bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2024–04–28
twenty papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Adipocyte PI3K links adipostasis with baseline insulin secretion at fasting through an adipoincretin effect.
  2. Dynamics of Single-Cell Protein Covariation during Epithelial-Mesenchymal Transition.
  3. phuEGO: A network-based method to reconstruct active signalling pathways from phosphoproteomics datasets.
  4. Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1.
  5. The G1/S transition in mammalian stem cells in vivo is autonomously regulated by cell size.
  6. Endogenous tagging using split mNeonGreen in human iPSCs for live imaging studies.
  7. Identification of genes that promote PI3K pathway activation and prostate tumour formation.
  8. Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
  9. Extensive protein pyrophosphorylation revealed in human cell lines.
  10. Maximum entropy determination of mammalian proteome dynamics.
  11. Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility.
  12. Exponential family measurement error models for single-cell CRISPR screens.
  13. A heterogeneous pharmaco-transcriptomic landscape induced by targeting a single oncogenic kinase.
  14. Ploidy inference from single-cell data: application to human and mouse cell atlases.
  15. Analysis of synthetic cellular barcodes in the genome and transcriptome with BARtab and bartools.
  16. Imaging findings of children with PTEN-related hamartoma tumor syndrome: a 20-year multicentric pediatric cohort.
  17. The Dark Side of Activated Phosphoinositide 3-Kinase-δ Syndrome 2: A Story Rewritten through FDG-PET.
  18. CASCC: a co-expression assisted single-cell RNA-seq data clustering method.
  19. Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses.
  20. Spontaneous Akt2 deficiency in a colony of NOD mice exhibiting early diabetes.
  1. Cell Rep. 2024 Apr 23. pii: S2211-1247(24)00460-1. [Epub ahead of print]43(5): 114132
    Adipocyte PI3K links adipostasis with baseline insulin secretion at fasting through an adipoincretin effect.
    Barbara Becattini, Angela Molinaro, Marcus Henricsson, Jan Borén, Giovanni Solinas.
      Insulin-PI3K signaling controls insulin secretion. Understanding this feedback mechanism is crucial for comprehending how insulin functions. However, the role of adipocyte insulin-PI3K signaling in controlling insulin secretion in vivo remains unclear. Using adipocyte-specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we show that PI3Kα and PI3Kβ activities are functionally redundant in adipocyte insulin signaling. PI3Kβ-selective inhibitors have no effect on adipocyte AKT phosphorylation in control mice but blunt it in adipocytes of PI3KαAdQ mice, demonstrating adipocyte-selective pharmacological PI3K inhibition in the latter. Acute adipocyte-selective PI3K inhibition increases serum free fatty acid (FFA) and potently induces insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect operates in fasted mice with increasing FFA and decreasing glycemia, indicating that it is not primarily a control system for blood glucose. This feedback control system defines the rates of adipose tissue lipolysis and chiefly controls basal insulin secretion during fasting.
    Keywords:  AKT; CP: Metabolism; PI3K; diabetes; growth factors; incretin; insulin; insulin resistance; insulin secretion; mTOR; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2024.114132
  2. J Proteome Res. 2024 Apr 25.
    Dynamics of Single-Cell Protein Covariation during Epithelial-Mesenchymal Transition.
    Saad Khan, Rachel Conover, Anand R Asthagiri, Nikolai Slavov.
      Physiological processes, such as the epithelial-mesenchymal transition (EMT), are mediated by changes in protein interactions. These changes may be better reflected in protein covariation within a cellular cluster than in the temporal dynamics of cluster-average protein abundance. To explore this possibility, we quantified proteins in single human cells undergoing EMT. Covariation analysis of the data revealed that functionally coherent protein clusters dynamically changed their protein-protein correlations without concomitant changes in the cluster-average protein abundance. These dynamics of protein-protein correlations were monotonic in time and delineated protein modules functioning in actin cytoskeleton organization, energy metabolism, and protein transport. These protein modules are defined by protein covariation within the same time point and cluster and, thus, reflect biological regulation masked by the cluster-average protein dynamics. Thus, protein correlation dynamics across single cells offers a window into protein regulation during physiological transitions.
