bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024‒07‒14
fourteen papers selected by
Oltea Sampetrean, Keio University
  1. IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses in glioblastoma.
  2. Multi-scale signaling and tumor evolution in high-grade gliomas.
  3. PET imaging of gliomas: Status quo and quo vadis?
  4. Tumor biomechanics as a novel imaging biomarker to assess response to immunotherapy in a murine glioma model.
  5. Streamlined intraoperative brain tumor classification and molecular subtyping in stereotactic biopsies using stimulated Raman histology and deep learning.
  6. Reply to "A Call for Action: Formalin Exposure and Broader Occupational Hazards and Assessing the Risk of Glioblastoma in Clinician Scientists."
  7. Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas.
  8. Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment.
  9. Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma.
  10. In Vivo Mouse Models for Adult Brain Tumors: Exploring Tumorigenesis and Advancing Immunotherapy Development.
  11. Optical microscopy and transcriptomics reveal the origins of fluorescence in glioma surgery.
  12. Letter to the Editor in Reply to: Reply to "A Call for Action: Formalin Exposure and Broader Occupational Hazards and Assessing the Risk of Glioblastoma in Clinician Scientists.
  13. Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade.
  14. Directional integration and pathway enrichment analysis for multi-omics data.
  1. Neuro Oncol. 2024 Jul 10. pii: noae126. [Epub ahead of print]
    IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses in glioblastoma.
    Andrew J Hou, Ryan M Shih, Benjamin R Uy, Amanda Shafer, Ze Nan L Chang, Begonya Comin-Anduix, Miriam Guemes, Zoran Galic, Su Phyu, Hideho Okada, Katie B Grausam, Joshua J Breunig, Christine E Brown, David A Nathanson, Robert M Prins, Yvonne Y Chen.
      BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies targeting glioblastoma (GBM)-associated antigens such as interleukin-13 receptor subunit alpha-2 (IL-13Rα2) have achieved limited clinical efficacy to date, in part due to an immunosuppressive tumor microenvironment (TME) characterized by inhibitory molecules such as transforming growth factor-beta (TGF-β). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-β-mediated immune suppression in the TME.METHODS: We engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-β, which programs tumor-specific T cells to convert TGF-β from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-β CAR-T cells were evaluated for efficacy and safety against both patient-derived GBM xenografts and syngeneic models of murine glioma.
    RESULTS: Treatment with IL-13Rα2/TGF-β CAR-T cells leads to greater T-cell infiltration and reduced suppressive myeloid cell presence in the tumor-bearing brain compared to treatment with conventional IL-13Rα2 CAR-T cells, resulting in improved survival in both patient-derived GBM xenografts and syngeneic models of murine glioma.
    CONCLUSION: Our findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-β, bispecific IL-13Rα2/TGF-β CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.
    Keywords:  CAR-T cell therapy; Immunotherapy; TGF-β; glioblastoma; tumor microenvironment
    DOI:  https://doi.org/10.1093/neuonc/noae126
  2. Cancer Cell. 2024 Jul 08. pii: S1535-6108(24)00229-0. [Epub ahead of print]42(7): 1217-1238.e19
    Multi-scale signaling and tumor evolution in high-grade gliomas.
    Philadelphia Coalition for a Cure
      Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.
    Keywords:  CPTAC; glioblastoma; glycoproteomics; lipidome; metabolome; proteomics; single nuclei ATAC-seq; single nuclei RNA-seq; tumor recurrence
    DOI:  https://doi.org/10.1016/j.ccell.2024.06.004
  3. Neuro Oncol. 2024 Jul 06. pii: noae078. [Epub ahead of print]
    PET imaging of gliomas: Status quo and quo vadis?
    Norbert Galldiks, Philipp Lohmann, Michel Friedrich, Jan-Michael Werner, Isabelle Stetter, Michael M Wollring, Garry Ceccon, Carina Stegmayr, Sandra Krause, Gereon R Fink, Ian Law, Karl-Josef Langen, Joerg-Christian Tonn.
