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Journal articles on the topic 'PIK3R1'

Author: Grafiati
Published: 4 June 2021
Last updated: 18 February 2022

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1

Kim, Jin-Mo, Hyun Yoo, Jee-Youn Kim, Sang Ho Oh, Jeong Wook Kang, Byung Rok Yoo, Song Yee Han, et al. "Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3." Cellular Physiology and Biochemistry 48, no. 3 (2018): 959–70. http://dx.doi.org/10.1159/000491964.

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Background/Aims: Radiation-induced skin fibrosis is a common side effect of clinical radiotherapy. Our previous next-generation sequencing (NGS) study demonstrated the reduced expression of the regulatory α subunit of phosphatidylinositol 3-kinase (PIK3r1) in irradiated murine skin. Metformin has been reported to target the PIK3-FOXO3 pathway. In this study, we investigated the effects of metformin on radiation-induced skin fibrosis. Methods: Metformin was orally administered to irradiated mice. Skin fibrosis was analyzed by staining with H&E and Masson’s trichrome stain. The levels of cytokines and chemokines associated with fibrosis were analyzed by immunohistochemistry and quantitative RT-PCR. The roles of PIK3rl and FOXO3 in radiation-induced skin fibrosis were studied by overexpressing PIK3rl and transfecting FOXO3 siRNA in NIH3T3 cells and mouse-derived dermal fibroblasts (MDF). Results: The oral administration of metformin significantly reduced radiation-induced skin thickening and collagen accumulation and significantly reduced the radiation-induced expression of FOXO3 in murine skin. Additionally, the overexpression of PIK3r1 reduced the radiation-induced expression of FOXO3, while FOXO3 silencing decreased the radiation-induced expression of TGFβ in vitro. Conclusions: The results indicated that metformin suppresses radiation-induced skin injuries by modulating the expression of FOXO3 through PIK3r1. Collectively, the data obtained in this study suggested that metformin could be a potent therapeutic agent for alleviating radiation-induced skin fibrosis.
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Dirican, Ebubekir, İpek Erbarut Seven, Handan Kaya, M. Ümit Uğurlu, İrem Peker, Bahadır M. Güllüoğlu, Ayşe Özer, and Mustafa Akkiprik. "PIK3CA and TP53 MUTATIONS and SALL4, PTEN and PIK3R1 GENE EXPRESSION LEVELS in BREAST CANCER." Turkish Journal of Biochemistry 45, no. 5 (March 2, 2020): 515–23. http://dx.doi.org/10.1515/tjb-2019-0137.

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AbstractObjectiveA high frequency of PI3K signalling pathway abnormalities and TP53 mutations are critical in the development and progression of breast cancer (BCa). We aimed to detect PIK3CA and TP53 mutations via an expression analysis of PIK3R1, PTEN and SALL4 and correlate the expression of these genes with clinical parameters of BCa.Materials and methodsPIK3CA and TP53 mutations in BCa samples were analysed by High-Resolution Melting (HRM) analysis, followed by Sanger sequencing, and the expression levels of PIK3R1, PTEN and SALL4 were evaluated by RT-PCR methods.ResultsThe frequency of PIK3CA and TP53 mutations was 42% and 38% according to the HRM and Sanger sequencing. There was a significantly high frequency of these mutations in ER( +), N0 and HER2( −) tumour samples. PIK3R1 and PTEN expression levels were high in tumour samples, whereas SALL4 expression was low. In patients with TP53 mutations, PIK3R1 expression was low, and this finding was statistically significant. PIK3R1 and PTEN expression levels showed statistically significant, respectively in G3 grades, ER(+), (PR)( +), HER2(+) and ER( +).ConclusionsWe suggest that these candidate genes could be potential prognostic biomarkers of BCa and that they should be considered in the evaluation of clinical parameters of BCa.
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3

Herrero-Gonzalez, Sandra, and Antonio Di Cristofano. "New Routes to Old Places: PIK3R1 and PIK3R2 Join PIK3CA and PTEN as Endometrial Cancer Genes." Cancer Discovery 1, no. 2 (July 2011): 106–7. http://dx.doi.org/10.1158/2159-8290.cd-11-0116.

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4

Vallejo-Díaz, Jesús, Monica Chagoyen, Manuel Olazabal-Morán, Ana González-García, and Ana Clara Carrera. "The Opposing Roles of PIK3R1/p85α and PIK3R2/p85β in Cancer." Trends in Cancer 5, no. 4 (April 2019): 233–44. http://dx.doi.org/10.1016/j.trecan.2019.02.009.

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5

Yazdani, Reza, Zahra Hamidi, Fateme Babaha, Gholamreza Azizi, Saba Fekrvand, Hassan Abolhassani, and Asghar Aghamohammadi. "PIK3R1 Mutation Associated with Hyper IgM (APDS2 Syndrome): A Case Report and Review of the Literature." Endocrine, Metabolic & Immune Disorders - Drug Targets 19, no. 7 (October 11, 2019): 941–58. http://dx.doi.org/10.2174/1871530319666190225114739.

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Background and Objective: APDS [Activated phosphoinositide 3-kinase (PI3K) δ Syndrome] is a newly found special form of primary immunodeficiency caused by mutations in genes encoding PI3Kδ subunits and over-activation of the PI3K signaling pathway. Gain-of-function and loss-of-function mutations in PIK3CD (encoding P110δ) and PIK3R1 (encoding p85α, p55α and p50α) lead to APDS1 and APDS2, respectively. The subsequent irregular PI3K downstream signaling cascade is associated with abnormalities in B cells and T cells and the consequent heterogeneous clinical manifestations including respiratory tract infections, autoimmunity, lymphoproliferation and not to mention primary antibody deficiency. In this study, we report a 12-year-old girl with a mutation in the PIK3R1 gene who manifested immunological phenotypes resembling hyper IgM syndrome along with a review of the literature of the previously reported patients. Methods: Whole exome sequencing was performed to detect the underlying genetic mutation in this patient. Results: A de novo heterozygous splice site mutation in the hot spot of the PIK3R1 gene within the intron 10 was found (c.1425+1G>A). Conclusion: Further investigations are required for evaluation of the underlying genetic defects and the possible associations between genetic underpinning and heterogeneous severity and features of the disease.
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Thorpe, Lauren M., Jennifer M. Spangle, Carolynn E. Ohlson, Hailing Cheng, Thomas M. Roberts, Lewis C. Cantley, and Jean J. Zhao. "PI3K-p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85α." Proceedings of the National Academy of Sciences 114, no. 27 (June 19, 2017): 7095–100. http://dx.doi.org/10.1073/pnas.1704706114.

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Mutation or loss of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is emerging as a transforming factor in cancer, but the mechanism of transformation has been controversial. Here we find that hemizygous deletion of the PIK3R1 gene encoding p85α is a frequent event in breast cancer, with PIK3R1 expression significantly reduced in breast tumors. PIK3R1 knockdown transforms human mammary epithelial cells, and genetic ablation of Pik3r1 accelerates a mouse model of HER2/neu-driven breast cancer. We demonstrate that partial loss of p85α increases the amount of p110α–p85 heterodimers bound to active receptors, augmenting PI3K signaling and oncogenic transformation. Pan-PI3K and p110α-selective pharmacological inhibition effectively blocks transformation driven by partial p85α loss both in vitro and in vivo. Together, our data suggest that p85α plays a tumor-suppressive role in transformation, and suggest that p110α-selective therapeutics may be effective in the treatment of breast cancer patients with PIK3R1 loss.
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Shi, Ting, Xiongjie Shen, and Ge Gao. "Gene Expression Profiles of Peripheral Blood Monocytes in Osteoarthritis and Analysis of Differentially Expressed Genes." BioMed Research International 2019 (November 26, 2019): 1–12. http://dx.doi.org/10.1155/2019/4291689.

