bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–07–13
seventeen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Evolution of growth factor signaling to the TSC complex to regulate mTORC1.
  2. Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants.
  3. AKT and DUBs: a bidirectional relationship.
  4. Calling all data.
  5. A rapid and robust protocol for generating loss-of-function alleles in pluripotent stem cells.
  6. PTEN deficiency in postnatally developing Purkinje cells disrupts metabolic signaling, leading to dendritic abnormalities and sex-specific behavioral deficits.
  7. Fluctuation structure predicts genome-wide perturbation outcomes.
  8. KRAS codon-specific mutations differentially toggle PI3K pathway signaling and alter sensitivity to inavolisib (GDC-0077).
  9. Paraspinal Arteriovenous Shunt Associated with PTEN Hamartoma Tumor Syndrome: A Case Report and Literature Review.
  10. Live-Cell NanoBRET Assay to Measure AKT Inhibitor Binding to Conformational States of AKT.
  11. Unlocking the therapeutic potential of rigosertib as a selective therapy for ovarian cancer.
  12. SeuratExtend: streamlining single-cell RNA-seq analysis through an integrated and intuitive framework.
  13. Image-based, pooled phenotyping reveals multidimensional, disease-specific variant effects.
  14. Cell Marker Accordion: interpretable single-cell and spatial omics annotation in health and disease.
  15. An enzyme-free alcohol-based organoid harvesting solution.
  16. Dynamic serum biomarkers in infantile hemangioma: the role of VEGF-B, AKT, and eNOS in lesion regression.
  17. PerturbNet predicts single-cell responses to unseen chemical and genetic perturbations.
  1. Sci Signal. 2025 Jul 08. 18(894): eadw4165
    Evolution of growth factor signaling to the TSC complex to regulate mTORC1.
    Kun Wang, Sophie E Lockwood, Brendan D Manning.
      The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates signals from factors that both stimulate (exogenous growth factors) and are essential for (intracellular nutrients and energy) cellular growth. Activation of the protein kinase mTOR within mTORC1 results in the phosphorylation of downstream substrates that collectively stimulate biomass accumulation to drive cell growth. Many upstream signals, especially growth factors, regulate mTORC1 by inducing the phosphorylation of the tuberous sclerosis complex 2 (TSC2) subunit of the TSC protein complex, a conserved brake on mTORC1 activation and its promotion of cell growth. Cryo-electron microscopy studies of the TSC protein complex have revealed that this phosphoregulation of TSC2 occurs almost exclusively on residues in loops that are outside of the evolutionarily conserved core structural elements and that did not resolve in these structures. These phosphorylation-rich unstructured loops evolved with metazoans, suggesting that the regulation of mTORC1 by diverse growth factors likely evolved with the emergence of complex body plans and diverse cell types to coordinate cell growth and metabolism within and across distinct tissues. Unlike the core structure of TSC2, these loops lack disease-associated missense mutations. These features suggest that the regulatory loops on TSC2 are more amenable to evolutionary changes that enable diverse signals to converge on the TSC protein complex to regulate mTORC1.
    DOI:  https://doi.org/10.1126/scisignal.adw4165
  2. bioRxiv. 2025 Jul 02. pii: 2025.06.30.662374. [Epub ahead of print]
    Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants.
    Anne E van Vlimmeren, Ross M Giglio, Ziyuan Jiang, Minhee Lee, José L McFaline-Figueroa, Neel H Shah.
      The protein tyrosine phosphatase SHP2, encoded by PTPN11 , is an important regulator of Ras/MAPK signaling that acts downstream of receptor tyrosine kinases and other transmembrane receptors. Germline PTPN11 mutations cause developmental disorders such as Noonan Syndrome, whereas somatic mutations drive various cancers. While many pathogenic mutations enhance SHP2 catalytic activity, others are inactivating or affect protein interactions, confounding our understanding of SHP2-driven disease. Here, we combine single-cell transcriptional profiling of cells expressing clinically diverse SHP2 variants with protein biochemistry, structural analysis, and cell biology to explain how pathogenic mutations dysregulate signaling. Our analyses reveal that loss of catalytic activity does not phenocopy SHP2 knock-out at the gene expression level, that some mechanistically distinct mutations have convergent phenotypic effects, and that different mutations at the same hotspot residue can yield divergent cell states. These findings provide a framework for understanding the connection between SHP2 structural perturbations, cellular outcomes, and human diseases.
