bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–04–27
nineteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Ibaqpy: A scalable Python package for baseline quantification in proteomics leveraging SDRF metadata.
  2. The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer.
  3. Far-red chemigenetic kinase biosensors enable multiplexed and super-resolved imaging of signaling networks.
  4. Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition.
  5. PI3K/AKT signaling mediates stress-inducible amyloid formation through c-Myc.
  6. Synchronized temporal-spatial analysis via microscopy and phosphoproteomics (STAMP) of quiescence.
  7. FGFR2 residence in primary cilia is necessary for epithelial cell signaling.
  8. Metabolic and Vascular Insulin Resistance: Partners in the Pathogenesis of Cardiovascular Disease in Diabetes.
  9. Cell Painting PLUS: expanding the multiplexing capacity of Cell Painting-based phenotypic profiling using iterative staining-elution cycles.
  10. CellPhePy: A python implementation of the CellPhe toolkit for automated cell phenotyping from microscopy time-lapse videos.
  11. Temporal and spatial omics technologies for 4D profiling.
  12. Pooled tagging and hydrophobic targeting of endogenous proteins for unbiased mapping of unfolded protein responses.
  13. A protein tunnel that shuttles lipids around the cell.
  14. Analysis of multiple insulin actions in single muscle fibres from insulin resistant mice reveals selective defect in endogenous GLUT4 translocation.
  15. Thoracic Giant Venous Malformation in a Stillbirth with Pik3ca Somatic Mutation.
  16. MIQE 2.0: Revision of the Minimum Information for Publication of Quantitative Real-Time PCR Experiments Guidelines.
  17. Endothelial dysfunction in cardiovascular diseases: mechanisms and in vitro models.
  18. Science sleuths flag hundreds of papers that use AI without disclosing it.
  19. BRD9 functions as a methylarginine reader to regulate AKT-EZH2 signaling.
  1. J Proteomics. 2025 Apr 21. pii: S1874-3919(25)00067-3. [Epub ahead of print] 105440
    Ibaqpy: A scalable Python package for baseline quantification in proteomics leveraging SDRF metadata.
    Ping Zheng, Enrique Audain, Henry Webel, Chengxin Dai, Joshua Klein, Marc-Phillip Hitz, Timo Sachsenberg, Mingze Bai, Yasset Perez-Riverol.
      Intensity-based absolute quantification (iBAQ) is essential in proteomics as it allows for the assessment of a protein's absolute abundance in various samples or conditions. However, the computation of these values for increasingly large-scale and high-throughput experiments, such as those using DIA, TMT, or LFQ workflows, poses significant challenges in scalability and reproducibility. Here, we present ibaqpy (https://github.com/bigbio/ibaqpy), a Python package designed to compute iBAQ values efficiently for experiments of any scale. Ibaqpy leverages the Sample and Data Relationship Format (SDRF) metadata standard to incorporate experimental metadata into the quantification workflow. This allows for automatic normalization and batch correction while accounting for key aspects of the experimental design, such as technical and biological replicates, fractionation strategies, and sample conditions. Designed for large-scale proteomics datasets, ibaqpy can also recompute iBAQ values for existing experiments when an SDRF is available. We showcased ibaqpy's capabilities by reanalyzing 17 public proteomics datasets from ProteomeXchange, covering HeLa cell lines with 4921 samples and 5766 MS runs, quantifying a total of 11,014 proteins. In our reanalysis, ibaqpy is a key component in automating reproducible quantification, reducing manual effort and making quantitative proteomics more accessible while supporting FAIR principles for data reuse. SIGNIFICANCE: Proteomics studies often rely on intensity-based absolute quantification (iBAQ) to assess protein abundance across various biological conditions. Despite its widespread use, computing iBAQ values at scale remains challenging due to the increasing complexity and volume of proteomics experiments. Existing tools frequently lack metadata integration, limiting their ability to handle experimental design intricacies such as replicates, fractions, and batch effects. Our work introduces ibaqpy, a scalable Python package that leverages the Sample and Data Relationship Format (SDRF) to compute iBAQ values efficiently while incorporating critical experimental metadata. By enabling automated normalization and batch correction, ibaqpy ensures reproducible and comparable quantification across large-scale datasets. We validated the utility of ibaqpy through the reanalysis of 17 public HeLa datasets, comprising over 200 million peptide features and quantifying 11,000 proteins across thousands of samples. This comprehensive reanalysis highlights the robustness and scalability of ibaqpy, making it an essential tool for researchers conducting large-scale proteomics experiments. Moreover, by promoting FAIR principles for data reuse and interoperability, ibaqpy offers a transformative approach to baseline protein quantification, supporting reproducible research and data integration within the proteomics community.
