Sci Rep. 2025 Jul 1;15(1):20560. doi: 10.1038/s41598-025-05054-5.

ABSTRACT

GBM is one of the most aggressive malignancies, having the greatest fatality rate and average life years lost. The current standard medicine, temozolomide (TMZ), is ineffective, requiring the development of new treatments. However, identifying and introducing a novel medicine takes time and money. In this context, repurposing FDA-approved drugs can be a novel yet efficient alternative method. Here, we, therefore, investigated the differential expression signatures of genes of patients suffering from GBM from publicly available GEO datasets and constructed a connectivity map. Functional annotation and KEGG pathway analysis showed dysregulated molecular activities and pathways. Based on their gene ontologies, putative key genes and hub genes linked with the disease were identified, and the C-MAP database was scanned for FDA-approved medicinal compounds that could alter hub gene expression or associated pathways. Our in-silico investigation showed that Gemfibrozil (Gem) and Doxylamine (Doxy) might reverse GBM disease patterns by deregulating GBM-related genes. Evaluation of the GBM inhibitory potential of these drugs through in-vitro and three-dimensional spheroid assay showed promising results. These drugs were more cytotoxic than TMZ; however, they synergised with TMZ as well. Interestingly, the cellular homeostatic process autophagy which has been implicated significantly in GBM pathogenesis and therapy resistance, was found to be inhibited by the drugs Gemfibrozil and Doxylamine, signifying their prospective potential. Therefore, in this study, we, for the first time, identify drugs with the ability to cross the blood brain barrier (BBB), with potential cytotoxic effects beyond TMZ, and with autophagy inhibitory potential, which can be further explored for repurposing against GBM.

PMID:40595852 | DOI:10.1038/s41598-025-05054-5

Sci Rep. 2025 Jul 1;15(1):22331. doi: 10.1038/s41598-025-07989-1.

ABSTRACT

Abdominal aortic aneurysm (AAA) is a non-communicable disease (NCD) with high morbidity and mortality, commonly observed worldwide. Understanding its molecular mechanisms and identifying potential therapeutic targets are crucial for disease screening, diagnosis, and treatment. In this study, we conducted a meta-analysis of multiple genome-wide association studies (GWASs) to identify genetic variants associated with AAA and explored the functional implications of these variants in disease pathology. We identified differentially expressed genes (DEGs) based on significant single nucleotide polymorphisms (SNPs) from expression quantitative trait loci (eQTL) and transcriptome-wide association study (TWAS) analyses. Using these DEGs, we constructed an AAA-related protein-protein interaction (PPI) network and prioritized key genes for further analysis. Furthermore, we performed drug repurposing by identifying drug-gene and drug-protein interactions in existing databases and validated potential candidates through molecular docking. Our findings reveal 42 novel disease-associated SNPs and 52 previously unreported disease-related genes. Some residual confounding factors cannot be fully ruled out and may represent a limitation of our study. However, it is worth noting that only a minority of SNPs exhibited heterogeneity. Functional pathways analysis highlighted key processes, including lipid and cholesterol metabolism, tissue remodeling, and acetylcholine activation. We identified 74 DEGs through eQTL and TWAS analyses, with PPI network analysis highlighting CD40 and LRP1 as key proteins. Drug repurposing and molecular docking suggested abciximab and paclitaxel as potential therapeutic agents targeting CD40, while ivermectin emerged as a strong candidate for LRP1 binding. In conclusion, our integrative bioinformatics frameworks links genomics and transcriptomics with network biology and structural modeling, providing valuable insights into the molecular mechanisms of AAA and potential therapeutic strategies.

PMID:40595262 | DOI:10.1038/s41598-025-07989-1

Sci Rep. 2025 Jul 1;15(1):21171. doi: 10.1038/s41598-025-07751-7.