      PET imaging, particularly using amino acid tracers, has become a valuable adjunct to anatomical MRI in the clinical management of patients with glioma. Collaborative international efforts have led to the development of clinical and technical guidelines for PET imaging in gliomas. The increasing readiness of statutory health insurance agencies, especially in European countries, to reimburse amino acid PET underscores its growing importance in clinical practice. Integrating artificial intelligence and radiomics in PET imaging of patients with glioma may significantly improve tumor detection, segmentation, and response assessment. Efforts are ongoing to facilitate the clinical translation of these techniques. Considerable progress in computer technology developments (eg quantum computers) may be helpful to accelerate these efforts. Next-generation PET scanners, such as long-axial field-of-view PET/CT scanners, have improved image quality and body coverage and therefore expanded the spectrum of indications for PET imaging in Neuro-Oncology (eg PET imaging of the whole spine). Encouraging results of clinical trials in patients with glioma have prompted the development of PET tracers directing therapeutically relevant targets (eg the mutant isocitrate dehydrogenase) for novel anticancer agents in gliomas to improve response assessment. In addition, the success of theranostics for the treatment of extracranial neoplasms such as neuroendocrine tumors and prostate cancer has currently prompted efforts to translate this approach to patients with glioma. These advancements highlight the evolving role of PET imaging in Neuro-Oncology, offering insights into tumor biology and treatment response, thereby informing personalized patient care. Nevertheless, these innovations warrant further validation in the near future.
    Keywords:   IDH ; FET; glioblastoma; supercomputing; vorasidenib
    DOI:  https://doi.org/10.1093/neuonc/noae078
  4. Sci Rep. 2024 Jul 06. 14(1): 15613
    Tumor biomechanics as a novel imaging biomarker to assess response to immunotherapy in a murine glioma model.
    Yannik Streibel, Michael O Breckwoldt, Jessica Hunger, Chenchen Pan, Manuel Fischer, Verena Turco, Berin Boztepe, Hannah Fels-Palesandro, Jonas G Scheck, Volker Sturm, Kianush Karimian-Jazi, Dennis A Agardy, Giacomo Annio, Rami Mustapha, Shreya S Soni, Abdulrahman Alasa, Ina Weidenfeld, Christopher B Rodell, Wolfgang Wick, Sabine Heiland, Frank Winkler, Michael Platten, Martin Bendszus, Ralph Sinkus, Katharina Schregel.
      Glioblastoma is the most common and aggressive primary malignant brain tumor with poor prognosis. Novel immunotherapeutic approaches are currently under investigation. Even though magnetic resonance imaging (MRI) is the most important imaging tool for treatment monitoring, response assessment is often hampered by therapy-related tissue changes. As tumor and therapy-associated tissue reactions differ structurally, we hypothesize that biomechanics could be a pertinent imaging proxy for differentiation. Longitudinal MRI and magnetic resonance elastography (MRE) were performed to monitor response to immunotherapy with a toll-like receptor 7/8 agonist in orthotopic syngeneic experimental glioma. Imaging results were correlated to histology and light sheet microscopy data. Here, we identify MRE as a promising non-invasive imaging method for immunotherapy-monitoring by quantifying changes in response-related tumor mechanics. Specifically, we show that a relative softening of treated compared to untreated tumors is linked to the inflammatory processes following therapy-induced re-education of tumor-associated myeloid cells. Mechanistically, combined effects of myeloid influx and inflammation including extracellular matrix degradation following immunotherapy form the basis of treated tumors being softer than untreated glioma. This is a very early indicator of therapy response outperforming established imaging metrics such as tumor volume. The overall anti-tumor inflammatory processes likely have similar effects on human brain tissue biomechanics, making MRE a promising tool for gauging response to immunotherapy in glioma patients early, thereby strongly impacting patient pathway.