    Keywords:  Big data; Bioinformatics; Data integration; Proteomics; Quantification
    DOI:  https://doi.org/10.1016/j.jprot.2025.105440
  2. NPJ Breast Cancer. 2025 Apr 22. 11(1): 36
    The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer.
    Valentina Cutano, Ming Li Chia, Eleanor M Wigmore, Lorna Hopcroft, Stuart C Williamson, Amanda L Christie, Brandon Willis, James Kerr, Jenny Ashforth, Rhys Fox, Sophie D'Arcy, Lauren Bradshaw, Catherine Blaker, Cath Eberlein, Lambert Montava-Garriga, Elza C de Bruin, Susan E Critchlow, Kevin M Brindle, Simon T Barry, Susana Ros.
      Loss of PTEN expression, via homozygous or hemizygous deletion, is common in PIK3CA mutant ER + BC tumors. We assessed reduction of PTEN protein expression on AKT inhibitor capivasertib efficacy in PIK3CA altered tumors. In PIK3CA altered, PTEN protein high models, PI3Kα and AKT inhibition was effective, however ablation and partial PTEN expression reduction attenuated PI3Kαi but not AKTi efficacy, alone or combined with fulvestrant. Efficacy was FOXO3 dependent and associated with FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, and increased FOXM1 expression. Long term capivasertib exposure of ER+ BC cells upregulated FOXM1 expression. Downregulating FOXM1 expression reversed resistance to capivasertib, while FOXM1 overexpression reduced capivasertib efficacy. Collectively this suggests the AKT-FOXO3-FOXM1 axis plays a pivotal role in response to AKTi in ER+ breast cancer with PIK3CA mutations with and without expression of PTEN, that FOXO3 expression loss can mediate resistance, and that FOXM1 downregulation is a potential biomarker of response.
    DOI:  https://doi.org/10.1038/s41523-025-00752-9
  3. Nat Biotechnol. 2025 Apr 21.
    Far-red chemigenetic kinase biosensors enable multiplexed and super-resolved imaging of signaling networks.
    Michelle S Frei, Samantha A Sanchez, Xinchang He, Longwei Liu, Falk Schneider, Zichen Wang, Hiroyuki Hakozaki, Yajuan Li, Anne C Lyons, Theresa V Rohm, Jerrold M Olefsky, Lingyan Shi, Johannes Schöneberg, Scott E Fraser, Sohum Mehta, Yingxiao Wang, Jin Zhang.
      Fluorescent biosensors have advanced biomedical research by enabling direct live-cell measurements of signaling activities. However, current technology offers limited resolution and dimensionality, impeding our ability to resolve and interrogate spatiotemporally regulated networks of signaling activities. Here we introduce highly sensitive chemigenetic kinase activity biosensors that combine the genetically encodable self-labeling tag, HaloTag7, with far-red-emitting synthetic fluorophores. This technology enables both four-dimensional activity imaging and functional super-resolution imaging using stimulated emission depletion and other high-resolution microscopy techniques, permitting signaling activity to be detected across scales with the necessary resolution. Stimulated emission depletion imaging enabled the investigation of protein kinase A activity at individual clathrin-coated pits. We further demonstrate imaging of up to five analytes in single living cells, an increase in the dimensionality of biosensor multiplexing. Multiplexed imaging of cellular responses to the activation of different G-protein-coupled receptors (GPCRs) allowed quantitative measurements of spatiotemporal network states downstream of individual GPCR-ligand pairs.
    DOI:  https://doi.org/10.1038/s41587-025-02642-8
  4. Neuron. 2025 Apr 14. pii: S0896-6273(25)00247-8. [Epub ahead of print]
    Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition.
    Sung Min Son, Farah H Siddiqi, Ana Lopez, Rizwan Ansari, Sylwia D Tyrkalska, So Jung Park, Tilo Kunath, Emmanouil Metzakopian, Angeleen Fleming, David C Rubinsztein.