ABSTRACT

The rising prevalence and rapid spread of multidrug-resistant bacteria have resulted in ineffective treatments, impacting millions of lives globally. In response to these challenges, drug repurposing has garnered attention as a viable alternative to traditional drug discovery and development processes. This study aimed to investigate the synergistic effects of dimetridazole and cefotaxime by evaluating their efficacy against E. coli. A checkerboard assay was performed to examine the synergy of dimetridazole in combination with cefotaxime against drug-resistant E. coli NX400. The results showed synergistic effects. Additionally, a growth curve was used to assess the growth inhibitory effects. Membrane permeability and membrane integrity were evaluated using fluorescence microscopy and scanning electron microscopy. We also analyzed the composition of membrane fatty acids and the expression of fatty acid biosynthesis-related genes. Finally, a Galleria mellonella infection model was employed to evaluate the synergistic antibacterial activity. The results showed that dimetridazole in combination with cefotaxime had significant antibacterial activity against MDR E. coli. This finding was confirmed by an in vivo G. mellonella larval infection model, in which dimetridazole revived the activity of cefotaxime. The antibacterial mechanisms are related to the bacterial membrane. Combination of dimetridazole and cefotaxime disrupts membrane integrity, permeability, and biosynthesis.

PMID:40594620 | DOI:10.1038/s41598-025-07751-7

Sci Rep. 2025 Jul 1;15(1):22382. doi: 10.1038/s41598-025-05013-0.

ABSTRACT

Ovarian cancer (OvCa) is the sixth most common gynaecological cancer in the UK, accounting for over 200,000 deaths worldwide. Cancerous Inhibitor of Phosphatase 2 A (CIP2A) is an oncoprotein and an endogenous inhibitor of PP2A. CIP2A is a key regulator for cellular processes (e.g. proliferation, DNA damage) and is involved in the progression of many malignancies. In this study we provide a comprehensive overview of its role in OvCa making use of in silico tools, clinical samples and in vitro models. CIP2A is overexpressed in OvCa patients, with metastatic patients having significantly higher expression when compared to patients with malignant and benign ovarian tumours. High CIP2A expression reduces both overall-and progression-free survival, whereas an R530T mutation is predicted to cause structural destabilisation of the CIP2A dimer. We also provide evidence for microRNA (miRNA) and mRNA target interactions with CIP2A. Finally, we have studied the effects of CIP2A inhibition in an in vitro BRCA2 model compared to BRCA2 wild-type OvCa cells, using RNA-sequencing. Gene enrichment pointed towards changes p53 pathway, protein metabolism, transporter activity, DNA replication, and cell cycle. Our data provide a novel insight into the role of CIP2A in OvCa and the potential of drug repurposing for therapeutic interventions.

PMID:40594400 | DOI:10.1038/s41598-025-05013-0

Sci Rep. 2025 Jul 2;15(1):22881. doi: 10.1038/s41598-025-05715-5.

ABSTRACT

Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a significant challenge in oncology despite advances in targeted and immune-based therapies. NSCLC accounts for approximately 85% of all lung cancer cases, with five-year survival rates ranging from 4 to 17%, depending on disease stage and regional factors. Chemotherapy resistance remains a major hurdle, contributing to poor patient prognosis. This study explores the therapeutic potential of Sd-021, a novel decursinol derivative, compared to its parent compound, decursin, within various NSCLC cell lines. Our results reveal that Sd-021 demonstrates enhanced anticancer activity, highlighted by a more significant reduction in cell viability, increased induction of apoptosis, and more pronounced cell cycle arrest. Notably, Sd-021 shows increased inhibition of the EGFR/STAT3 signaling pathway in EGFR wild-type cell lines, including A549, H460, and H1299 cells. Moreover, in vivo experiments employing a subcutaneous xenograft mouse model reveal that Sd-021 reduces tumor volume with minimal systemic toxicity, as indicated by histopathological assessments revealing reduced tumor proliferation and heightened apoptosis. The minimal toxicity of Sd-021 offers reassurance regarding its safety for potential clinical applications. In conclusion, these findings highlight the promise of Sd-021 as a therapeutic agent against NSCLC.

