of adverse effects, especially if appropriate dose titration protocols are not followed. This case highlights the recognition of acute pancreatitis as a potential adverse effect of GLP-1 agonists when initiating or transitioning GLP-1 therapies and following titration protocols to help avoid this complication. GLP-1 agonists, including tirzepatide, offer significant therapeutic benefits for T2DM and obesity but carry risks of rare adverse effects like acute pancreatitis. Greater awareness, careful dose adjustments, and vigilant monitoring are essential to optimizing patient safety. Further research is needed to elucidate the safety profile of switching between GLP-1 agonists to guide clinical practice and improve patient outcomes.

PMID:39834977 | PMC:PMC11743417 | DOI:10.7759/cureus.76007

Front Pharmacol. 2025 Jan 6;15:1466875. doi: 10.3389/fphar.2024.1466875. eCollection 2024.

ABSTRACT

BACKGROUND: Urinary retention (UR) is a clinical condition where patients cannot fully empty their bladder. Although numerous drugs are associated with UR, comprehensive and reliable studies identifying drugs that induce UR are scarce.

METHODS: This study leveraged data from the FDA Adverse Event Reporting System (FAERS) and the Canadian Vigilance Adverse Reaction (CVAR) database to explore adverse events (AEs) related to UR from 2004 to Q1 2024. The top 50 drugs were analyzed for annual reporting trends using linear regression. Disproportionality analysis using the reporting odds ratio (ROR) method, with P-values adjusted via Bonferroni correction, identified significant signals, which were then validated against drug labels and re-evaluated using the CVAR database. Time-to-onset analysis was also performed.

RESULTS: From 2004 to Q1 2024, FAERS recorded 17,785,793 AEs, with 16,183 (0.09%) identified as UR cases. The median age among these cases was 65 years, with males comprising 53.4%. There were significant annual increases in UR reports associated with antineoplastic agents (0.19% per year) and antidiabetic drugs (0.09% per year), while reports linked to bronchodilators decreased (-0.53% per year). Disproportionality analysis revealed significant signals for 34 drugs (68%), with the highest RORs observed in Fesoterodine, Mirabegron, and Solifenacin. Initial signal detection identified potential new UR signals for Abiraterone, Valacyclovir, Fluoxetine, Empagliflozin, Clopidogrel, and Amlodipine, with CVAR confirming signals for Abiraterone, Fluoxetine, and Empagliflozin. The median time to onset of UR was 29 days, with over half of the cases occurring within 30 days of initiating medication.

CONCLUSION: The study identifies a rising trend in drug-related UR reports over the past 2 decades. The validation of new signals for Abiraterone, Fluoxetine, and Empagliflozin underscores the critical need for continuous drug safety monitoring and targeted research to better understand the mechanisms behind drug-induced UR.

PMID:39834827 | PMC:PMC11744018 | DOI:10.3389/fphar.2024.1466875

Respir Med Case Rep. 2024 Dec 27;53:102160. doi: 10.1016/j.rmcr.2024.102160. eCollection 2025.

ABSTRACT

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK TKIs) show robust efficacy and has revolutionized the treatment of NSCLC patients harboring an ALK-rearrangement. Side effects, sometimes even serious such as pneumonitis, can occur with ALK TKIs. We report a case of a patient with ALK positive advanced NSCLC who developed pneumonitis during treatment with first-line alectinib. With no alternative etiology of pneumonitis identified, the patient was treated with corticosteroids and discontinuation of alectinib. Following rapid clinical recovery and radiographic resolution of the opacities, the patient was started with brigatinib, with no recurrence of the clinical symptoms or radiographic findings of pneumonitis. While further descriptions are needed, our experience suggests that switching to a second ALK-TKI may be a safe therapeutic option in some patients who develop drug-induced pneumonitis on ALK TKIs.

PMID:39834688 | PMC:PMC11743586 | DOI:10.1016/j.rmcr.2024.102160

Heliyon. 2024 Dec 25;11(1):e41483. doi: 10.1016/j.heliyon.2024.e41483. eCollection 2025 Jan 15.

