bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2023‒04‒30
seventeen papers selected by
Ralitsa Radostinova Madsen
MRC-PPU
  1. Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2-, PIK3CA-mutated breast cancers.
  2. Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations.
  3. Automated Enrichment of Phosphotyrosine Peptides for High-Throughput Proteomics.
  4. Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.
  5. Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain.
  6. The Warburg effect: a signature of mitochondrial overload.
  7. Svep1 is a binding ligand of Tie1 and affects specific aspects of facial lymphatic development in a Vegfc-independent manner.
  8. Beyond Skin Rash: Alpelisib-Induced Anaphylactic Reactions.
  9. A complex systems approach to aging biology.
  10. An automated proximity proteomics pipeline for subcellular proteome and protein interaction mapping.
  11. An unexpected timer for cell division.
  12. Copper catalyses changes in cell state.
  13. Semi-automated optimized method to isolate CRISPR/Cas9 edited human pluripotent stem cell clones.
  14. deMULTIplex2: robust sample demultiplexing for scRNA-seq.
  15. A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.
  16. Fibroadipose vascular anomaly: a clinicopathological study of 75 cases.
  17. The p-rpS6-zone delineates wounding responses and the healing process.
  1. Genome Med. 2023 Apr 26. 15(1): 28
    Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2-, PIK3CA-mutated breast cancers.
    Katherine E Hutchinson, Jessica W Chen, Heidi M Savage, Thomas J Stout, Frauke Schimmoller, Javier Cortés, Susan Dent, Nadia Harbeck, William Jacot, Ian Krop, Sally E Trabucco, Smruthy Sivakumar, Ethan S Sokol, Timothy R Wilson.
      BACKGROUND: Mutations in the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), encoded by the PIK3CA gene, cause dysregulation of the PI3K pathway in 35-40% of patients with HR+/HER2- breast cancer. Preclinically, cancer cells harboring double or multiple PIK3CA mutations (mut) elicit hyperactivation of the PI3K pathway leading to enhanced sensitivity to p110α inhibitors.METHODS: To understand the role of multiple PIK3CAmut in predicting response to p110α inhibition, we estimated the clonality of multiple PIK3CAmut in circulating tumor DNA (ctDNA) from patients with HR+/HER2- metastatic breast cancer enrolled to a prospectively registered clinical trial of fulvestrant ± taselisib, and analyzed the subgroups against co-altered genes, pathways, and outcomes.
    RESULTS: ctDNA samples with clonal multiple PIK3CAmut had fewer co-alterations in receptor tyrosine kinase (RTK) or non-PIK3CA PI3K pathway genes compared to samples with subclonal multiple PIK3CAmut indicating a strong reliance on the PI3K pathway. This was validated in an independent cohort of breast cancer tumor specimens that underwent comprehensive genomic profiling. Furthermore, patients whose ctDNA harbored clonal multiple PIK3CAmut exhibited a significantly higher response rate and longer progression-free survival vs subclonal multiple PIK3CAmut.
    CONCLUSIONS: Our study establishes clonal multiple PIK3CAmut as an important molecular determinant of response to p110α inhibition and provides rationale for further clinical investigation of p110α inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.
    Keywords:  Breast cancer; Clonal; Double PIK3CA mutation; PI3K inhibitor; PI3K signaling; PIK3CA; Taselisib; ctDNA
    DOI:  https://doi.org/10.1186/s13073-023-01181-8
  2. J Pers Med. 2023 Apr 17. pii: 673. [Epub ahead of print]13(4):
    Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations.
    Jun Zhang, Jacob Croft, Alexander Le.