    Keywords:  EMT; SCoPE2; cell adhesion; dynamics; epithelial−mesenchymal transition; metabolism; nPOP; protein correlations; protein covariation; single-cell proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00277
  3. Mol Cell Proteomics. 2024 Apr 18. pii: S1535-9476(24)00061-6. [Epub ahead of print] 100771
    phuEGO: A network-based method to reconstruct active signalling pathways from phosphoproteomics datasets.
    Girolamo Giudice, Haoqi Chen, Thodoris Koutsandreas, Evangelia Petsalaki.
      Signalling networks are critical for virtually all cell functions. Our current knowledge of cell signalling has been summarised in signalling pathway databases, which, while useful, are highly biassed towards well-studied processes, and do not capture context specific network wiring or pathway cross-talk. Mass spectrometry-based phosphoproteomics data can provide a more unbiased view of active cell signalling processes in a given context, however, it suffers from low signal-to-noise ratio and poor reproducibility across experiments. While progress in methods to extract active signalling signatures from such data has been made, there are still limitations with respect to balancing bias and interpretability. Here we present phuEGO, which combines up-to-three-layer network propagation with ego network decomposition to provide small networks comprising active functional signalling modules. PhuEGO boosts the signal-to-noise ratio from global phosphoproteomics datasets, enriches the resulting networks for functional phosphosites and allows the improved comparison and integration across datasets. We applied phuEGO to five phosphoproteomics data sets from cell lines collected upon infection with SARS CoV2. PhuEGO was better able to identify common active functions across datasets and to point to a subnetwork enriched for known COVID-19 targets. Overall, phuEGO provides a flexible tool to the community for the improved functional interpretation of global phosphoproteomics datasets.
    DOI:  https://doi.org/10.1016/j.mcpro.2024.100771
  4. bioRxiv. 2024 Apr 09. pii: 2024.04.09.587573. [Epub ahead of print]
    Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1.
    Jennifer deRiso, Malini Mukherjee, Madhusudhana Janga, Alicia Simmons, Michael Kareta, Jianning Tao, Indra Chandrasekar, Kameswaran Surendran.
      The plasticity and diversity of cell types with specialized functions likely defines the capacity of multicellular organisms to adapt to physiologic stressors. The kidney collecting ducts contribute to water, electrolyte, and pH homeostasis and are composed of mature intermingled epithelial cell types that are susceptible to transdifferentiate. The conversion of kidney collecting duct principal cells to intercalated cells is actively inhibited by Notch signaling to ensure urine concentrating capability. Here we identify Hes1, a target of Notch signaling, allows for maintenance of functionally distinct epithelial cell types within the same microenvironment by regulating mechanistic target of rapamycin complex 1 (mTORC1) activity. Hes1 directly represses the expression of insulin receptor substrate 1 ( Irs1 ), an upstream component of mTOR pathway and suppresses mTORC1 activity in principal cells. Genetic inactivation of tuberous sclerosis complex 2 ( Tsc2 ) to increase mTORC1 activity in mature principal cells is sufficient to promote acquisition of intercalated cell properties, while inhibition of mTORC1 in adult kidney epithelia suppresses intercalated cell properties. Considering that mTORC1 integrates environmental cues, the linkage of functionally distinct epithelial cell types to mTORC1 activity levels likely allows for cell plasticity to be regulated by physiologic and metabolic signals and the ability to sense/transduce these signals.
    DOI:  https://doi.org/10.1101/2024.04.09.587573
  5. bioRxiv. 2024 Apr 11. pii: 2024.04.09.588781. [Epub ahead of print]
    The G1/S transition in mammalian stem cells in vivo is autonomously regulated by cell size.
    Shicong Xie, Shuyuan Zhang, Gustavo de Medeiros, Prisca Liberali, Jan M Skotheim.
      Cell growth and division must be coordinated to maintain a stable cell size, but how this coordination is implemented in multicellular tissues remains unclear. In unicellular eukaryotes, autonomous cell size control mechanisms couple cell growth and division with little extracellular input. However, in multicellular tissues we do not know if autonomous cell size control mechanisms operate the same way or whether cell growth and cell cycle progression are separately controlled by cell-extrinsic signals. Here, we address this question by tracking single epidermal stem cells growing in adult mice. We find that a cell-autonomous size control mechanism, dependent on the RB pathway, sets the timing of S phase entry based on the cell's current size. Cell-extrinsic variations in the cellular microenvironment affect cell growth rates but not this autonomous coupling. Our work reassesses long-standing models of cell cycle regulation within complex metazoan tissues and identifies cell-autonomous size control as a critical mechanism regulating cell divisions in vivo and thereby a major contributor to stem cell heterogeneity.