PMID:40594251 | DOI:10.1038/s41598-025-05715-5

Sci Rep. 2025 Jul 1;15(1):21211. doi: 10.1038/s41598-025-01448-7.

ABSTRACT

The exact cause of psoriasis is still unclear and there is no treatment available for its permanent reemission. The available biologics for disease treatment, are stated to be associated with a high cost of treatment, a significantly increased risk of serious infections, and have also been reported to show major contradictions in patients with tuberculosis and cardiovascular disorders. Therefore, drug repurposing could be an appealing strategy to find novel treatments for psoriasis, saving time, cost and with viable chance of success. The goal of the present study was to identify the FDA approved drugs which can be proposed as potential anti-psoriasis drugs. The known drug target interactions of 19 autoimmune diseases, 4 cardiovascular risk factors, and each of infectious, lung, and mood disorders were retrieved using various public databases, i.e., DrugBank, PharmGKB, clinicaltrial.gov database, TTD, CTD, and the Unified Medical Language System NDF-RT. The drug target interaction of prioritised drugs, obtained using molecular function GO mappings from the QuickGO database through NBI score was analysed using a molecular docking approach. Further, one-SVM algorithm prediction was done to validate the docking outcome and molecular dynamics simulation of top drug-target molecule was performed to propose potential anti-psoriasis drugs. The study identified Pioglitazone, Trimipramine and Dimetindene as top three contender amongst many other drugs as a new indication against psoriasis.

PMID:40593806 | DOI:10.1038/s41598-025-01448-7

Orphanet J Rare Dis. 2025 Jul 1;20(1):319. doi: 10.1186/s13023-024-03464-8.

ABSTRACT

BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. The current standard of care for MPS II is intravenous enzyme replacement therapy (ERT), which has been shown to improve somatic signs and symptoms and to increase life expectancy by approximately 12 years. This study reported on the somatic disease burden and clinical requirements of adult male patients in the Hunter Outcome Survey (ClinicalTrials.gov Identifier: NCT03292887).

RESULTS: Of the 373 patients in the analysis, 88 (23.6%) had cognitive impairment and 332 (89.0%) had received ERT. Almost half of all ERT-treated patients (47.0%) had undergone surgery in adulthood; the most common surgery was hernia repair (17.8% of patients). Over one-third (38.6%) reported hearing aid use. The median 6-min walk test distance for 151 treated patients was 436.0 m at the latest assessment after 18 years of age. Cardiovascular signs and symptoms were present in 71.6% (192/268) of patients and 27.3% (60/220) reported oxygen dependency after 18 years of age. Approximately half (50.9%) of ERT-treated patients experienced at least one serious adverse event in adulthood, with the most common being respiratory disorders. Intravenous ERT was well tolerated, with a rate of serious infusion-related reactions in adulthood of 0.03 per 10 patient-years.

CONCLUSIONS: Overall, adult patients with neuronopathic and non-neuronopathic MPS II had a high disease burden and requirement for surgeries, emphasizing the need to continue multidisciplinary management and regular assessments in adulthood. Further research into the differences in care needs of adult patients with MPS II is warranted. Trial registration NCT03292887 .

PMID:40598289 | DOI:10.1186/s13023-024-03464-8

Genome Med. 2025 Jul 1;17(1):72. doi: 10.1186/s13073-025-01494-w.

ABSTRACT

BACKGROUND: RNA sequencing (RNA-seq) is emerging as a valuable tool for identifying disease-causing RNA transcript aberrations that cannot be identified by DNA-based testing alone. Previous studies demonstrated some success in utilizing RNA-seq as a first-line test for rare inborn genetic conditions. However, DNA-based testing (increasingly, whole genome sequencing) remains the standard initial testing approach in clinical practice. The indications for RNA-seq after a patient has undergone DNA-based sequencing remain poorly defined, which hinders broad implementation and funding/reimbursement.