      Triplications and certain point mutations in the SNCA gene, encoding alpha-synuclein (α-Syn), cause Parkinson's disease (PD). Here, we demonstrate that the PD-causing A53T α-Syn mutation and elevated α-Syn expression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons and in the CNS of zebrafish and mice. This dysregulation is mediated by activation of ATP-citrate lyase (ACLY), a key enzyme that generates acetyl-CoA in the cytoplasm, via two mechanisms. First, ACLY activity increases acetyl-CoA levels, which activate p300. Second, ACLY activation increases LKB1 acetylation, which inhibits AMPK, leading to increased cytoplasmic and decreased nuclear p300. This lowers histone acetylation and increases acetylation of cytoplasmic p300 substrates, like raptor, which causes mechanistic target of rapamycin complex 1 (mTORC1) hyperactivation, thereby impairing autophagy. ACLY inhibitors rescue pathological phenotypes in PD neurons, organoids, zebrafish, and mouse models, suggesting that this pathway is a core feature of α-Syn toxicity and that ACLY may be a suitable therapeutic target.
    Keywords:  ACLY; AMPK; Parkinson's disease; acetyl-CoA; acetylation; alpha-synuclein; autophagy; mTORC1; nucleocytoplasmic shuttling of p300
    DOI:  https://doi.org/10.1016/j.neuron.2025.03.028
  5. Cell Rep. 2025 Apr 23. pii: S2211-1247(25)00388-2. [Epub ahead of print]44(5): 115617
    PI3K/AKT signaling mediates stress-inducible amyloid formation through c-Myc.
    Emma Lacroix, Evgenia A Momchilova, Sahil Chandhok, Mythili Padavu, Richard Zapf, Timothy E Audas.
      In response to environmental stress, eukaryotic cells reversibly form functional amyloid aggregates called amyloid bodies (A-bodies). While these solid-like biomolecular condensates share many biophysical characteristics with pathological amyloids, A-bodies are non-toxic, and they induce a protective state of cellular dormancy. As a recently identified structure, the modulators of A-body biogenesis remain uncharacterized, with the seeding noncoding RNA being the only known regulatory factor. Here, we use an image-based high-throughput screening approach to identify candidate pathways regulating A-body biogenesis. Our data demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling axis meditates A-body formation during stress exposure, with AKT activation repressing glycogen synthase kinase-3 (GSK3)-mediated degradation of c-Myc. This enhances c-Myc binding to regulatory elements of the seeding noncoding RNA, upregulating the transcripts that nucleate A-body formation. Identifying a link between PI3K/AKT signaling, c-Myc, and physiological amyloid aggregates extends the range of activity for these well-established regulators while providing insight into cellular components whose dysregulation could underly amyloidogenic disorders.
    Keywords:  Akt; CP: Cell biology; CP: Neuroscience; PI3K; amyloids; biomolecular condensates; c-Myc; environmental stress; heat shock; noncoding RNA; nucleolus; signal transduction
    DOI:  https://doi.org/10.1016/j.celrep.2025.115617
  6. Sci Adv. 2025 Apr 25. 11(17): eadt9712
    Synchronized temporal-spatial analysis via microscopy and phosphoproteomics (STAMP) of quiescence.
    Mohammad Ovais Azizzanjani, Rachel E Turn, Anushweta Asthana, Karen Y Linde-Garelli, Lucy Artemis Xu, Leilani E Labrie, Mohammadamin Mobedi, Peter K Jackson.
      Coordinated cell cycle regulation is essential for homeostasis, with most cells in the body residing in quiescence (G0). Many pathologies arise due to disruptions in tissue-specific G0, yet little is known about the temporal-spatial mechanisms that establish G0 and its signaling hub, primary cilia. Mechanistic insight is limited by asynchronous model systems and failure to connect context-specific, transient mechanisms to function. To address this gap, we developed STAMP (synchronized temporal-spatial analysis via microscopy and phosphoproteomics) to track changes in cellular landscape occurring throughout G0 transition and ciliogenesis. We synchronized ciliogenesis and G0 transition in two cell models and combined microscopy with phosphoproteomics to order signals for further targeted analyses. We propose that STAMP is broadly applicable for studying temporal-spatial signaling in many biological contexts. The findings revealed through STAMP provide critical insight into healthy cellular functions often disrupted in pathologies, paving the way for targeted therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.adt9712
  7. J Cell Biol. 2025 Jul 07. pii: e202311030. [Epub ahead of print]224(7):
    FGFR2 residence in primary cilia is necessary for epithelial cell signaling.
