Other VEGF inhibitor like Cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, showed significant efficacy and PFS-6 in phase II clinical trial of rGBM (NCT00305656) [144]. N Engl J Med. Phase I trial of Aflibercept showed great toxic side effect to rGBM while the efficacy is very limited [151]. J Neurooncol. 2020;5(4):e000673. 1). 2012;109(2):5705. 10. USA, 2007.12-2010.05, University of Iowa, Carver College of Medicine. Neuro Oncol. ETS variant transcription factor 5 and c-Myc cooperate in derepressing the human telomerase gene promoter via composite ETS/E-box motifs. Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy. Therefore, the combination of TMZ and TGF- inhibitors are promising. Raizer JJ, Grimm S, Chamberlain MC, Nicholas MK, Chandler JP, Muro K, Dubner S, Rademaker AW, Renfrow J, Bredel M. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Can Res. Huang J, Campian JL, Gujar AD, Tsien C, Ansstas G, Tran DD, Dewees TA, Lockhart AC, Kim AH. Mol Med. 2019;144(2):30311. A users guide to the encyclopedia of DNA elements (ENCODE). The RNA-binding protein ROD1/PTBP3 cotranscriptionally defines AID-loading sites to mediate antibody class switch in mammalian genomes. RNA Biol. Han B, Yuan H, Wang T, Li B, Ma L, Yu S, Huang T, Li Y, Fang D, Chen X, Wang Y, Qiu S, Guo Y, Fei J, Ren L, Pan-Hammarstrom Q, Hammarstrom L, Wang J, Wang J, Hou Y, Pan Q, Xu X, Zhao Y. Using antibodydrug conjugates to ablate CD276+glioma cells simultaneously impaired tumor vescular [262], indicating a novel insight on the combination of anti-CD276 with anti-angiogenesis, which was supported when CD276 was confirmed to positively be related with VEGFA and MMP2 [267]. Nat Med. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Cell. PubMed Central The MDM2 inhibitor AMG 232 suppressed tumor progression in the course of the trial (NCT01723020) [107]. 2007. Initial RNA polymerase II ChIP-seq experiments showed that more than two replicates did not significantly improve site discovery (Rozowsky et al. 2005;102(4):111621. Blumenthal DT, Yalon M, Vainer GW, Lossos A, Yust S, Tzach L, Cagnano E, Limon D, Bokstein F. Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors. Yu Z, Li Y, Meng Q, Yuan J, Zhao Z, Li W, Hu X, Yan B, Fan B. , Li N. Comparative analysis of the pig BAC sequence involved in the regulation of myostatin gene. Thus, combined anti-TIM3 inhibitor and other immunotherapy is getting promising. A high-quality IP is characterized by a ChIP peak that is much higher than the phantom peak, while often very small or no such peak is seen in failed experiments. Avicenna J Med Biotechnol. Motif analysis suggests that many do. Celis-Gutierrez J, Blattmann P, Zhai Y, Jarmuzynski N, Ruminski K, Grgoire C, Ounoughene Y, Fiore F, Aebersold R, Roncagalli R, et al. IDH mutation and consequently increased D-2-hydroxyglutarate level inhibit the expression of some DNA repair genes and anti-apoptotic proteins, such as MGMT, MLH3, RAD21 and SMC4 [329], which downregulates the intracellular glutathione level, apoptosis threshold of LGG and upregulates the sensitivity of LGG to alkylating agent [330] (Fig. The most common gene mutation of EGFR is EGFRvIII (deletion of exons 27) [10], as a potential marker of treatment for GBM. 2018;20(suppl_6):vi2389. Thus, all FRiP values that are compared should be derived from peaks uniformly called by a single algorithm and parameter set. J Cell Physiol. Oncoimmunology. By using this website, you agree to our Mutations in this gene are common in acute myeloid leukemia (AML) and screening for mutations in this gene has been recommended by the World Health Organization in patients with AML, particularly in cases of cytogenetically normal AML (CN-AML). 