bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2024–12–08
fourteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. PDGFRα signaling regulates Srsf3 transcript binding to affect PI3K signaling and endosomal trafficking.
  2. Covalent inhibitor engages oncogenic AKT kinase.
  3. Technical challenges of intracellular flow cytometry-based assays as a functional complement to diagnosis of signaling defects of inborn errors of immunity: PI3K pathway as a case of study.
  4. Interpreting single-cell and spatial omics data using deep neural network training dynamics.
  5. Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery.
  6. The signaling landscape of insulin-like growth factor 1.
  7. From sampling to simulating: Single-cell multiomics in systems pathophysiological modeling.
  8. PIK3CA-Related Overgrowth Spectrum: Exploring Brain Growth From Fetal to Infant.
  9. Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes.
  10. Parallel measurement of transcriptomes and proteomes from same single cells using nanodroplet splitting.
  11. Phosphatidylinositol 4,5-bisphosphate drives the formation of EGFR and EphA2 complexes.
  12. Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma.
  13. From nuclear to extracellular PTEN: Multiple roles in tumor suppression and immune modulation.
  14. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.
  1. Elife. 2024 Dec 04. pii: RP98531. [Epub ahead of print]13
    PDGFRα signaling regulates Srsf3 transcript binding to affect PI3K signaling and endosomal trafficking.
    Thomas E Forman, Marcin P Sajek, Eric D Larson, Neelanjan Mukherjee, Katherine A Fantauzzo.
      Signaling through the platelet-derived growth factor receptor alpha (PDGFRα) plays a critical role in craniofacial development. Phosphatidylinositol 3-kinase (PI3K)/Akt is the primary effector of PDGFRα signaling during mouse skeletal development. We previously demonstrated that Akt phosphorylates the RNA-binding protein serine/arginine-rich splicing factor 3 (Srsf3) downstream of PI3K-mediated PDGFRα signaling in mouse embryonic palatal mesenchyme (MEPM) cells, leading to its nuclear translocation. We further showed that ablation of Srsf3 in the murine neural crest lineage results in severe midline facial clefting and widespread alternative RNA splicing (AS) changes. Here, we demonstrated via enhanced UV-crosslinking and immunoprecipitation of MEPM cells that PDGF-AA stimulation leads to preferential binding of Srsf3 to exons and loss of binding to canonical Srsf3 CA-rich motifs. Through the analysis of complementary RNA-seq data, we showed that Srsf3 activity results in the preferential inclusion of exons with increased GC content and lower intron to exon length ratio. We found that Srsf3 activity downstream of PDGFRα signaling leads to retention of the receptor in early endosomes and increases in downstream PI3K-mediated Akt signaling. Taken together, our findings reveal that growth factor-mediated phosphorylation of an RNA-binding protein underlies gene expression regulation necessary for mammalian craniofacial development.
    Keywords:  PDGFRa; Srsf3; genetics; genomics; mouse; mouse embryonic palatal mesenchyme
    DOI:  https://doi.org/10.7554/eLife.98531
  2. Nat Rev Drug Discov. 2024 Dec 03.
    Covalent inhibitor engages oncogenic AKT kinase.
    Alex Eccleston.
      
    DOI:  https://doi.org/10.1038/d41573-024-00197-y
  3. Front Immunol. 2024 ;15 1476218
    Technical challenges of intracellular flow cytometry-based assays as a functional complement to diagnosis of signaling defects of inborn errors of immunity: PI3K pathway as a case of study.
    Lucía Del Pino Molina, Keren Reche Yebra, Yolanda Soto Serrano, Álvaro Clemente Bernal, Carmen L Avendaño-Monje, J Gonzalo Ocejo-Vinyals, Rebeca Rodríguez Pena, Eduardo López Granados.
       Background: The use of next-generation sequencing in inborn errors of immunity (IEI) has considerably increased the identification of novel gene variants, many of which are identified in patients without the described clinical phenotype or with variants of uncertain pathogenic significance in previously described genes. Properly designed functional and cellular assays, many necessarily accomplished by research-based laboratories, reveal the pathogenic consequences of the gene variants and contribute to diagnosis. Activated PI3Kδ syndrome (APDS) is a rare disease that can be divided into APDS1, caused by gain of function (GOF) mutations in PIK3CD gene, and APDS2, with loss of function (LOF) variants in the PIK3R1 gene. Both entities present hyperactivation of the PI3K pathway, which can be analyzed through Akt and S6 phosphorylation status.
