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Background Despite advances in whole-genome sequencing and identifying cancer-associated genetic alterations, understanding the influence of multiple genetic alterations collectively on cancer phenotypes remains challenging, owing to mutation pattern complexity and variability. Here, we present the NETwork-based Genotype-to-Phenotype Transformation (NetG2P), which utilizes network propagation to translate genomic information into pathway interaction networks. Using the Cancer Genome Atlas dataset across 10 cancer types, we conducted a pan-cancer analysis using NetG2P to uncover critical oncogenic features associated with cancer prognosis using machine learning and explainable artificial intelligence models. Results Our results suggest that these features, which primarily represent signaling crosstalk, can serve as functional units for determining cancer prognosis. Network analysis of these critical oncogenic features reveals distinct patterns among cancer types, categorizing them into “distributed” and “modular” networks based on pathway interactions. Applying this technique to cancer cell line data has helped predict novel drug targets for high-risk groups and proposed candidates for drug repurposing. Conclusions NetG2P generates patient-specific networks of critical oncogenic features and suggests personalized treatments, hence advancing precision medicine in oncology.

Phenotype transformation in pituitary neuroendocrine tumors is a little-known and unpredictable clinical phenomenon. Previous studies have not clearly defined and systematically concluded on the causes of this rare phenomenon. Additionally, the mechanisms of phenotype transformation are not well known. We reviewed cases reported in the literature with the aim of defining phenotype transformation in pituitary neuroendocrine tumors. We present an overview of the wide spectrum of phenotype transformation and its clinical features. We also discuss findings on the potential mechanism of this rare transformation, which may be related to PC1/3, the bioactivity of secretory hormones, gene mutations and the plasticity of pituitary neuroendocrine tumors. Clinicians should be aware of this rare phenomenon and more studies on the underlying mechanisms are required.

AimsNuclear protein 1 (Nupr1) is a multifunctional stress-induced protein involved in the regulation of tumorigenesis, apoptosis, and autophagy. However, its role in pulmonary hypertension (PH) after METH exposure remains unexplored. In this study, we aimed to investigate whether METH can induce PH and describe the role and mechanism of Nupr1 in the development of PH.Methods and resultsMice were made to induce pulmonary hypertension (PH) upon chronic intermittent treatment with METH. Their right ventricular systolic pressure (RVSP) was measured to assess pulmonary artery pressure. Pulmonary artery morphometry was determined by H&E staining and Masson staining. Nupr1 expression and function were detected in human lungs, mice lungs exposed to METH, and cultured pulmonary arterial smooth muscle cells (PASMCs) with METH treatment. Our results showed that chronic intermittent METH treatment successfully induced PH in mice. Nupr1 expression was increased in the cultured PASMCs, pulmonary arterial media from METH-exposed mice, and METH-ingested human specimens compared with control. Elevated Nupr1 expression promoted PASMC phenotype change from contractile to synthetic, which triggered pulmonary artery remodeling and resulted in PH formation. Mechanistically, Nupr1 mediated the opening of store-operated calcium entry (SOCE) by activating the expression of STIM1, thereby promoting Ca2+ influx and inducing phenotypic conversion of PASMCs.ConclusionsNupr1 activation could promote Ca2+ influx through STIM1-mediated SOCE opening, which promoted METH-induced pulmonary artery remodeling and led to PH formation. These results suggested that Nupr1 played an important role in METH-induced PH and might be a potential target for METH-related PH therapy.1. Chronic intermittent methamphetamine exposure can induce the development of pulmonary arterial hypertension.2. Nupr1 plays a key role in the development of methamphetamine-related pulmonary arterial hypertension.3. Nupr1 mediates PASMCs phenotypic transformation via STIM1signal axis, which results in the development of methamphetamine-related pulmonary arterial hypertension.

