JAMA. 2025 Apr 28. doi: 10.1001/jama.2025.2680. Online ahead of print.

ABSTRACT

IMPORTANCE: Non-cystic fibrosis (CF) bronchiectasis is a chronic lung condition caused by permanent bronchial dilatation and inflammation and is characterized by daily cough, sputum, and recurrent exacerbations. Approximately 500 000 people in the US have non-CF bronchiectasis.

OBSERVATIONS: Non-CF bronchiectasis may be associated with prior pneumonia, infection with nontuberculous mycobacteria or tuberculosis, genetic conditions (eg, α1-antitrypsin deficiency, primary ciliary dyskinesia), autoimmune diseases (eg, rheumatoid arthritis, inflammatory bowel disease), allergic bronchopulmonary aspergillosis, and immunodeficiency syndromes (eg, common variable immunodeficiency). Up to 38% of cases are idiopathic. According to US data, conditions associated with non-CF bronchiectasis include gastroesophageal reflux disease (47%), asthma (29%), and chronic obstructive pulmonary disease (20%). The prevalence of non-CF bronchiectasis increases substantially with age (7 per 100 000 in individuals 18-34 years vs 812 per 100 000 in those ≥75 years) and is more common in women than men (180 vs 95 per 100 000). Diagnosis is confirmed with noncontrast chest computed tomography showing dilated airways and often airway thickening and mucus plugging. Initial diagnostic evaluation involves blood testing (complete blood cell count with differential); immunoglobulin quantification testing (IgG, IgA, IgE, and IgM); sputum cultures for bacteria, mycobacteria, and fungi; and prebronchodilator and postbronchodilator spirometry. Treatment includes airway clearance techniques; nebulization of saline to loosen tenacious secretions; and regular exercise, participation in pulmonary rehabilitation, or both. Inhaled bronchodilators (β-agonists and antimuscarinic agents) and inhaled corticosteroids are indicated for patients with bronchiectasis who have asthma or chronic obstructive pulmonary disease. Exacerbations of bronchiectasis, which typically present with increased cough and sputum and worsened fatigue, are associated with progressive decline in lung function and decreased quality of life. Exacerbations should be treated with oral or intravenous antibiotics. Individuals with 3 or more exacerbations of bronchiectasis annually may benefit from long-term inhaled antibiotics (eg, colistin, gentamicin) or daily oral macrolides (eg, azithromycin). Lung transplant may be considered for patients with severely impaired pulmonary function, frequent exacerbations, or both. Among patients with non-CF bronchiectasis, mortality is higher for those with frequent and severe exacerbations, infection with Pseudomonas aeruginosa, and comorbidities, such as chronic obstructive pulmonary disease.

CONCLUSIONS AND RELEVANCE: Non-CF bronchiectasis is a chronic lung condition that typically causes chronic cough and daily sputum production. Exacerbations are associated with progressive decline in lung function and decreased quality of life. Management involves treatment of conditions associated with bronchiectasis, airway clearance techniques, oral or intravenous antibiotics for acute exacerbations, and consideration of long-term inhaled antibiotics or oral macrolides for patients with 3 or more exacerbations annually.

PMID:40293759 | DOI:10.1001/jama.2025.2680

J Inflamm Res. 2025 Apr 23;18:5499-5517. doi: 10.2147/JIR.S505229. eCollection 2025.

ABSTRACT

AIM: To identify the molecular signature of differentially expressed genes (DEGs) associated with PANoptosis in idiopathic pulmonary fibrosis (IPF) and to interpret their immune landscape and cellular distribution characteristics.

METHODS AND RESULTS: We acquired two IPF datasets from the Gene Expression Omnibus (GEO) database to identify PANoptosis-related DGEs (PAN-DEGs), initially identifying thirty PAN-DEGs. Utilizing machine learning algorithms, we established a five-gene PANoptosis-related signature comprising IGF1, GPX3, GADD45β, SMAD7, and TIMP3, each demonstrating robust diagnostic performance. The expression of these hub genes was subsequently validated using a third GEO dataset and a bleomycin-induced pulmonary fibrosis model. Immune infiltration analysis revealed a close association of these genes with various immune cells, and single-cell RNA sequencing indicated significant expression changes in diverse pulmonary cell types, particularly endothelial cells and fibroblasts.