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Background. There is little understanding of the molecular processes involved in the pathogenesis of osteoarthritis, limiting early diagnosis and effective treatment of OA. Use of genechips can provide insights into the molecular pathogenesis of diseases. In this study, determination of gene expression profiles of osteoarthritis peripheral blood mononuclear cells will allow exploration of the molecular pathogenesis of OA and find out more candidate biomarkers and potential drug targets of OA. Result. A total of 1231 DEGs were screened out including 791 upregulated DEGs and 440 downregulated DEGs. The most significant upregulated DEG was RPL38, which may inhibit chondrocyte differentiation and synthesis of the extracellular matrix. PIK3CA, PIK3CB, PIK3CD, PIK3R1, MAPK14, IL1A, JUND, FOSL2, and PPP3CA were the gene symbols of the osteoclast differentiation pathway which was the most significant pathway enriched by DEGs. However, the MAPK signaling pathway occupied the core position of all the pathways which can regulate apoptosis, cell cycle, wnt signaling pathway, p53 signaling pathway, and phosphatidylinositol signaling system. Furthermore, PI3Ks may regulate IL1A, JUND, FOSL2 and PPP3CA through the MAPK signaling pathway. Conclusion. These identified DEGs and pathways may be novel biomarkers to monitor the changes of OA and can be a potential drug target for the treatment of OA.
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8

Cobleigh, Melody A., and Abde M. Abukhdeir. "Binimetinib activity in PIK3R1-mutant patient-derived xenografts (PDX) implanted into immunodeficient mice." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e13062-e13062. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13062.

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e13062 Background: The PIK3R1 gene is genetically altered in ̃3% of breast cancers in the Western and ̃17% in the Eastern worlds. We recently reported that breast cancer cells lacking protein expression of PIK3R1 had elevated levels of activated MEK, sensitizing them to the MEK inhibitor trametinib. To better understand whether MEK inhibition is a therapeutic option for breast cancer patients with mutated PIK3R1, we tested the newer generation MEK inhibitor, binimetinib, in a PDX mouse model. Methods: Two PDx models (table) were tested in athymic nude-foxn1nu (immune-compromised) mice. Both patients had had metastatic, grade 3 breast cancer and expressed moderate RNA levels of PIK3R1. Results: Body weights of treatment arms were unchanged throughout the experiment. The TNBC PDx study was halted early at 13 days because tumors reached the predefined maximum size of 1500 mm2. The binimetinib treated mice experienced slowed tumor growth (522.8 +/- 172.8%) compared to the vehicle control (720.7 +/- 229.1%), (p=0.0693). In the HR+ PDx model, the combination of binimetinib plus tamoxifen resulted in a statistically significant decrease (371.5 +/- 108.1%) in tumor volume compared to tamoxifen alone (525.0 +/- 154.1%; p = 0.0302). Conclusions: Our previous and current results suggest that mutation in PIK3R1 sensitizes cells to MEK inhibitors. Binimetinib inhibited growth in both models. This inhibition was of borderline significance in the TNBC model and was statistically significant in the ER+, HER2- model. To the best of our knowledge, these results provide the first evidence of binimetinib efficacy in PIK3R1-mutant, HR+, HER2- PDX immunodeficient mice. Plans for a phase II trial in patients with PIK3R1-mutant, HR+, HER2- breast cancer are underway.[Table: see text]
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Calixto-Hope, Lucas, Julieann Lee, Emily Sloan, Jeffrey Hofmann, Jessica Van Ziffle, Courtney Onodera, James Grenert, et al. "PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS." Neuro-Oncology 21, Supplement_6 (November 2019): vi151—vi152. http://dx.doi.org/10.1093/neuonc/noz175.634.

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Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.
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Goodwin, Charles B., Zhenyun Yang, Sasidhar Vemula, Fuqin Yin, Reuben Kapur, and Rebecca J. Chan. "Genetic Disruption of the PI3K Regulatory Subunit, p85α Partially Normalizes Gain-of-Function PTPN11-Induced Hypersensitivity to GM-CSF in Hematopoietic Progenitors." Blood 114, no. 22 (November 20, 2009): 3968. http://dx.doi.org/10.1182/blood.v114.22.3968.3968.

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Abstract Abstract 3968 Poster Board III-904 Juvenile Myelomonocytic Leukemia (JMML) is a lethal myeloproliferative disorder (MPD) of children, characterized by hyperproliferation of myelomonocytic cells and hypersensitivity to Granulocyte-Monocyte Colony-Stimulating Factor (GM-CSF). Most patients show hyperactivation of Ras via one or more mutations, including in the PTPN11 gene, which encodes the protein tyrosine phosphatase, Shp2. It has been demonstrated that gain-of-function mutant Shp2 (Shp2 E76K and Shp2 D61Y) causes hyperactivation of the Mitogen-Activated Protein Kinase (MAPK) pathway. Additionally, we have previously shown that macrophage progenitor cells transduced with Shp2 D61Y or Shp2 E76K showed elevated levels of phospho-Akt, both at baseline and following 1 hour of GM-CSF stimulation, indicating a role for the Phospho-Inositol-3-Kinase (PI3K)/Akt pathway in the phenotype of elevated proliferation and survival in mutant Shp2-expressing cells (Yang, et al, 2008). However, it remains to be elucidated how PI3K contributes to the phenotype of increased proliferation and survival in cells bearing gain-of-function mutations in Shp2. Class IA PI3K is a lipid kinase heterodimer consisting of one of three catalytic subunits (p110α, p110β, or p110δ) and one of two regulatory subunits (p85α or p85β). It has been demonstrated that knocking out the main regulatory subunit, p85α, abrogated the hyperproliferative phenotype in mast cell progenitors bearing an oncogenic mutation in Kit in a model of another MPD, Systemic Mastocytosis (Munugalavadla, et al, 2007). In order to examine whether eliminating expression of p85α would cause a similar correction in cells expressing gain-of-function mutant Shp2, we performed timed matings of mice heterozygous for the knock-out of Pik3r1, which encodes the p85α subunit as well as its isoforms, p55α and p50α, since homozygous Pik3r1-/- is lethal in utero. WT and Pik3r1-/- fetal liver cells were isolated from 14.5 day embryos and transduced with either WT Shp2 or mutant Shp2 E76K. Transduced cells were subjected to serum deprivation followed by a 24-hour treatment with increasing doses of GM-CSF, and proliferation was then measured with H3-thymidine incorporation assays. We found that the absence of all the Pik3r1 isoforms resulted in a significant but incomplete correction of GM-CSF hypersensitivity in Shp2 E76K-expressing cells. To further investigate this observation, WT Pik3r1 and Pik3r1-/- macrophage progenitors, transduced with WT Shp2 or mutant Shp2 E76K as described above, were serum- and growth factor-deprived and then stimulated for 1 hour with GM-CSF. Western blot analysis showed that there was an expected increase in phospho-Akt in WT Pik3r1 cells following GM-CSF stimulation and that this increase was larger in Shp2 E76K-expressing cells than in WT Shp2-expressing cells, as previously observed. Upon genetic disruption of Pik3r1, Akt activation was reduced in both WT Shp2- and Shp2 E76K-expressing cells; however, the phospho-Akt in the Shp2 E76K-expressing cells was not reduced to WT levels. The phospho-Akt levels mirrored the proliferation pattern displayed by these cells in the H3-thymidine incorporation assays, where a modest reduction in proliferation in Pik3r1-/-, Shp2 E76K cells corresponded to the modest reduction in phospho-Akt levels in the same cells. Additionally, we found that Pik3r1-/-, Shp2 E76K cells also showed a blunted increase in phospho-Erk levels following GM-CSF stimulation compared to the WT Pik3r1, Shp2 E76K cells, indicating that knocking out Pik3r1 affects the MAPK pathway as well, which likely also contributes to the reduction in proliferation seen in Pik3r1-/-, Shp2 E76K cells following GM-CSF stimulation. Based on these data, we conclude that: (1) gain-of-function Shp2 activity results in dysregulated PI3K signaling, contributing to the leukemic phenotype of increased proliferation and survival; (2) PI3K signaling is reduced but not completely normalized in the absence of the main regulatory subunit, p85α and its isoforms, in gain-of-function mutant Shp2-expressing cells; and (3) there is cross-talk between the PI3K and MAPK pathways in the presence of Shp2 activating mutations, which is revealed by knocking out Pik3r1. Disclosures: No relevant conflicts of interest to declare.
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Barros, Tamiris, Vinicius Venancio, Lívia Hernandes, Lusania Antunes, Elaine Hillesheim, Roberta Salomão, Mariana Mathias, et al. "DNA Damage, n-3 Long-Chain PUFA Levels and Proteomic Profile in Brazilian Children and Adolescents." Nutrients 13, no. 8 (July 21, 2021): 2483. http://dx.doi.org/10.3390/nu13082483.