    DOI:  https://doi.org/10.1101/2024.04.09.588781
  6. Elife. 2024 Apr 23. pii: RP92819. [Epub ahead of print]12
    Endogenous tagging using split mNeonGreen in human iPSCs for live imaging studies.
    Mathieu C Husser, Nhat P Pham, Chris Law, Flavia R B Araujo, Vincent J J Martin, Alisa Piekny.
      Endogenous tags have become invaluable tools to visualize and study native proteins in live cells. However, generating human cell lines carrying endogenous tags is difficult due to the low efficiency of homology-directed repair. Recently, an engineered split mNeonGreen protein was used to generate a large-scale endogenous tag library in HEK293 cells. Using split mNeonGreen for large-scale endogenous tagging in human iPSCs would open the door to studying protein function in healthy cells and across differentiated cell types. We engineered an iPS cell line to express the large fragment of the split mNeonGreen protein (mNG21-10) and showed that it enables fast and efficient endogenous tagging of proteins with the short fragment (mNG211). We also demonstrate that neural network-based image restoration enables live imaging studies of highly dynamic cellular processes such as cytokinesis in iPSCs. This work represents the first step towards a genome-wide endogenous tag library in human stem cells.
    Keywords:  cell biology; crispr; cytokinesis; endogenous tagging; gene editing; human; ipsc; live imaging
    DOI:  https://doi.org/10.7554/eLife.92819
  7. Oncogene. 2024 Apr 23.
    Identification of genes that promote PI3K pathway activation and prostate tumour formation.
    Jeffrey C Francis, Amy Capper, Alistair G Rust, Klea Ferro, Jian Ning, Wei Yuan, Johann de Bono, Stephen J Pettitt, Amanda Swain.
      We have performed a functional in vivo mutagenesis screen to identify genes that, when altered, cooperate with a heterozygous Pten mutation to promote prostate tumour formation. Two genes, Bzw2 and Eif5a2, which have been implicated in the process of protein translation, were selected for further validation. Using prostate organoid models, we show that either Bzw2 downregulation or EIF5A2 overexpression leads to increased organoid size and in vivo prostate growth. We show that both genes impact the PI3K pathway and drive a sustained increase in phospho-AKT expression, with PTEN protein levels reduced in both models. Mechanistic studies reveal that EIF5A2 is directly implicated in PTEN protein translation. Analysis of patient datasets identified EIF5A2 amplifications in many types of human cancer, including the prostate. Human prostate cancer samples in two independent cohorts showed a correlation between increased levels of EIF5A2 and upregulation of a PI3K pathway gene signature. Consistent with this, organoids with high levels of EIF5A2 were sensitive to AKT inhibitors. Our study identified novel genes that promote prostate cancer formation through upregulation of the PI3K pathway, predicting a strategy to treat patients with genetic aberrations in these genes particularly relevant for EIF5A2 amplified tumours.
    DOI:  https://doi.org/10.1038/s41388-024-03028-x
  8. Science. 2024 Apr 26. 384(6694): 438-446
    Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
    Sinika Henschke, Hendrik Nolte, Judith Magoley, Tatjana Kleele, Claus Brandt, A Christine Hausen, Claudia M Wunderlich, Corinna A Bauder, Philipp Aschauer, Suliana Manley, Thomas Langer, F Thomas Wunderlich, Jens C Brüning.
      Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.
    DOI:  https://doi.org/10.1126/science.adk1005
  9. Nat Chem Biol. 2024 Apr 25.
    Extensive protein pyrophosphorylation revealed in human cell lines.
    Jeremy A M Morgan, Arpita Singh, Leonie Kurz, Michal Nadler-Holly, Max Ruwolt, Shubhra Ganguli, Sheenam Sharma, Martin Penkert, Eberhard Krause, Fan Liu, Rashna Bhandari, Dorothea Fiedler.