    Methods: Our objective was to perform an accurate, robust, and reproducible functional assay to analyze the phosphorylation status of proteins in the PI3K-Akt-S6 pathway by flow cytometry, to contribute to diagnosis, to monitor treatments, and to establish intra-assay standardization.
    Results: We illustrate the robustness and reproducibility of our experimental procedure in patients with APDS who had high Akt and/or S6 phosphorylation levels at baseline, and after anti-IgM stimulation in B cells. We show the relevance of an appropriate cohort of samples from healthy donors, processed within the same conditions as the suspected samples, in particular the time frame for sample processing once blood is collected.
    Discussion: We highlight the importance of B cell stimulation through B cell receptor signaling, which is highly recommended, especially for samples that would be processed more than 24 hours after blood extraction. Also, having a defined experimental procedure is important, including the cytometer setup, which allows cytometer reproducibility for a period of time, enabling the comparison of a sample at different times.
    Keywords:  activated PI3Kδ syndrome (APDS); flow cytometry; functional assays; inborn errors of immunity (IEI); monitoring PI3K-Akt-S6 pathway; standardization
    DOI:  https://doi.org/10.3389/fimmu.2024.1476218
  4. Nat Comput Sci. 2024 Dec 04.
    Interpreting single-cell and spatial omics data using deep neural network training dynamics.
    Jonathan Karin, Reshef Mintz, Barak Raveh, Mor Nitzan.
      Single-cell and spatial omics datasets can be organized and interpreted by annotating single cells to distinct types, states, locations or phenotypes. However, cell annotations are inherently ambiguous, as discrete labels with subjective interpretations are assigned to heterogeneous cell populations on the basis of noisy, sparse and high-dimensional data. Here we developed Annotatability, a framework for identifying annotation mismatches and characterizing biological data structure by monitoring the dynamics and difficulty of training a deep neural network over such annotated data. Following this, we developed a signal-aware graph embedding method that enables downstream analysis of biological signals. This embedding captures cellular communities associated with target signals. Using Annotatability, we address key challenges in the interpretation of genomic data, demonstrated over eight single-cell RNA sequencing and spatial omics datasets, including identifying erroneous annotations and intermediate cell states, delineating developmental or disease trajectories, and capturing cellular heterogeneity. These results underscore the broad applicability of annotation-trainability analysis via Annotatability for unraveling cellular diversity and interpreting collective cell behaviors in health and disease.
    DOI:  https://doi.org/10.1038/s43588-024-00721-5
  5. Nat Neurosci. 2024 Dec;27(12): 2292-2309
    Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery.
    Boyan Bonev, Castelo-Branco Gonçalo, Fei Chen, Simone Codeluppi, M Ryan Corces, Jean Fan, Myriam Heiman, Kenneth Harris, Fumitaka Inoue, Manolis Kellis, Ariel Levine, Mo Lotfollahi, Chongyuan Luo, Kristen R Maynard, Mor Nitzan, Vijay Ramani, Rahul Satijia, Lucas Schirmer, Yin Shen, Na Sun, Gilad S Green, Fabian Theis, Xiao Wang, Joshua D Welch, Ozgun Gokce, Genevieve Konopka, Shane Liddelow, Evan Macosko, Omer Bayraktar, Naomi Habib, Tomasz J Nowakowski.
      Over the past decade, single-cell genomics technologies have allowed scalable profiling of cell-type-specific features, which has substantially increased our ability to study cellular diversity and transcriptional programs in heterogeneous tissues. Yet our understanding of mechanisms of gene regulation or the rules that govern interactions between cell types is still limited. The advent of new computational pipelines and technologies, such as single-cell epigenomics and spatially resolved transcriptomics, has created opportunities to explore two new axes of biological variation: cell-intrinsic regulation of cell states and expression programs and interactions between cells. Here, we summarize the most promising and robust technologies in these areas, discuss their strengths and limitations and discuss key computational approaches for analysis of these complex datasets. We highlight how data sharing and integration, documentation, visualization and benchmarking of results contribute to transparency, reproducibility, collaboration and democratization in neuroscience, and discuss needs and opportunities for future technology development and analysis.