CONCLUSION: We identified and validated a PANoptosis-related gene signature in IPF, providing insights into their immune infiltration and potential cellular distribution. Further research is necessary to elucidate the biological functions and mechanisms of these genes in the pathogenesis of IPF.

PMID:40291456 | PMC:PMC12034268 | DOI:10.2147/JIR.S505229

Toxicol Res. 2024 Dec 28;41(3):235-244. doi: 10.1007/s43188-024-00269-6. eCollection 2025 May.

ABSTRACT

Protein kinase B (PKB/AKT) is a very important member of the protein kinase family, playing significant roles in various crucial processes including insulin-signaling, cell survival, growth, and metabolism. The carboxyl-terminal modulator protein 1 (CTMP1) inhibits PKB, primarily by attenuating its phosphorylation. Idiopathic pulmonary fibrosis (IPF) is an irreversible, chronic, progressive pulmonary disorder; the clinical treatment options are limited. Of the various experimental models, bleomycin-induced lung fibrosis is the most extensively studied. It closely resembles human lung fibrosis. We explored the impact of CTMP1 on bleomycin-induced fibrosis. In vitro experiments involved knockdown of CTMP1 in A549 cells (human alveolar epithelial cells), followed by bleomycin treatment. In vivo, lung fibrosis was induced in mice with ablated CTMP1 via intratracheal bleomycin administration at 2 mg/kg. CTMP1 deletion reduced pulmonary fibrosis and the epithelial-to-mesenchymal transition by inhibiting PKB phosphorylation. These findings suggest that CTMP1 plays a pivotal role in the regulation of lung fibrosis, offering new insights into potential therapeutic approaches for IPF patients.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43188-024-00269-6.

PMID:40291111 | PMC:PMC12021751 | DOI:10.1007/s43188-024-00269-6

Front Med (Lausanne). 2025 Apr 11;12:1526530. doi: 10.3389/fmed.2025.1526530. eCollection 2025.

ABSTRACT

BACKGROUND: For patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) with a progressive pulmonary fibrosis (PPF) phenotype, current knowledge of patient experience and symptom burden is limited. This study aimed to describe the patient journey for patients with PPF and IPF in a real-world setting in Japan.

METHODS: Data were analyzed from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey with elements of retrospective data collection of pulmonologists and rheumatologists in Japan from April to October 2022. Participants provided data for up to 12 consecutive patients with physician-confirmed ILD with a progressive phenotype. Analyses were descriptive, except Kappa (κ) statistic was used to measure the alignment between physician- and patient-reported symptom burden in the 4 weeks prior to survey date (poor agreement: κ =<0.00; slight 0.00-0.20; fair 0.21-0.40; moderate 0.41-0.60; substantial 0.61-0.80; almost perfect 1.00).

RESULTS: A total of 63 physicians (43 pulmonologists and 20 rheumatologists) provided data on 382 patients (312 with PPF and 70 with IPF). These patients were also asked to complete a voluntary survey on their experience and symptoms. Mean time from first symptom to consultation was 14.1 months for IPF, 8.0 months for non-connective tissue disease (CTD)-associated ILDs, and 10.7 months for CTD-ILDs. Mean times from consultation to diagnosis were 7.1, 4.8, and 3.6 months, respectively. Perception of symptoms differed between physicians and patients with alignment ranging from poor (dysphagia, κ = -0.0296, p = 0.6217) to substantial (weight loss, κ = 0.6174, p = 0.001). Health-related quality of life (HRQoL) was consistently impaired in patients overall, but too few patients completed HRQoL instruments to compare IPF with other forms of ILD.

CONCLUSIONS: This real-world study expands our understanding of the patient journey for patients with PPF and IPF in Japan. Greater communication between patients and physicians is needed to shorten diagnostic delays and target treatment strategies to improve patient experience and overall outcomes.

PMID:40291022 | PMC:PMC12023007 | DOI:10.3389/fmed.2025.1526530

J Med Internet Res. 2025 Apr 28;27:e66231. doi: 10.2196/66231.

ABSTRACT

BACKGROUND: A substantially lower proportion of female individuals participate in sufficient daily activity compared to male individuals despite the known health benefits of exercise. Investment in female sports and exercise medicine research may help close this gap; however, female individuals are underrepresented in this research. Hesitancy to include female participants is partly due to assumptions that biological rhythms driven by menstrual cycles and occurring on the timescale of approximately 28 days increase intraindividual biological variability and weaken statistical power. An analysis of continuous skin temperature data measured using a commercial wearable device found that temperature cycles indicative of menstrual cycles did not substantially increase variability in female individuals' skin temperature. In this study, we explore physical activity (PA) data as a variable more related to behavior, whereas temperature is more reflective of physiological changes.