      Reversible protein phosphorylation is a central signaling mechanism in eukaryotes. Although mass-spectrometry-based phosphoproteomics has become routine, identification of non-canonical phosphorylation has remained a challenge. Here we report a tailored workflow to detect and reliably assign protein pyrophosphorylation in two human cell lines, providing, to our knowledge, the first direct evidence of endogenous protein pyrophosphorylation. We manually validated 148 pyrophosphosites across 71 human proteins, the most heavily pyrophosphorylated of which were the nucleolar proteins NOLC1 and TCOF1. Detection was consistent with previous biochemical evidence relating the installation of the modification to inositol pyrophosphates (PP-InsPs). When the biosynthesis of PP-InsPs was perturbed, proteins expressed in this background exhibited no signs of pyrophosphorylation. Disruption of PP-InsP biosynthesis also significantly reduced rDNA transcription, potentially by lowering pyrophosphorylation on regulatory proteins NOLC1, TCOF1 and UBF1. Overall, protein pyrophosphorylation emerges as an archetype of non-canonical phosphorylation and should be considered in future phosphoproteomic analyses.
    DOI:  https://doi.org/10.1038/s41589-024-01613-5
  10. Proc Natl Acad Sci U S A. 2024 Apr 30. 121(18): e2313107121
    Maximum entropy determination of mammalian proteome dynamics.
    Alexander J Dear, Gonzalo A Garcia, Georg Meisl, Galen A Collins, Tuomas P J Knowles, Alfred L Goldberg.
      Full understanding of proteostasis and energy utilization in cells will require knowledge of the fraction of cell proteins being degraded with different half-lives and their rates of synthesis. We therefore developed a method to determine such information that combines mathematical analysis of protein degradation kinetics obtained in pulse-chase experiments with Bayesian data fitting using the maximum entropy principle. This approach will enable rapid analyses of whole-cell protein dynamics in different cell types, physiological states, and neurodegenerative disease. Using it, we obtained surprising insights about protein stabilities in cultured cells normally and upon activation of proteolysis by mTOR inhibition and increasing cAMP or cGMP. It revealed that >90% of protein content in dividing mammalian cell lines is long-lived, with half-lives of 24 to 200 h, and therefore comprises much of the proteins in daughter cells. The well-studied short-lived proteins (half-lives < 10 h) together comprise <2% of cell protein mass, but surprisingly account for 10 to 20% of measurable newly synthesized protein mass. Evolution thus appears to have minimized intracellular proteolysis except to rapidly eliminate misfolded and regulatory proteins.
    Keywords:  maximum entropy; protein degradation; protein half-lives; proteome; proteostasis
    DOI:  https://doi.org/10.1073/pnas.2313107121
  11. Stem Cell Reports. 2024 Apr 18. pii: S2213-6711(24)00084-5. [Epub ahead of print]
    Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility.
    David Pamies, Jason Ekert, Marie-Gabrielle Zurich, Olivier Frey, Sophie Werner, Monica Piergiovanni, Benjamin S Freedman, Adrian Kee Keong Teo, Hendrik Erfurth, Darwin R Reyes, Peter Loskill, Pelin Candarlioglu, Laura Suter-Dick, Shan Wang, Thomas Hartung, Sandra Coecke, Glyn N Stacey, Beren Atac Wagegg, Eva-Maria Dehne, Francesca Pistollato, Marcel Leist.
      Cell culture technology has evolved, moving from single-cell and monolayer methods to 3D models like reaggregates, spheroids, and organoids, improved with bioengineering like microfabrication and bioprinting. These advancements, termed microphysiological systems (MPSs), closely replicate tissue environments and human physiology, enhancing research and biomedical uses. However, MPS complexity introduces standardization challenges, impacting reproducibility and trust. We offer guidelines for quality management and control criteria specific to MPSs, facilitating reliable outcomes without stifling innovation. Our fit-for-purpose recommendations provide actionable advice for achieving consistent MPS performance.
    Keywords:  criteria; in vitro; microphysiological systems; organ on chip; organoids; quality control; recommendations; reproducibility; spheroids; standards
    DOI:  https://doi.org/10.1016/j.stemcr.2024.03.009
  12. Biostatistics. 2024 Apr 22. pii: kxae010. [Epub ahead of print]
    Exponential family measurement error models for single-cell CRISPR screens.
    Timothy Barry, Kathryn Roeder, Eugene Katsevich.