    DOI:  https://doi.org/10.1038/s41593-024-01806-0
  6. J Biol Chem. 2024 Dec 03. pii: S0021-9258(24)02549-3. [Epub ahead of print] 108047
    The signaling landscape of insulin-like growth factor 1.
    Muhammad Zahid Khan, Jose Luis Zugaza, Ignacio Torres Aleman.
      The sheer amplitude of biological actions of insulin-like growth factor I (IGF-1) affecting all type of cells in all tissues suggests a vast signaling landscape for this ubiquitous humoral signal. While the canonical signaling pathways primarily involve the Ras/MAPK and PI3K/AKT cascades, the evolutionary conservation of insulin-like peptides (ILPs) and their pathways hints at the potential for novel functions to emerge over time. Indeed, the evolutionary trajectory of ILPs open the possibility of either novel functions for these two pathways, novel downstream routes, or both. Evidence supporting this notion includes observations of neofunctionalization in bony fishes or crustaceans, and the involvement of ILPs pathways in invertebrate eusociality or in vertebrate bone physiology, respectively. Such evolutionary processes likely contribute to the rich diversity of ILPs signaling observed today. Moreover, the interplay between conserved signaling pathways, such as those implicated in aging (predominantly involving the PI3K-AKT route), and lesser-known pathways, such as those mediated by biased G-protein coupled receptors and others even less known, may underpin the context-dependent actions characteristic of ILPs signaling. While canonical IGF-1 signaling is often assumed to account for the intracellular pathways utilized by this growth factor, a comprehensive analysis of all the pathways mediated by the IGF-1 receptor (IGF-1R) remains lacking. This review aims to explore both canonical and non-canonical routes of IGF-1R action across various cell types, offering a detailed examination of the mechanisms underlying IGF-1 signaling and highlighting the significant gaps in our current understanding.
    Keywords:  AKT (PKB); Ras protein; insulin receptor substrate 1 (IRS-1); insulin-like growth factor; phosphatidylinositide-3 kinase (PI3K); signaling
    DOI:  https://doi.org/10.1016/j.jbc.2024.108047
  7. iScience. 2024 Dec 20. 27(12): 111322
    From sampling to simulating: Single-cell multiomics in systems pathophysiological modeling.
    Alexandra Manchel, Michelle Gee, Rajanikanth Vadigepalli.
      As single-cell omics data sampling and acquisition methods have accumulated at an unprecedented rate, various data analysis pipelines have been developed for the inference of cell types, cell states and their distribution, state transitions, state trajectories, and state interactions. This presents a new opportunity in which single-cell omics data can be utilized to generate high-resolution, high-fidelity computational models. In this review, we discuss how single-cell omics data can be used to build computational models to simulate biological systems at various scales. We propose that single-cell data can be integrated with physiological information to generate organ-specific models, which can then be assembled to generate multi-organ systems pathophysiological models. Finally, we discuss how generic multi-organ models can be brought to the patient-specific level thus permitting their use in the clinical setting.
    Keywords:  Biological constraints; Data processing in systems biology; In silico biology; Omics; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111322
  8. Pediatr Neurol. 2024 Nov 15. pii: S0887-8994(24)00388-6. [Epub ahead of print]163 12-14
    PIK3CA-Related Overgrowth Spectrum: Exploring Brain Growth From Fetal to Infant.
    Beatriz Parreira Andrade, Fátima Hierro, Jorge Castro, Josué Pereira, Joana Nunes, Joana Grenha.
       BACKGROUND: Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) is a rare neurological disorder characterized by abnormal brain size, vascular malformations, and body overgrowth. MCAP is caused by somatic mosaicism of PIK3CA, a crucial gene in regulation of cell growth and survival, and is one of the disorders in the PIK3CA-related overgrowth spectrum.
    METHODS: We present a unique clinical report of a male infant diagnosed with MCAP from prenatal stages to age 12 months. Prenatal imaging unveiled ventricular asymmetry, later confirmed postnatally as megalencephaly. Genetic analysis identified a PIK3CA mutation. The patient underwent early interventions, including ventriculoperitoneal shunt placement and posterior fossa decompression.