Skeletal muscle injuries caused by trauma, infections, or sports tear are common clinical diseases. Currently, the regeneration and repair of muscle tissue, which is highly heterogeneous, remains a significant challenge. Given the anisotropic structure, high strength and tensile characteristics of skeletal muscle, this study proposes a treatment strategy for muscle injury that combines materials nano-topological cues and biochemical cues. The approach aims to facilitate muscle injury repair through the use of heterogeneous nanofibers on the surface of the sandwich-like electrospun nanofibrous scaffold and macrophage phenotype transformation. Specifically, the outer layer of the sandwich-like scaffold consists of highly aligned fibers, while the middle layer is a core-shell structured random fibers containing hyaluronic acid, and the fiber matrix is composed of optimized proportions of polycaprolactone and gelatin. Mechanical testing shows that the sandwich-like scaffold combines the excellent tensile strength of the outer aligned fibers with the larger elongation at break and suture retention strength of the inner random fibers. Cell and animal experiments confirmed that the aligned fibers in the outer layers guide the cell adhesion, cytoskeleton and nuclear remodeling, and myogenic differentiation of myoblasts, and hyaluronic acid promotes both myogenic differentiation and macrophage phenotype transformation, ultimately accelerating skeletal muscle regeneration. This sandwich-like nanofibrous scaffold provides a novel cell-free, and factor-free approach for the regeneration of skeletal muscle injuries. [Display omitted] •A cell-free and growth factor-free strategy to promote skeletal muscle regeneration.•A sandwich-like scaffold with macrophage phenotype transformation and myogenic differentiation.•Nano-topological cues combined with biochemical cues mediate muscle regeneration and functional recovery.

Notably, the C‐X‐C Motif Chemokine Ligand 12/C‐X‐C Chemokine Receptor Type 4 (CXCL12/CXCR4) signalling pathway's activation is markedly increased in a mouse model of abdominal aortic aneurysms (AAA). Nonetheless, the precise contribution of this pathway to AAA development remains to be elucidated. The AAA mouse model was induced by local incubation with elastase and oral administration of β‐aminopropionitrile. The activity level of the CXCL12/CXCR4 axis was evaluated in both human AAA patients and the mouse model. Smooth muscle cell lineage tracing determined the expression and localisation of CXCR4 in normal aorta and AAA tissue. By transfecting the MiR206‐3p sponge to reduce the level of MiR206‐3p in AAA, the effects of the CXCL12/CXCR4 pathway on AAA progression as well as the apoptosis and phenotypic transformation of vascular smooth muscle cells (VSMCs) were studied in vivo and in vitro. Single‐cell RNA sequencing analysis, serum ELISA, and in vivo experiments indicate a pronounced activation of the CXCL12/CXCR4 axis in both AAA patients and the mouse model. Specific blocking of the CXCL12/CXCR4 axis significantly inhibited further expansion and rupture of the abdominal aorta and reduced the infiltration of inflammatory cells in the aorta and inhibited the phenotypic transformation of contractile VSMCs into a macrophage‐like state. Our findings propose that MiR206‐3p sponge represents an innovative therapeutic strategy to attenuate AAA progression and rupture risk, primarily through the suppression of the CXCL12/CXCR4 signalling pathway.

This study examined the effects of Stmn2 on phenotype transformation of vascular smooth muscle in vascular injury via RNA sequencing and experimental validation. Total RNA was extracted for RNA sequencing after 1, 3 and 5 days of injury to screen the differentially expressed genes (DEGs). Western blot was used to detect the protein expression of Stmn2 and its associated targets. The morphological changes of carotid arteries in rats were examined by hematoxylin and eosin (H&E) staining. The expression of vascular smooth muscle cell (VSMC) phenotype markers smooth muscle alpha-actin (α-SMA), vimentin and OPN were detected by immunohistochemistry. DEGs were related to the extracellular matrix and other cell components outside the plasma membrane. They were associated with protein binding, cytoskeleton protein binding, signal receptor binding and other molecular functions, actin cytoskeleton regulation and other Kyoto Encyclopedia of Genes and Genomes pathways. Stmn2 was identified as the hub gene of actin cytoskeleton pathway and vascular disease, and its expression followed the trend of decreasing initially and increasing afterwards during the progress of vascular injury. Western blot assay showed that the expression of Stmn2 and Tubulin decreased immediately after vascular injury; Stmn2 overexpression significantly up-regulated the expression of osteopontin and α-SMA and vimentin in VSMCs. The results of morphology analysis and immunostaining also showed that Stmn2 overexpression promoted the intima thickening and enhanced the proliferating cell nuclear antigen expression in the injured vascular tissues. In conclusion, our results implied that Stmn2 may play a potential role in vascular injury, which may be associated with VSMC phenotype transformation. Further studies are warranted to determine detailed molecular mechanisms of Stmn2 in vascular injury.