      CRISPR genome engineering and single-cell RNA sequencing have accelerated biological discovery. Single-cell CRISPR screens unite these two technologies, linking genetic perturbations in individual cells to changes in gene expression and illuminating regulatory networks underlying diseases. Despite their promise, single-cell CRISPR screens present considerable statistical challenges. We demonstrate through theoretical and real data analyses that a standard method for estimation and inference in single-cell CRISPR screens-"thresholded regression"-exhibits attenuation bias and a bias-variance tradeoff as a function of an intrinsic, challenging-to-select tuning parameter. To overcome these difficulties, we introduce GLM-EIV ("GLM-based errors-in-variables"), a new method for single-cell CRISPR screen analysis. GLM-EIV extends the classical errors-in-variables model to responses and noisy predictors that are exponential family-distributed and potentially impacted by the same set of confounding variables. We develop a computational infrastructure to deploy GLM-EIV across hundreds of processors on clouds (e.g. Microsoft Azure) and high-performance clusters. Leveraging this infrastructure, we apply GLM-EIV to analyze two recent, large-scale, single-cell CRISPR screen datasets, yielding several new insights.
    Keywords:  CRISPR; GLM; mixture model; parallel computing; single cell
    DOI:  https://doi.org/10.1093/biostatistics/kxae010
  13. bioRxiv. 2024 Apr 10. pii: 2024.04.08.587960. [Epub ahead of print]
    A heterogeneous pharmaco-transcriptomic landscape induced by targeting a single oncogenic kinase.
    Ross M Giglio, Nicholas Hou, Adeya Wyatt, Justin Hong, Lingting Shi, Mathini Vaikunthan, Henry Fuchs, Jose Pomarino Nima, Seth W Malinowski, Keith L Ligon, José R McFaline-Figueroa, Nir Yosef, Elham Azizi, José L McFaline-Figueroa.
      Over-activation of the epidermal growth factor receptor (EGFR) is a hallmark of glioblastoma. However, EGFR-targeted therapies have led to minimal clinical response. While delivery of EGFR inhibitors (EGFRis) to the brain constitutes a major challenge, how additional drug-specific features alter efficacy remains poorly understood. We apply highly multiplex single-cell chemical genomics to define the molecular response of glioblastoma to EGFRis. Using a deep generative framework, we identify shared and drug-specific transcriptional programs that group EGFRis into distinct molecular classes. We identify programs that differ by the chemical properties of EGFRis, including induction of adaptive transcription and modulation of immunogenic gene expression. Finally, we demonstrate that pro-immunogenic expression changes associated with a subset of tyrphostin family EGFRis increase the ability of T-cells to target glioblastoma cells.
    DOI:  https://doi.org/10.1101/2024.04.08.587960
  14. Genetics. 2024 Apr 23. pii: iyae061. [Epub ahead of print]
    Ploidy inference from single-cell data: application to human and mouse cell atlases.
    Fumihiko Takeuchi, Norihiro Kato.
      Ploidy is relevant to numerous biological phenomena, including development, metabolism, and tissue regeneration. Single-cell RNA-seq and other omics studies are revolutionizing our understanding of biology, yet they have largely overlooked ploidy. This is likely due to the additional assay step required for ploidy measurement. Here, we developed a statistical method to infer ploidy from single-cell ATAC-seq data, addressing this gap. When applied to data from human and mouse cell atlases, our method enabled systematic detection of polyploidy across diverse cell types. This method allows for the integration of ploidy analysis into single-cell studies. Additionally, this method can be adapted to detect the proliferating stage in the cell cycle and copy number variations in cancer cells. The software is implemented as the scPloidy package of the R software and is freely available from CRAN.
    Keywords:  ATAC-seq; Ploidy; cancer; cell cycle; copy number variation; single-cell; single-nucleus
    DOI:  https://doi.org/10.1093/genetics/iyae061
  15. Cell Rep Methods. 2024 Apr 19. pii: S2667-2375(24)00094-8. [Epub ahead of print] 100763
    Analysis of synthetic cellular barcodes in the genome and transcriptome with BARtab and bartools.
    Henrietta Holze, Laure Talarmain, Katie A Fennell, Enid Y Lam, Mark A Dawson, Dane Vassiliadis.