    Alexandru Nita, Sara P Abraham, Eman R Elrefaay, Bohumil Fafilek, Eliska Cizkova, Vlad Constantin Ursachi, Iva Gudernova, Adolf Koudelka, Pooja Dudeja, Tomas Gregor, Zuzana Feketova, Gustavo Rico, Katerina Svozilova, Canan Celiker, Aleksandra A Czyrek, Tomas Barta, Lukas Trantirek, Antoni Wiedlocha, Pavel Krejci, Michaela Bosakova.
      Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues. In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor. Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.
    DOI:  https://doi.org/10.1083/jcb.202311030
  8. Am J Physiol Heart Circ Physiol. 2025 Apr 21.
    Metabolic and Vascular Insulin Resistance: Partners in the Pathogenesis of Cardiovascular Disease in Diabetes.
    William B Horton, Kaitlin M Love, Justin M Gregory, Zhenqi Liu, Eugene J Barrett.
      Vascular insulin resistance has emerged as a pivotal factor in the genesis of cardiovascular disease (CVD) in people with diabetes. It forms a complex pathogenic partnership with metabolic insulin resistance to significantly amplify the CVD risk of diabetes and other affected populations. Metabolic insulin resistance (characterized by quantitatively diminished insulin action on glucose metabolism in skeletal muscle, liver, and adipose tissue) is a hallmark of diabetes, obesity, and related conditions. In contrast, vascular insulin resistance is a less appreciated and not well-quantified complication of these conditions. Importantly, an impaired vascular response to insulin contributes directly to vascular dysfunction and over 40 years of research has convincingly shown that vascular and metabolic insulin resistance synergize to create an environment that predisposes individuals to CVD. In this review, we examine the multifaceted vascular actions of insulin, including its roles in regulating blood pressure, blood flow, endothelial health, and arterial stiffness. We also examine how these processes become disrupted in the setting of vascular insulin resistance which subsequently undermines endothelial function, compromises tissue microvascular perfusion, and promotes vascular rigidity and atherosclerosis. We then highlight potential therapeutic strategies with demonstrated efficacy to improve vascular insulin sensitivity in people with diabetes and suggest that targeting disordered vascular insulin signaling holds promise not only for refining the functional understanding of vascular insulin resistance but also for developing innovative treatments with potential to reduce CVD risk and improve cardiovascular outcomes in people with diabetes.
    Keywords:  cardiovascular diseases; endothelial cells; insulin resistance; microvessels; type 1 diabetes mellitus; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1152/ajpheart.00826.2024
  9. Nat Commun. 2025 Apr 24. 16(1): 3857
    Cell Painting PLUS: expanding the multiplexing capacity of Cell Painting-based phenotypic profiling using iterative staining-elution cycles.
    Elena von Coburg, Marlene Wedler, Jose M Muino, Christopher Wolff, Nils Körber, Sebastian Dunst, Shu Liu.
      Phenotypic changes in the morphology and internal organization of cells can indicate perturbations in cell functions. Therefore, imaging-based high-throughput phenotypic profiling (HTPP) applications such as Cell Painting (CP) play an important role in basic and translational research, drug discovery, and regulatory toxicology. Here we present the Cell Painting PLUS (CPP) assay, an efficient, robust and broadly applicable approach that further expands the versatility of available HTPP methods and offers additional options for addressing mode-of-action specific research questions. An iterative staining-elution cycle allows multiplexing of at least seven fluorescent dyes that label nine different subcellular compartments and organelles including the plasma membrane, actin cytoskeleton, cytoplasmic RNA, nucleoli, lysosomes, nuclear DNA, endoplasmic reticulum, mitochondria, and Golgi apparatus. In this way, CPP significantly expands the flexibility, customizability, and multiplexing capacity of the original CP method and, importantly, also improves the organelle-specificity and diversity of the phenotypic profiles due to the separate imaging and analysis of single dyes in individual channels.
    DOI:  https://doi.org/10.1038/s41467-025-58765-8
  10. J Microsc. 2025 Apr 24.
    CellPhePy: A python implementation of the CellPhe toolkit for automated cell phenotyping from microscopy time-lapse videos.