METHODS: In this study, we identified four specific and familiar clinical scenarios, and investigated in each the diagnostic utility of RNA-seq on clinically accessible tissues: (i) clarifying the impact of putative intronic or exonic splice variants (outside of the canonical splice sites), (ii) evaluating canonical splice site variants in patients with atypical phenotypes, (iii) defining the impact of an intragenic copy number variation on gene expression, and (iv) assessing variants within regulatory elements and genic untranslated regions.

RESULTS: These hypothesis-driven RNA-seq analyses confirmed a molecular diagnosis and pathomechanism for 45% of participants with a candidate variant, provided supportive evidence for a DNA finding for another 21%, and allowed us to exclude a candidate DNA variant for an additional 24%. We generated evidence that supports two novel Mendelian gene-disease associations (caused by variants in PPP1R2 and MED14) and several new disease mechanisms, including the following: (1) a splice isoform switch due to a non-coding variant in NFU1, (2) complete allele skew from a transcriptional start site variant in IDUA, and (3) evidence of a germline gene fusion of MAMLD1-BEND2. In contrast, RNA-seq in individuals with suspected rare inborn genetic conditions and negative whole genome sequencing yielded only a single new potential diagnostic finding.

CONCLUSIONS: In summary, RNA-seq had high diagnostic utility as an ancillary test across specific real-world clinical scenarios. The findings also underscore the ability of RNA-seq to reveal novel disease mechanisms relevant to diagnostics and treatment.

PMID:40597352 | DOI:10.1186/s13073-025-01494-w

Sci Rep. 2025 Jul 2;15(1):22678. doi: 10.1038/s41598-025-08866-7.

ABSTRACT

Caregivers of persons with rare diseases (RDs) face elevated stress levels, caregiver burden (CB), financial pressure, and decreased quality of life (QoL). Since the Polish Rare Diseases Plan for 2024-2025 does not address caregivers' psychosocial needs, this study aimed to assess the experiences of Polish parents of persons with RD. A self-administered, anonymous, computer-assisted online survey was conducted between March and August 2024 to examine the relationship between parenting a person with RD and caregivers' QoL, CB, and financial well-being. The survey included 942 Polish caregivers of individuals with RDs. The study demonstrated a statistically significant negative association between perceived CB and all dimensions of parents' QoL - physical health, psychological health, social relationships, and environment - indicating a broad decline in QoL as CB increases. Financial well-being emerged as a consistent positive predictor of QoL and was shown to buffer the negative effects of CB, underscoring its role as a critical resource for caregivers. Additionally, CB was associated with adverse experiences related to the diagnostic odyssey and its perceived consequences. Our findings highlight that long-term caregiving for individuals with RDs imposes substantial emotional, financial, and social burdens. To effectively address these challenges, Polish health policy must move beyond the biomedical model and adopt a comprehensive approach that integrates psychological, social, and financial support for RD families. Future research should explore targeted interventions that strengthen caregiver resources and reduce systemic barriers to support.

PMID:40595391 | DOI:10.1038/s41598-025-08866-7

Sci Rep. 2025 Jul 2;15(1):22732. doi: 10.1038/s41598-025-08829-y.

ABSTRACT

Although significant advances have been made in the early detection of many cancers, challenges remain in the early diagnosis of rare cancers, including Wilms tumor, Clear Cell Sarcoma of the Kidney, Neuroblastoma, Osteosarcoma, and Acute Myeloid Leukemia, perhaps due to their relative obscurity and scarce data compared to common cancers. Application of artificial intelligence or deep learning has shown promising results in disease diagnosis including in their ability to diagnose cancers and detect their tissue of origin. However, their ability to detect rare cancers is yet to be comprehensively assessed. This motivated us to develop, RareNet, which leverages transfer learning of an established deep learning model, namely, CancerNet, to classify rare cancers. The transfer learning framework of RareNet utilized DNA methylation data of various biopsied rare cancers to learn epigenetic signatures of rare cancers. RareNet achieved an overall accuracy (F1 score) of ~ 96%, outperforming other machine learning models including Random Forest, K Nearest Neighbors, Decision Tree Classifier, and Support Vector Classifier.