      Cellular barcoding is a lineage-tracing methodology that couples heritable synthetic barcodes to high-throughput sequencing, enabling the accurate tracing of cell lineages across a range of biological contexts. Recent studies have extended these methods by incorporating lineage information into single-cell or spatial transcriptomics readouts. Leveraging the rich biological information within these datasets requires dedicated computational tools for dataset pre-processing and analysis. Here, we present BARtab, a portable and scalable Nextflow pipeline, and bartools, an open-source R package, designed to provide an integrated end-to-end cellular barcoding analysis toolkit. BARtab and bartools contain methods to simplify the extraction, quality control, analysis, and visualization of lineage barcodes from population-level, single-cell, and spatial transcriptomics experiments. We showcase the utility of our integrated BARtab and bartools workflow via the analysis of exemplar bulk, single-cell, and spatial transcriptomics experiments containing cellular barcoding information.
    Keywords:  CP: Biotechnology; CP: Systems biology; Nextflow pipeline; R package; cellular barcoding; lineage tracing; single cell; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100763
  16. Pediatr Radiol. 2024 Apr 22.
    Imaging findings of children with PTEN-related hamartoma tumor syndrome: a 20-year multicentric pediatric cohort.
    Claudia Martinez-Rios, Laura S De Leon Benedetti, Luis Octavio Tierradentro-Garcia, Ozge Aksel Kilicarslan, Pablo Caro-Dominguez, Hansel J Otero.
       BACKGROUND: PTEN-related hamartoma tumor syndrome results from a mutation in the PTEN gene located at 10q23.31. This syndrome represents a spectrum of different phenotypes of variable expressions, now recognized as part of the same condition. Patients with this mutation have an increased risk of developing a wide range of findings, including malignancies. Although widely described in adults, there are no large series describing the imaging findings in patients before adulthood. Knowledge of the findings seen in children and adolescents with PTEN-related hamartoma tumor syndrome can help guide further management and improve surveillance recommendations.
    OBJECTIVE: To describe the spectrum of imaging abnormalities in pediatric patients with PTEN-related hamartoma tumor syndrome.
    MATERIALS AND METHODS: We performed a retrospective, cross-sectional, multicenter study conducted between January 2000 and October 2021 in three tertiary pediatric institutions evaluating the imaging findings in children and adolescents (≤ 18 years) with confirmed diagnoses of a PTEN mutation. For each patient, the imaging findings, histopathology reports, and at least a 2-year follow-up of clinical outcomes for non-operative cases were documented.
    RESULTS: The cohort included 78 children (37 girls), with a mean age at diagnosis of 7.5 years (range 0 days to 18 years). Benign brain findings included enlarged Virchow-Robin perivascular spaces, white matter changes, developmental venous anomalies, and cerebellar hamartomas. Benign thyroid findings were common, but 5/45 (11.1%) with thyroid abnormalities had a malignant nodule. Soft tissue adipocytic tumors, GI/GU polyps, other soft tissue abnormalities, along with vascular anomalies in various anatomic locations were common.
    CONCLUSION: Brain abnormalities, benign non-vascular soft tissue abnormalities, and vascular anomalies are commonly seen in children and adolescents with PTEN-related hamartoma tumor syndrome. However, malignancies involving the thyroid gland are not uncommon. Familiarity with the phenotype of PTEN-related hamartoma tumor syndrome in the pediatric population can improve diagnosis and prompt appropriate clinical surveillance of abnormal findings that warrant further management.
    Keywords:  Cancer predisposition; Children; Imaging; PTEN protein; PTEN-related hamartoma tumor syndrome; Thyroid
    DOI:  https://doi.org/10.1007/s00247-024-05922-8
  17. J Clin Med. 2024 Apr 11. pii: 2203. [Epub ahead of print]13(8):
    The Dark Side of Activated Phosphoinositide 3-Kinase-δ Syndrome 2: A Story Rewritten through FDG-PET.
    Arianna Catelli, Cristina Nanni, Rita Mulè, Pier Luigi Zinzani, Elena Sabattini, Marcello Lanari, Francesca Conti.
      Background: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is characterized by lymphoproliferation and increased risk of malignancy. FDG-PET/CT may represent a helpful diagnostic tool for differentiating these clinical features and correctly diagnosing inborn errors of immunity (IEI). Case report: We present the case of a female patient diagnosed with Hodgkin's lymphoma at 19 years of age, although atypical imaging aspects emerged: baseline FDG-PET/CT revealed several hot lymph nodes with a symmetrical distribution, and increased tracer uptake in spleen, axial, and appendicular bone marrow. Imaging repeated after chemotherapy and autologous stem cell transplantation showed persistent increased FDG uptake at multiple supradiaphragmatic nodes and in bone marrow. After the diagnosis of APDS2 and rapamycin treatment, FDG-PET/CT confirmed complete metabolic normalization of all sites. Conclusions: In the IEI scenario, FDG-PET/CT plays an effective role in differentiating malignant proliferation and immune dysregulation phenotypes. Atypical patterns at FDG-PET/CT should be interpreted as a red flag for the need of an early immunological evaluation.