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Fatty acids play a significant role in maintaining cellular and DNA protection and we previously found an inverse relationship between blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DNA damage. The aim of this study was to explore differences in proteomic profiles, for 117 pro-inflammatory proteins, in two previously defined groups of individuals with different DNA damage and EPA and DHA levels. Healthy children and adolescents (n = 140) aged 9 to 13 years old in an urban area of Brazil were divided by k-means cluster test into two clusters of DNA damage (tail intensity) using the comet assay (cluster 1 = 5.9% ± 1.2 and cluster 2 = 13.8% ± 3.1) in our previous study. The cluster with higher DNA damage and lower levels of DHA (6.2 ± 1.6 mg/dL; 5.4 ± 1.3 mg/dL, p = 0.003) and EPA (0.6 ± 0.2 mg/dL; 0.5 ± 0.1 mg/dL, p < 0.001) presented increased expression of the proteins CDK8–CCNC, PIK3CA–PIK3R1, KYNU, and PRKCB, which are involved in pro-inflammatory pathways. Our findings support the hypothesis that low levels of n-3 long-chain PUFA may have a less protective role against DNA damage through expression of pro-inflammatory proteins, such as CDK8–CCNC, PIK3CA–PIK3R1, KYNU, and PRKCB.
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Hunter, Zachary, Yang Cao, Megan Lewicki, Jenny Sun, Hsiuyi Tseng, Christina Hanzis, Philip Brodsky, et al. "Aberrant Expression of Regulatory miRNAs and Transcripts for IRS-PI3K Growth and Survival Signaling In Waldenstrom's Macroglobulinemia." Blood 116, no. 21 (November 19, 2010): 1912. http://dx.doi.org/10.1182/blood.v116.21.1912.1912.

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Abstract Abstract 1912 Background: Waldenstrom's Macroglobulinemia (WM) is a rare low grade non-Hodgkin's lymphoma characterized by the accumulation of IgM secreting lymphoplasmacytic cells in (LPC) the bone marrow, an elevated serum IgM, and frequently accompanied with hyperviscosity syndrome. The insulin receptor substrates (IRS) are important mediators of the insulin like receptor family and PI3K signaling leading to PKC and AKT activation. Methods: TaqMan low density arrays were used to evaluate the relative levels of 667 miRNAs in 11 WM patient and 5 age matched healthy donor (HD) CD19+ bone marrow cells. The results of this screen were validated using individual stem loop RT-PCR assays. Additional mRNA targets were identified using an existing gene expression profiling (GEP) data set of 22 WM patients and 8 HD using the Affymetrix U133 plus 2 platform. GEP findings were validated using an independent cohort of 18 WM patients and 7 HD. Results: Aberrant miRNAs identified were miR-21 (+3.27 fold p=0.035), miR-29c (+3.17 fold; p=0.003), miR-155 (+5.53 fold; p=0.082), miR-9* (-3.94 fold; p=0.001), miR-27b (-4.94 fold; p=0.001), miR-126 (-21.52 fold; p=0.006), miR-126* (-25.55 fold; p=0.039), miR-145 (-34.27 fold; p<0.001), miR-223 (-24.25 fold; p=0.041), and miR-886-5p (-3.01 fold; p=0.004). Importantly, 5 of these 10 miRNAs targeted members of the IRS-PI3K signaling pathway, a pathway important for growth and survival of WM cells: miR-29c (PIK3R1); R-155 (SHIP1); miR-21 (PTEN); miR-145 (IRS1); miR-126 (IRS1 and PIK3R2), and predict for increased protein levels for PIK3R2 and IRS1 with lower protein levels for PIK3R1, PTEN and SHIP1. Moreover, GEP and confirmatory RT-PCR revealed down-regulation of the IRS-PI3K pathway members IRS2 (-2.0 fold; p=0.004) and PIK3R1 (-2.0 fold; p=0.04). Conclusions: The results of this demonstrate aberrant expression of regulatory miRNAs and transcripts for IRS-PI3K growth and survival signaling in WM, and provide support for the development of IRS/PI3K targeted therapeutics in WM. Disclosures: No relevant conflicts of interest to declare.
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Quayle, Steven N., Jennifer Y. Lee, Lydia W. T. Cheung, Li Ding, Ruprecht Wiedemeyer, Robert W. Dewan, Emmet Huang-Hobbs, et al. "Somatic Mutations of PIK3R1 Promote Gliomagenesis." PLoS ONE 7, no. 11 (November 14, 2012): e49466. http://dx.doi.org/10.1371/journal.pone.0049466.

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14

Dyment, David A., Amanda C. Smith, Diana Alcantara, Jeremy A. Schwartzentruber, Lina Basel-Vanagaite, Cynthia J. Curry, I. Karen Temple, et al. "Mutations in PIK3R1 Cause SHORT Syndrome." American Journal of Human Genetics 93, no. 1 (July 2013): 158–66. http://dx.doi.org/10.1016/j.ajhg.2013.06.005.

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Xu, Hui, and Jianping Jia. "Immune-Related Hub Genes and the Competitive Endogenous RNA Network in Alzheimer’s Disease." Journal of Alzheimer's Disease 77, no. 3 (September 29, 2020): 1255–65. http://dx.doi.org/10.3233/jad-200081.

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Background: The pathogenesis of Alzheimer’s disease (AD) involves various immune-related phenomena; however, the mechanisms underlying these immune phenomena and the potential hub genes involved therein are unclear. An understanding of AD-related immune hub genes and regulatory mechanisms would help develop new immunotherapeutic targets. Objective: The aim of this study was to explore the hub genes and the mechanisms underlying the regulation of competitive endogenous RNA (ceRNA) in immune-related phenomena in AD pathogenesis. Methods: We used the GSE48350 data set from the Gene Expression Omnibus database and identified AD immune-related differentially expressed RNAs (DERNAs). We constructed protein–protein interaction (PPI) networks for differentially expressed mRNAs and determined the degree for screening hub genes. By determining Pearson’s correlation coefficient and using StarBase, DIANA-LncBase, and Human MicroRNA Disease Database (HMDD), the AD immune-related ceRNA network was generated. Furthermore, we assessed the upregulated and downregulated ceRNA subnetworks to identify key lncRNAs. Results: In total, 552 AD immune-related DERNAs were obtained. Twenty hub genes, including PIK3R1, B2M, HLA-DPB1, HLA-DQB1, PIK3CA, APP, CDC42, PPBP, C3AR1, HRAS, PTAFR, RAB37, FYN, PSMD1, ACTR10, HLA-E, ARRB2, GGH, ALDOA, and VAMP2 were identified on PPI network analysis. Furthermore, upon microRNAs (miRNAs) inhibition, we identified LINC00836 and DCTN1-AS1 as key lncRNAs regulating the aforementioned hub genes. Conclusion: AD-related immune hub genes include B2M, FYN, PIK3R1, and PIK3CA, and lncRNAs LINC00836 and DCTN1-AS1 potentially contribute to AD immune-related phenomena by regulating AD-related hub genes.
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Weber, Genevieve L., Marie-Odile Parat, Zev A. Binder, Gary L. Gallia, and Gregory J. Riggins. "Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells." Oncotarget 2, no. 11 (November 5, 2011): 833–49. http://dx.doi.org/10.18632/oncotarget.346.

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Chung, B. K., and W. T. Gibson. "Autosomal dominant PIK3R1 mutations cause SHORT syndrome." Clinical Genetics 85, no. 3 (September 23, 2013): 228–29. http://dx.doi.org/10.1111/cge.12262.

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Lucas, Carrie L., Yu Zhang, Anthony Venida, Ying Wang, Jason Hughes, Joshua McElwee, Morgan Butrick, et al. "Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K." Journal of Experimental Medicine 211, no. 13 (December 8, 2014): 2537–47. http://dx.doi.org/10.1084/jem.20141759.