PMID:40594942 | DOI:10.1038/s41598-025-08829-y

Front Immunol. 2025 Jun 17;16:1605727. doi: 10.3389/fimmu.2025.1605727. eCollection 2025.

ABSTRACT

In contrast to hereditary angioedema (HAE) due to C1-inhibitor deficiency, the detection of pathogenic variants in genes linked to HAE with normal C1 inhibitor levels (HAE-nC1INH) is required for the diagnosis of the corresponding types of the disease. The mainstreaming of genomic technology and the increasing use of next generation sequencing have increased the possibility of an unintentional detection of HAE-nC1INH pathogenic variants and allowed the incidental finding of variants of uncertain significance (VUS) in the relevant genes. Apart from F12 and PLG pathogenic variants, the current level of evidence on the prevalence and penetrance of variants associated with HAE-nC1INH does not support the reporting of their incidental finding. On the other hand, although VUS should not be used in clinical decision-making, further consideration is warranted (a) for VUS found in exon 9 of the F12 gene after a diagnostic genetic analysis of individuals either with or without personal or family history of angioedema, and (b) for VUS found in any of the other genes linked to HAE-nC1INH, after genetic analysis performed in the context of differential diagnosis of angioedema cases. Given the complexity of interpreting, reporting and communicating incidental findings, a close partnership between patients, clinicians, laboratory geneticists and genetic counsellors is essential to optimize the management of these results.

PMID:40599776 | PMC:PMC12208851 | DOI:10.3389/fimmu.2025.1605727

J Proteome Res. 2025 Jul 1. doi: 10.1021/acs.jproteome.4c00989. Online ahead of print.

ABSTRACT

This study utilized multiomics combined with a comprehensive machine learning-based predictive modeling approach to identify, validate, and prioritize circulating immunometabolic biomarkers in distinguishing tuberculosis (TB) from nontuberculous mycobacteria (NTM) infections, latent tuberculosis infection (LTBI), and other lung diseases (ODx). Functional omics data were collected from two discovery cohorts (76 patients in the TB-NTM cohort and 72 patients in the TB-LTBI-ODx cohort) and one validation cohort (68 TB patients and 30 LTBI patients). Mutiomics integrative analysis identified three plasma multiome biosignatures that could distinguish active TB from non-TB with promising performance, achieving area under the receiver operating characteristic curve (AUC) values of 0.70-0.90 across groups in both the discovery and validation cohorts. The lipid PC(14:0_22:6) emerged as the most important predictor for differentiating active TB from non-TB controls, consistently presenting at lower levels in the active TB group compared with its counterparts. Further validation using two independent external data sets demonstrated AUCs of 0.77-1.00, confirming the biomarkers' efficacy in distinguishing active TB from other non-TB groups. Our investigation highlights lipids as promising biomarkers for classifying TB, NTM, LTBI, and ODx. Rigorous validation further indicates PC(14:0_22:6) as a TB differential diagnostic biomarker candidate.

PMID:40598791 | DOI:10.1021/acs.jproteome.4c00989

BMC Cancer. 2025 Jul 1;25(1):1044. doi: 10.1186/s12885-025-14419-y.