    DOI:  https://doi.org/10.1101/2025.06.30.662374
  3. Cell Mol Biol Lett. 2025 Jul 07. 30(1): 77
    AKT and DUBs: a bidirectional relationship.
    Valentina Serratore, Maria Lucibello, Donatella Malanga, Giuseppe Viglietto, Carmela De Marco.
      The serine/threonine kinase Akt is crucial for cell physiology and can also contribute to pathology if its activation and regulation is disturbed. This kinase phosphorylates several substrates involved in mechanisms that are altered in human disease. AKT is regulated by several post-translational modifications (PTMs), including ubiquitination/deubiquitination. Ubiquitination can both target AKT to the proteasome and promote its activation. The interplay with the deubiquitination mechanism plays a crucial role in almost all biological activities of AKT. Information on the mechanisms of AKT deubiquitination and its key players has evolved rapidly in recent years along with the development of potential targeting strategies, although many of them are still unclear. Nevertheless, AKT in turn regulates various deubiquitinases (DUBs), suggesting further targeting strategies for human diseases. In this review, we aim to provide an up-to-date overview of the dual relationship between AKT and DUBs with respect to potential translational aim.
    Keywords:  AKT kinase; Deubiquitinases; Phosphorylation; Post-translational modifications
    DOI:  https://doi.org/10.1186/s11658-025-00753-3
  4. Nat Methods. 2025 Jul;22(7): 1387
    Calling all data.
      
    DOI:  https://doi.org/10.1038/s41592-025-02759-3
  5. STAR Protoc. 2025 Jul 04. pii: S2666-1667(25)00322-3. [Epub ahead of print]6(3): 103916
    A rapid and robust protocol for generating loss-of-function alleles in pluripotent stem cells.
    Erdene Baljinnyam, Laura Grisanti, Shalini Tattari, Chiara Pedicone, Bhavana Shewale, Nicole Dubois, Alison M Goate, William G Kerr, Samuele G Marro.
      The generation of loss-of-function alleles in human pluripotent stem cells (hPSCs) is used to interrogate gene function and validate reagents; however, identifying clones harboring true loss-of-function alleles remains inefficient. To address this, we present BOLT (barcoded oligos for loss-of-function targeting), a streamlined protocol that simplifies the screening process, facilitating rapid validation of loss-of-function mutations. We describe steps for designing editing tools, nucleofection, and clonal density plating. We then detail procedures for bridging PCR, isolating clones derived from a single hPSC, single-clone screening, and Sanger barcode detection. For complete details on the use and execution of this protocol, please refer to Matera et al.1.
    Keywords:  CRISPR; Cell Biology; Cell culture; Genomics; Molecular Biology; Sequencing; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2025.103916
  6. Sci Rep. 2025 Jul 08. 15(1): 24460
    PTEN deficiency in postnatally developing Purkinje cells disrupts metabolic signaling, leading to dendritic abnormalities and sex-specific behavioral deficits.
    Lindsay J Walsh, Izabella M Espinal-San Miguel, Ana V Rodriguez, Ursula M Peña, Kiley E Flynn, Will C Remillard, Siena R Brazier, Natalia I Anderson, Aidan J Clark, Tiffany A De Varona, Ileana Soto.