    Laura Wiggins, Stuart Lacy, Graeme Park, Joanne Marrison, Ben Powell, Beth Cimini, Peter O'Toole, Julie Wilson, William J Brackenbury.
      We previously developed the CellPhe toolkit, an open-source R package for automated cell phenotyping from ptychography time-lapse videos. To align with the growing adoption of python-based image analysis tools and to enhance interoperability with widely used software for cell segmentation and tracking, we developed a python implementation of CellPhe, named CellPhePy. CellPhePy preserves all of the core functionality of the original toolkit, including single-cell phenotypic feature extraction, time-series analysis, feature selection and cell type classification. In addition, CellPhePy introduces significant enhancements, such as an improved method for identifying features that differentiate cell populations and extended support for multiclass classification, broadening its analytical capabilities. Notably, the CellPhePy package supports CellPose segmentation and TrackMate tracking, meaning that a set of microscopy images are the only required input with segmentation, tracking and feature extraction fully automated for downstream analysis, without reliance on external applications. The workflow's increased flexibility and modularity make it adaptable to different imaging modalities and fully customisable to address specific research questions. CellPhePy can be installed via PyPi or GitHub, and we also provide a CellPhePy GUI to aid user accessibility.
    Keywords:  cell phenotyping; image analysis; machine learning; microscopy; open‐source; segmentation; timelapse; tracking
    DOI:  https://doi.org/10.1111/jmi.13416
  11. Nat Methods. 2025 Apr 22.
    Temporal and spatial omics technologies for 4D profiling.
    David E Reynolds, Yoon Ho Roh, Daniel Oh, Phoebe Vallapureddy, Rong Fan, Jina Ko.
      Cells have distinct molecular repertoires on their surfaces and unique intracellular biomolecular profiles that play pivotal roles in orchestrating a myriad of biological responses in the context of growth, development and disease. A persistent challenge in the deep exploration of these cues has been in our inability to effectively and precisely capture the temporal and spatial characteristics of living cells. In this Perspective, we delve into techniques for temporal and two- and three-dimensional spatial omics analyses and underscore how their harmonious fusion promises to unlock insights into the dynamics and diversity of individual cells within biological systems such as tissues and organoids. We then explore four-dimensional profiling, a nascent but promising frontier that adds a temporal (fourth-dimension) component to three-dimensional omics; highlight the advancements, challenges and gaps in the field; and discuss potential strategies for further technological development.
    DOI:  https://doi.org/10.1038/s41592-025-02683-6
  12. Mol Cell. 2025 Apr 18. pii: S1097-2765(25)00305-3. [Epub ahead of print]
    Pooled tagging and hydrophobic targeting of endogenous proteins for unbiased mapping of unfolded protein responses.
    Stephanie E Sansbury, Yevgeniy V Serebrenik, Tomer Lapidot, David G Smith, George M Burslem, Ophir Shalem.
      To achieve system-level insights into proteome organization, regulation, and function, we developed an approach to generate complex cell pools with endogenously tagged proteins amenable to high-throughput visualization and perturbation. Pooled imaging coupled to in situ barcode sequencing identified the subcellular localization of each HaloTag-tagged protein, and subsequent ligand-induced misfolding of the library followed by single-cell RNA sequencing revealed responses to spatially restricted protein misfolding. These datasets characterized protein quality control responses in previously uninterrogated cellular compartments, and cross-compartment analyses revealed mutually exclusive rather than collaborative responses, whereby the heat shock response (HSR) is induced in some compartments and repressed in others where autophagy genes are induced. We further assign protein quality control functions to previously uncharacterized genes based on shared transcriptional responses to protein misfolding across cellular compartments. Altogether, we present an efficient method for large-scale studies of proteome dynamics, function, and homeostasis.
    Keywords:  hydrophobic targeting; in situ sequencing; pooled tagging; protein localization; protein misfolding; proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.002
  13. Nature. 2025 Apr 23.
    A protein tunnel that shuttles lipids around the cell.
      
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-025-01167-z
  14. Diabetes. 2025 Apr 24. pii: db250022. [Epub ahead of print]
    Analysis of multiple insulin actions in single muscle fibres from insulin resistant mice reveals selective defect in endogenous GLUT4 translocation.
    Sebastian Judge, Stewart Wc Masson, Søren Madsen, Meg Potter, David E James, James G Burchfield, Alexis Diaz-Vegas.