Background Abnormally high shear stress (HSS) is strongly associated with intracranial aneurysm (IA) formation. Endothelial Piezo1 is sensitive to shear stress stimulation, but the mechanism by which it mediates this mechanobiological coupling process is unclear. Methods The correlation between shear stress and the Piezo1 expression was investigated using human IA samples and a parallel‐plate flow chamber system. To determine the effects of endothelial Piezo1 on the phenotype of neighboring vascular smooth muscle cells (VSMCs) and IA formation, the CRISPR/Cas9 system was used to inhibit endothelial Piezo1 gene expression in vitro. Piezo1ΔEC mice were produced by injecting AAV2‐BR1‐Tie2‐Cre into 8‐week‐old male Piezo1flox/flox mice, which were further used to construct the IA mouse model. Single‐cell RNA sequencing and intercellular communication analyses of co‐cultured endothelial cells (ECs) and VSMCs were used to screen for receptor‐ligand pairs after inhibiting EC Piezo1 in vitro. The role of the screened receptor‐ligand pair was further validated via in vivo and in vitro experiments. Additionally, the underlying mechanisms were investigated. Result Piezo1 expression correlated negatively with the shear stress in human IA. HSS reduced EC Piezo1 expression and promoted VSMC phenotypic transformation compared with physiological shear stress. Depletion of EC Piezo1 resulted in the VSMC phenotypic transformation and, more importantly, promoted aneurysmal vascular remodeling in the mouse IA model. The platelet‐derived growth factor subunit B (PDGFB)_Platelet‐derived growth factor receptor β (PDGFRβ) was identified as being involved in this process. Moreover, the PDGFRβ antagonist reversed the VSMC phenotypic transformation and attenuated IA progression. Mechanistically, Piezo1 depletion promoted PDGFB expression via YAP/β‐catenin pathway. Conclusion HSS downregulates Piezo1 expression in ECs, which subsequently enhances PDGF‐BB expression through the YAP/β‐catenin signaling pathway. The elevated PDGF‐BB facilitates phenotypic transition of VSMCs via PDGFRβ binding, ultimately contributing to IA formation. HSS downregulates Piezo1 expression in ECs, which subsequently enhances PDGF‐BB expression through the YAP/β‐catenin signaling pathway. The elevated PDGF‐BB facilitates phenotypic transition of VSMCs via PDGFRβ binding, ultimately contributing to IA formation.

Background miR‐145 is closely related to vascular smooth muscle cells (VSMC) phenotype transformation; however, the regulatory mechanisms through which miR‐145 regulates the VSMC phenotype transformation under mechanical stretching are unclear. In this study, we evaluated the roles of miR‐145 in VSMCs subjected to mechanical stretching in aortic dissection (AD). Methods The expression of miR‐145 in the aortic vessel wall of model animals and patients with AD was analyzed by quantitative polymerase chain reaction. miR‐145‐related protein‐protein interaction networks and Wikipathways were used to analyze VSMC phenotypic transformation pathways regulated by miR‐145. We used gain‐ and loss‐of‐function studies to evaluate the effects of miR‐145 on VSMC differentiation under mechanical stretch induction and assessed whether Krüppel‐like factor 4 (KLF4) was regulated by miR‐145 in the aorta under mechanical stretch conditions. Results miR‐145 was abundantly expressed in the walls of the normal human aorta, but was significantly downregulated in animal models and the walls of patients with dissection. We found that contractile phenotype‐related proteins were downregulated in VSMCs subjected to mechanical stretching, whereas the expression of secreted phenotype‐related proteins increased. miR‐145 overexpression also downregulated contractile phenotype‐related proteins in VSMCs and suppressed upregulation of phenotype‐related proteins. Finally, under mechanical stretching, KLF4 expression was significantly increased in VSMCs, and overexpression of miR‐145 blocked this effect. Conclusion Our results confirmed that mechanical stretch‐induced phenotypic transformation of VSMCs to promote AD via upregulation of KLF4; this mechanism was regulated by miR‐145, which directly modulated KLF4 expression and VSMC differentiation. miR‐145 was abundantly expressed in the walls of the normal human aorta, but was significantly downregulated in animal models and the walls of patients with dissection. Contractile phenotype‐related proteins were downregulated in VSMCs subjected to mechanical stretching, whereas the expression of secreted phenotype‐related proteins increased. Mechanical stretch induced phenotypic transformation of VSMCs to promote AD via upregulation of KLF4. This mechanism was regulated by miR‐145, which directly modulated KLF4 expression and VSMC differentiation.