ABSTRACT

BACKGROUND: Genetic testing has led to a considerable enhancement in the ability to identify individuals at risk of Hereditary Breast and Ovarian Cancer syndrome related to BRCA1/2 pathogenic variants, thus necessitating personalised prevention programs. However, barriers related to intrafamilial communication, privacy regulations, and genetic information dissemination hinder preventive care, particularly in Italy, where legal constraints limit the disclosure of genetic risks to at-risk relatives. This study examines the relationship between BRCA1/2 carriers' communication challenges and three factors: cancer status, comprehension of genetic information, and the genetic counseling pathway accessed (Traditional Genetic Counseling, TGC vs. Mainstream Cancer Genetics, MCG).

METHODS: This multicenter, prospective, observational study included 277 BRCA1/2 carriers (probands and relatives) aged 18-80 from various Italian centers. Participants completed a sociodemographic form, a self-administered survey, and psychological assessments (Impact of Event Scale, IES and Distress Thermometer, DT). Categorical variables were compared using Pearson's Chi-squared test or Fisher's exact test based on sample size and expected frequencies, whereas continuous variables were analyzed using the Wilcoxon rank-sum test because of non-normal data distribution.

RESULTS: Among the 277 carriers (115 probands, 162 relatives), 79.4% received TGC and 20.6% MCG. The cancer prevalence was higher in probands (83%) than in relatives (22%). The probands exhibited greater psychological distress (higher IES and DT scores), and cancer-affected relatives had higher distress levels than healthy relatives (p = 0.008). While no severe psychological distress or PTSD was found, distress was more associated with cancer diagnosis than genetic status. Genetic comprehension was significantly higher in relatives (p = 0.007) and in those who underwent TGC compared to MCG (p < 0.001). TGC carriers also better understood genetic risks and management strategies (p < 0.001).

CONCLUSIONS: Psychological distress and genetic comprehension significantly influenced the communication. TGC enhances understanding more effectively than MCG, highlighting the need for tailored support for both carriers and healthcare professionals to improve cascade counseling and testing rates, and cancer prevention. As we look into the future, we need to critically approach MCG, and determine how to address carriers understanding and prevention needs and reincorporate a more comprehensive genetic risk assessment into the MCG model.

PMID:40596937 | DOI:10.1186/s12885-025-14419-y

BMC Nephrol. 2025 Jul 1;26(1):321. doi: 10.1186/s12882-025-04272-3.

ABSTRACT

BACKGROUND: Critically ill patients receiving continuous renal replacement therapy (CRRT) are at increased risk for multidrug-resistant infections and infection-related mortality. Altered pharmacokinetics in CRRT may contribute to inadequate antimicrobial exposure and therapeutic failure. However, limited data exist on infection burden and resistance patterns specific to this population.

METHODS: We conducted a retrospective cohort study of ICU patients receiving continuous venovenous hemodialysis (CVVHD) at a tertiary academic center between May 2016 and April 2020. Patients were included if they received CRRT for ≥ 48 h, had at least one positive microbial culture, and received at least one antimicrobial of interest. Data were collected on infection sources, pathogens, resistance patterns, and mortality.

RESULTS: Among 661 CRRT recipients, 394 (59.6%) had at least one positive culture. The most common infection sites were respiratory (69.0%), skin and soft tissue (53.8%), and intra-abdominal (38.8%). Intra-abdominal and bloodstream infections had the highest mortality (63.7% and 57.7%, respectively). Vancomycin-resistant E. faecium (83.3%), cefepime-resistant A. baumannii (100%), and P. aeruginosa with high β-lactam resistance were prominent. These resistance profiles diverged from general ICU trends.

CONCLUSION: ICU patients receiving CRRT experience high rates of multidrug-resistant infections and associated mortality. Tailored dosing strategies, including dual empiric coverage in select cases, and CRRT-specific antimicrobial stewardship are essential to improve outcomes in this high-risk population.

PMID:40596911 | DOI:10.1186/s12882-025-04272-3

Sci Rep. 2025 Jul 1;15(1):21777. doi: 10.1038/s41598-025-07275-0.