      Accurate measurement of GLUT4 translocation is crucial for understanding insulin resistance in skeletal muscle, a key factor in the development of metabolic diseases. However, current methods rely on overexpressed epitope-tagged GLUT4 constructs or indirect measurements, limiting their physiological relevance and applicability. To overcome these challenges, we developed an innovative high-sensitivity imaging-based method that enables the direct assessment of endogenous GLUT4 translocation in primary skeletal muscle fibres. This approach utilises antibodies targeting exofacial epitopes on native GLUT4. Our method allows multiplexed analysis of multiple insulin-sensitive processes, including transferrin receptor trafficking and FOXO nuclear exclusion, alongside mitochondrial oxidative stress. This comprehensive approach provides a unique opportunity to simultaneously assess insulin action across different signalling branches within individual muscle fibres. We validated this method across multiple inbred mouse strains and models of insulin resistance, including chronic insulin exposure, palmitate treatment, and high-fat diet-induced obesity. Notably, we identified a selective defect in GLUT4 trafficking in insulin-resistant muscle fibres, while other insulin-dependent processes remained intact. By offering a high-fidelity model that maintains physiological relevance, this novel approach represents a significant advancement in the study of skeletal muscle insulin resistance and provides a powerful tool for dissecting gene-environment interactions that underlpin metabolic disease.
    DOI:  https://doi.org/10.2337/db25-0022
  15. Fetal Pediatr Pathol. 2025 Apr 24. 1-10
    Thoracic Giant Venous Malformation in a Stillbirth with Pik3ca Somatic Mutation.
    Nunzio Cosimo Mario Salfi, Sabrina Gismondi, Anna Martinelli, Elisa Tidu, Patrizio Giovanni Maria Antonazzo, Stefano Faiola, Mariano Matteo Lanna, Elisa Cattaneo, Enrico Farnetti, Davide Nicoli, Maria Paola Bonasoni.
      Introduction: Congenital venous malformations (VMs) are typically located in the skin of the head and neck, but extension to deep tissues and visceral organs may occur. In 20% of cases, sporadic VMs are caused by somatic mutations in the PIK3CA gene, which determines aberrant angiogenesis. Case report: Intrauterine death of a fetus with a known extensive vascular lesion of the right hemithorax occurred at 28 weeks + 6 days. Autopsy revealed abundant bilateral pleural effusions, and histology showed a VM. High-depth next-generation sequencing for PIK3CA and TEK on amniocytes was negative. Postmortem real-time polymerase chain reaction for PIK3CA on paraffin-embedded samples of the lesion revealed somatic p.H1047X hotspot mutation in the exon 20. Conclusion: To the best of our knowledge, this is the first case of a VM in a stillbirth. Extensive lesions carry a high risk of fetal demise due to high-output cardiac failure.
    Keywords:  PIK3CA gene; Venous malformation; somatic p.H1047X hotspot mutation exon 20
    DOI:  https://doi.org/10.1080/15513815.2025.2493721
  16. Clin Chem. 2025 Apr 24. pii: hvaf043. [Epub ahead of print]
    MIQE 2.0: Revision of the Minimum Information for Publication of Quantitative Real-Time PCR Experiments Guidelines.
    Stephen A Bustin, Jan M Ruijter, Maurice J B van den Hoff, Mikael Kubista, Michael W Pfaffl, Gregory L Shipley, Nham Tran, Stefan Rödiger, Andreas Untergasser, Reinhold Mueller, Tania Nolan, Mojca Milavec, Malcolm J Burns, Jim F Huggett, Jo Vandesompele, Carl T Wittwer.
       BACKGROUND: In 2009, the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines established standards for the design, execution, and reporting of quantitative PCR (qPCR) in research. The expansion of qPCR into numerous new domains has driven the development of new reagents, methods, consumables, and instruments, requiring revisions to best practices that are tailored to the evolving complexities of contemporary qPCR applications.