      Cerebral cavernous malformations (CCMs) are abnormally dilated intracranial capillaries that form cerebrovascular lesions with a high risk of hemorrhagic stroke. Recently, several somatic "activating" gain-of-function (GOF) point mutations in PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α) were discovered as a dominant mutation in the lesions of sporadic forms of cerebral cavernous malformation (sCCM), raising the possibility that CCMs, like other types of vascular malformations, fall in the PIK3CA-related overgrowth spectrum (PROS). However, this possibility has been challenged with different interpretations. In this review, we will continue our efforts to expound the phenomenon of the coexistence of gain-of-function (GOF) point mutations in the PIK3CA gene and loss-of-function (LOF) mutations in CCM genes in the CCM lesions of sCCM and try to delineate the relationship between mutagenic events with CCM lesions in a temporospatial manner. Since GOF PIK3CA point mutations have been well studied in reproductive cancers, especially breast cancer as a driver oncogene, we will perform a comparative meta-analysis for GOF PIK3CA point mutations in an attempt to demonstrate the genetic similarities shared by both cancers and vascular anomalies.
    Keywords:  CCM signaling complex (CSC); Cerebral cavernous malformations (CCMs); PIK3CA-related overgrowth spectrum (PROS); developmental venous anomalies (DVAs); familial CCM (fCCM); gain-of-function (GOF); phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α (PIK3CA); sporadic CCM (sCCM); tumor driver mutations; tumor passenger mutations; vascular malformations (VMs); venous malformations (VeMs)
    DOI:  https://doi.org/10.3390/jpm13040673
  3. J Proteome Res. 2023 Apr 25.
    Automated Enrichment of Phosphotyrosine Peptides for High-Throughput Proteomics.
    Alexis Chang, Mario Leutert, Ricard A Rodriguez-Mias, Judit Villén.
      Phosphotyrosine (pY) enrichment is critical for expanding the fundamental and clinical understanding of cellular signaling by mass spectrometry-based proteomics. However, current pY enrichment methods exhibit a high cost per sample and limited reproducibility due to expensive affinity reagents and manual processing. We present rapid-robotic phosphotyrosine proteomics (R2-pY), which uses a magnetic particle processor and pY superbinders or antibodies. R2-pY can handle up to 96 samples in parallel, requires 2 days to go from cell lysate to mass spectrometry injections, and results in global proteomic, phosphoproteomic, and tyrosine-specific phosphoproteomic samples. We benchmark the method on HeLa cells stimulated with pervanadate and serum and report over 4000 unique pY sites from 1 mg of peptide input, strong reproducibility between replicates, and phosphopeptide enrichment efficiencies above 99%. R2-pY extends our previously reported R2-P2 proteomic and global phosphoproteomic sample preparation framework, opening the door to large-scale studies of pY signaling in concert with global proteome and phosphoproteome profiling.
    Keywords:  affinity purification; automated; high-throughput; phosphoproteomics; phosphorylation signaling; phosphotyrosine; sample preparation
    DOI:  https://doi.org/10.1021/acs.jproteome.2c00850
  4. Nat Aging. 2023 Feb;3(2): 162-172
    Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.
    C P Hedges, B Shetty, S C Broome, C MacRae, P Koutsifeli, E J Buckels, C MacIndoe, J Boix, T Tsiloulis, B G Matthews, S Sinha, M Arendse, J K Jaiswal, K M Mellor, A J R Hickey, P R Shepherd, T L Merry.
      Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.
    DOI:  https://doi.org/10.1038/s43587-022-00349-y
  5. bioRxiv. 2023 Apr 12. pii: 2023.04.12.536585. [Epub ahead of print]
    Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain.
    Noah J Harris, Meredith L Jenkins, Sung-Eun Nam, Manoj K Rathinaswamy, Matthew Ah Parson, Harish Ranga-Prasad, Udit Dalwadi, Brandon E Moeller, Eleanor Sheekey, Scott D Hansen, Calvin K Yip, John E Burke.