    Keywords:  Glioma; Immunotherapy; MR elastography; Tissue biomechanics; Tumor stiffness
    DOI:  https://doi.org/10.1038/s41598-024-66519-7
  5. Clin Cancer Res. 2024 Jul 08.
    Streamlined intraoperative brain tumor classification and molecular subtyping in stereotactic biopsies using stimulated Raman histology and deep learning.
    David Reinecke, Daniel Ruess, Anna-Katharina Meissner, Gina Fürtjes, Niklas von Spreckelsen, Adrian Ion-Margineau, Florian Khalid, Tobias Blau, Thomas Stehle, Abdulkader Al-Shughri, Reinhard Büttner, Roland Goldbrunner, Maximilian I Ruge, Volker Neuschmelting.
      PURPOSE: Recent artificial intelligence (AI) algorithms aided intraoperative decision-making via stimulated Raman histology (SRH) during craniotomy. This study assesses deep-learning algorithms for rapid intraoperative diagnosis from SRH images in small stereotactic-guided brain biopsies. It defines a minimum tissue sample size threshold to ensure diagnostic accuracy.EXPERIMENTAL DESIGN: A prospective single-center study examined 121 SRH images from 84 patients with unclear intracranial lesions undergoing stereotactic brain biopsy. Unprocessed, label-free samples were imaged with a portable fiber-laser Raman scattering microscope. Three deep-learning models were tested to (I) identify tumorous/non-tumorous tissue as qualitative biopsy control, (II) subclassify into high-grade glioma (CNS WHO grade 4), diffuse low-grade glioma (CNS WHO grade 2-3), metastases, lymphoma, or gliosis, and (III) molecularly subtype IDH- and 1p/19q-status of adult-type diffuse gliomas. Model predictions were evaluated against frozen section analysis and final neuropathological diagnoses.
    RESULTS: The first model identified tumorous/non-tumorous tissue with 91.7% accuracy. Sample size on slides impacted accuracy in brain tumor subclassification (81.6%, κ=0.72 frozen section; 73.9%, κ=0.61 second model), with SRH being smaller than H&E (4.1±2.5mm² vs 16.7±8.2mm², p<0.001). SRH images with over 140 high-quality patches and a mean squeezed sample of 5.26mm² yielded 89.5% accuracy in subclassification and 93.9% in molecular subtyping of adult-type diffuse gliomas.
    CONCLUSIONS: AI-based SRH image analysis is non-inferior to frozen section analysis in detecting and subclassifying brain tumors during small stereotactic-guided biopsies once a critical squeezed sample size is reached. Beyond frozen section analysis, it enables valid molecular glioma subtyping, allowing faster treatment decisions in the future. Refinement is needed for long-term application.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3842
  6. Clin Dermatol. 2024 Jul 08. pii: S0738-081X(24)00128-7. [Epub ahead of print]
    Reply to "A Call for Action: Formalin Exposure and Broader Occupational Hazards and Assessing the Risk of Glioblastoma in Clinician Scientists."
    Zachary Neubauer, Carrie Forman, Shari R Lipner.
      
    Keywords:  carcinogen; dermatologic surgeons; dermatologists; dermatopathologists; environment; formaldehyde; formalin; glioblastoma; high-risk profession; neurotoxin; occupational exposure; statistics
    DOI:  https://doi.org/10.1016/j.clindermatol.2024.07.003
  7. medRxiv. 2024 Jun 27. pii: 2024.06.25.24309146. [Epub ahead of print]
    Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas.