ABSTRACT

Cisplatin (CDDP) is one of the main chemotherapeutic drugs that is widely used in many cancers. However, CDDP resistance is a frequent therapeutic challenge that reduces prognosis in cancer patients. Since, CDDP has noticeable side effects in normal tissues and organs, it is necessary to assess the molecular mechanisms associated with CDDP resistance to improve the therapeutic methods in cancer patients. Drug efflux, detoxifying systems, DNA repair mechanisms, and drug-induced apoptosis are involved in multidrug resistance in CDDP-resistant tumor cells. Mammalian target of rapamycin (mTOR), as a serine/threonine kinase has a pivotal role in various cellular mechanisms such as autophagy, metabolism, drug efflux, and cell proliferation. Although, mTOR is mainly activated by PI3K/AKT pathway, it can also be regulated by many other signaling pathways. PI3K/Akt/mTOR axis functions as a key modulator of drug resistance and unfavorable prognosis in different cancers. Regarding, the pivotal role of mTOR in CDDP response, in the present review we discussed the molecular mechanisms that regulate mTOR mediated CDDP response in tumor cells.

PMID:39834411 | PMC:PMC11743095 | DOI:10.1016/j.heliyon.2024.e41483

Psychiatry Clin Neurosci. 2025 Jan 21. doi: 10.1111/pcn.13785. Online ahead of print.

ABSTRACT

AIM: This study aimed to explore the comparative risks for dystonia among different second-generation antipsychotics (SGAs), the influence of sex, and the relationship between the time-to-onset of dystonia and its outcomes.

METHODS: We analyzed data from the Japanese Adverse Drug Event Report database from April 2004 to November 2023. Cases involving oral SGAs, excluding clozapine, were extracted. We used the odds ratios to assess the reporting proportions among SGAs and sex, analyzed the median time-to-onset and interquartile ranges (IQRs), and conducted a receiver operating characteristic (ROC) curve analysis to investigate the time-to-onset of dystonia and its relationship to outcomes.

RESULTS: We extracted 9837 cases involving oral SGAs. Lurasidone was associated with a significantly higher proportion of dystonia reports than risperidone, aripiprazole, quetiapine, and olanzapine. The reporting proportion of dystonia associated with aripiprazole was lower than that of paliperidone and risperidone, but higher than that of quetiapine and olanzapine. Female sex was significantly associated with a higher reporting proportion of dystonia compared with males. Among the 148 cases of oral SGA-induced dystonia, the median time-to-onset was 125 days (IQR, 19.75-453.25 days). Divided into the three outcome groups (recovered, improved, and unrecovered/residual), those with better outcomes had a shorter time-to-onset than those with poorer outcomes. ROC curve analysis suggested a threshold of 91.5 days for discriminating outcomes, with a sensitivity of 71.7% and specificity of 69.9%.

CONCLUSIONS: The risks of dystonia may vary among SGAs and between sexes. SGA-induced dystonia often manifests in the tardive form.

PMID:39834274 | DOI:10.1111/pcn.13785

bioRxiv [Preprint]. 2025 Jan 7:2025.01.07.631715. doi: 10.1101/2025.01.07.631715.

ABSTRACT

WNT2B is Wnt ligand which is able to support intestinal stem cells (ISC) in culture and support the intestinal epithelium in vivo. We have previously shown that WNT2B is critical for resistance to colitis, but not small intestinal injury, in the adult mouse. WNT2B is thought to coordinate with WNT3 in supporting ISC, and we have also shown that WNT3 expression is low in the early postnatal ileum in mice. Here, we hypothesized that WNT2B may be more critical in the small intestine during early development, and we challenged Wnt2b KO mice and controls with experimental necrotizing enterocolitis (NEC) on postnatal days 5-8. Wnt2b KO mice had similar ileum histology and injury scores to control mice. Molecular analyses showed that Wnt2b KO mice have differences in Lgr5 and Tlr4 expression compared to wild type controls in untreated conditions, but under experimental NEC expression of epithelial markers and inflammatory genes associated with NEC were similar to wild type. Periodic acid Schiff positive cells were lower in the villi of Wnt2b KO mice during NEC, however expression of goblet cell markers was not different compared to wild type mice. We also used an organoid-based NEC model to highlight the epithelium in isolation and also found no impact of WNT2B KO in the setting of NEC. These data further affirm that WNT2B is critical for inflammation responses in the mouse colon, but does not appear to play a major role in the small intestine, no matter the developmental period.