      PI3Kγ is a critical immune signaling enzyme activated downstream of diverse cell surface molecules, including Ras, PKCβ activated by the IgE receptor, and Gβγ subunits released from activated GPCRs. PI3Kγ can form two distinct complexes, with the p110γ catalytic subunit binding to either a p101 or p84 regulatory subunit, with these complexes being differentially activated by upstream stimuli. Here using a combination of Cryo electron microscopy, HDX-MS, and biochemical assays we have identified novel roles of the helical domain of p110γ in regulating lipid kinase activity of distinct PI3Kγ complexes. We defined the molecular basis for how an allosteric inhibitory nanobody potently inhibits kinase activity through rigidifying the helical domain and regulatory motif of the kinase domain. The nanobody did not block either p110γ membrane recruitment or Ras/Gβγ binding, but instead decreased ATP turnover. We also identified that p110γ can be activated by dual PKCβ helical domain phosphorylation leading to partial unfolding of an N-terminal region of the helical domain. PKCβ phosphorylation is selective for p110γ-p84 compared to p110γ-p101, driven by differential dynamics of the helical domain of these different complexes. Nanobody binding prevented PKCβ mediated phosphorylation. Overall, this works shows an unexpected allosteric regulatory role of the helical domain of p110γ that is distinct between p110γ-p84 and p110γ-p101, and reveals how this can be modulated by either phosphorylation or allosteric inhibitory binding partners. This opens possibilities of future allosteric inhibitor development for therapeutic intervention.
    DOI:  https://doi.org/10.1101/2023.04.12.536585
  6. Trends Cell Biol. 2023 Apr 26. pii: S0962-8924(23)00070-3. [Epub ahead of print]
    The Warburg effect: a signature of mitochondrial overload.
    Yahui Wang, Gary J Patti.
      A long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload.
    Keywords:  Warburg effect; aerobic fermentation; aerobic glycolysis; cancer metabolism; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.013
  7. Elife. 2023 Apr 25. pii: e82969. [Epub ahead of print]12
    Svep1 is a binding ligand of Tie1 and affects specific aspects of facial lymphatic development in a Vegfc-independent manner.
    Melina Hußmann, Dörte Schulte, Sarah Weischer, Claudia Carlantoni, Hiroyuki Nakajima, Naoki Mochizuki, Didier Y R Stainier, Thomas Zobel, Manuel Koch, Stefan Schulte-Merker.
      Multiple factors are required to form functional lymphatic vessels. Here, we uncover an essential role for the secreted protein Svep1 and the transmembrane receptor Tie1 during the development of subpopulations of the zebrafish facial lymphatic network. This specific aspect of the facial network forms independently of Vascular endothelial growth factor C (Vegfc) signalling, which otherwise is the most prominent signalling axis in all other lymphatic beds. Additionally, we find that multiple specific and newly uncovered phenotypic hallmarks of svep1 mutants are also present in tie1, but not in tie2 or vegfc mutants. These phenotypes are observed in the lymphatic vasculature of both head and trunk, as well as in the development of the dorsal longitudinal anastomotic vessel under reduced flow conditions. Therefore, our study demonstrates an important function for Tie1 signalling during lymphangiogenesis as well as blood vessel development in zebrafish. Furthermore, we show genetic interaction between svep1 and tie1 in vivo, during early steps of lymphangiogenesis, and demonstrate that zebrafish as well as human Svep1/SVEP1 protein bind to the respective Tie1/TIE1 receptors in vitro. Since compound heterozygous mutations for SVEP1 and TIE2 have recently been reported in human glaucoma patients, our data have clinical relevance in demonstrating a role for SVEP1 in TIE signalling in an in vivo setting.
    Keywords:  cell biology; cell migration; developmental biology; endothelial cells; lymphangiogenesis; zebrafish
    DOI:  https://doi.org/10.7554/eLife.82969
  8. Oncologist. 2023 Apr 22. pii: oyad092. [Epub ahead of print]
    Beyond Skin Rash: Alpelisib-Induced Anaphylactic Reactions.
    Tim Schutte, Laurien J Zeverijn, Birgit S Geurts, Gijsbrecht F de Wit, Marleen Kok, Frans L Opdam.