    Michelle Monje, Jasia Mahdi, Robbie Majzner, Kristen Yeom, Liora M Schultz, Rebecca M Richards, Valentin Barsan, Kun-Wei Song, Jen Kamens, Christina Baggott, Michael Kunicki, Alexandria Sung Lim, Agnes Reschke, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Shabnum Patel, Harshini Chinnasamy, Courtney Erickson, Ashley Jacobs, Allison K Duh, Skyler P Rietberg, Ramya Tunuguntla, Dorota Danuta Klysz, Carley Fowler, Sean Green, Barbara Beebe, Casey Carr, Michelle Fujimoto, Annie Kathleen Brown, Ann-Louise G Petersen, Catherine McIntyre, Aman Siddiqui, Nadia Lepori-Bui, Katlin Villar, Kymhuynh Pham, Rachel Bove, Eric Musa, Warren Reynolds, Adam Kuo, Snehit Prabhu, Lindsey Rasmussen, Timothy T Cornell, Sonia Partap, Paul G Fisher, Cynthia J Campen, Gerald Grant, Laura Prolo, Xiaobu Ye, Bita Sahaf, Kara L Davis, Steven A Feldman, Sneha Ramakrishna, Crystal Mackall.
      H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.
    DOI:  https://doi.org/10.1101/2024.06.25.24309146
  8. Nat Commun. 2024 Jul 10. 15(1): 5790
    Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment.
    Adrian B Levine, Liana Nobre, Anirban Das, Scott Milos, Vanessa Bianchi, Monique Johnson, Nicholas R Fernandez, Lucie Stengs, Scott Ryall, Michelle Ku, Mansuba Rana, Benjamin Laxer, Javal Sheth, Stefanie-Grace Sbergio, Ivana Fedoráková, Vijay Ramaswamy, Julie Bennett, Robert Siddaway, Uri Tabori, Cynthia Hawkins.
      With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile a diverse range of 1382 samples with detailed clinical and molecular annotation. In low-grade gliomas we identify distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors. In high-grade gliomas, we observe immune activation and T-cell infiltrates in tumors that have historically been considered immune cold, as well as genomic correlates of inflammation levels. In mismatch repair deficient high-grade gliomas, we find that high tumor inflammation signature is a significant predictor of response to immune checkpoint inhibition, and demonstrate the potential for multimodal biomarkers to improve treatment stratification. Importantly, while overall patterns of immune activation are observed for histologically and genetically defined tumor types, there is significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine.
    DOI:  https://doi.org/10.1038/s41467-024-49595-1
  9. Commun Biol. 2024 Jul 06. 7(1): 824
    Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma.
    Zhen Yang, Xiaocen Liu, Hao Xu, Andrew E Teschendorff, Lingjie Xu, Jingyi Li, Minjie Fu, Jun Liu, Hanyu Zhou, Yingying Wang, Licheng Zhang, Yungang He, Kun Lv, Hui Yang.
      The expression dysregulation of microRNAs (miRNA) has been widely reported during cancer development, however, the underling mechanism remains largely unanswered. In the present work, we performed a systematic integrative study for genome-wide DNA methylation, copy number variation and miRNA expression data to identify mechanisms underlying miRNA dysregulation in lower grade glioma. We identify 719 miRNAs whose expression was associated with alterations of copy number variation or promoter methylation. Integrative multi-omics analysis revealed four subtypes with differing prognoses. These glioma subtypes exhibited distinct immune-related characteristics as well as clinical and genetic features. By construction of a miRNA regulatory network, we identified candidate miRNAs associated with immune evasion and response to immunotherapy. Finally, eight prognosis related miRNAs were validated to promote cell migration, invasion and proliferation through in vitro experiments. Our study reveals the crosstalk among DNA methylation, copy number variation and miRNA expression for immune regulation in glioma, and could have important implications for patient stratification and development of biomarkers for immunotherapy approaches.
    DOI:  https://doi.org/10.1038/s42003-024-06488-9
  10. Neuro Oncol. 2024 Jul 11. pii: noae131. [Epub ahead of print]
    In Vivo Mouse Models for Adult Brain Tumors: Exploring Tumorigenesis and Advancing Immunotherapy Development.
    John Figg, Dongjiang Chen, Laura Falceto Font, Catherine Flores, Dan Jin.