    CONTENT: Transparent, clear, and comprehensive description and reporting of all experimental details are necessary to ensure the repeatability and reproducibility of qPCR results. These revised MIQE guidelines reflect recent advances in qPCR technology, offering clear recommendations for sample handling, assay design, and validation, along with guidance on qPCR data analysis. Instrument manufacturers are encouraged to enable the export of raw data to facilitate thorough analyses and re-evaluation by manuscript reviewers and interested researchers. The guidelines emphasize that quantification cycle (Cq) values should be converted into efficiency-corrected target quantities and reported with prediction intervals, along with detection limits and dynamic ranges for each target, based on the chosen quantification method. Additionally, best practices for normalization and quality control are outlined and reporting requirements have been clarified and streamlined. The aim is to encourage researchers to provide all necessary information without undue burden, thereby promoting more rigorous and reproducible qPCR research.
    SUMMARY: Building on the collaborative efforts of an international team of researchers, we present updates, simplifications, and new recommendations to the original MIQE guidelines, designed to maintain their relevance and applicability in the context of emerging technologies and evolving qPCR applications.
    DOI:  https://doi.org/10.1093/clinchem/hvaf043
  17. Mol Cell Biochem. 2025 Apr 21.
    Endothelial dysfunction in cardiovascular diseases: mechanisms and in vitro models.
    Ana Grego, Cristiana Fernandes, Ivo Fonseca, Marina Dias-Neto, Raquel Costa, Adelino Leite-Moreira, Sandra Marisa Oliveira, Fábio Trindade, Rita Nogueira-Ferreira.
      Endothelial cells (ECs) are arranged side-by-side to create a semi-permeable monolayer, forming the inner lining of every blood vessel (micro and macrocirculation). Serving as the first barrier for circulating molecules and cells, ECs represent the main regulators of vascular homeostasis being able to respond to environmental changes, either physical or chemical signals, by producing several factors that regulate vascular tone and cellular adhesion. Healthy endothelium has anticoagulant properties that prevent the adhesion of leukocytes and platelets to the vessel walls, contributing to resistance to thrombus formation, and regulating inflammation, and vascular smooth muscle cell proliferation. Many risk factors of cardiovascular diseases (CVDs) promote the endothelial expression of chemokines, cytokines, and adhesion molecules. The resultant endothelial activation can lead to endothelial cell dysfunction (ECD). In vitro models of ECD allow the study of cellular and molecular mechanisms of disease and provide a research platform for screening potential therapeutic agents. Even though alternative models are available, such as animal models or ex vivo models, in vitro models offer higher experimental flexibility and reproducibility, making them a valuable tool for the understanding of pathophysiological mechanisms of several diseases, such as CVDs. Therefore, this review aims to synthesize the currently available in vitro models regarding ECD, emphasizing CVDs. This work will focus on 2D cell culture models (endothelial cell lines and primary ECs), 3D cell culture systems (scaffold-free and scaffold-based), and 3D cell culture models (such as organ-on-a-chip). We will dissect the role of external stimuli-chemical and mechanical-in triggering ECD.
    Keywords:  Endothelial cell dysfunction; in vitro models; Chemical/Mechanical stimulation; Cardiovascular diseases
    DOI:  https://doi.org/10.1007/s11010-025-05289-w
  18. Nature. 2025 Apr 24.
    Science sleuths flag hundreds of papers that use AI without disclosing it.
    Diana Kwon.
      
    Keywords:  Machine learning; Publishing
    DOI:  https://doi.org/10.1038/d41586-025-01180-2
  19. Sci Adv. 2025 Apr 25. 11(17): eads6385
    BRD9 functions as a methylarginine reader to regulate AKT-EZH2 signaling.
    Shasha Yin, Charles Brobbey, Lauren E Ball, Tianmin Fu, Daniel J Sprague, Wenjian Gan.
      Recognition of methylarginine marks by effector proteins ("readers") is a critical link between arginine methylation and various cellular processes. Recently, we identified methylation of AKT1 at arginine-391 (R391), but the reader for this methylation has yet to be characterized. Here, we show that bromodomain-containing protein 9 (BRD9), a reader of acetylated lysine, unexpectedly recognizes methylated R391 of AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA sequencing data show that BRD9 and AKT coregulate a hallmark transcriptional program in part through enhancer of zeste homolog 2 (EZH2)-mediated methylation of histone-3 lysine-27. We also find that inhibitors of BRD9 and EZH2 display synergistic effects on suppression of cell proliferation and tumor growth. Collectively, our study reveals a previously unknown function of BRD9 and a potential therapeutic strategy for cancer treatment by combining BRD9 and EZH2 inhibitors.
    DOI:  https://doi.org/10.1126/sciadv.ads6385
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