ABSTRACT

Asthma is a prevalent chronic respiratory condition. Most patients can manage their symptoms with standard treatments but approximately 5-10% experience severe uncontrolled asthma (SUA), characterized by persistent symptoms and frequent exacerbations despite optimized therapy. This retrospective, observational, multicentre study conducted in southern Spain aimed to evaluate the effectiveness of benralizumab in patients with SUA and identify predictive markers of response. A total of 99 patients were selected. Mean age of participants was 63 ± 15.3 years. Results showed that 79.8% of patients achieved a 50% reduction in oral corticosteroid (OCS) use, 81.8% experienced at least a 50% reduction in exacerbations, and 75.7% had a ≥ 10% improvement or maintained %forced expiratory volume in 1 s (FEV1) above 80%. Significant improvements were observed in lung function, asthma control, and a reduction in eosinophil levels (p < 0.001). The frequency of exacerbations and OCS cycles significantly decreased (p < 0.001), and ACT scores improved. The presence of concomitant COPD was associated with a lower probability of lung function improvement, highlighting the importance of phenotypic characterization in treatment response. Importantly, higher baseline eosinophil counts were associated with better clinical outcomes, suggesting their potential as predictive biomarkers. This study supports the real-world effectiveness of benralizumab in reducing OCS dependency, exacerbations, and enhancing pulmonary function in patients with severe uncontrolled asthma.

PMID:40596465 | DOI:10.1038/s41598-025-07275-0

Nat Commun. 2025 Jul 1;16(1):5616. doi: 10.1038/s41467-025-60745-x.

ABSTRACT

Macrophages infiltrate solid tumors and either support survival or induce cancer cell death through phagocytosis or cytotoxicity. To uncover regulators of macrophage cytotoxicity towards cancer cells, we perform two co-culture CRISPR screens using CAR-macrophages targeting different tumor associated antigens. Both identify ATG9A as an important regulator of this cytotoxic activity. In vitro and in vivo, ATG9A depletion in cancer cells sensitizes them to macrophage-mediated killing. Proteomic and lipidomic analyses reveal that ATG9A deficiency impairs the cancer cell response to macrophage-induced plasma membrane damage through defective lysosomal exocytosis, reduced ceramide production, and disrupted caveolar endocytosis. Depleting non-cytotoxic macrophages using CSF1R inhibition while preventing ATG9A-mediated tumor membrane repair enhances the anti-tumor activity of therapeutic antibodies in mice. Thus, macrophage cytotoxicity plays an important role in tumor elimination during antibody or CAR-macrophage treatment, and inhibiting tumor membrane repair via ATG9A, particularly in combination with cytotoxic macrophage enrichment through CSF1R inhibition, improves tumor-targeting macrophage efficacy.

PMID:40595560 | DOI:10.1038/s41467-025-60745-x

Nat Commun. 2025 Jul 1;16(1):5887. doi: 10.1038/s41467-025-60836-9.

ABSTRACT

It has been estimated that 15%-20% of human cancers are attributable to infections, mostly by carcinogenic viruses. The incidence varies worldwide, with a majority affecting developing countries. Here, we conduct a comparative analysis of virus-positive and virus-negative tumors in nine cancers linked to five viruses. We observe a higher frequency of virus-positive tumors in males, with notable geographic differences in incidence. Our genomic analysis of 1971 tumors reveals a lower somatic burden, distinct mutation signatures, and driver gene mutations in virus-positive tumors. Compared to virus-negative cases, virus-positive cases have fewer mutations of TP53, CDKN2A, and deletions of 9p21.3/CDKN2A-CDKN1A while exhibiting more mutations in RNA helicases DDX3X and EIF4A1. Furthermore, an analysis of clinical trials of PD-(L)1 inhibitors suggests an association of virus-positivity with higher treatment response rate, particularly evident in gastric cancer and head and neck squamous cell carcinoma. Both cancer types also show evidence of increased CD8 + T cell infiltration and T cell receptor clonal selection in virus-positive tumors. These results illustrate the epidemiological, genetic, and therapeutic trends across virus-associated malignancies.