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Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8+ T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434–475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α–p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity.
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Bittinger, Sophie, Maria Alexiadis, and Peter J. Fuller. "Expression Status and Mutational Analysis of the PTEN and P13K Subunit Genes in Ovarian Granulosa Cell Tumors." International Journal of Gynecologic Cancer 19, no. 3 (March 2009): 339–42. http://dx.doi.org/10.1111/igc.0b013e3181a1cdfd.

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Granulosa cell tumors (GCT) are a unique subset of ovarian tumors which have a molecular phenotype resembling that of follicle stimulating hormone (FSH)-stimulated pre-ovulatory granulosa cells. FSH acts via its receptor to stimulate signaling pathways including the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Activation of this pathway occurs in solid tumors, including ovarian epithelial tumors, through mutation of the PI3K subunit genes or inactivation of the tumor suppressor, PTEN. Activation of this pathway would be predicted to be tumorigenic in granulosa cells.Expression of the 2 PI3K subunit genes, PIK3CA, which encodes the catalytic subunit, and PIK3R1, which encodes the regulatory subunit, together with the PTEN gene was determined in a panel of GCT, 2 human GCT-derived cell lines, COV434 and KGN, and normal ovary. Direct sequence analysis was used to screen for mutations. Expression of all 3genes was observed in the GCT without evidence of overexpression for the PI3K subunit genes or loss of expression for PTEN. Sequence analysis of amplicons spanning exons 9and 20, in which greater than 75% of mutations occur in the PIK3CA gene did not identify any missense mutations. Similarly, the previously reported deletions in exons 12 and 13 of the PIK3R1 were not found in the GCT. Three amplicons spanning the entire coding sequence of the PTEN gene were sequenced; neither deletions nor mutations were identified.These findings suggest that activation of PI3K signaling through PI3K/PTEN mutation or altered expression, in contrast to many other types of solid tumor, is not associated with GCT.
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Zhang, Kang, Yun Han, Yabo Zhao, Yingfei Sun, Mengyun Zou, Yali Fu, and Xiuli Peng. "Upregulated gga-miR-16-5p Inhibits the Proliferation Cycle and Promotes the Apoptosis of MG-Infected DF-1 Cells by Repressing PIK3R1-Mediated the PI3K/Akt/NF-κB Pathway to Exert Anti-Inflammatory Effect." International Journal of Molecular Sciences 20, no. 5 (February 27, 2019): 1036. http://dx.doi.org/10.3390/ijms20051036.

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Mycoplasma gallisepticum (MG) mainly infects chickens to initiate chronic respiratory disease (CRD). microRNAs (miRNAs) play vital roles according to previously reported studies. Our previous study showed that gga-miR-16-5p, in MG-infected lungs of chicken embryo, was upregulated by Illumina sequencing. The study aimed to reveal what role gga-miR-16-5p plays in CRD progression. gga-miR-16-5p was upregulated in MG-infected fibroblast cells (DF-1). Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was demonstrated as the target gene of gga-miR-16-5p. Furthermore, PIK3R1 expression was lower in MG-infected groups than it in noninfected controls measured by qPCR. Additionally, overexpressed gga-miR-16-5p could downregulate PIK3R1 and phosphorylated serine/threonine kinase (p-Akt) to express protein, whereas there is an opposite effect on inhibition. Overexpressed gga-miR-16-5p resulted in decreased activity of tumor necrosis factor alpha (TNF-α) and the nuclear factor-kappaB (NF-κB) by qPCR. Furthermore, overexpressed gga-miR-16-5p restricted cell multiplication, cycle progression, and increased apoptosis of MG-infected DF-1 cells, whereas inhibited gga-miR-16-5p led to the opposite effect. Collectively, upregulated gga-miR-16-5p could decrease multiplication, cycle progression, and increase apoptosis of MG-infected DF-1 cells, at least partly through directly targeting PIK3R1 and inhibiting PI3K/Akt/NF-κB pathway to exert an anti-inflammatory effect. Our results will provide more experimental evidence to bring pathogenesis of MG infection to light.
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Krebs, Markus, Christoph Behrmann, Charis Kalogirou, Ioannis Sokolakis, Susanne Kneitz, Marianna Kruithof-de Julio, Eugenio Zoni, et al. "miR-221 Augments TRAIL-Mediated Apoptosis in Prostate Cancer Cells by Inducing Endogenous TRAIL Expression and Targeting the Functional Repressors SOCS3 and PIK3R1." BioMed Research International 2019 (November 14, 2019): 1–11. http://dx.doi.org/10.1155/2019/6392748.

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miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent.
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Balar, Arjun Vasant, Gopa Iyer, Hikmat Al-Ahmadie, Manickam Janakiraman, Irina Ostrovnaya, Ashley Marie Regazzi, Ilana Rebecca Garcia-Grossman, et al. "Alterations in the PI3K/Akt signaling pathway and association with outcome in invasive high-grade urothelial cancer (UC)." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 277. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.277.

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277 Background: Activating mutations in PIK3CA have been associated with improved outcomes in patients (pts) with breast cancer (Kalinsky, Clin Cancer Res 2009). Molecular profiling of invasive high-grade UC demonstrates that PI3K/Akt pathway alterations occur in up to 15% of cases. The prognostic value of PI3K/Akt pathway alterations in invasive UC is unknown. Methods: Clinically annotated archival frozen surgical specimens from 95 pts (94 cystectomies, 1 nephroureterectomy) with high-grade invasive UC were genotyped for mutations in all coding exons of PIK3CA, PIK3R1, TSC1, PTEN and the AKT isoforms using high-throughput Sanger sequencing. Copy number alterations were examined using an Agilent 1M oligonucleotide array. Clinical variables including time to recurrence (TTR) and overall survival (OS) were correlated with the presence of mutations or copy number events in PIK3CA, PIK3R1, TSC1, PTEN and the AKT isoforms. Results: Specimens from 95 pts (71 M; 24 F) with a median age of 71 years (41-88) were evaluated. 34 (36%) received neoadjuvant chemotherapy and 75 (79%) were prior smokers. 4 pts (4%) had Stage 0, 11 (12%) had Stage I, 15 (16%) had Stage II, 33 (35%) had Stage III and 32 (34%) had Stage IV disease at surgery. The median follow-up was 31.5 months. Alterations (mutations or copy number gains/losses) in PI3K/Akt signaling pathway genes were identified in 26 (27%) specimens and were associated with a trend toward longer TTR, hazard ratio 0.53 (95%CI 0.24, 1.14) (p=0.08). Conclusions: Alterations in PI3K/Akt signaling in pts with invasive UC may be associated with an improvement in outcome similar to that observed in breast cancer. Further analysis in a large independent tumor set is ongoing.
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Gao, Huiqiao, and Zhenyu Zhang. "Systematic Analysis of Endometrial Cancer-Associated Hub Proteins Based on Text Mining." BioMed Research International 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/615825.

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Objective. The aim of this study was to systematically characterize the expression of endometrial cancer- (EC-) associated genes and to analysis the functions, pathways, and networks of EC-associated hub proteins.Methods. Gene data for EC were extracted from the PubMed (MEDLINE) database using text mining based on NLP. PPI networks and pathways were integrated and obtained from the KEGG and other databases. Proteins that interacted with at least 10 other proteins were identified as the hub proteins of the EC-related genes network.Results. A total of 489 genes were identified as EC-related withP<0.05, and 32 pathways were identified as significant (P<0.05,FDR<0.05). A network of EC-related proteins that included 271 interactions was constructed. The 17 proteins that interact with 10 or more other proteins (P<0.05,FDR<0.05) were identified as the hub proteins of this PPI network of EC-related genes. These 17 proteins are EGFR, MET, PDGFRB, CCND1, JUN, FGFR2, MYC, PIK3CA, PIK3R1, PIK3R2, KRAS, MAPK3, CTNNB1, RELA, JAK2, AKT1, and AKT2.Conclusion. Our data may help to reveal the molecular mechanisms of EC development and provide implications for targeted therapy for EC. However, corrections between certain proteins and EC continue to require additional exploration.
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Shatara, Margaret, Elizabeth A. Varga, Daniel R. Boué, Lisa Martin, Jerome A. Rusin, Diana P. Rodriguez, Jeremy Jones, et al. "RARE-37. NOONAN SYNDROME AND GLIONEURONAL TUMORS: A CENTRAL NERVOUS SYSTEM CANCER PREDISPOSITION ASSOCIATION?" Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii450. http://dx.doi.org/10.1093/neuonc/noaa222.747.