OBJECTIVE: We aimed to determine whether intraindividual variability of PA is affected by biological sex, and if so, whether having menstrual cycles (as indicated by temperature rhythms) contributes to increased female intraindividual PA variability. We then sought to compare the effect of sex and menstrual cycles on PA variability to the effect of PA rhythms on the timescales of days and weeks and to the effect of nonrhythmic temporal structure in PA on the timescale of decades of life (age).

METHODS: We used minute-level metabolic equivalent of task data collected using a wearable device across a 206-day study period for each of 596 individuals as an index of PA to assess the magnitudes of variability in PA accounted for by biological sex and temporal structure on different timescales. Intraindividual variability in PA was represented by the consecutive disparity index.

RESULTS: Female individuals (regardless of whether they had menstrual cycles) demonstrated lower intraindividual variability in PA than male individuals (Kruskal-Wallis H=29.51; P<.001). Furthermore, individuals with menstrual cycles did not have greater intraindividual variability than those without menstrual cycles (Kruskal-Wallis H=0.54; P=.46). PA rhythms differed at the weekly timescale: individuals with increased or decreased PA on weekends had larger intraindividual variability (Kruskal-Wallis H=10.13; P=.001). In addition, intraindividual variability differed by decade of life, with older age groups tending to have less variability in PA (Kruskal-Wallis H=40.55; P<.001; Bonferroni-corrected significance threshold for 15 comparisons: P=.003). A generalized additive model predicting the consecutive disparity index of 24-hour metabolic equivalent of task sums (intraindividual variability of PA) showed that sex, age, and weekly rhythm accounted for only 11% of the population variability in intraindividual PA variability.

CONCLUSIONS: The exclusion of people from PA research based on their biological sex, age, the presence of menstrual cycles, or the presence of weekly rhythms in PA is not supported by our analysis.

PMID:40293784 | DOI:10.2196/66231

Synth Syst Biotechnol. 2025 Apr 8;10(3):827-834. doi: 10.1016/j.synbio.2025.03.011. eCollection 2025 Sep.

ABSTRACT

Synthetic RNA-based switches provide distinctive merits in modulating gene expression. Simple and flexible RNA-based switches are crucial for advancing the field of gene regulation, paving the way for innovative tools that can sense and manipulate cellular processes. In this research, we have developed programmable ribozymes that are capable of suppressing gene expression in response to specific, endogenously expressed trigger RNAs. We engineer ribozymes by introducing upstream antisense sequences (anti-ribozymes) to inhibit the self-cleaving activity of the hammerhead ribozyme and open the expression of the target gene. The trigger RNA is designed to recognize and bind to complementary sequences within the anti-ribozymes, thereby inhibiting their ability to direct protein synthesis. The anti-ribozyme performance is optimized by regulating the essential sequence modules that play a crucial role in determining the specificity and efficiency of the anti-ribozyme's interaction with its trigger RNA. By applying this switch mechanism to various ribozyme designs, we have shown that it is possible to achieve control over gene expression across a wide range of trigger RNAs. By exploiting these programmable anti-ribozymes, we aim to create a powerful tool for controlling gene expression in mammalian cells, which could have important implications for basic research, disease diagnosis, and therapeutic interventions.

PMID:40291978 | PMC:PMC12033390 | DOI:10.1016/j.synbio.2025.03.011

F1000Res. 2024 Sep 5;13:792. doi: 10.12688/f1000research.153244.2. eCollection 2024.

ABSTRACT

Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-coupled protein receptor that induces crucial biological processes when bound by sphingosine 1-phosphate. Here, we have characterized nine S1PR1 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

PMID:40291769 | PMC:PMC12022542 | DOI:10.12688/f1000research.153244.2

ACS Omega. 2025 Apr 8;10(15):15204-15218. doi: 10.1021/acsomega.4c10939. eCollection 2025 Apr 22.