      Brain tumors, particularly glioblastoma (GBM), are devastating and challenging to treat, with a low 5-year survival rate of only 6.6%. Mouse models are established to understand tumorigenesis and develop new therapeutic strategies. Large-scale genomic studies have facilitated the identification of genetic alterations driving human brain tumor development and progression. Genetically engineered mouse models (GEMMs) with clinically relevant genetic alterations are widely used to investigate tumor origin. Additionally, syngeneic implantation models, utilizing cell lines derived from GEMMs or other sources, are popular for their consistent and relatively short latency period, addressing various brain cancer research questions. In recent years, the success of immunotherapy in specific cancer types has led to a surge in cancer immunology-related research which specifically necessitates the utilization of immunocompetent mouse models. In this review, we provide a comprehensive summary of GEMMs and syngeneic mouse models for adult brain tumors, emphasizing key features such as model origin, genetic alteration background, oncogenic mechanisms, and immune-related characteristics. Our review serves as a valuable resource for the brain tumor research community, aiding in the selection of appropriate models to study cancer immunology.
    Keywords:  Adult brain tumor; Genetically engineered mouse models; Immunotherapy response; Syngeneic implantation model
    DOI:  https://doi.org/10.1093/neuonc/noae131
  11. Nat Biomed Eng. 2024 Jul 11.
    Optical microscopy and transcriptomics reveal the origins of fluorescence in glioma surgery.
      
    DOI:  https://doi.org/10.1038/s41551-024-01218-2
  12. Clin Dermatol. 2024 Jul 06. pii: S0738-081X(24)00127-5. [Epub ahead of print]
    Letter to the Editor in Reply to: Reply to "A Call for Action: Formalin Exposure and Broader Occupational Hazards and Assessing the Risk of Glioblastoma in Clinician Scientists.
    Zachary Neubauer, Carrie Forman, Shari R Lipner, Hossein Akbarialiabad, Jane M Grant-Kels, Dedee F Murrell.
      
    Keywords:  American Cancer Society; carcinogen; dermatologic surgeons; dermatologists; dermatopathologists; environment; formaldehyde; formalin; glioblastoma; herpes simplex virus; high-risk profession; neurotoxin; occupational exposure; statistics
    DOI:  https://doi.org/10.1016/j.clindermatol.2024.07.002
  13. Nat Commun. 2024 Jul 12. 15(1): 5871
    Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade.
    Christina A von Roemeling, Jeet A Patel, Savannah L Carpenter, Oleg Yegorov, Changlin Yang, Alisha Bhatia, Bently P Doonan, Rylynn Russell, Vrunda S Trivedi, Kelena Klippel, Daniel H Ryu, Adam Grippin, Hunter S Futch, Yong Ran, Lan B Hoang-Minh, Frances L Weidert, Todd E Golde, Duane A Mitchell.
      There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability.
    DOI:  https://doi.org/10.1038/s41467-024-49989-1
  14. Nat Commun. 2024 Jul 07. 15(1): 5690
    Directional integration and pathway enrichment analysis for multi-omics data.
    Mykhaylo Slobodyanyuk, Alexander T Bahcheli, Zoe P Klein, Masroor Bayati, Lisa J Strug, Jüri Reimand.
      Omics techniques generate comprehensive profiles of biomolecules in cells and tissues. However, a holistic understanding of underlying systems requires joint analyses of multiple data modalities. We present DPM, a data fusion method for integrating omics datasets using directionality and significance estimates of genes, transcripts, or proteins. DPM allows users to define how the input datasets are expected to interact directionally given the experimental design or biological relationships between the datasets. DPM prioritises genes and pathways that change consistently across the datasets and penalises those with inconsistent directionality. To demonstrate our approach, we characterise gene and pathway regulation in IDH-mutant gliomas by jointly analysing transcriptomic, proteomic, and DNA methylation datasets. Directional integration of survival information in ovarian cancer reveals candidate biomarkers with consistent prognostic signals in transcript and protein expression. DPM is a general and adaptable framework for gene prioritisation and pathway analysis in multi-omics datasets.
    DOI:  https://doi.org/10.1038/s41467-024-49986-4
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