      Conditional deletion of the Pten gene in cerebellar Purkinje cells (PCs) results in cellular hypertrophy, neurodegeneration, and autism-like behaviors in adult mice. Here, we investigated the effects of PTEN conditional deficiency on PC dendritic development and early postnatal motor, spontaneous, and social behaviors. We found that Pten loss disrupts dendritic growth by altering mTOR signaling and reducing AMPK phosphorylation, leading to early motor deficits and sex-specific behavioral alterations. In vivo analysis revealed significant reductions in mitochondrial and lysosomal volume in developing dendrites. Notably, ex vivo treatment with AICAR (an AMPK activator) or Torin1 (an mTOR inhibitor) partially restored dendritic organelle content in Pten-deficient PCs. These findings suggest that PTEN is critical for maintaining metabolic balance during postnatal dendritic maturation, and its loss leads to structural and functional impairments in PCs that contribute to behavioral phenotypes in a sex- and age-dependent manner.
    Keywords:  AICAR; AMPK; Lysosomes; Mitochondria; PTEN; Purkinje cells; Torin1; mTORC1
    DOI:  https://doi.org/10.1038/s41598-025-09059-y
  7. bioRxiv. 2025 Jul 01. pii: 2025.06.27.661814. [Epub ahead of print]
    Fluctuation structure predicts genome-wide perturbation outcomes.
    Benjamin Kuznets-Speck, Leon Schwartz, Hanxiao Sun, Madeline E Melzer, Nitu Kumari, Benjamin Haley, Ekta Prashnani, Suriyanarayanan Vaikuntanathan, Yogesh Goyal.
      Pooled single-cell perturbation screens represent powerful experimental platforms for functional genomics, yet interpreting these rich datasets for meaningful biological conclusions remains challenging. Most current methods fall at one of two extremes: either opaque deep learning models that obscure biological meaning, or simplified frameworks that treat genes as isolated units. As such, these approaches overlook a crucial insight: gene co-fluctuations in unperturbed cellular states can be harnessed to model perturbation responses. Here we present CIPHER (Covariance Inference for Perturbation and High-dimensional Expression Response), a conceptual framework leveraging linear response theory from statistical physics to predict transcriptome-wide perturbation outcomes using gene co-fluctuations in unperturbed cells. We validated CIPHER on synthetic regulatory networks before applying it to 11 large-scale single-cell perturbation datasets covering 4,234 perturbations and over 1.36M cells. CIPHER robustly recapitulated genome-wide responses to single and double perturbations by exploiting baseline gene covariance structure. Importantly, eliminating gene-gene covariances, while retaining gene-intrinsic variances, reduced model performance by 11-fold, demonstrating the rich information stored within baseline fluctuation structures. Moreover, gene-gene correlations transferred successfully across independent experiments of the same cell type, revealing stereotypic fluctuation structures. Furthermore, CIPHER outperformed conventional differential expression metrics in identifying true perturbations while providing uncertainty-aware effect size estimates through Bayesian inference. Finally, most genome-wide responses propagated through the covariance matrix along approximately three independent and global gene modules. CIPHER underscores the importance of theoretically-grounded models in capturing complex biological responses, highlighting fundamental design principles encoded in cellular fluctuation patterns.
    DOI:  https://doi.org/10.1101/2025.06.27.661814
  8. Mol Cancer Ther. 2025 Jul 08.
    KRAS codon-specific mutations differentially toggle PI3K pathway signaling and alter sensitivity to inavolisib (GDC-0077).
    Kyung W Song, Christy C Ong, Eva Lin, Jeff Lau, Nicole M Sodir, Dexter X Jin, Katherine E Hutchinson, Shiqi Xie, Jenille Tan, Yuxin Liang, Zora Modrusan, Scott E Martin, Danilo Maddalo, Marc Hafner, Anwesha Dey.