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Abstract BACKGROUND Noonan syndrome (NS) is associated with germline Ras signaling pathway mutations, RAS overactivation and increased tumorigenesis risk. Rosette-forming glioneuronal tumors (RFGT) are rare indolent tumors. We report the molecular profiling of two patients with NS and RFGT. PATIENT 1: A 22-year-old male with NS was diagnosed with RFGT after partial tumor resection followed by focal irradiation. He was enrolled on a comprehensive genomic profiling study involving paired tumor-normal whole exome sequencing and RNA sequencing of the disease-involved tissue, revealing a germline PTPN11 alteration (p.Gly60Ala) consistent with NS, and a somatic deletion (p.Ile442_Thr454del) in PIK3R1 and a somatic variant (p.Lys656Glu) in FGFR1 with concomitant increased expression of PIK3R1 and FGFR1 by RNA-sequencing. The patient remains without tumor progression now nine months since irradiation. PATIENT 2: A 19-year-old male with persistent headaches, underwent a brain MRI demonstrated multiple abnormal signals in the pineal region and midbrain. He had a stereotactic biopsy revealing RFGT. He was enrolled on the genomic study revealing a germline PTPN11 alteration (p.Asn308Asp) resulting in a new diagnosis of NS. Several family members were subsequently identified with clinical features of NS, including his mother and two siblings, enabling appropriate counseling. Two somatic variants were found in trans in PIK3R1 (p.Thr454_Phe456del and p.Glu451_Asn453delinsAsp), and a somatic variant (p.Val695Met) in FGFR1, with resultant overexpression of PIK3R1. The patient is monitored with surveillance imaging. CONCLUSION We report the molecular profiling of two patients with NS and RFGT; strongly suggesting their connection to RASopathies through the overactivation of the MAPK and PI3K/AKT/mTOR signaling pathways.
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Makram, John, Haneen Mallah, Alexandra Wichmann, Barbara Mantilla, David Sotello Aviles, and Kenneth Nugent. "PIK3R1 MUTATION: A RARE GENETIC CAUSE OF BRONCHIECTASIS." Chest 158, no. 4 (October 2020): A1364. http://dx.doi.org/10.1016/j.chest.2020.08.1236.

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Kim, Yoon-Jin, Hyun-Ji Kim, Ki Yong Chung, Inho Choi, and Sang Hoon Kim. "Transcriptional activation of PIK3R1 by PPARγ in adipocytes." Molecular Biology Reports 41, no. 8 (May 24, 2014): 5267–72. http://dx.doi.org/10.1007/s11033-014-3398-9.

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Thauvin-Robinet, Christel, Martine Auclair, Laurence Duplomb, Martine Caron-Debarle, Magali Avila, Judith St-Onge, Martine Le Merrer, et al. "PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy." American Journal of Human Genetics 93, no. 1 (July 2013): 141–49. http://dx.doi.org/10.1016/j.ajhg.2013.05.019.

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Shi, Diana, Adam Wang, Wenhua Gao, Januka Khanal, Michael Levitt, Rebecca Jennings, Dennis Bonal, et al. "TMOD-14. CREATION OF A GENETICALLY ENGINEERED MOUSE MODEL OF ANAPLASTIC ASTROCYTOMA DRIVEN BY THE IDH1-R132H ONCOGENE." Neuro-Oncology 22, Supplement_2 (November 2020): ii230—ii231. http://dx.doi.org/10.1093/neuonc/noaa215.965.

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Abstract Despite the high prevalence of IDH1-R132H mutations in lower grade gliomas, the ability to study this mutation in vivo has been hampered by a lack of faithful mouse models. Therefore, we used a CRISPR/Cas9- and AAV-based strategy to create a genetically engineered mouse model (GEMM) of astrocytoma driven by IDH1-R132H that recreates the genetic landscape of human IDH1 mutant astrocytoma. IDH1 mutations in astrocytomas often co-occur with mutations in TP53, ATRX, and either PIK3R1 or PIK3CA. Using human astrocytes immortalized via expression of telomerase (which phenocopies ATRX loss) and HPV E6 and E7 oncoproteins (which phenocopy p53 and pRb loss, respectively), we found that PIK3R1 and IDH1 oncogenes cooperate to promote anchorage-independent cell growth in vitro and orthotopic brain tumor formation in vivo. These data identified a combination of clinically relevant mutations that we hypothesized could be leveraged to cause spontaneous astrocytoma formation in mice. To simultaneously engineer Idh1, Pik3ca, Tp53, and Atrx mutations in mouse brain tissue, we intracranially injected adeno-associated virus (AAV) expressing Cre recombinase and sgRNAs targeting murine Atrx and Tp53 genes into four mouse strains with the following conditional alleles: 1) LSL-Cas9; 2) LSL-Cas9; LSL-Pik3caH1047R, 3) LSL-Cas9; LSL-Idh1R132H, and 4) LSL-Cas9; LSL-Idh1R132H; LSL-Pik3caH1047R. Grade III anaplastic astrocytomas preferentially formed 9-14 months after injecting the mice carrying both the Idh1 and Pik3ca conditional alleles. These astrocytomas harbored all intended mutations, expressed astrocytoma lineage markers, and displayed elevated (R)-2-hydroxyglutarate, the oncometabolite produced by mutant Idh1. To create an additional model with shorter tumor latency, we transplanted glioma stem-like cells derived from our GEMM into recipient mice to produce Idh1 mutant astrocytoma allografts. These allografts provide a tractable platform for preclinical therapeutic studies. Taken together, our findings show that IDH1 and PI3K oncoproteins cooperate to promote gliomagenesis and unveil new genetically faithful mouse models of mutant IDH1-driven astrocytoma.
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Lucas, Calixto-Hope G., Rohit Gupta, Pamela Doo, Matthew Wood, Marjorie Grafe, Han Lee, B. K. Kleinschmidt-Demasters, et al. "PATH-22. COMPREHENSIVE ANALYSIS OF DIVERSE LOW-GRADE NEUROEPITHELIAL TUMORS WITH FGFR1 ALTERATIONS REVEALS A DISTINCT MOLECULAR SIGNATURE OF ROSETTE-FORMING GLIONEURONAL TUMOR." Neuro-Oncology 22, Supplement_2 (November 2020): ii168—ii169. http://dx.doi.org/10.1093/neuonc/noaa215.703.

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Abstract The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.
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Chen, Kana, Shujie Xie, and Wujun Jin. "Crucial lncRNAs associated with adipocyte differentiation from human adipose-derived stem cells based on co-expression and ceRNA network analyses." PeerJ 7 (September 6, 2019): e7544. http://dx.doi.org/10.7717/peerj.7544.

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Background Injection of adipose-derived stem cells (ASCs) is a promising treatment for facial contour deformities. However, its treatment mechanisms remain largely unknown. The study aimed to explain the molecular mechanisms of adipogenic differentiation from ASCs based on the roles of long noncoding RNAs (lncRNAs). Methods Datasets of mRNA–lncRNA (GSE113253) and miRNA (GSE72429) expression profiling were collected from Gene Expression Omnibus database. The differentially expressed genes (DEGs), lncRNAs (DELs) and miRNAs (DEMs) between undifferentiated and adipocyte differentiated human ASCs were identified using the Linear Models for Microarray Data method. DELs related co-expression and competing endogenous RNA (ceRNA) networks were constructed. Protein–protein interaction (PPI) analysis was performed to screen crucial target genes. Results A total of 748 DEGs, 17 DELs and 51 DEMs were identified. A total of 13 DELs and 279 DEGs with Pearson correlation coefficients > 0.9 and p-value < 0.01 were selected to construct the co-expression network. A total of 151 interaction pairs among 112 nodes (10 DEMs; eight DELs; 94 DEGs) were obtained to construct the ceRNA network. By comparing the lncRNAs and mRNAs in two networks, five lncRNAs (SNHG9, LINC02202, UBAC2-AS1, PTCSC3 and myocardial infarction associated transcript (MIAT)) and 32 genes (i.e., such as phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), protein tyrosine phosphatase receptor type B (PTPRB)) were found to be shared. PPI analysis demonstrated PIK3R1 , forkhead box O1 (FOXO1; a transcription factor) and estrogen receptor 1 (ESR1) were hub genes, which could be regulated by the miRNAs that interacted with the above five lncRNAs, such as LINC02202-miR-136-5p-PIK3R1, LINC02202-miR-381-3p-FOXO1 and MIAT-miR-18a-5p-ESR1. LINC02202 also could directly co-express with PIK3R1. Furthermore, PTPRB was predicted to be modulated by co-expression with LINC01119. Conclusion MIAT, LINC02202 and LINC01119 may be potentially important, new lncRNAs associated with adipogenic differentiation of ASCs. They may be involved in adipogenesis by acting as a ceRNA or co-expressing with their targets.
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Stringer, Erica M., and Gini F. Fleming. "Hormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma." Oncology & Hematology Review (US) 09, no. 01 (2013): 41. http://dx.doi.org/10.17925/ohr.2013.09.1.41.