      Alpelisib is a specific oral PI3K inhibitor used combined with fulvestrant for the treatment of patients with HR+/HER2-/PIK3CA-mutated metastatic breast cancer. Adverse drug reactions with alpelisib are common, including hyperglycemia and rash. Here we describe extraordinary and life-threatening reactions beyond skin rash in two patients with progressive PIK3CA-mutated metastatic cancer in whom alpelisib was initiated. Case-A (vaginal cancer): After 10 days on treatment, she developed dry eyes, generalized rash and itching. Alpelisib was interrupted and symptomatic treatment initiated. Because of an initial tumor response, a rechallenge was done. Ninety minutes after a reduced dose of alpelisib, she developed an anaphylactic reaction with angioedema, hypotension, and skin rash. Case-B (breast cancer): After 11 days on treatment, she developed skin rash and alpelisib was interrupted. At re-initiation, she felt tingles in her face and ears and some skin erythema. Given the mild rash, a second rechallenge with premedication was performed. Ninety minutes after a reduced dose of alpelisib, she developed a type-1 allergic reaction with angioedema, tingles, and skin rash. In both cases, a type-1 allergic reaction was diagnosed and symptomatic treatment was initiated, alpelisib was permanently discontinued and the patients fully recovered the next week(s). This report underlines the critical importance to consider type-I allergic reactions in the differential diagnosis in cases of rash associated with alpelisib. Even if a reaction develops after days on treatment, a type-I allergic reaction cannot be excluded. A rechallenge can be dangerous and should always be well contemplated or even avoided.
    DOI:  https://doi.org/10.1093/oncolo/oyad092
  9. Nat Aging. 2022 Jul;2(7): 580-591
    A complex systems approach to aging biology.
    Alan A Cohen, Luigi Ferrucci, Tamàs Fülöp, Dominique Gravel, Nan Hao, Andres Kriete, Morgan E Levine, Lewis A Lipsitz, Marcel G M Olde Rikkert, Andrew Rutenberg, Nicholas Stroustrup, Ravi Varadhan.
      Having made substantial progress understanding molecules, cells, genes and pathways, aging biology research is now moving toward integration of these parts, attempting to understand how their joint dynamics may contribute to aging. Such a shift of perspective requires the adoption of a formal complex systems framework, a transition being facilitated by large-scale data collection and new analytical tools. Here, we provide a theoretical framework to orient researchers around key concepts for this transition, notably emergence, interaction networks and resilience. Drawing on evolutionary theory, network theory and principles of homeostasis, we propose that organismal function is accomplished by the integration of regulatory mechanisms at multiple hierarchical scales, and that the disruption of this ensemble causes the phenotypic and functional manifestations of aging. We present key examples at scales ranging from sub-organismal biology to clinical geriatrics, outlining how this approach can potentially enrich our understanding of aging.
    DOI:  https://doi.org/10.1038/s43587-022-00252-6
  10. bioRxiv. 2023 Apr 12. pii: 2023.04.11.536358. [Epub ahead of print]
    An automated proximity proteomics pipeline for subcellular proteome and protein interaction mapping.
    Xiaofang Zhong, Qiongyu Li, Benjamin J Polacco, Trupti Patil, Jeffrey F DiBerto, Rasika Vartak, Jiewei Xu, Aaron Marley, Helene Foussard, Bryan L Roth, Manon Eckhardt, Mark Von Zastrow, Nevan J Krogan, Ruth Hüttenhain.
      Proximity labeling (PL) coupled with mass spectrometry has emerged as a powerful technique to map proximal protein interactions in living cells. Large-scale sample processing for proximity proteomics necessitates a high-throughput workflow to reduce hands-on time and increase quantitative reproducibility. To address this issue, we developed a scalable and automated PL pipeline, including generation and characterization of monoclonal cell lines, automated enrichment of biotinylated proteins in a 96-well format, and optimization of the quantitative mass spectrometry (MS) acquisition method. Combined with data-independent acquisition (DIA) MS, our pipeline outperforms manual enrichment and data-dependent acquisition (DDA) MS regarding reproducibility of protein identification and quantification. We apply the pipeline to map subcellular proteomes for endosomes, late endosomes/lysosomes, the Golgi apparatus, and the plasma membrane. Moreover, using serotonin receptor (5HT 2A ) as a model, we investigated agonist-induced dynamics in protein-protein interactions. Importantly, the approach presented here is universally applicable for PL proteomics using all biotinylation-based PL enzymes, increasing both throughput and reproducibility of standard protocols.