ABSTRACT

Selective serotonin reuptake inhibitors (SSRIs) are known to have anticancer activity against different types of cancer. In this study, an integrative informatics approach was applied to identify compound and genetic perturbations that produce similar effects to SSRIs to formulate systems biology hypotheses and identify biological pathways involved in the putative anticancer effects of SSRIs in prostate cancer. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay assessed the antiproliferative effects of SSRIs and drug combinations. Cell death mechanisms were studied using annexin V-FITC/PI staining, and the cell cycle analysis was carried out by counterstaining with propidium iodide. Relative gene expression was assessed using a real-time polymerase chain reaction (PCR). Computational results hypothesized that SSRIs could potentially exert anticancer effects in prostate cancer cell lines by modulating apoptotic and tumorigenesis pathways and significantly inhibiting the growth of prostate cancer cells in a time and concentration-dependent manner. The combination of SSRIs with cisplatin, 5-fluorouracil, and raloxifene resulted in either synergistic or additive effects. SSRIs resulted in a significant increase in the early and late apoptotic activity in PC3 cells. Dapoxetine, paroxetine, and sertraline resulted in cell cycle arrest at the G0/G1 phase. Treatment with either dapoxetine or paroxetine decreases the expression of Bcl-2, CASP8, DR5, and VEGF. At the same time, sertraline decreases the expression of Bcl-2 and VEGF and increases the expression of CASP8 and DR5. Results revealed that SSRIs can potentially act as antiproliferative agents against prostate cancer cells, and their activity is mediated through different signaling pathways.

PMID:40290959 | PMC:PMC12019733 | DOI:10.1021/acsomega.4c10939

JHEP Rep. 2025 Jan 30;7(5):101340. doi: 10.1016/j.jhepr.2025.101340. eCollection 2025 May.

ABSTRACT

BACKGROUND & AIMS: Actionable candidates of hepatocarcinogenesis remain elusive, and tools for early detection are suboptimal. Our aim was to demonstrate that serum metabolome profiles reflect the initiation of hepatocellular carcinoma (HCC) and enable the identification of biomarkers for early HCC detection and actionable candidates for chemoprevention.

METHODS: This global cohort study included 654 patients and 801 biospecimens. Following serum metabolome profiling across the spectrum of hepatocarcinogenesis, we conducted a phase II biomarker case-control study for early HCC detection. Findings were independently validated through in silico analysis, mRNA sequencing, and proteome profiling of primary HCC and non-tumoral tissue, and in vitro experiments.

RESULTS: Aspartic acid, glutamic acid, taurine, and hypoxanthine were differentially abundant in the serum across chronic liver disease, cirrhosis, initial HCC, and progressed HCC, independent of sex, age, and etiology. In a phase II biomarker case-control study, a blood-based metabolite signature yielded an AUC of 94% to discriminate between patients with early-stage HCC and controls with cirrhosis, including independent validation. Unsupervised biclustering (MoSBi), lipid network analysis (LINEX2), and pathway enrichment analysis confirmed alterations in amino acid-, lipid-, and nucleotide-related pathways. In tumor tissue, these pathways were significantly deregulated regarding gene and protein expression in two independent datasets, including actionable targets RRM2, GMPS, BCAT1, PYCR2, and NEU1. In vitro knockdown confirmed a functional role in proliferation and migration, as exemplified for PYCR2.

CONCLUSIONS: These findings demonstrate that serum metabolome profiling indicates deregulated metabolites and pathways during hepatocarcinogenesis. Our liquid biopsy approach accurately detects early-stage HCC outperforming currently recommended surveillance tools and facilitates identification of actionable candidates for chemoprevention.

IMPACT AND IMPLICATIONS: Deregulated cellular metabolism is a hallmark of cancer. In smaller studies, circulating metabolite profiles have been associated with HCC, although mainly in the context of fatty liver disease. Translation strategies for primary prevention or early detection are lacking. In this global study, we present an unsupervised landscape of the altered serum metabolome profile during hepatocarcinogenesis, independent of age, sex, and etiology. We provide a blood-based metabolite signature that accurately identifies early-stage HCC in a phase II biomarker study including independent validation. Further RRM2, GMPS, BCAT1, PYCR2, and NEU1 are identified in tumor tissue as actionable candidates for prevention. Our data provide the rationale for clinical trials testing liquid biopsy metabolome-based signatures for early HCC detection and the development of chemoprevention strategies.