      PIK3CA and KRAS are among the most frequently mutated oncogenes and often co-mutated in colorectal cancers. Understanding how KRAS codon-specific mutations affect cross-talks between the PI3K and MAPK pathways and response to targeted therapies, such as the p110α-specific inhibitor inavolisib (GDC-0077), is critical for advancing precision oncology. Focusing on colorectal PIK3CA+KRAS co-mutated models, we found that KRAS G12D-mutated cells were more sensitive to inavolisib than models with KRAS G13D, or other MAPK pathway mutations, even though the PI3K and MAPK pathways were active in both genotypes. In most co-mutated models, regardless of the type of KRAS alteration, combination of inavolisib with MAPK pathway inhibitors showed synergy in vitro and in vivo. Our work highlights how specific codon substitutions in KRAS differentially toggle pathway activity and alter sensitivity to inavolisib, which could inform whether patients would benefit more from single-agent inavolisib or combination with MAPK pathway inhibitors.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0995
  9. Acta Neurochir Suppl. 2025 ;136 69-71
    Paraspinal Arteriovenous Shunt Associated with PTEN Hamartoma Tumor Syndrome: A Case Report and Literature Review.
    Sayaka Ito, Naoki Hatsuda.
      Having a paraspinal arteriovenous shunt located in the paraspinal region outside the spinal canal is rare. Germline phosphatase and tensin homolog gene (PTEN) mutations have been noted in cases with a specific paraspinal arteriovenous shunt. We report a patient with a paraspinal arteriovenous shunt with multiple primary cancers and report a germline mutation diagnosed with PTEN hamartoma syndrome. PTEN hamartoma syndrome can manifest as various cancers. Early diagnosis of PTEN hamartoma syndrome is essential for improving patient prognosis and life expectancy. The coexistence of multiple primary cancers and vascular malformations can be considered red flags for PTEN hamartoma syndrome.
    Keywords:  Diagnosis; Germline mutation; Multiple primary cancers; Paravertebral arteriovenous shunt; Thoracic spine
    DOI:  https://doi.org/10.1007/978-3-031-89844-0_8
  10. ACS Chem Biol. 2025 Jul 09.
    Live-Cell NanoBRET Assay to Measure AKT Inhibitor Binding to Conformational States of AKT.
    Jeremy W Harris, Flávio Antônio de Oliveira Simões, Erin N Ryerson, William M Marsiglia.
      AKT is the main protein kinase of the PI3K-AKT pathway, interacting with over one hundred protein partners to facilitate cellular processes that allow cancer cells to survive and proliferate. It is an attractive target due to its control over many cellular outputs. However, ATP-competitive and allosteric AKT inhibitors have performed poorly in clinical trials. AKT inhibitor interactions with AKT are multifaceted and influence the catalytic activity of AKT, its conformation, its ability to interact with binding partners, and its phosphorylation state. Therefore, a better understanding of how these inhibitors influence these parameters is needed, especially in a cellular context. Using a live-cell NanoBRET target engagement assay to query the binding of AKT inhibitors to all isoforms of AKT, we found that ATP-competitive inhibitors bind similarly across all three isoforms and allosteric inhibitors bind more heterogeneously. Further, assaying gain-of-function pathological mutants and myristoylated active versions of all AKT isoforms revealed that T308 phosphorylation enhances the binding of ATP-competitive inhibitors. We found that this phosphorylation is a good indicator of cell viability sensitivity to ATP-competitive inhibitors when comparing effects on known resistant and sensitive triple-negative breast cancer cell lines. Taken together, these findings are useful for screening new AKT inhibitors, and these findings represent important considerations in developing the next generation of AKT inhibitors.
    DOI:  https://doi.org/10.1021/acschembio.5c00213
  11. Cell Rep Med. 2025 Jul 03. pii: S2666-3791(25)00291-5. [Epub ahead of print] 102218
    Unlocking the therapeutic potential of rigosertib as a selective therapy for ovarian cancer.
    Shalini Nath, Sally Claridge, Genesis Lara Granados, Majd Al Assaad, Eric Park, Julie-Ann Cavallo, Ufuoma Nuwere, Maame Esi Ackon, Lamberto De Boni, Stacey Baker, E Premkumar Reddy, Stephanie V Blank, Olivier Elemento, Rachel Brody, Benjamin D Hopkins.