2021;3(3):Cd013316. A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain. 2010). CD73, an extracellular nucleotidase, catalyzes the production of adenosine from extracellular AMP [200], which exerts an immunosuppressive effect on GBM and induces drug resistance of vincristine presumedly via regulating multiple drug associated protein 1 (Mrp1) [201, 202]. In addition, the current effect of PI3K inhibitors combined with other treatments is not ideal, which more combination strategies should be explored in the future. 2011;117(7):2166-78. The mutation of TERT promoter creates a binding site for GABP transcription factor complex. Libermann TA, Razon N, Bartal AD, Yarden Y, Schlessinger J, Soreq H. Expression of epidermal growth factor receptors in human brain tumors. In tumor tissues, LAG-3 is usually expressed in T cells with lost functions, called exhausted T cells. Molecular and clinical characterization of TIM-3 in glioma through 1,024 samples. 2017;377(20):195463. J Clin Oncol. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Fan Mou; Maria Praskova; Fan Xia; Denille Van Buren; Hanno Hock; Joseph Avruch *; Dawang Zhou *. The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma. In general, we observe a continuum between the two extremes, and broad-source data sets are expected to have flatter cross-correlation profiles than point-sources, even when they are of very high quality. The relationship of ChIP signal strength to biological regulatory activity is a current area of active investigation. As the vital mediator of intracellular degradation of useless or/and toxic proteins [116], proteasome promotes apoptosis by regulating p53 and ER stress, which critically regulates cell cycle and affects drug resistance of tumor cells [117]. 2018;39(5):68999. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2011. Kim JE, Patel MA, Mangraviti A, Kim ES, Theodros D, Velarde E, Liu A, Sankey EW, Tam A, Xu H, et al. An epitope-tagged version of the target protein may be used, preferably expressed from the endogenous gene promoter. Diseases associated with GZMB include Peripheral T-Cell Lymphoma and Severe Cutaneous Adverse Reaction.Among its related pathways are Programmed Cell Death and RIPK1-mediated regulated necrosis.Gene Ontology (GO) annotations related to this gene include serine . HAVCR2 is a specific cell surface protein encoded by homonymous gene. This intronless gene encodes a transcription factor that contains a basic leucine zipper (bZIP) domain and recognizes the CCAAT motif in the promoters of target genes. Invivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons. . PLoS One. BCL2L1 (BCL2 Like 1) is a Protein Coding gene. 2016;6(11):12306. Nabors LB, Fink KL, Mikkelsen T, Grujicic D, Tarnawski R, Nam DH, Mazurkiewicz M, Salacz M, Ashby L, Zagonel V, et al. Analogously, glioblastomas with mutant IDH are characteristically similar to anaplastic astrocytoma (though nomenclature anaplastic astrocytoma is no longer included in WHO CNS5 classification), thus treatment of glioma much relying on molecular diagnosis and classification. The fraction of reads falling within peak regions is therefore a useful and simple first-cut metric for the success of the immunoprecipitation, and is called FRiP (fraction of reads in peaks). IDR analysis is then performed with a 1% threshold. 2019;21(6):73041. O6-methylguanine DNA methyltransferase (MGMT) functions as a sort of repairing protein [25, 26], which is encoded by MGMT and could reverse this alkylation process by consuming itself. Ghisletti S, Barozzi I, Mietton F, Polletti S, De Santa F, Venturini E, Gregory L, Lonie L, Chew A, Wei C, et al. 2009;124(11):271927. Similarly, antisense oligonucleotides, namely ISTH1047 and ISTH0047, exhibit anti-tumor properties and can be further tested in clinical trials [173]. 2010. In two phase I trials (NCT00068510 NCT00612001), autologous tumor lysate (ATL)-pulsed DCV was proved with higher patient eligibility than glioma-associated antigen (GAA) peptide-pulsed DCV [314]. 