Exosomes are nanoscale membrane vesicles secreted by both normal and cancer cells, and cancer cell-derived exosomes play an important role in the cross-talk between cancer cells and other cellular components in the tumor microenvironment. Mesenchymal stem cells (MSCs) have tropism for tumors and have been used as tumor-tropic vectors for tumor therapy; however, the safety of such therapeutic use of MSCs is unknown. In this study, we investigated the role of glioma cell-derived exosomes in the tumor-like phenotype transformation of human bone marrow mesenchymal stem cells (hBMSCs) and explored the underlying molecular mechanisms. The effect of exosomes from U251 glioma cells on the growth of hBMSCs was evaluated with the CCK-8 assay, KI67 staining, and a cell cycle distribution assessment. The migration and invasion of hBMSCs were evaluated with a Transwell assay. A proteomics and bioinformatics approach, together with Western blotting and reverse transcriptase-polymerase chain reaction, was used to investigate the effect of U251 cell-derived exosomes on the proteome of hBMSCs. U251 cell-derived exosomes induced a tumor-like phenotype in hBMSCs by enhancing their proliferation, migration, and invasion and altering the production of proteins involved in the regulation of the cell cycle. Moreover, U251 cell-derived exosomes promoted the production of the metastasis-related proteins MMP-2 and MMP-9, glioma marker GFAP, and CSC markers (CD133 and Nestin). The ten differentially expressed proteins identified participated in several biological processes and exhibited various molecular functions, mainly related to the inactivation of glycolysis. Western blotting showed that U251 cell-derived exosomes upregulated the levels of Glut-1, HK-2, and PKM-2, leading to the induction of glucose consumption and generation of lactate and ATP. Treatment with 2-deoxy-D-glucose significantly reversed these effects of U251 cell-derived exosomes on hBMSCs. Our data demonstrate that glioma cell-derived exosomes activate glycolysis in hBMSCs, resulting in their tumor-like phenotype transformation. This suggests that interfering with the interaction between exosomes and hBMSCs in the tumor microenvironment has potential as a therapeutic approach for glioma. ᅟ.

Background Skeletal muscle is comprised of heterogeneous myofibers that differ in their physiological and metabolic parameters. Of these, slow-twitch (type I; oxidative) myofibers have more myoglobin, more mitochondria, and higher activity of oxidative metabolic enzymes compared to fast-twitch (type II; glycolytic) myofibers. Methods In our previous study, we found a novel LncRNA-TBP (for “LncRNA directly binds TBP transcription factor”) is specifically enriched in the soleus (which has a higher proportion of slow myofibers). The primary myoblast cells and animal model were used to assess the biological function of the LncRNA-TBP in vitro or in vivo. Meanwhile, we performed a RNA immunoprecipitation (RIP) and pull-down analysis to validate this interaction between LncRNA-TBP and TBP. Results Functional studies demonstrated that LncRNA-TBP inhibits myoblast proliferation but promotes myogenic differentiation in vitro. In vivo, LncRNA-TBP reduces fat deposition, activating slow-twitch muscle phenotype and inducing muscle hypertrophy. Mechanistically, LncRNA-TBP acts as a regulatory RNA that directly interacts with TBP protein to regulate the transcriptional activity of TBP-target genes (such as KLF4 , GPI , TNNI2 , and CDKN1A ). Conclusion Our findings present a novel model about the regulation of LncRNA-TBP , which can regulate the transcriptional activity of TBP-target genes by recruiting TBP protein, thus modulating myogenesis progression and inducing slow-twitch fibers. -DFPHBQnDUMKtGyF_FPyKx Video Abstract