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Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mTOR pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA, and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus, and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesized that mTOR inhibition would enhance sensitivity to hormonal therapy.
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Stringer, Erica M., and Gini F. Fleming. "Hormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma." European Endocrinology 9, no. 1 (2010): 18. http://dx.doi.org/10.17925/ee.2013.09.01.18.

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Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesised that mTOR inhibition would enhance sensitivity to hormonal therapy.
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Abdul Jalil, Khairun Izlinda, Katherine M. Sheehan, Sinead Toomey, Jasmin Schmid, Anthony O'grady, Robert Cummins, Brian O'Neill, et al. "The frequencies and clinical implications of mutations in 33 kinase-related genes in locally advanced rectal cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3549. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3549.

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3549 Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with pre-operative chemoradiotherapy (pCRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP-kinase (MAPK) and related pathways have been implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic variations in these pathways and clinical outcomes in LARC. Methods: We genotyped a total of 234 Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations in 33 cancer related genes including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET and NRAS using the Sequenom platform. DNA samples utilized herein were extracted from pre-treatment rectal cancer biopsies of 201 patients who were then treated with long-course pCRT followed by surgical resection. Results: 62 different mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (n=93, 47%), PIK3CA (n=29, 14%), MET (n=27, 13%), STK11 (n=13, 6.3%), CTNNB1 (n=12, 6%), BRAF (n=8, 4%) and NRAS (n=7, 3.5%). Mutations were also detected in AKT, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK and TNK2, but at frequencies of less than 2%. Pathologic complete response (pCR) was associated with excellent (97%) 5-year Recurrence-Free Survival (RFS) (Hazard ratio [HR], 0.076; 95% CI, 0.01-0.50, P=0.001). We found: 1) Mutations in PI3K pathway-related genes (PIK3CA, AKT, STK11) were significantly associated with absence of pCR (odd ratio [OR], 5.40; 95% CI, 1.24-23.54, P=0.024). However, mutations in MAPK pathway-related genes (KRAS, BRAF, NRAS, MEK) was not found to be significantly associated with pCR (P=0.805). 2) In contrast, in patients who did not achieve pCR (non-pCR), mutations in PI3K pathway-related genes were not associated with RFS. However, in these patients, codon 12 (G12D/G12V/G12S) and 13 mutations in KRAS were associated with poor RFS (HR, 0.336; 95% CI, 0.115-0.981, P=0.046). Conclusions: These results suggest that mutations in kinase signaling pathways may modulate treatment responsiveness and clinical outcomes in locally advanced rectal cancer and thus may constitute rational targets for novel therapies.
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Hauck, Fabian, Thomas Magg, Ana Krolo, Ivan Bilic, Tatjana Hirschmugl, Martin Laass, Angela Rösen-Wolff, Hella Luksch, Kaan Boztug, and Joachim Roesler. "Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma." Klinische Pädiatrie 229, no. 03 (May 2017): 113–17. http://dx.doi.org/10.1055/s-0043-104218.

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Abstract Background Heterozygous point mutations in the GT splice donor consensus sequence of exon 11 of the PIK3R1 gene (coding for p85α, p55α, and p50α regulatory subunits of PI3K) lead to exon skipping and thereby to an aberrant protein that leaves PI3K hyperactivated. Several patients with this particular variant of PI3 kinase delta syndrome (APDS) suffering from sinopulmonary infections and lymphoproliferation have been described. Methods (Whole exome) sequencing, evaluation of cellular and clinical phenotypes. Results We here report a family with a new heterozygous mutation in this gene, a 9 bp deletion (c.1418_1425+1del) that, however, leads to the same skipping of exon 11. The clinical phenotypes of their members partly overlap features of patients of other reports. Conclusions We found a new mutation in PIK3R1 and show how broad the resulting clinical spectrum can be.
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Xu, Guangyu, Xu Liu, Chunmei Wang, He Li, Chengyi Zhang, Jianguang Chen, and Jinghui Sun. "The Mechanisms of Shcisandrol A in Immune Function Modulation in Immunosuppressed Mice." Natural Product Communications 13, no. 2 (February 2018): 1934578X1801300. http://dx.doi.org/10.1177/1934578x1801300216.

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The population of people with immunodeficiency is increasing due to the accelerating pace of life, increase in work pressure, and lack of exercise, irregularity of diet and rest, and problems of environmental pollution. Chinese herbal medicines have been shown to improve immunity, with little to no side effects. In recent years, studies have shown that Shcisandrol A (Sch A) regulates immune functioning and inhibits inflammation of the nervous system. The current study used gene expression profiling of spleen tissue to screen differentially expressed genes related to Sch A treatment on cyclophosphamide (Cy)-induced immunosuppressed mice. The differentially expressed gene-related pathways were analyzed by gene ontology function cluster analysis and qPCR. Five genes related to immune functioning were found to be regulated by Sch A treatment: Mapk3, Pik3r1, Pik3r5, Ikbkg, and Cd247. qPCR analysis showed that all five genes were significantly down-regulated in mice treated with Sch A compared to untreated immunosuppressed mice. These results suggest potential mechanisms through which Sch A regulates immune functioning.
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Adorno, Jennifer Ocasio, Laura Hover, Chen He, Xiaoyan Zhu, David Goldhamer, Angel Carcaboso, Sridevi Yadavilli, Javad Nazarian, and Suzanne Baker. "DIPG-51. ACVR1 MUTATIONS PROMOTE TUMOR GROWTH IN MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii296—iii297. http://dx.doi.org/10.1093/neuonc/noaa222.096.

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Abstract Mutations in the gene encoding activin A receptor type 1 (ACVR1) are found in approximately 25% of diffuse intrinsic pontine gliomas (DIPGs), a pediatric glioma with 2-year survival rate of less than 10%. ACVR1mutations frequently coincide with activating PIK3CA or PIK3R1 mutations, indicating a potential cooperative effect of BMP and PI3K signaling in gliomagenesis. We used genetically engineered mice with inducible knock-in of Acvr1R206H or Pik3caE545K alleles, such that cre-mediated recombination resulted in expression of the gain of function mutated genes from their endogenous promoters at physiological levels. Cre-mediated deletion in GFAP-CreER;Pik3caE545K/+;p53cKO mice (Pik3ca;p53) mediated Trp53 deletion and expression of Pik3caE545K in glial progenitors, and spontaneously induced high-grade glioma (HGG) in mice with complete penetrance. Heterozygous knock-in of the Acvr1R206H allele accelerated tumorigenesis and impaired survival in Pik3ca;p53 mice (Acvr1;Pik3ca;p53). Transcriptomic analysis of Acvr1;Pik3ca;p53 tumors compared to Pik3ca;p53 littermate controls, as in patient-derived tumors, revealed broad molecular signatures associated with cell fate commitment and chromosome maintenance. Pharmacologic inhibition of ACVR1 was sufficient to impair growth in human patient-derived DIPG cell lines. Together, our studies show that ACVR1 activation promotes tumor growth in spontaneous mouse HGG and patient-derived DIPG cells, suggesting that ACVR1 inhibition may produce a clinically significant therapeutic effect in DIPG.
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Hu, Shimin, Shujuan Ma, Xun Li, Zhengwen Tian, Huiling Liang, Junxia Yan, Mengshi Chen, and Hongzhuan Tan. "Relationships of SLC2A4, RBP4, PCK1, and PI3K Gene Polymorphisms with Gestational Diabetes Mellitus in a Chinese Population." BioMed Research International 2019 (January 20, 2019): 1–9. http://dx.doi.org/10.1155/2019/7398063.