      Precision oncology seeks to exploit tumor-specific drug sensitivities. Traditionally, this is accomplished through the identification and targeting of highly recurrent mutations. This paradigm falls short in ovarian cancer where the oncogenic alterations are more diverse, necessitating an alternate approach for the identification of tumor-specific vulnerabilities. To address this, we have used a functional modeling approach, integrating drug screening with a Kinome Atlas-based assessment of signaling, to nominate a therapeutic regimen for ovarian tumors. This approach identifies a small-molecule RAS mimetic, rigosertib, as a tumor-selective agent and leads us to identify the combination of rigosertib with phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibition as effective combinations that prevent rigosertib-induced survival signaling while inducing regressions in ovarian cancer xenografts. These data support further exploration of these combinations for the treatment of ovarian cancer.
    Keywords:  Kinome Atlas; PI3K/MAPK signaling; high-throughput drug screening; ovarian cancer; precision oncology; rigosertib
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102218
  12. Gigascience. 2025 Jan 06. pii: giaf076. [Epub ahead of print]14
    SeuratExtend: streamlining single-cell RNA-seq analysis through an integrated and intuitive framework.
    Yichao Hua, Linqian Weng, Fang Zhao, Florian Rambow.
      Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of cellular heterogeneity, but the rapid expansion of analytical tools has proven to be both a blessing and a curse, presenting researchers with significant challenges. Here, we present SeuratExtend, a comprehensive R package built upon the widely adopted Seurat framework, which streamlines scRNA-seq data analysis by strategically integrating essential tools and databases. SeuratExtend offers a user-friendly and intuitive interface for performing a wide range of analyses, including functional enrichment, trajectory inference, gene regulatory network reconstruction, and denoising. The package integrates multiple databases, such as Gene Ontology and Reactome, and incorporates popular Python tools like scVelo, Palantir, and SCENIC through a unified R interface. We illustrate SeuratExtend's capabilities through case studies investigating tumor-associated high-endothelial venules and autoinflammatory diseases, as well as showcase its novel applications in pathway-level analysis and cluster annotation. SeuratExtend enhances data visualization with optimized plotting functions and carefully curated color schemes, ensuring both aesthetic appeal and scientific rigor. The package's effectiveness has been demonstrated through successful workshops and training programs, establishing its value in both research and educational contexts. SeuratExtend empowers researchers to harness the full potential of scRNA-seq data, making complex analyses accessible to a wider audience. The package, along with comprehensive documentation, tutorials, and educational resources, is freely available at GitHub, providing a valuable resource for the single-cell genomics community.
    Keywords:  R package; Seurat framework; bioinformatics; education; multitool integration; pathway analysis; single-cell RNA-seq; visualization
    DOI:  https://doi.org/10.1093/gigascience/giaf076
  13. bioRxiv. 2025 Jul 05. pii: 2025.07.03.663081. [Epub ahead of print]
    Image-based, pooled phenotyping reveals multidimensional, disease-specific variant effects.
    Sriram Pendyala, Katie Partington, Nicholas Bradley, Abbye E McEwen, Gwenneth Straub, Hyeon-Jin Kim, Shawn Fayer, Daniel Lee Holmes, Katherine A Sitko, Allyssa J Vandi, Rachel L Powell, Clayton E Friedman, Evan McDermot, Nishka Kishore, Frederick P Roth, Alan F Rubin, Kai-Chun Yang, Lea M Starita, William S Noble, Douglas M Fowler.