PMID:40595559 | DOI:10.1038/s41467-025-60836-9

Nat Commun. 2025 Jul 1;16(1):5812. doi: 10.1038/s41467-025-60370-8.

ABSTRACT

The canonical Alzheimer's Disease (AD) pathological cascade posits that the accumulation of amyloid beta (Aβ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a multi-cohort study (ADNI, A4, HABS-HD) of 1354 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and APOE-ε4 homozygotes are more susceptible to the effects of Aβ on the primary accumulation of tau, with greater EC tau for a given level of Aβ. Furthermore, we observed for individuals who have rare risk variants in TREM2 and/or APOE-ε4 homozygotes there was a greater spread of primary tau from the EC into the neocortex. These findings offer insights into the function of sex, APOE and microglia in AD progression and have implications for determining personalised treatment with drugs targeting Aβ and tau.

PMID:40595476 | DOI:10.1038/s41467-025-60370-8

Sci Rep. 2025 Jul 1;15(1):20824. doi: 10.1038/s41598-025-91571-2.

ABSTRACT

In the field of cancer therapy, the diversity and heterogeneity of cancer genomes in clinical patients complicate and challenge the effective use of non-targeted drugs, as these drugs often fail to address specific genetic events. Recent advancements in large-scale in vitro drug screening assays have generated extensive drug testing and genomic data, providing valuable resources to explore the relationship between genomic features and drug responses. In this study, we developed a deep neural network model, DrugS (Drug Response prediction Utilizing Genomic features Screening), utilizing gene expression and drug testing data from human-derived cancer cell lines to predict cellular responses to drugs. Leveraging gene expression and mutation data, we elucidated potential molecular mechanisms underlying SN-38 resistance. Additionally, we used DrugS to evaluate the effects of drugs on cancer cell proliferation in patient-derived xenograft models. In in vitro combination drug experiments, DrugS revealed that CDK inhibitors, mTOR inhibitors, and apoptosis inhibitors effectively reverse Ibrutinib resistance, providing new therapeutic strategies to overcome drug resistance. Furthermore, we assessed the applicability of the DrugS model in drug screening and patient prognosis evaluation using drug information and gene expression data from The Cancer Genome Atlas. In summary, our study offers a novel approach for drug response prediction and mechanism research in cancer therapy from a genomic perspective and demonstrates the potential applications of the DrugS model in personalized therapy and resistance mechanism elucidation.

PMID:40595000 | DOI:10.1038/s41598-025-91571-2

Sci Rep. 2025 Jul 1;15(1):21626. doi: 10.1038/s41598-025-04962-w.

ABSTRACT

This study examined the prognostic significance of immunoscore within consensus molecular subtypes (CMS), tumour budding (TB), and macrophage infiltration in colorectal cancer (CRC). A retrospective series was analysed using immunohistochemical staining, immunoscore evaluation, and CMS classification, according to established methods. Among the 255 patients with CRC, 34.9% had stage III disease. The CMS classification showed a predominance of CMS2/3 (69.4%), with relapse occurring across all the subtypes. Low immunoscore was frequent in conventional and serrated adenocarcinomas, as well as in CMS2/3, whereas MSI-H correlated with intermediate-high immunoscore. TB was prevalent in relapsed patients, particularly in CMS2/3 and CMS4, and was linked to serrated histology. TB of ≥ 20 foci was correlated with hepatic metastases. CD163+ macrophage infiltration was common in CMS1 and CMS2/3, and was associated with high immune scores. TB influenced overall and relapse-free survival, whereas CMS affected the overall survival. Immunoscore were not associated with survival. The associations identified between CMS subtypes and clinical as well as pathological characteristics enhance the understanding of CMS behaviour in clinical practice.

PMID:40594059 | DOI:10.1038/s41598-025-04962-w