PMID:40290517 | PMC:PMC12023797 | DOI:10.1016/j.jhepr.2025.101340

N Engl J Med. 2025 Apr 28. doi: 10.1056/NEJMoa2503704. Online ahead of print.

ABSTRACT

BACKGROUND: Innovative oral targeted therapies are warranted for patients with human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible, HER2-selective tyrosine kinase inhibitor that has been shown to have efficacy in persons with advanced or metastatic solid tumors with HER2 alterations in a phase 1 study.

METHODS: We evaluated zongertinib in a multicohort, phase 1a-1b trial involving patients with advanced or metastatic HER2-mutant NSCLC. Here we report the primary analysis of zongertinib in previously treated patients: those with tumors harboring a mutation in the tyrosine kinase domain (cohort 1), those with tumors harboring a mutation in the tyrosine kinase domain previously treated with a HER2-directed antibody-drug conjugate (cohort 5), and those with tumors harboring a non-tyrosine kinase domain mutation (cohort 3). In cohort 1, patients were initially randomly assigned to receive zongertinib at a dose of 120 mg or 240 mg once daily. Patients in cohorts 5 and 3 initially received 240 mg daily. After an interim analysis of data from cohort 1, subsequently recruited patients across all cohorts received zongertinib at a dose of 120 mg. The primary end point was an objective response assessed by blinded independent central review (cohorts 1 and 5) or by investigator review (cohort 3). Secondary end points included the duration of response and progression-free survival.

RESULTS: In cohort 1, a total of 75 patients received zongertinib at a dose of 120 mg. At the data cutoff (November 29, 2024), 71% of these patients (95% confidence interval [CI], 60 to 80; P<0.001 against a ≤30% benchmark) had a confirmed objective response; the median duration of response was 14.1 months (95% CI, 6.9 to not evaluable), and the median progression-free survival was 12.4 months (95% CI, 8.2 to not evaluable). Grade 3 or higher drug-related adverse events occurred in 13 patients (17%). In cohort 5 (31 patients), 48% of the patients (95% CI, 32 to 65) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 1 patient (3%). In cohort 3 (20 patients), 30% of the patients (95% CI, 15 to 52) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 5 patients (25%). Across all three cohorts, no cases of drug-related interstitial lung disease occurred.

CONCLUSIONS: Zongertinib showed clinical benefit with mainly low-grade adverse events in patients with previously treated HER2-mutant NSCLC. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).

PMID:40293180 | DOI:10.1056/NEJMoa2503704

Cureus. 2025 Mar 27;17(3):e81305. doi: 10.7759/cureus.81305. eCollection 2025 Mar.

ABSTRACT

Attention-deficit hyperactivity disorder (ADHD) is generally treated with stimulant medications without significant complications. Delusional parasitosis (Ekbom syndrome) can occur secondary to ADHD treatment. It is a rare condition defined as having a fixed, false belief that one is infected with insects, parasites, or organisms and that one experiences cutaneous sensations without any clinical evidence of infestation. Although stimulant treatment with methylphenidate or mixed amphetamine salts has been associated with delusional parasitosis, there is yet a case in the literature illustrating delusional infestation secondary to lisdexamfetamine. The following case is unique in that lisdexamfetamine caused delusional parasitosis in a 53-year-old man with ADHD who previously tolerated mixed amphetamine salts and armodafinil without side effects. The discontinuation of lisdexamfetamine, coupled with a second-generation antipsychotic, quickly resolved the delusion. For those who may prescribe lisdexamfetamine or treat patients with ADHD, it is crucial to carefully assess medication use, as discontinuation or dose adjustment of the suspected causative drug can have a positive impact on the course of delusional parasitosis.

PMID:40291316 | PMC:PMC12034334 | DOI:10.7759/cureus.81305

Cureus. 2025 Mar 28;17(3):e81364. doi: 10.7759/cureus.81364. eCollection 2025 Mar.