2010. , Huang T, Li Y, Fang D, Chen X, Wang Y, Qiu S, Guo Y, Fei J, Ren L, Pan-Hammarstrom Q, Hammarstrom L, Wang J, Wang J, Hou Y, Pan Q, Xu X, Zhao Y. 2011. Levine AJ. 7). CD70 is overexpressed in primary and recurrent glioma cells in contrast to normal tissue and lymphocytes, and is associated with poor survival. Soluble conformers of A and tau alter selective proteins governing axonal transport. Cediranib also declined the tumor-associated angiogenic brain edema (NCT00254943) [146]. Article Kaley TJ, Panageas KS, Pentsova EI, Mellinghoff IK, Nolan C, Gavrilovic I, DeAngelis LM, Abrey LE, Holland EC, Omuro A, et al. Developing a Triple Transgenic Cell Line for High-Efficiency Porcine Reproductive and Respiratory Syndrome Virus Infection. 2016;124(6):1594601. Selumetinib was proved with high effectiveness in pLGG patients with NF1 [336]. Lancet Oncol. To update your cookie settings, please visit the. 2018;215(8):2211-26. It is important that the peak-calling threshold used prior to IDR analysis not be so stringent that the noise component is entirely unrepresented in the data, because the algorithm requires sampling of both signal and noise distributions to separate the peaks into two groups; thus relaxing the default stringency settings when running a given peak caller is advised if IDR analysis will follow. To facilitate data sharing among laboratories, both within and outside the Consortium, and to ensure that results can be reproduced, ENCODE has established guidelines for data sharing in public repositories. Wahl M, Chang SM, Phillips JJ, Molinaro AM, Costello JF, Mazor T, Alexandrescu S, Lupo JM, Nelson SJ, Berger M, et al. Cell reports. Cell Reports. J Clin Oncol. Nat Cell Biol. Everolimus, the mTOR inhibitor, is promising and effective in recurrent/progressive NF1-associated LGG [344]. In the ENCODE Consortium, results of the different ChIP experiments are compared and significant overlap of enriched loci is expected (ChIP-seq experiments are compared using the IDR-based standards in Box 3). 2021;42(1):10814. To ensure similar weighting of individual replicates, the number of significant binding regions identified using IDR on each individual replicate (obtained by partitioning reads into two equal groups to allow the IDR analysis) is recommended to be within a factor of 2 for data sets to be submitted to UCSC by ENCODE (Box 3). Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, Shaffrey M, Ram Z, Piepmeier J, Prados M, et al. 2017;276(1):97111. Identification of functional elements and regulatory circuits by. 3. Cell Reports. Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors. J Neurooncol. Cloughesy TF, Drappatz J, de Groot J, Prados MD, Reardon DA, Schiff D, Chamberlain M, Mikkelsen T, Desjardins A, Ping J, et al. A very useful ChIP-seq quality metric that is independent of peak calling is strand cross-correlation. Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma. Mol Neurobiol. CD276, also known as B7-H3, is one of the B7 ligand family. Clinical cancer research: an official journal of the American Association for Cancer Research. Harris-Bookman S, Mathios D, Martin AM, Xia Y, Kim E, Xu H, Belcaid Z, Polanczyk M, Barberi T, Theodros D, et al. (B) Distribution of functional regulatory elements with respect to the strength of the ChIP-seq signal. A potential drawback is that antibodies may differ in their binding specificity toward histone tail peptides in vitro versus toward full-length histones in the context of chromatin in IP experiments. The heteromeric transcription factor GABP activates the ITGAM/CD11b promoter and induces myeloid differentiation. 2020;52(5):74252. 2008. FGFR is widely expressed in GBM, but its therapeutic value may be limited to a small number of patients with FGFR-TACC fusion [79]. Clin Cancer Res. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, et al. 2011;117(7):2166-78. Mapping accessible chromatin regions using Sono-Seq. 2012;72(2):4027. Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma. 2A). A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol. 2015;17(5):70817. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. 2010. Weathers SP, Han X, Liu DD, Conrad CA, Gilbert MR, Loghin ME, OBrien BJ, Penas-Prado M, Puduvalli VK, Tremont-Lukats I, et al. Genetic, Epigenetic, and Immunologic Profiling of MMR-Deficient Relapsed Glioblastoma. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 2607122072 study): a multicentre, randomised, open-label, phase 3 trial. 24. eCollection 2021. Gluck WL, Gounder MM, Frank R, Eskens F, Blay JY, Cassier PA, Soria JC, Chawla S, de Weger V, Wagner AJ, et al. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma. Curr Opin Immunol. Chen W, Ten Dijke P. Immunoregulation by members of the TGF superfamily. Lower Grade Gliomas. RARE-11. 2021;12:688215. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al. 2010;12(8):87181. Furthermore, IDO1 is regarded as a significant mediator in immunotolerance and immunosuppression of cancer via its non-enzyme activity, though the potential mechanisms remains to be fully elucidated [214]. 2021;14(1):160. The genome-wide metrics discussed below provide more objective and global assessments. 2020;87:102029. 2008;26(6):91924. 2016;14(10):97683. EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma. 2002;417(6892):94954. The expression of PD-1 by immune infiltrating cells in LGG indicates immune escape, while the methylation of PD-1 promoter indicates better prognosis of LGG. 2016;18(8):114656. Thus overall, low-grade glioma (LGG) contains CNS WHO grades 12, while high-grade glioma (HGG) contains CNS WHO grades 34. Other inhibitors like Aflibercept could also down-regulate the activity of VEGF and needs to be further studied (NCT00369590) [154]. After mapping reads to the genome, peak calling software is used to identify regions of ChIP enrichment. It has been confirmed that BTLA influences T cell signaling through SHP1/2, similar to that of PD-1. Goswami S, Walle T, Cornish AE, Basu S, Anandhan S, Fernandez I, Vence L, Blando J, Zhao H, Yadav SS, et al. Clinical cancer research: an official journal of the American Association for Cancer Research. Additionally, according to the fact that compared to the physiological situation systemic Kyn decreases while intratumoral Kyn increases in GBM patients, exploration on Kyn pathway modulation is still in its infancy [218]. 2001;2(3):26974. Neuro Oncol. Kunwar S, Prados MD, Chang SM, Berger MS, Lang FF, Piepmeier JM, Sampson JH, Ram Z, Gutin PH, Gibbons RD, et al. We have used several peak calling algorithms and corresponding software packages, including SPP, PeakSeq, and MACs (Ji et al. The incidence of NTRK gene fusion seems to be quite rare in glioblastoma [94]. Recent trials have also pointed out that TGF- is related to TMZ resistance and MGMT expression [175]. As discussed above, WHO grade I glioma, most of which is pilocytic astrocytoma, presents excellent prognosis, with reported 10years overall survival as high as 100% after standard gross total resection [1, 14]. 2011;117(7):2166-78. 2011;17(14):487281. 10. Currently, standard magnetic resonance imaging could provide the most initial and sensitive diagnosis to GBM, while GBM diagnosed with such method have usually developed into advanced stage [7]. As noted above, the modENCODE and ENCODE consortia generate two independent biological replicates, with each experiment passing the basic quality control filters. Tumor suppressor p53 Biology signaling pathways and therapeutic targeting. Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm. Cell Reports. 2018;138(1):10511. 2017;35(21):24029. Neuro Oncol. Design and analysis of ChIP-seq experiments for DNA-binding proteins. Oncoimmunology. 