PMID:39829885 | PMC:PMC11741354 | DOI:10.1101/2025.01.07.631715

Nat Neurosci. 2025 Jan 20. doi: 10.1038/s41593-024-01834-w. Online ahead of print.

ABSTRACT

Psychiatric disorders are multifactorial and effective treatments are lacking. Probable contributing factors to the challenges in therapeutic development include the complexity of the human brain and the high polygenicity of psychiatric disorders. Combining well-powered genome-wide and brain-wide genetics and transcriptomics analyses can deepen our understanding of the etiology of psychiatric disorders. Here, we leverage two landmark resources to infer the cell types involved in the etiology of schizophrenia, other psychiatric disorders and informative comparison of brain phenotypes. We found both cortical and subcortical neuronal associations for schizophrenia, bipolar disorder and depression. These cell types included somatostatin interneurons, excitatory neurons from the retrosplenial cortex and eccentric medium spiny-like neurons from the amygdala. In contrast we found T cell and B cell associations with multiple sclerosis and microglial associations with Alzheimer's disease. We provide a framework for a cell-type-based classification system that can lead to drug repurposing or development opportunities and personalized treatments. This work formalizes a data-driven, cellular and molecular model of complex brain disorders.

PMID:39833308 | DOI:10.1038/s41593-024-01834-w

Sci Rep. 2025 Jan 20;15(1):2581. doi: 10.1038/s41598-024-79377-0.

ABSTRACT

Human organic cation transporter 2 (hOCT2/SLC22A2) is a key drug transporter that facilitates the transport of endogenous and exogenous organic cations. Because hOCT2 is responsible for the development of adverse effects caused by platinum-based anti-cancer agents, drugs with OCT2 inhibitory effects may serve as prophylactic agents against the toxicity of platinum-based anti-cancer agents. In the present study, we established a machine learning-based quantitative structure-activity relationship (QSAR) model for hOCT2 inhibitors based on the public ChEMBL database and explored novel hOCT2 inhibitors among the FDA-approved drugs. Using our QSAR model, we identified 162 candidate hOCT2 inhibitors among the FDA-approved drugs registered in the DrugBank database. After manual selection and in vitro assays, we found that dequalinium, a quaternary ammonium cation antimicrobial agent, is a potent hOCT2 inhibitor (IC50 = 88.16 ± 7.14 nM). Moreover, dequalinium inhibited hOCT2-mediated transport of platinum anti-cancer agents (cisplatin and oxaliplatin) in a concentration-dependent manner. Our study is the first to demonstrate the construction of a novel machine learning-based QSAR model for hOCT2 inhibitors and identify a novel hOCT2 inhibitor among FDA-approved drugs using this model.

PMID:39833227 | DOI:10.1038/s41598-024-79377-0

J Transl Med. 2025 Jan 20;23(1):86. doi: 10.1186/s12967-025-06069-2.

ABSTRACT

BACKGROUND: Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program.

METHODS: Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization. This strategy was applied to 6500 individuals including 6267 index patients and 233 NGS-based carrier screenings.

RESULTS: Causative variants were identified in 2061 index patients (average 32.9%, ranging from 12 to 62% by condition). Also, 131 autosomal-recessive cases could be partially genetically diagnosed. These results led to over 5000 additional studies including carrier, prenatal and preimplantational tests or pharmacological and gene therapy treatments.

CONCLUSION: This strategy has shown promising improvements in the diagnostic rate, facilitating timely diagnosis and gradually expanding our services portfolio for rare diseases. The steps taken towards the integration of clinical and genomic data are opening new possibilities for conducting both retrospective and prospective healthcare studies. Overall, this study represents a major milestone in the ongoing efforts to improve our understanding and clinical management of rare diseases, a crucial area of medical research and care.

PMID:39833864 | DOI:10.1186/s12967-025-06069-2

Genome Med. 2025 Jan 20;17(1):7. doi: 10.1186/s13073-025-01431-x.