ABSTRACT

Drug-induced thrombocytopenia (DITP) is a rare but serious immune-mediated reaction characterized by drug-dependent antibodies that bind platelet surface glycoproteins, leading to severe thrombocytopenia. Biologic therapies, including IL-23 inhibitors like risankizumab, have been implicated in such adverse events. We present the case of a 47-year-old male with a history of psoriasis and prior deep vein thrombosis, who developed severe bleeding manifestations shortly after initiating risankizumab therapy for psoriatic arthritis. Clinical evaluation included mucocutaneous bleeding, petechiae, and a precipitous drop in platelet count to 3 x 10^3/uL. Management strategies involved platelet transfusions, high-dose steroids, intravenous immunoglobulin (IVIG), and thrombopoietin receptor agonists due to inadequate initial response. Despite aggressive treatment, the patient's thrombocytopenia persisted, necessitating prolonged hospitalization and consideration of alternative therapies. This case underscores the critical importance of recognizing and managing rare hematologic complications associated with biologic therapies. Vigilance in monitoring platelet counts during IL-23 inhibitor therapy is essential to mitigate severe adverse outcomes.

PMID:40291297 | PMC:PMC12034315 | DOI:10.7759/cureus.81364

Front Public Health. 2025 Apr 11;13:1572611. doi: 10.3389/fpubh.2025.1572611. eCollection 2025.

ABSTRACT

INTRODUCTION: Pharmacovigilance plays a vital role in ensuring drug safety and protecting public health. Oropharyngeal adverse drug reactions (O-ADRs) are found to be under-reported, especially by oral health professionals, limiting the identification and management of these events.

AIMS: This study aimed to evaluate the knowledge, attitudes, and practices (KAP) of healthcare professionals and students regarding O-ADRs and to assess their specific expertise by a self-e-learning test.

MATERIALS AND METHODS: A cross-sectional survey was conducted using a KAP questionnaire between April 2023 and April 2024, involving 943 participants, including physicians, dentists, dental hygienists, and students. Additionally, three sets of self-e-learning tests on O-ADRs were administered. The study employed descriptive statistics, Kruskal-Wallis tests, and logistic regression to analyze factors affecting KAP and reporting behaviors.

RESULTS: Significant gaps in KAP were identified. Only 26.5% of participants demonstrated frequent best practices for reporting O-ADRs, with dentists and dental hygienists showing lower reporting rates (13.8% and 9.3%, respectively) compared to physicians (18.8%). The results of logistic regression analyses showed that practical knowledge was significantly associated with work experience (OR = 2.15, p = 0.026). Students exhibited the lowest levels of practical knowledge and reporting proficiency, with only 17.6% demonstrating competence. The self-e-learning test highlighted knowledge deficits: only 22.9% of participants correctly identified O-ADR associated with antiseptic mouth rinses, additional 30.2% recognized those linked to antimicrobial drugs.

CONCLUSIONS: This study highlights the need for targeted educational interventions to address gaps in O-ADR knowledge and practice. Tailored training, user-friendly digital tools, and a strong pharmacovigilance culture are crucial for improving reporting rates and ensuring patient safety.

PMID:40290502 | PMC:PMC12021887 | DOI:10.3389/fpubh.2025.1572611

In Silico Pharmacol. 2025 Apr 24;13(2):70. doi: 10.1007/s40203-025-00355-z. eCollection 2025.

ABSTRACT

Marburg Virus (MARV) presents a significant threat to human health, highlighting the urgent need for effective therapeutics. The MARV genome encodes a multifunctional 'large' L protein that plays a crucial role in polymerase, capping, and methyltransferase activities. Within this protein, the 2'-O-methyltransferase (2'-O-MTase) domain is essential for viral replication and immune evasion, making it a promising therapeutic target. However, the lack of structural data on this domain limits drug discovery efforts. To address this challenge, we utilized AlphaFold2 to predict a 3D structure of the MARV 2'-O-MTase domain. Molecular docking with its natural ligand, S-adenosyl methionine (SAM), allowed us to identify key active-site residues involved in ligand binding. We then screened 62 known inhibitors against this domain and identified four promising candidates: Lifirafenib (- 9.5 kcal/mol), Dolutegravir (- 8.5 kcal/mol), BRD3969 (- 8.3 kcal/mol), and JFD00244 (- 8.2 kcal/mol). Further, we assessed the pharmacokinetic and pharmacodynamic properties of these compounds to evaluate their drug-likeness. Molecular dynamics simulations, along with MM/GBSA free energy calculations, confirmed stable interactions between the selected inhibitors and the target domain. While these findings highlight promising candidates for MARV, experimental validation through in vitro and in vivo assays is essential to assess their safety and efficacy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00355-z.

PMID:40291443 | PMC:PMC12018677 | DOI:10.1007/s40203-025-00355-z

ACS Omega. 2025 Feb 22;10(15):14980-14993. doi: 10.1021/acsomega.4c10338. eCollection 2025 Apr 22.