    RESULTS: Despite early interventions, the patient developed progressive macrocrania, hydrocephalus, and significant neurodevelopmental delay. Multidisciplinary management and continuous neuroimaging were crucial in addressing complications associated with the disorder.
    CONCLUSIONS: This case underscores the critical need for multidisciplinary care and continual neuroimaging surveillance to effectively navigate the progressive complications associated with PIK3CA-related overgrowth spectrum. The diagnostic hurdles and management challenges intrinsic to the disorder's natural course are elucidated. Although current treatments manage symptoms, emerging therapies hold promise for improving patient outcomes.
    Keywords:  Brain growth; Megalencephaly; PIK3CA; Pediatric
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2024.11.002
  9. Nat Biomed Eng. 2024 Dec 04.
    Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes.
    Jiang-An Yin, Lukas Frick, Manuel C Scheidmann, Tingting Liu, Chiara Trevisan, Ashutosh Dhingra, Anna Spinelli, Yancheng Wu, Longping Yao, Dalila Laura Vena, Britta Knapp, Jingjing Guo, Elena De Cecco, Kathi Ging, Andrea Armani, Edward J Oakeley, Florian Nigsch, Joel Jenzer, Jasmin Haegele, Michal Pikusa, Joachim Täger, Salvador Rodriguez-Nieto, Vangelis Bouris, Rafaela Ribeiro, Federico Baroni, Manmeet Sakshi Bedi, Scott Berry, Marco Losa, Simone Hornemann, Martin Kampmann, Lucas Pelkmans, Dominic Hoepfner, Peter Heutink, Adriano Aguzzi.
      Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms. The quadruple-sgRNA libraries yielded high perturbation efficacies in deletion (75-99%) and silencing (76-92%) experiments and substantial fold changes in activation experiments. Moreover, an arrayed activation screen of 1,634 human transcription factors uncovered 11 novel regulators of the cellular prion protein PrPC, screening with a pooled version of the ablation library led to the identification of 5 novel modifiers of autophagy that otherwise went undetected, and 'post-pooling' individually produced lentiviruses eliminated template-switching artefacts and enhanced the performance of pooled screens for epigenetic silencing. Quadruple-sgRNA arrayed libraries are a powerful and versatile resource for targeted genome-wide perturbations.
    DOI:  https://doi.org/10.1038/s41551-024-01278-4
  10. Nat Commun. 2024 Dec 05. 15(1): 10614
    Parallel measurement of transcriptomes and proteomes from same single cells using nanodroplet splitting.
    James M Fulcher, Lye Meng Markillie, Hugh D Mitchell, Sarah M Williams, Kristin M Engbrecht, David J Degnan, Lisa M Bramer, Ronald J Moore, William B Chrisler, Joshua Cantlon-Bruce, Johannes W Bagnoli, Wei-Jun Qian, Anjali Seth, Ljiljana Paša-Tolić, Ying Zhu.
      Single-cell multiomics provides comprehensive insights into gene regulatory networks, cellular diversity, and temporal dynamics. Here, we introduce nanoSPLITS (nanodroplet SPlitting for Linked-multimodal Investigations of Trace Samples), an integrated platform that enables global profiling of the transcriptome and proteome from same single cells via RNA sequencing and mass spectrometry-based proteomics, respectively. Benchmarking of nanoSPLITS demonstrates high measurement precision with deep proteomic and transcriptomic profiling of single-cells. We apply nanoSPLITS to cyclin-dependent kinase 1 inhibited cells and found phospho-signaling events could be quantified alongside global protein and mRNA measurements, providing insights into cell cycle regulation. We extend nanoSPLITS to primary cells isolated from human pancreatic islets, introducing an efficient approach for facile identification of unknown cell types and their protein markers by mapping transcriptomic data to existing large-scale single-cell RNA sequencing reference databases. Accordingly, we establish nanoSPLITS as a multiomic technology incorporating global proteomics and anticipate the approach will be critical to furthering our understanding of biological systems.
    DOI:  https://doi.org/10.1038/s41467-024-54099-z
  11. Sci Adv. 2024 Dec 06. 10(49): eadl0649
    Phosphatidylinositol 4,5-bisphosphate drives the formation of EGFR and EphA2 complexes.