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Background. Solute carrier family 2 member 4- (SLC2A4-) retinol binding protein-4- (RBP4-) phosphoenolpyruvate carboxykinase 1 (PCK1)/phosphoinositide 3-kinase (PI3K) is an adipocyte derived “signalling pathway” that may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). We explored whether single nucleotide polymorphisms (SNPs) of these “signalling pathway” genes are associated with gestational diabetes mellitus (GDM). Methods. Case-control studies were conducted to compare GDM and control groups. A total of 334 cases and 367 controls were recruited. Seventeen candidate SNPs of the pathway were selected. Chi-square tests, logistic regression, and linear regression were used to estimate the relationships of SNPs with GDM risk and oral glucose tolerance test (OGTT), fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) levels. Model-based multifactor dimensionality reduction was used to estimate the adjusted interactions between genes. Regression and interaction analyses were adjusted by maternal age, prepregnancy BMI, and weekly BMI growth. The Bonferroni correction was applied for multiple comparisons. Results. RBP4 rs7091052 was significantly associated with GDM risk. SLC2A4 rs5435, RBP4 rs7091052, PCK1 rs1042531 and rs2236745, and PIK3R1 (coding gene of the PI3K P85 subunit) rs34309 were associated with OGTT, fasting insulin, and HOMA-IR levels in the linear regression analysis. The gene-gene interaction analysis showed that, compared with pregnant women with other genotype combinations, women with SLC2A4 rs5435 (CC/CT), RBP4 rs7091052 (CC), PCK1 rs1042531 (TT/TG) and rs2236745 (TT), and PIK3R1 rs34309 (AA) had lower GDM risk. Conclusion. SLC2A4, RBP4, PCK1, and PIK3R1 genes may be involved in the pathogenesis of GDM.
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Cheung, Lydia W. T., Bryan T. Hennessy, Jie Li, Shuangxing Yu, Andrea P. Myers, Bojana Djordjevic, Yiling Lu, et al. "High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability." Cancer Discovery 1, no. 2 (June 7, 2011): 170–85. http://dx.doi.org/10.1158/2159-8290.cd-11-0039.

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39

Qian, Zhi Rong, Monica Ter-Minassian, Jennifer A. Chan, Yu Imamura, Susanne M. Hooshmand, Aya Kuchiba, Teppei Morikawa, et al. "Prognostic Significance of MTOR Pathway Component Expression in Neuroendocrine Tumors." Journal of Clinical Oncology 31, no. 27 (September 20, 2013): 3418–25. http://dx.doi.org/10.1200/jco.2012.46.6946.

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Purpose Clinical studies have implicated the mechanistic target of rapamycin (serine/threonine kinase; MTOR) pathway in the regulation of neuroendocrine tumor (NET) growth. We explored whether expression of MTOR pathway components has prognostic significance in NET patients. Patients and Methods We evaluated immunohistochemical expression of MTOR and phospho (p) –MTOR; its downstream targets RPS6KB1, RPS6, and EIF4EBP1; and its upstream regulators, in a cohort of 195 archival neuroendocrine tumors. We correlated expression levels with clinical outcomes, after adjusting for other prognostic variables. Results We observed anticipated correlations between expression of upstream components of the MTOR pathway and their downstream targets. Expression of PIK3CA, MTOR, or p-EIF4EBP1 was associated with high MKI67 (Ki-67) labeling index. We failed to identify clinical correlations associated with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA. In contrast, high expression of MTOR or its activated downstream targets p-RPS6KB1, p-RPS6, or p-EIF4EBP1 was associated with adverse clinical outcomes. Conclusion Our observations suggest that expression of MTOR or its downstream targets may be adverse prognostic factors in neuroendocrine tumors.
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Deau, Marie-Céline, Lucie Heurtier, Pierre Frange, Felipe Suarez, Christine Bole-Feysot, Patrick Nitschke, Marina Cavazzana, et al. "A human immunodeficiency caused by mutations in the PIK3R1 gene." Journal of Clinical Investigation 125, no. 4 (April 1, 2015): 1764–65. http://dx.doi.org/10.1172/jci81746.

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Deau, Marie-Céline, Lucie Heurtier, Pierre Frange, Felipe Suarez, Christine Bole-Feysot, Patrick Nitschke, Marina Cavazzana, et al. "A human immunodeficiency caused by mutations in the PIK3R1 gene." Journal of Clinical Investigation 124, no. 9 (August 18, 2014): 3923–28. http://dx.doi.org/10.1172/jci75746.

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42

Tang, Paoyun, Julia E. M. Upton, Michelle A. Barton-Forbes, Marina I. Salvadori, Meghan P. Clynick, April K. Price, and Sharan L. Goobie. "Autosomal Recessive Agammaglobulinemia Due to a Homozygous Mutation in PIK3R1." Journal of Clinical Immunology 38, no. 1 (November 25, 2017): 88–95. http://dx.doi.org/10.1007/s10875-017-0462-y.

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43

Ueki, Kohjiro, David A. Fruman, Saskia M. Brachmann, Yu-Hua Tseng, Lewis C. Cantley, and C. Ronald Kahn. "Molecular Balance between the Regulatory and Catalytic Subunits of Phosphoinositide 3-Kinase Regulates Cell Signaling and Survival." Molecular and Cellular Biology 22, no. 3 (February 1, 2002): 965–77. http://dx.doi.org/10.1128/mcb.22.3.965-977.2002.

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ABSTRACT Class Ia phosphoinositide (PI) 3-kinase is a central component in growth factor signaling and is comprised of a p110 catalytic subunit and a regulatory subunit, the most common family of which is derived from the p85α gene (Pik3r1). Optimal signaling through the PI 3-kinase pathway depends on a critical molecular balance between the regulatory and catalytic subunits. In wild-type cells, the p85 subunit is more abundant than p110, leading to competition between the p85 monomer and the p85-p110 dimer and ineffective signaling. Heterozygous disruption of Pik3r1 results in increased Akt activity and decreased apoptosis by insulin-like growth factor 1 (IGF-1) through up-regulated phosphatidylinositol (3,4,5)-triphosphate production. Complete depletion of p85α, on the other hand, results in significantly increased apoptosis due to reduced PI 3-kinase-dependent signaling. Thus, a reduction in p85α represents a novel therapeutic target for enhancing IGF-1/insulin signaling, prolongation of cell survival, and protection against apoptosis.
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Fan, Demin, Qiang Liu, Fei Wu, Na Liu, Hongyi Qu, Yijiao Yuan, Yong Li, et al. "Prognostic significance of PI3K/AKT/ mTOR signaling pathway members in clear cell renal cell carcinoma." PeerJ 8 (June 1, 2020): e9261. http://dx.doi.org/10.7717/peerj.9261.