ABSTRACT

Huntington's disease (HD) and Spinocerebellar Ataxia (SCA) are debilitating neurological disorders triggered by the expansion of CAG sequences within the specific genes (HTT and ATXN, respectively). These are characterized as poly glutamine (polyQ) disorders, which are marked by widespread neurodegeneration and metabolic irregularities across systemic, cellular, and intracellular levels. This study aimed to identify small molecules that specifically interact with and target the toxic CAG repeat RNA. Here, we investigated the neuroprotective effects of Oseltamivir, an antiviral drug, against the HD and SCA-causing CAG repeats, through biophysical, cellular, and Drosophila model-based studies. Using a multidimensional approach encompassing biophysical techniques, cellular assays, and a Drosophila model, we explored Oseltamivir's interaction with toxic CAG repeat RNA. Our comprehensive analyses, including circular dichroism (CD), isothermal titration calorimetry (ITC), electrophoretic mobility shift assay (EMSA), and nuclear magnetic resonance (NMR) spectroscopy, demonstrated Oseltamivir's specific binding affinity for AA mismatches and its potential to mitigate the toxicity associated with polyQ aggregation. Moreover, the identified U.S. FDA-approved drug effectively mitigated polyQ-induced toxicity in both HD cells and the Drosophila model of the disease. The results obtained from this drug repurposing approach are indicative of the neuro-shielding role of Oseltamivir in HD and several SCAs, paving the way for its translation into clinical practice to benefit patients afflicted with these devastating diseases.

PMID:40290909 | PMC:PMC12019426 | DOI:10.1021/acsomega.4c10338

EClinicalMedicine. 2025 Mar 25;82:103102. doi: 10.1016/j.eclinm.2025.103102. eCollection 2025 Apr.

ABSTRACT

The kidney disease: Improving Global Outcomes (KDIGO) guideline recommends assessing kidney function using glomerular filtration rate (GFR) either through direct measurement or through estimation (eGFR) and describes a standardised classification of reduced kidney function. KDIGO guidelines have been adopted by most internal medicine specialities for the assessment and classification of kidney function, but not by cancer medicine. The development of the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) aims to overcome the perceived challenges with KDIGO recommendations by describing their utility in patients with cancer. Two virtual, consensus building workshops were held consecutively, involving international, multidisciplinary participants (Part 1 of ADDIKD development). During these workshops, three consensus recommendations were agreed upon based on KDIGO's principles; to standardise kidney function assessment, classify kidney function, and determine a uniform approach to dose anticancer drugs in patients with reduced kidney function. Cancer clinicians attending the workshops identified issues regarding the adoption of KDIGO's recommendations. These issues were addressed by nephrologists, clinical pharmacologists, and other clinicians with extensive experience in the contemporary assessment of kidney function. The key concern for cancer specialists was a hesitancy to move away from the familiar and long-standing practice of using the Cockcroft-Gault equation to estimate creatinine clearance. The consensus building within the two multidisciplinary workshops allowed a thorough assessment of the evidence and clarified how directly measured GFR and eGFR, rather than creatinine clearance, could be optimally utilised in cancer care. The development of Part 1 of the ADDIKD guideline represents a standardised, contemporary approach to the assessment, classification, and utility of kidney function in the setting of cancer care and it harmonises with the approach used in other areas of medicine internationally.

FUNDING: Development of the ADDIKD guideline is funded by the Cancer Institute NSW as part of the NSW Government and received no funding from external commercial sources.

PMID:40290845 | PMC:PMC12034077 | DOI:10.1016/j.eclinm.2025.103102

EClinicalMedicine. 2025 Mar 25;82:103161. doi: 10.1016/j.eclinm.2025.103161. eCollection 2025 Apr.

ABSTRACT

Part 2 of the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) offers drug-specific consensus recommendations based on both evidence and practical experience. These recommendations build upon the kidney function assessment and classification guidelines established in Part 1 of ADDIKD. Here we illustrate how dosing recommendations differ between ADDIKD and existing guidance for four commonly used drugs: methotrexate, cisplatin, carboplatin and nivolumab. We then describe how the recommendations can be distilled into practice points for methotrexate and cisplatin. While ADDIKD is a significant improvement from previous guidelines, adoption of this new guideline requires further endorsement from key external stakeholders, 'change championing' by clinicians locally and encouraging its integration into existing reference sources, clinical trial protocols and electronic prescribing systems.