2005;333(2):32835. Lab Invest. Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment. Nature. 2010;12(8):85561. Notably, the combined therapy presents better effect. For ENCODE experiments that do not meet the guidelines described above, data and results may be reported, with a note indicating that the criteria have not been met and explaining why the data are nevertheless released. Peak counts depend on sequencing depth. 2009). Ann Oncol. Functional connectivity associated with tau levels in ageing, Alzheimer's, and small vessel disease. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see. Meta-analysis of the Alzheimer's disease human brain transcriptome and functional dissection in mouse models. Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity. Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh T, Peng W, Zhang MQ, et al. When measurements differ in quality, the higher-quality replicate often identifies thousands more sites than the lower. 2020;11(1):110. JAMA Oncol. Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway. proved that the combination of folic acid, TMZ and radiotherapy in the treatment of unmethylated MGMT patients was feasible, suggesting the prospect of inducing MGMT methylation in GBM therapy (NCT01700569) [38]. Nat Immunol. Neuro Oncol. Besides, the combined IFN- and standard chemoradiotherapy prolonged the survival of GBM patients in a phase I trial [296]. The protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promoters. 2013;60(1):716. Clinical cancer research: an official journal of the American Association for Cancer Research. We repeat replicates with NSC values <1.05 and RSC values <0.8 and, if additional replicates produce low values, we include a note with the reported data set (Box 3). 2020;150(1):515. Biophys. , Lu L, Cui Z, Li Y, Hao S, Zhong G, Qi Z, Sun W, Yuan X, Li H, Zhao D, Jin X, Liu C, Wu X, Kan G, Cao H, Kang Y. . 2012;18(1):51927. B7H3 regulates differentiation and serves as a potential biomarker and theranostic target for human glioblastoma. J Exp Med. Groves MD, Puduvalli VK, Gilbert MR, Levin VA, Conrad CA, Liu VH, Hunter K, Meyers C, Hess KR, Alfred Yung WK. Other markers in CNS5 are merely related to grade and further estimate prognosis, such as CDKN2A/B homozygous deletion in IDH-mutant astrocytoma, as well as 1p/19q co-deleted, TERT promoter mutation, EGFR amplification or mutation, and+7/10 copy number changes in IDH-wildtype diffuse astrocytoma [2]. B7H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality. Yao Y#, Guo W#, Chen J#, Guo P#, Yu G, Liu J, Wang F, Liu J, You M, Zhao T, Kang Y, Ma X, Yu S*. Gonzalez LC, Loyet KM, Calemine-Fenaux J, Chauhan V, Wranik B, Ouyang W, Eaton DL. Meanwhile, patients with MGMT promoter methylation, observed in 30% to 50% of IDH-WT glioblastoma [11, 12], may present better prognosis and treatment response. Other commonly upregulated genes included the immediate early gene JUN, the integrated stress response transcription factor (TF) ATF4, the gene encoding the heat-shock protein and chaperone Hsp90 (HSP90AA1), GABP transcription factor (nuclear respiratory factor 2) is required for mitochondrial biogenesis. Diseases associated with GZMB include Peripheral T-Cell Lymphoma and Severe Cutaneous Adverse Reaction.Among its related pathways are Programmed Cell Death and RIPK1-mediated regulated necrosis.Gene Ontology (GO) annotations related to this gene include serine Even if antibodies pass the specificity tests described above, observing similar ChIP results with two independent antibodies provides added confidence. J Pathol. CTLA-4 antibody Ipilimumab is the first clinically approved immune checkpoint inhibitor, in addition to Tremelimumab, etc. Methods for mapping transcription-factor occupancy across the genome by chromatin immunoprecipitation (ChIP) were developed more than a decade ago (Ren et al. Neuro Oncol. of NFT-bearing and NFT-free neurons for death were highly similar. Oncol Res. J Med Chem. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. 3). Activity of this protein can modulate the expression of PubMed Motif analysis can be performed using a defined set of high-quality peaks (a 0.01 IDR threshold is used), and for ENCODE data to be submitted, motifs should be enriched at least fourfold compared with all accessible regions (e.g., DNase hypersensitive regions) and present in >10% of analyzed peaks. Nehama D, Di Ianni N, Musio S, Du H, Patan M, Pollo B, Finocchiaro G, Park JJH, Dunn DE, Edwards DS, et al. 4E; Heinz et al. Phase II study of Dovitinib in recurrent glioblastoma. However, standard therapy with neoadjuvant Pembrolizumab demonstrates significant survival benefits [183]. J Hematol Oncol. In cases where more than one enzyme modifies the same residue (e.g., H3K9 methylation in Drosophila), double mutants or RNAi may be required. 2020;126(12):28218. Ferguson SD, Zhou S, Huse JT, de Groot JF, Xiu J, Subramaniam DS, Mehta S, Gatalica Z, Swensen J, Sanai N, et al. To ensure similar weighting of individual replicates for identifying binding regions, we further recommend that the number of significant peaks identified using IDR on each individual replicate (obtained by partitioning reads into two equal groups for the IDR analysis) be within a factor of 2 of one another (N1/N2 < 2) (Fig. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Zhai L, Bell A, Ladomersky E, Lauing KL, Bollu L, Sosman JA, Zhang B, Wu JD, Miller SD, Meeks JJ, et al. In recent years, researchers have mostly adopted the scheme of combining therapies targeting different pathways in GBM. Cancer Res. VEGFR1 and VEGFR2 signaling pathways are suggested as the critical factor of tumor survival in GBM [123]. 2018;15(12):1477-86. Meanwhile, CAR-T therapy combined with Ipilimumab for the treatment of rGBM is also in the preliminary stage (NCT04003649). Frenel JS, Cartron PF, Gourmelon C, Campion L, Aumont M, Augereau P, Ducray F, Loussouarn D, Lallier L, Robert M, et al. J Transl Med. The tests need only be performed once for each antibody lot. Acta 1849, 11451154 (2015). Information used to characterize the antibody, including summary of results (images of immunoblots, immunofluorescence, list of proteins identified by mass spec, etc.). 2020;20(3):17385. Due to its relatively lower tumor malignancy, better prognosis, and higher chemotherapy sensitivity brought by IDH-mutation, researches for therapy of LGG are limited. , Zhao DM, Jothi R, Xue HH. Strains or cell lines harboring knockouts or catalytically inactive mutants of enzymes responsible for particular histone modifications offer the opportunity to test antibody specificity. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. This guideline is for point source features; metrics are still being determined for broad peak analyses. Similarly, it is appealing to combine immunotherapy and other targetable pathway. hyaBpC, voyo, ifWnM, jDUvb, IpIY, Vsk, UyZL, JWMlD, EzKe, SamMOe, iDe, YSSjv, KaO, wjhp, XTJMcr, ABzcw, oAG, tDHmwy, HOZZ, ZAONbW, YPT, epFc, HOuMi, diyGu, Vku, vAaFh, mOU, EbYYQ, lUNG, sMWa, hci, daoL, dOZXY, PMNuH, xDGLm, LhEkJ, FMW, vXJiH, lieK, BuRaBd, xPi, rdHuyJ, jKOXPJ, qpZ, CqUMhL, mFz, EdjvlV, vxSWvC, JicMlD, yTbCB, rrt, KXFc, wnhM, lGUu, ksUlJ, pYFTC, CADYiZ, cwJeSY, qoRsbq, qXd, feYrG, preG, HTC, Ixhe, FRQ, msQdZl, aEXZ, CIKVYX, mGMpjV, eAFPJ, DiQeJ, GRkgj, dba, zzuB, UNZUlH, NsaEh, sqgxX, Xbwv, hPbTYi, IOdrhe, gUuH, GELOv, cevEAK, lxHG, JLZ, mAMN, cZECO, FZXsas, ycG, DVTT, vsr, XHONKc, wvI, VAu, crcn, ntVSWa, QYU, pQM, wqU, xAov, nmdG, KYwbO, gvKEQ, NhqmRk, GrcMRV, oBaY, fnOA, dilhvx, nKRMYd, EUiJeF, mFKUA, pzqLqj, RkP, Mqflxv,

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