    Keywords:  APDS2; FDG-PET; immunodeficiency; lymphoma; lymphoproliferation
    DOI:  https://doi.org/10.3390/jcm13082203
  18. Bioinformatics. 2024 Apr 25. pii: btae283. [Epub ahead of print]
    CASCC: a co-expression assisted single-cell RNA-seq data clustering method.
    Lingyi Cai, Dimitris Anastassiou.
       SUMMARY: Existing clustering methods for characterizing cell populations from single-cell RNA sequencing are constrained by several limitations stemming from the fact that clusters often cannot be homogeneous, particularly for transitioning populations. On the other hand, dominant cell populations within samples can be identified independently by their strong gene co-expression signatures using methods unrelated to partitioning. Here, we introduce a clustering method, CASCC, designed to improve biological accuracy using gene co-expression features identified using an unsupervised adaptive attractor algorithm. CASCC outperformed other methods as evidenced by multiple evaluation metrics, and our results suggest that CASCC can improve the analysis of single-cell transcriptomics, enabling potential new discoveries related to underlying biological mechanisms.
    AVAILABILITY AND IMPLEMENTATION: The CASCC R package is publicly available at https://github.com/LingyiC/CASCC and https://zenodo.org/doi/10.5281/zenodo.10648327.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btae283
  19. Sci Adv. 2024 Apr 26. 10(17): eadm9281
    Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses.
    Sandra March, Niketa Nerurkar, Anisha Jain, Linda Andrus, Daniel Kim, Charles A Whittaker, Edward K W Tan, Sabine Thiberge, Heather E Fleming, Liliana Mancio-Silva, Charles M Rice, Sangeeta N Bhatia.
      Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, circadian rhythms play fundamental roles in maintaining organ homeostasis. Here, we established and characterized an in vitro liver experimental system in which primary human hepatocytes display self-sustained oscillations. By generating gene expression profiles of these hepatocytes over time, we demonstrated that their transcriptional state is dynamic across 24 hours and identified a set of cycling genes with functions related to inflammation, drug metabolism, and energy homeostasis. We designed and tested a treatment protocol to minimize atorvastatin- and acetaminophen-induced hepatotoxicity. Last, we documented circadian-dependent induction of pro-inflammatory cytokines when triggered by LPS, IFN-β, or Plasmodium infection in human hepatocytes. Collectively, our findings emphasize that the phase of the circadian cycle has a robust impact on the efficacy and toxicity of drugs, and we provide a test bed to study the timing and magnitude of inflammatory responses over the course of infection in human liver.
    DOI:  https://doi.org/10.1126/sciadv.adm9281
  20. Sci Rep. 2024 04 20. 14(1): 9100
    Spontaneous Akt2 deficiency in a colony of NOD mice exhibiting early diabetes.
    Julie Hervé, Karine Haurogné, Marie Allard, Sophie Sourice, Pierre Lindenbaum, Jean-Marie Bach, Blandine Lieubeau.
      Diabetes constitutes a major public health problem, with dramatic consequences for patients. Both genetic and environmental factors were shown to contribute to the different forms of the disease. The monogenic forms, found both in humans and in animal models, specially help to decipher the role of key genes in the physiopathology of the disease. Here, we describe the phenotype of early diabetes in a colony of NOD mice, with spontaneous invalidation of Akt2, that we called HYP. The HYP mice were characterised by a strong and chronic hyperglycaemia, beginning around the age of one month, especially in male mice. The phenotype was not the consequence of the acceleration of the autoimmune response, inherent to the NOD background. Interestingly, in HYP mice, we observed hyperinsulinemia before hyperglycaemia occurred. We did not find any difference in the pancreas' architecture of the NOD and HYP mice (islets' size and staining for insulin and glucagon) but we detected a lower insulin content in the pancreas of HYP mice compared to NOD mice. These results give new insights about the role played by Akt2 in glucose homeostasis and argue for the ß cell failure being the primary event in the course of diabetes.
    DOI:  https://doi.org/10.1038/s41598-024-60021-w
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