      Genetic variants often produce complex phenotypic effects that confound current assays and predictive models. We developed Variant in situ sequencing (VIS-seq), a pooled, image-based method that measures variant effects on molecular and cellular phenotypes in diverse cell types. Applying VIS-seq to ~3,000 LMNA and PTEN variants yielded high-dimensional morphological profiles that captured variant-driven changes in protein abundance, localization, activity and cell architecture. We identified gain-of-function LMNA variants that reshape the nucleus and autism-associated PTEN variants that mislocalize. Morphological profiles predicted variant pathogenicity with near-perfect accuracy and distinguished autism-linked from tumor syndrome-linked PTEN variants. Most variants impacted a multidimensional continuum of phenotypes not recapitulated by any single functional readout. By linking protein variation to cell images at scale, we illuminate how variant effects cascade from molecular to subcellular to cell morphological phenotypes, providing a framework for resolving the complexity of variant function.
    DOI:  https://doi.org/10.1101/2025.07.03.663081
  14. Nat Commun. 2025 Jul 07. 16(1): 5399
    Cell Marker Accordion: interpretable single-cell and spatial omics annotation in health and disease.
    Emma Busarello, Giulia Biancon, Ilaria Cimignolo, Fabio Lauria, Zuhairia Ibnat, Christian Ramirez, Gabriele Tomè, Marianna Ciuffreda, Giorgia Bucciarelli, Alessandro Pilli, Stefano Maria Marino, Vittorio Bontempi, Federica Ress, Kristin R Aass, Jennifer VanOudenhove, Luca Tiberi, Maria Caterina Mione, Therese Standal, Paolo Macchi, Gabriella Viero, Stephanie Halene, Toma Tebaldi.
      Single-cell technologies offer a unique opportunity to explore cellular heterogeneity in health and disease. However, reliable identification of cell types and states represents a bottleneck. Available databases and analysis tools employ dissimilar markers, leading to inconsistent annotations and poor interpretability. Furthermore, current tools focus mostly on physiological cell types, limiting their applicability to disease. We present the Cell Marker Accordion, a user-friendly platform providing automatic annotation and unmatched biological interpretation of single-cell populations, based on consistency weighted markers. We validate our approach on multiple single-cell and spatial datasets from different human and murine tissues, improving annotation accuracy in all cases. Moreover, we show that the Cell Marker Accordion can identify disease-critical cells and pathological processes, extracting potential biomarkers in a wide variety of disease contexts. The breadth of these applications elevates the Cell Marker Accordion as a fast, flexible, faithful and standardized tool to annotate and interpret single-cell and spatial populations in studying physiology and disease.
    DOI:  https://doi.org/10.1038/s41467-025-60900-4
  15. Biotechniques. 2025 Jul 10. 1-11
    An enzyme-free alcohol-based organoid harvesting solution.
    Jimmy Maillard, Lisa Pickard, Udai Banerji.
      Three-dimensional (3D) cell culture is a more physiologically relevant model for drug development than two-dimensional (2D) cell culture. A common method to culture cells in 3D consists in embedding cells in synthetic or animal-based matrices that provide structural support for cell growth. They partially mimic in vivo conditions and enable scalable culture. Here, we introduce an alcohol-based Solution for Harvesting Organoids Efficiently, denoted SHOE. We tested its harvesting potential on 2 cell lines grown as spheroids and 2 patient-derived organoids. It enables rapid, high-yield cell recovery, at room temperature (RT), and bypasses prolonged cold incubation of standard protocols. It preserves 3D structure and growth in subsequent passages.
    Keywords:  3D cell culture; Enzyme free; harvesting solution; matrix dissolution; organoids
    DOI:  https://doi.org/10.1080/07366205.2025.2527540
  16. Eur J Pediatr. 2025 Jul 11. 184(8): 476
    Dynamic serum biomarkers in infantile hemangioma: the role of VEGF-B, AKT, and eNOS in lesion regression.
    Hatice Mine Cakmak, Ilker Kiliccioglu, Gorkem Dulger.