ABSTRACT

BACKGROUND: Large-scale pharmacogenomic resources, such as the Connectivity Map (CMap), have greatly assisted computational drug discovery. However, despite their widespread use, CMap-based methods have thus far been agnostic to the biological activity of drugs as well as to the genomic effects of drugs in multiple disease contexts. Here, we present a network-based statistical approach, Pathopticon, that uses CMap to build cell type-specific gene-drug perturbation networks and integrates these networks with cheminformatic data and diverse disease phenotypes to prioritize drugs in a cell type-dependent manner.

METHODS: We build cell type-specific gene-drug perturbation networks from CMap data using a statistical procedure we call Quantile-based Instance Z-score Consensus (QUIZ-C). Using these networks and a large-scale disease-gene network consisting of 569 disease signatures from the Enrichr database, we calculate Pathophenotypic Congruity Scores (PACOS) between input gene signatures and drug perturbation signatures and combine these scores with cheminformatic data from ChEMBL to prioritize drugs. We benchmark our approach by calculating area under the receiver operating characteristic curves (AUROC) for 73 gene sets from the Molecular Signatures Database (MSigDB) using target gene expression profiles from the Comparative Toxicogenomics Database (CTD). We validate the drugs predicted in our proofs-of-concept using real-time polymerase chain reaction (qPCR) experiments.

RESULTS: Cell type-specific gene-drug perturbation networks built using QUIZ-C are topologically distinct, reflecting the biological uniqueness of the cell lines in CMap, and are enriched in known drug targets. Pathopticon demonstrates a better prediction performance than solely cheminformatic measures as well as state-of-the-art network and deep learning-based methods. Top predictions made by Pathopticon have high chemical structural diversity, suggesting their potential for building compound libraries. In proof-of-concept applications on vascular diseases, we demonstrate that Pathopticon helps guide in vitro experiments by identifying pathways that are potentially regulated by the predicted therapeutic candidates.

CONCLUSIONS: Our network-based analytical framework integrating pharmacogenomics and cheminformatics (available at https://github.com/r-duh/Pathopticon ) provides a feasible blueprint for a cell type-specific drug discovery and repositioning platform with broad implications for the efficiency and success of drug development.

PMID:39833831 | DOI:10.1186/s13073-025-01431-x

Cell Death Differ. 2025 Jan 20. doi: 10.1038/s41418-024-01430-2. Online ahead of print.

ABSTRACT

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.

PMID:39833374 | DOI:10.1038/s41418-024-01430-2

BMJ Open Respir Res. 2025 Jan 19;12(1):e002960. doi: 10.1136/bmjresp-2024-002960.

ABSTRACT

BACKGROUND: The most common cause of death in those with cystic fibrosis (CF) is respiratory failure due to bronchiectasis resulting from repeated cycles of respiratory infection and inflammation. Protease-activated receptor 1 (PAR1) is a cell surface receptor activated by serine proteases including neutrophil elastase, which is recognised as a potent modulator of inflammation. While PAR1 is known to play an important role in regulating inflammation, nothing is known about any potential role of this receptor in CF pathogenesis.

METHODS: PAR1 (PAR1-/- ) and intestinal-corrected CFTR (Cftr-/- ) deficient mice were crossed to generate double knock-out (DKO) mutants lacking both PAR1 and CFTR, as well as matching sibling single mutant and wildtype (WT) littermate controls. Mice were weighed weekly to 15 weeks of age; then, the lungs and intestines were examined.

RESULTS: Cftr-deficient mice gained body weight at a significantly slower rate than WT controls and presented with no lung inflammation, but had increased weights of their ilea and proximal colons. DKO mice (lacking both CFTR and PAR1) gained body weight at a similar rate to Cftr-/- mice but only gained weight in their proximal colons. Weight gain in the ilea of Cftr-/- but not DKO mice was associated with increased ileal levels in the pro-inflammatory cytokine interleukin (IL)-6.

CONCLUSIONS: This study provides the first evidence of PAR1 contributing to the pathological effects of Cftr deficiency in the intestine and suggests a possible effect of PAR1 on the regulation of IL-6 in CF pathogenesis.

PMID:39832889 | DOI:10.1136/bmjresp-2024-002960