FUNDING: Development of the ADDIKD guideline is funded by the NSW Government as part of the Cancer Institute NSW and received no funding from external commercial sources.

PMID:40290844 | PMC:PMC12034076 | DOI:10.1016/j.eclinm.2025.103161

Bioinform Biol Insights. 2025 Apr 12;19:11779322251328269. doi: 10.1177/11779322251328269. eCollection 2025.

ABSTRACT

Drug repositioning holds great promise for reducing the time and cost associated with traditional drug discovery, but it faces significant challenges related to data imbalance and noise in negative samples. In this article, we introduce a novel method leveraging high negative oversampling (HNO) to address these challenges. Our approach integrates HNO with advanced techniques such as network-based graph mining, matrix factorization, and Bayesian inference, specifically designed for imbalanced data scenarios. Constructing high-quality negative samples is crucial to mitigate the detrimental effects of noisy negative data and enhance model performance. Experimental results demonstrate the efficacy of our approach in enhancing the performance of drug discovery models by effectively managing data imbalance and refining the selection of negative samples. This methodology provides a robust framework for improving drug repositioning, with potential applications in broader biomedical domains.

PMID:40290635 | PMC:PMC12033409 | DOI:10.1177/11779322251328269

Acta Derm Venereol. 2025 Apr 28;105:adv40697. doi: 10.2340/actadv.v105.40697.

ABSTRACT

In recent years, molecular target drugs have become integral in treating malignant tumours. Multikinase inhibitors (MKIs) have been associated with serious skin disorders, including hand-foot skin reaction (HFSR), which impair patient quality of life, often disrupting activities of daily living necessitating dose reduction or discontinuation. As the pathogenic mechanisms of these skin disorders are unknown, no effective treatments have been established. Previously, by drug repurposing using an in vitro culture system, certain azole antifungal drugs (AFDs) were identified that prevented sorafenib-induced cell death of normal human epidermal keratinocytes. In this study, topical ketoconazole demonstrated clinical improvement in hyperkeratosis and pain associated with sorafenib-induced HFSR. Investigation of the mechanism using the in vitro culture system revealed sorafenib to be particularly cytotoxic among MKIs. Annexin V and TUNEL staining revealed apoptosis was mainly involved in this cytotoxicity. Antibody arrays and western blot showed increased levels of secretion of interleukin-1 receptor antagonist and macrophage migration inhibitory factor in culture supernatants. AFDs suppressed the secretion of these cytokines and reduced apoptosis in keratinocytes. This study reveals one aspect of the pathogenesis of sorafenib-induced HFSR and demonstrates that AFDs may be an effective treatment.

PMID:40289816 | DOI:10.2340/actadv.v105.40697

J Mater Chem B. 2025 Apr 28. doi: 10.1039/d5tb00365b. Online ahead of print.

ABSTRACT

The rapid advancement of implantable biomedical materials necessitates a comprehensive understanding of macrophage interactions to optimize implant immunocompatibility. Macrophages, key immune regulators, exhibit phenotypic plasticity by polarizing into pro-inflammatory (M1) or anti-inflammatory (M2) subtypes. Conventional phenotyping techniques, such as flow cytometry and immunostaining, provide insights but have limitations related to fixation and endpoint analysis. This study presents a high-throughput, label-free macrophage phenotyping approach integrating AI-driven image classification with quantitative phase imaging (QPI). THP-1-derived macrophages were differentiated into M0, M1, M2a, and M2c phenotypes, and their morphological and refractive index properties were analyzed using QPI. Although QPI alone could not fully distinguish phenotypes, deep learning models, including GoogLeNet, ShuffleNet, VGG-16, and ResNet-18, were evaluated, with ResNet-18 achieving over 90% accuracy. Additionally, macrophage responses to collagen coatings (types I, III, and IV) were assessed using machine learning-based phenotyping and cytokine profiling. Collagen I induced an M1 response, collagen III supported a balanced M1/M2 profile, and collagen IV promoted a controlled immune environment. These findings demonstrate the potential of AI-driven QPI as a non-invasive tool for macrophage characterization, offering insights into biomaterial immunocompatibility and informing implant design strategies.

PMID:40289902 | DOI:10.1039/d5tb00365b