    DOI:  https://doi.org/10.1101/2023.04.11.536358
  11. Nature. 2023 Apr 26.
    An unexpected timer for cell division.
    Silke Hauf.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-023-01355-9
  12. Nature. 2023 Apr 26.
    Copper catalyses changes in cell state.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-023-01330-4
  13. Stem Cell Res Ther. 2023 Apr 27. 14(1): 110
    Semi-automated optimized method to isolate CRISPR/Cas9 edited human pluripotent stem cell clones.
    Elie Frank, Michel Cailleret, Constantin Nelep, Pascal Fragner, Jérome Polentes, Elise Herardot, Lina El Kassar, Karine Giraud-Triboult, Christelle Monville, Karim Ben M'Barek.
      BACKGROUND: CRISPR/Cas9 editing systems are currently used to generate mutations in a particular gene to mimic a genetic disorder in vitro. Such "disease in a dish" models based on human pluripotent stem cells (hPSCs) offer the opportunity to have access to virtually all cell types of the human body. However, the generation of mutated hPSCs remains fastidious. Current CRISPR/Cas9 editing approaches lead to a mixed cell population containing simultaneously non-edited and a variety of edited cells. These edited hPSCs need therefore to be isolated through manual dilution cloning, which is time-consuming, labor intensive and tedious.METHODS: Following CRISPR/Cas9 edition, we obtained a mixed cell population with various edited cells. We then used a semi-automated robotic platform to isolate single cell-derived clones.
    RESULTS: We optimized CRISPR/Cas9 editing to knock out a representative gene and developed a semi-automated method for the clonal isolation of edited hPSCs. This method is faster and more reliable than current manual approaches.
    CONCLUSIONS: This novel method of hPSC clonal isolation will greatly improve and upscale the generation of edited hPSCs required for downstream applications including disease modeling and drug screening.
    Keywords:  CRISPR/Cas9; Clonal isolation; Gene edition; Human pluripotent stem cell
    DOI:  https://doi.org/10.1186/s13287-023-03327-2
  14. bioRxiv. 2023 Apr 12. pii: 2023.04.11.536275. [Epub ahead of print]
    deMULTIplex2: robust sample demultiplexing for scRNA-seq.
    Qin Zhu, Daniel N Conrad, Zev J Gartner.
      Single-cell sample multiplexing technologies function by associating sample-specific barcode tags with cell-specific barcode tags, thereby increasing sample throughput, reducing batch effects, and decreasing reagent costs. Computational methods must then correctly associate cell-tags with sample-tags, but their performance deteriorates rapidly when working with datasets that are large, have imbalanced cell numbers across samples, or are noisy due to cross-contamination among sample tags - unavoidable features of many real-world experiments. Here we introduce deMULTIplex2, a mechanism-guided classification algorithm for multiplexed scRNA-seq data that successfully recovers many more cells across a spectrum of challenging datasets compared to existing methods. deMULTIplex2 is built on a statistical model of tag read counts derived from the physical mechanism of tag cross-contamination. Using generalized linear models and expectation-maximization, deMULTIplex2 probabilistically infers the sample identity of each cell and classifies singlets with high accuracy. Using Randomized Quantile Residuals, we show the model fits both simulated and real datasets. Benchmarking analysis suggests that deMULTIplex2 outperforms existing algorithms, especially when handling large and noisy single-cell datasets or those with unbalanced sample compositions.
    DOI:  https://doi.org/10.1101/2023.04.11.536275
  15. J Clin Invest. 2023 May 01. pii: e164283. [Epub ahead of print]133(9):
    A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.
    Jing Li, Xiangdong Zhu, Matt T Oberdier, Chunpei Lee, Shaoxia Lin, Sarah J Fink, Cody N Justice, Kevin Qin, Andrew W Begeman, Frederick C Damen, Hajwa Kim, Jiwang Chen, Kejia Cai, Henry R Halperin, Terry L Vanden Hoek.
      Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20-amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.
    Keywords:  Cardiovascular disease; Drug therapy; Peptides; Therapeutics
    DOI:  https://doi.org/10.1172/JCI164283
  16. Histopathology. 2023 Apr 26.
    Fibroadipose vascular anomaly: a clinicopathological study of 75 cases.
    Shuang Xue, Qiuyu Liu, Yuewu Zhao, Lingfei Kong, Fangfang Fu, Yubin Gong, Xiaonan Guo, Changxian Dong, Meiyun Wang.
      AIMS: Fibroadipose vascular anomaly (FAVA) is a complex vascular malformation that is likely to be under-recognised. In this study we aimed to report the pathological features and somatic PIK3CA mutations associated with the most common clinicopathological features.METHODS AND RESULTS: Cases were identified by reviewing the lesions resected from patients with FAVA registered at our Haemangioma Surgery Centre and unusual intramuscular vascular anomalies in our pathology database. There were 23 males and 52 females, who ranged in age from 1 to 51 years. Most cases occurred in the lower extremities (n = 62). The majority of the lesions were intramuscular, with a few disrupting the overlying fascia and involving subcutaneous fat (19 of 75), and a minority of the cases had cutaneous vascular stains (13 of 75). Histopathologically, the lesion was composed of anomalous vascular components that were intertwined with mature adipocytic and dense fibrous tissues and vascular components with: (a) clusters of thin-walled channels, some with blood-filled nodules and others with thin walls resembling pulmonary alveoli; (b) numerous small vessels (arteries, veins and indeterminate channels) - proliferative small blood vessels were often mixed with adipose tissue; (c) larger abnormal venous channels usually irregularly and sometimes excessively muscularised; (d) lymphoid aggregates or lymphoplasmacytic aggregates were usually observed; and (e) lymphatic malformations were sometimes seen as minor elements. All patients had their lessons subjected to PCR, and 53 patients had somatic PIK3CA mutations (53 of 75).
    CONCLUSIONS: FAVA is a slow-flow vascular malformation with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for targeted therapy.
    Keywords:  PIK3CA; fibroadipose vascular anomaly; vascular malformation
    DOI:  https://doi.org/10.1111/his.14923
  17. Dev Cell. 2023 Apr 18. pii: S1534-5807(23)00154-5. [Epub ahead of print]
    The p-rpS6-zone delineates wounding responses and the healing process.
    Nadja Anneliese Ruth Ring, Helene Dworak, Barbara Bachmann, Barbara Schädl, Karla Valdivieso, Tomaz Rozmaric, Patrick Heimel, Ines Fischer, Eirini Klinaki, Aniko Gutasi, Kornelia Schuetzenberger, Gabriele Leinfellner, James Ferguson, Susanne Drechsler, Michael Mildner, Markus Schosserer, Paul Slezak, Oded Meyuhas, Florian Gruber, Johannes Grillari, Heinz Redl, Mikolaj Ogrodnik.
      The spatial boundaries of tissue response to wounding are unknown. Here, we show that in mammals, the ribosomal protein S6 (rpS6) is phosphorylated in response to skin injury, forming a zone of activation surrounding the region of the initial insult. This p-rpS6-zone forms within minutes after wounding and is present until healing is complete. The zone is a robust marker of healing as it encapsulates features of the healing process, including proliferation, growth, cellular senescence, and angiogenesis. A mouse model that is unable to phosphorylate rpS6 shows an initial acceleration of wound closure, but results in impaired healing, identifying p-rpS6 as a modulator but not a driver of healing. Finally, the p-rpS6-zone accurately reports on the status of dermal vasculature and the effectiveness of healing, visually dividing an otherwise homogeneous tissue into regions with distinct properties.
    Keywords:  S6; cellular senescence; immediate response; mTOR; p-rpS6; p-rpS6-zone; regeneration; tissue damage; wound healing; wound marker
    DOI:  https://doi.org/10.1016/j.devcel.2023.04.001
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