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Background Renal cell carcinoma (RCC) is a fatal disease, in which the PI3K/AKT/mTOR signaling pathway serves an important role in the tumorigenesis. Previous studies have reported the prognostic significance of PI3K/AKT/mTOR signaling pathway members in RCC; however, there is insufficient evidence to date to confirm this. Thus, the present study aimed to systematically investigate the prognostic roles of multiple PI3K/AKT/mTOR signaling proteins in clear cell RCC (ccRCC) using online large-scale databases. Methods The mRNA expression profiles of PI3K/AKT/mTOR signaling pathway proteins PTEN, PIK3CA, PIK3CB, PIK3CD, PIK3CG, AKT1, AKT2, AKT3 and mTOR were investigated using the Gene Expression Profiling Interactive Analysis (GEPIA) and Oncomine databases, and the protein expression levels of PI3K, AKT and mTOR were detected using western blotting (WB) analysis. In addition, the correlation between mRNA or protein expression levels and the prognostic significance was analyzed using the Kaplan-Meier (K-M) plotter (n = 530), the Human Protein Atlas (HPA; n = 528) and The Cancer Protein Atlas (TCPA; n = 445) databases. Results The GEPIA revealed that the mRNA expression of major PI3K/AKT/mTOR pathway members, including PTEN, PIK3CA, PIK3CB, AKT1, AKT2 and AKT3, were negatively correlated with ccRCC stages (P < 0.05), though most of their mRNA and protein expression levels were notsignificantly different between ccRCC and normal tissues using GEPIA, Oncomine and WB analyses (P < 0.05). Meanwhile, using the K-M plotter and HPA prognostic analysis, it was found that the mRNA expression levels of the majority of the PI3K/AKT/mTOR signaling pathway members, including PTEN, PIK3CA, PIK3CB, PIK3CG, AKT3 and mTOR were positively correlated with overall survival (OS), whereas PIK3CD mRNA expression was negatively correlated with OS (P < 0.05). Furthermore, TCPA prognostic analysis observed that several of the key molecules of the PI3K/AKT/mTOR signaling pathway [PTEN, p-AKT (S473) and p-mTOR (S2448)] were also positively correlated with OS in patients with ccRCC (P < 0.05). In conclusion, the present study suggested that several members of the PI3K/AKT/mTOR signaling pathway, especially PTEN, may be favorable prognostic factors in ccRCC, which indicated that the PI3K/AKT/mTOR signaling pathway may be implicated in ccRCC initiation and progression.
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Ju, Zhenlin, Shannon Neville Westin, Russell Broaddus, Jie Li, Navdeep Pal, Karen H. Lu, Robert L. Coleman, et al. "PTEN loss as a context-dependent determinant of patient outcomes in obese and non-obese endometrioid endometrial cancer patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 5521. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.5521.

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5521 Background: Aberrations in the PI3K pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid endometrial cancers. We explored the prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss, in the context of patient weight. Methods: Patients (pts) treated for endometrial cancer at a single institution between 2000 and 2009 were identified. Tumor DNA was extracted and exome sequencing performed using a 454 platform with confirmation of hot spot mutations by Sequenom. PTEN protein expression was determined by immunohistochemistry and reverse phase protein array (RPPA). RPPA for 135 relevant proteins was performed using a GeneTAC arrayer to create spot arrays. Slides were scanned, analyzed, and quantitated using Microvigene software. Results: One hundred eighty seven endometrioid endometrial cancer specimens were included. Median age was 61 yrs and median body mass index (BMI) was 33.5 kg/m2. The majority of pts had early stage (I/II) disease (74%) and grade 2 tumors (66%). There were no statistically significant associations between progression free survival (PFS) and PIK3CA, PIK3R1, PTEN mutation or loss. However, when stratified by BMI, PTEN loss was associated with a significantly improved PFS (p< 0.006) in obese (BMI > 30 kg/m2) pts. In contrast, PTEN loss was associated with a worse PFS (p<0.06) in non-obese (BMI < 30 kg/m2) pts. Further, PTEN loss in obese and non-obese pts resulted in distinct protein changes by RPPA, with canonical PI3K pathway activation observed only in the non-obese PTEN loss cohort. PTEN loss in obese pts was associated with decreased expression of CATENIN and phosphorylated FOXO3A. Conclusions: These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of BMI and provide potential explanation for prior discrepant findings on effect of PTEN status on prognosis in endometrial cancer. These data describe a clinically important interaction between metabolic state and tumor genetics that could potentially unveil the biologic underpinning of obesity-related cancers and may be relevant to ongoing clinical trials with PI3K pathway inhibitors.
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Mir, Rashid, Imadeldin Elfaki, Faisel M. Abu Duhier, Maeidh A. Alotaibi, Adel Ibrahim AlAlawy, Jameel Barnawi, Abdullatif Taha Babakr, et al. "Molecular Determination of mirRNA-126 rs4636297, Phosphoinositide-3-Kinase Regulatory Subunit 1-Gene Variability rs7713645, rs706713 (Tyr73Tyr), rs3730089 (Met326Ile) and Their Association with Susceptibility to T2D." Journal of Personalized Medicine 11, no. 9 (August 29, 2021): 861. http://dx.doi.org/10.3390/jpm11090861.

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Type 2 diabetes is a metabolic disease characterized by elevated blood sugar. It has serious complications and socioeconomic impact. The MicroRNAs are short single-stranded and non-coding RNA molecules. They regulate gene expression at the post-transcriptional levels. They are important for many physiological processes including metabolism, growth, and others. The phosphoinositide 3-kinase (PI3K) is important for insulin signaling and glucose uptake. The genome wide association studies have identified the association of certain loci with diseases including T2D. In this study we have examined the association of miR126 rs4636297 and Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) gene Variations rs7713645, rs706713 (Tyr73Tyr), and rs3730089 (Met326Ile) with T2D using the amplification refractory mutation system PCR. Results indicated that there was a significant different (p-value < 0.05) in the Mir126 rs4636297 genotypes distribution between cases and controls, and the minor allele of the rs4636297 was also associated with T2D with OR = 0.58, p-value < 0.05. In addition results showed that there were significant differences (p-value < 0.05) of rs4636297 genotype distribution of patients with normal and patient with abnormal lipid profile. Results also showed that the PIK3R1 rs7713645 and rs3730089 genotype distribution was significantly different between cases and controls with a p-values < 0.05. In addition, the minor allele of the rs7713645 and rs3730089 were associated with T2D with OR = 0.58, p-value < 0.05). We conclude that the Mir126 rs4636297 and PIK3R1 SNPs (rs7713645 and rs3730089) were associated with T2D. These results need verification in future studies with larger sample sizes and in different populations. Protein-protein interaction and enzyme assay studies are also required to uncover the effect of the SNPs on the PI3K regulatory subunit (PI3KR1) and PI3K catalytic activity.
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Pinhel, Marcela A. S., Natália Y. Noronha, Carolina F. Nicoletti, Vanessa AB Pereira, Bruno AP de Oliveira, Cristiana Cortes-Oliveira, Wilson Salgado, et al. "Changes in DNA Methylation and Gene Expression of Insulin and Obesity-Related Gene PIK3R1 after Roux-en-Y Gastric Bypass." International Journal of Molecular Sciences 21, no. 12 (June 24, 2020): 4476. http://dx.doi.org/10.3390/ijms21124476.

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Weight regulation and the magnitude of weight loss after a Roux-en-Y gastric bypass (RYGB) can be genetically determined. DNA methylation patterns and the expression of some genes can be altered after weight loss interventions, including RYGB. The present study aimed to evaluate how the gene expression and DNA methylation of PIK3R1, an obesity and insulin-related gene, change after RYGB. Blood samples were obtained from 13 women (35.9 ± 9.2 years) with severe obesity before and six months after surgical procedure. Whole blood transcriptome and epigenomic patterns were assessed by microarray-based, genome-wide technologies. A total of 1966 differentially expressed genes were identified in the pre- and postoperative periods of RYGB. From these, we observed that genes involved in obesity and insulin pathways were upregulated after surgery. Then, the PIK3R1 gene was selected for further RT-qPCR analysis and cytosine-guanine nucleotide (CpG) sites methylation evaluation. We observed that the PI3KR1 gene was upregulated, and six DNA methylation CpG sites were differently methylated after bariatric surgery. In conclusion, we found that RYGB upregulates genes involved in obesity and insulin pathways.
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Park, Sang Wook, Mi Ran Kang, Hyeon Seok Eom, Ji Youn Han, Chang Hyeok Ahn, Sung Soo Kim, Sug Hyung Lee, and Nam Jin Yoo. "Somatic mutation of PIK3R1 gene is rare in common human cancers." Acta Oncologica 49, no. 1 (January 2010): 128–30. http://dx.doi.org/10.3109/02841860903107890.

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49

Ramirez, Lourdes, Wendy Tamayo, and Hanadys Ale. "APDS2 and SHORT Syndrome in a Teenager with PIK3R1 Pathogenic Variant." Journal of Clinical Immunology 40, no. 7 (August 10, 2020): 1020–25. http://dx.doi.org/10.1007/s10875-020-00843-1.

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Murugan, Avaniyapuram Kannan, Jianli Dong, Jingwu Xie, and Mingzhao Xing. "Uncommon GNAQ, MMP8, AKT3, EGFR, and PIK3R1 Mutations in Thyroid Cancers." Endocrine Pathology 22, no. 2 (April 13, 2011): 97–102. http://dx.doi.org/10.1007/s12022-011-9155-x.

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