    Pradeep Kumar Singh, Jennifer A Rybak, Ryan J Schuck, Amita R Sahoo, Matthias Buck, Francisco N Barrera, Adam W Smith.
      Receptor tyrosine kinases (RTKs) regulate many cellular functions and are important targets in pharmaceutical development, particularly in cancer treatment. EGFR and EphA2 are two key RTKs that are associated with oncogenic phenotypes. Several studies have reported functional interplay between these receptors, but the mechanism of interaction is still unresolved. Here, we use a time-resolved fluorescence spectroscopy called PIE-FCCS to resolve EGFR and EphA2 interactions in live cells. We tested the role of ligands and found that EGF, but not ephrin A1 (EA1), stimulated heteromultimerization between the receptors. To determine the effect of anionic lipids, we targeted phospholipase C (PLC) activity to alter the abundance of phosphatidylinositol 4,5-bisphosphate (PIP2). We found that higher PIP2 levels increased homomultimerization of both EGFR and EphA2, as well as heteromultimerization. This study provides a direct characterization of EGFR and EphA2 interactions in live cells and shows that PIP2 can have a substantial effect on the spatial organization of RTKs.
    DOI:  https://doi.org/10.1126/sciadv.adl0649
  12. Cancer Res. 2024 Dec 05.
    Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma.
    Catriona A Ford, Dana Koludrovic, Patricia P Centeno, Mona Foth, Elpida Tsonou, Nikola Vlahov, Nathalie Sphyris, Kathryn Gilroy, Courtney Bull, Colin Nixon, Bryan Serrels, Alison F Munro, John C Dawson, Neil O Carragher, Valeria Pavet, David C Hornigold, Philip D Dunne, Julian Downward, Heidi C Welch, Simon T Barry, Owen J Sansom, Andrew D Campbell.
      Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression. Here, we used genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. While PREX2 was dispensable for the initiation and progression of melanoma, its loss conferred sensitivity to clinically relevant therapeutics targeting the MAPK pathway. Importantly, genetic and pharmacological targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2814
  13. Dev Cell. 2024 Dec 02. pii: S1534-5807(24)00568-9. [Epub ahead of print]59(23): 3059-3060
    From nuclear to extracellular PTEN: Multiple roles in tumor suppression and immune modulation.
    Dan Lu, Yuxin Yin.
      In this issue of Developmental Cell, Zhang et al. report that secreted PTEN reprograms immunosuppressive tumor-associated macrophages into an inflammatory phenotype by binding to PLXDC2, which enhances antitumor immunity. This Preview discusses diverse functions of PTEN in the nucleus, cytoplasm, and extracellular matrix, highlighting its multifaceted roles in cancer.
    DOI:  https://doi.org/10.1016/j.devcel.2024.09.019
  14. Lancet Oncol. 2024 Dec;pii: S1470-2045(24)00673-9. [Epub ahead of print]25(12): e629-e638
    Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.
    Hope S Rugo, Florence Lerebours, Eva Ciruelos, Pamela Drullinsky, Manuel Ruiz-Borrego, Patrick Neven, Yeon Hee Park, Aleix Prat, Thomas Bachelot, Dejan Juric, Nicholas Turner, Nickolas Sophos, Juan Pablo Zarate, Christina Arce, Yu-Ming Shen, Stuart Turner, Hemanth Kanakamedala, Wei-Chun Hsu, Stephen Chia.
       BACKGROUND: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A.
    METHODS: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755.
    FINDINGS: Between Aug 14, 2017, and Jul 29, 2022 (data cutoff), 127 patients with at least 18 months' follow-up were enrolled into cohort A. 119 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 21·8 months (IQR 10·8-37·6). 64 (53·8%; 95% CI 44·4-63·0) of 119 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (37 [29%] of 127 patients), rash (13 [10%]), and rash maculopapular (11 [9%]). Serious adverse events occurred in 37 (29%) of 127 patients. No treatment-related deaths were reported.
    INTERPRETATION: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.
    FUNDING: Novartis Pharmaceuticals.
    DOI:  https://doi.org/10.1016/S1470-2045(24)00673-9
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