      Infantile hemangioma (IH) is the most common vascular tumor in infancy. This study aimed to investigate serum levels of VEGF-B, AKT, and eNOS in complicated versus uncomplicated cases of infantile hemangioma and evaluate their correlation with clinical regression scores over time. In this prospective study, we followed 64 patients with intrahospital hemorrhage (IH). Patients were grouped into two categories: complicated (n = 44) and uncomplicated (n = 20). Serum/plasma samples were collected on day 0 from all patients and on days 30 and 60 from complicated cases. ELISA techniques were used to quantify serum VEGF-B, AKT, and eNOS levels. A novel four-domain clinical regression scoring system (size, color, surface, and vascular activity; total 0-12 points) was developed and applied for the first 3 months of follow-up at each visit. VEGF-B, AKT, and eNOS serum levels were significantly higher at baseline in complicated IH and decreased over time with regression. However, AKT serum levels showed a significant decline only in the days of 60 (p = 0.043). Clinical regression scores increased in parallel, with substantial differences between healed and non-healed cases. ROC analysis revealed that day 30 and day 60 clinical scores strongly predicted complete healing (AUC = 0.739 and 0.850, respectively).
    CONCLUSION:  The VEGF-B/VEGFR-1, AKT/mTOR, and eNOS pathways appear central to IH pathogenesis. Serum levels of these molecules may serve as dynamic biomarkers of disease phase and response to therapy. This study contributes novel data supporting potential targets for future personalized treatment strategies with a novel 3-month follow-up regression score predicting resolution.
    WHAT IS KNOWN: • Angiogenic mediators such as VEGF-A, bFGF, Akt, and eNOS are elevated during the proliferative phase of infantile hemangioma and decline with propranolol treatment. • Previous studies have primarily investigated tissue-level expression, and there is limited clinical data on serum VEGF-B, Akt, and eNOS levels in IH patients.
    WHAT IS NEW: • This is the first clinical study to longitudinally measure serum VEGF-B, AKT, and eNOS levels in infantile hemangioma patients and track their changes during treatment-induced involution. • A novel, four-domain clinical regression scoring system (size, color, surface, vascular activity) was introduced and shown to predict treatment response within the first 60 days of follow-up.
    Keywords:  AKT serine-threonine kinase; Biomarkers; Endothelial nitric oxide synthase; Infantile hemangioma; Signal transduction; Treatment outcome; Vascular endothelial growth factor B
    DOI:  https://doi.org/10.1007/s00431-025-06311-5
  17. Mol Syst Biol. 2025 Jul 10.
    PerturbNet predicts single-cell responses to unseen chemical and genetic perturbations.
    Hengshi Yu, Weizhou Qian, Yuxuan Song, Joshua D Welch.
      Chemical and genetic perturbations, such as those induced by small molecules and CRISPR, effect complex changes in the molecular states of cells. Despite advances in high-throughput single-cell perturbation screening technology, the space of possible perturbations is far too large to measure exhaustively. Here, we introduce PerturbNet, a flexible deep generative model designed to predict the distribution of cell states induced by unseen chemical or genetic perturbations. PerturbNet accurately predicts gene expression changes in response to unseen small molecules based on their chemical structures while also accounting for key covariates such as dosage and cell type. Moreover, PerturbNet accurately predicts the distribution of single-cell gene expression states following CRISPR activation or CRISPR interference by leveraging gene functional annotations. Our approach significantly outperforms previous methods, particularly for predicting the effects of perturbing completely unseen genes. Finally, we demonstrate for the first time that amino acid sequence embeddings can be used to predict gene expression changes induced by missense mutations. We use PerturbNet to predict the effects of all point mutations in GATA1 and nominate variants that significantly impact the cell state distribution of human hematopoietic stem cells. Using a crystal structure of GATA1 bound to DNA, we validate that these large-effect variants occur in the core DNA-contact region of GATA1 and tend to involve large changes in amino acid side-chain volume.
    Keywords:  Deep Generative Model; Genome Editing; High-throughput Screening; Perturbation Prediction; Single-cell Transcriptomics
    DOI:  https://doi.org/10.1038/s44320-025-00131-3
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