AURKA

Gene Summary

Gene:AURKA; aurora kinase A
Aliases: AIK, ARK1, AURA, BTAK, STK6, STK7, STK15, AURORA2, PPP1R47
Location:20q13
Summary:The protein encoded by this gene is a cell cycle-regulated kinase that appears to be involved in microtubule formation and/or stabilization at the spindle pole during chromosome segregation. The encoded protein is found at the centrosome in interphase cells and at the spindle poles in mitosis. This gene may play a role in tumor development and progression. A processed pseudogene of this gene has been found on chromosome 1, and an unprocessed pseudogene has been found on chromosome 10. Multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:aurora kinase A
HPRD
Source:NCBIAccessed: 20 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 20 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • RTPCR
  • Aurora Kinase A
  • Risk Factors
  • Statistics as Topic
  • Urothelium
  • ras-GRF1
  • Chromosome 20
  • Promoter Regions
  • Spectral Karyotyping
  • Quinazolines
  • Transcription
  • Vincristine
  • Stomach Cancer
  • AURKA
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Messenger RNA
  • Survival Rate
  • Estrogen Receptors
  • Skin Cancer
  • Telomerase
  • Breast Cancer
  • alpha-Fetoproteins
  • Up-Regulation
  • Cancer Gene Expression Regulation
  • Subcellular Fractions
  • Valine
  • Transfection
  • Tumor Markers
  • Ribosomes
  • Xenopus Proteins
  • Tumor Suppressor Proteins
  • Gene Expression Profiling
  • Bladder Cancer
  • Pyrimidines
  • Uterine Cancer
  • fms-Like Tyrosine Kinase 3
  • p53 Protein
  • Xenograft Models
  • Testis
  • Ubiquitination
Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AURKA (cancer-related)

Ye Q, Lei L, Aili AX
Identification of potential targets for ovarian cancer treatment by systematic bioinformatics analysis.
Eur J Gynaecol Oncol. 2015; 36(3):283-9 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To provide a systematic overview to understand the mechanism of ovarian cancer.
MATERIALS AND METHODS: Data of GSE14407 downloaded from Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified. Gene ontology and pathway enrichment analysis were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). Furthermore, the authors constructed the protein-protein interaction (PPI) network and co-expression networks by Cytoscape.
RESULTS: A total 1,442 genes were identified to be differentially expressed. Regulatory effects of DEGs mainly focused on cell cycle, transcription regulation, and cellular protein metabolic process. Significant pathways were determined to be p53 signaling pathway, amino sugar, and nucleotide sugar metabolism. The most significant transcription factor was aryl hydrocarbon receptor nuclear translocator (ARNT). Abnormal spindle-like microcephaly-associated protein (ASPM), Aurora kinase (AURKA), Cyclin-A2 (CCNA2), G2/mitotic-specific cyclin-B1, (CCNB1), and Cyclin-dependent kinase 1 (CDK1) were significant nodes in PPI network.
CONCLUSION: The significant genes and pathways show potential targets for the treatment of ovarian cancer.

DiMario FJ, Sahin M, Ebrahimi-Fakhari D
Tuberous sclerosis complex.
Pediatr Clin North Am. 2015; 62(3):633-48 [PubMed] Related Publications
Tuberous sclerosis complex is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia. The genetic cause is mutations in the TSC1 gene, found on chromosome 9q34, and TSC2 gene, found on chromosome 16p13. The clinical phenotypes resulting from mutations in either of the 2 genes are variable in each individual. Herein, advances in the understanding of molecular mechanisms in tuberous sclerosis complex are reviewed, and current guidelines for diagnosis, treatment, follow-up, and management are summarized.

Shagisultanova E, Gaponova AV, Gabbasov R, et al.
Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases.
Gene. 2015; 567(1):1-11 [PubMed] Article available free on PMC after 01/08/2016 Related Publications
Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease.

Netravathi M, Kumari R, Kapoor S, et al.
Whole exome sequencing in an Indian family links Coats plus syndrome and dextrocardia with a homozygous novel CTC1 and a rare HES7 variation.
BMC Med Genet. 2015; 16:5 [PubMed] Article available free on PMC after 01/08/2016 Related Publications
BACKGROUND: Coats plus syndrome is an autosomal recessive, pleiotropic, multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is caused by compound heterozygous mutations in the CTC1 gene.
CASE PRESENTATION: We encountered a case of an eight-year old boy from an Indian family with manifestations of Coats plus syndrome along with an unusual occurrence of dextrocardia and situs inversus. Targeted resequencing of the CTC1 gene as well as whole exome sequencing (WES) were conducted in this family to identify the causal variations. The identified candidate variations were screened in ethnicity matched healthy controls. The effect of CTC1 variation on telomere length was assessed using Southern blot. A novel homozygous missense mutation c.1451A > C (p.H484P) in exon 9 of the CTC1 gene and a rare 3'UTR known dbSNP variation (c.*556 T > C) in HES7 were identified as the plausible candidates associated with this complex phenotype of Coats plus and dextrocardia. This CTC1 variation was absent in the controls and we also observed a reduced telomere length in the affected individual's DNA, suggesting its likely pathogenic nature. The reported p.H484P mutation is located in the N-terminal 700 amino acid regionthat is important for the binding of CTC1 to ssDNA through its two OB domains. WES data also showed a rare homozygous missense variation in the TEK gene in the affected individual. Both HES7 and TEK are targets of the Notch signaling pathway.
CONCLUSIONS: This is the first report of a genetically confirmed case of Coats plus syndrome from India. By means of WES, the genetic variations in this family with unique and rare complex phenotype could be traced effectively. We speculate the important role of Notch signaling in this complex phenotypic presentation of Coats plus syndrome and dextrocardia. The present finding will be useful for genetic diagnosis and carrier detection in the family and for other patients with similar disease manifestations.

Chang NS
Introduction to a thematic issue for WWOX.
Exp Biol Med (Maywood). 2015; 240(3):281-4 [PubMed] Related Publications
Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been aimed mainly toward this direction. In this thematic issue, updated information has been collected regarding the structure, function and signaling of WWOX, along with its critical role as a tumor suppressor and participation in metabolism, neurodegeneration, ataxia, epilepsy, neural disorders, neuronal damages, and interactions with oncogenic viruses. WWOX is not a driver of cancer initiation. Chromosomal alterations in the WWOX gene enhance cancer progression. Importantly, a homozygous nonsense mutation of WWOX gene in humans leads to neural pathologies and early death, rather than spontaneous cancer development. These findings suggest new physiological functions of WWOX in metabolism and neural diseases, and these areas require further investigation.

Lan L, Holland JD, Qi J, et al.
Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice.
EMBO J. 2015; 34(11):1493-508 [PubMed] Article available free on PMC after 03/06/2016 Related Publications
In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to the inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, focal adhesion kinase, and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies, which rely on senescence induction by inhibiting Shp2 or controlling its target gene products, may be useful in blocking breast cancer.

Murtaza M, Jolly LA, Gecz J, Wood SA
La FAM fatale: USP9X in development and disease.
Cell Mol Life Sci. 2015; 72(11):2075-89 [PubMed] Article available free on PMC after 03/06/2016 Related Publications
Deubiquitylating enzymes (DUBs), act downstream of ubiquitylation. As such, these post-post-translational modifiers function as the final arbitrators of a protein substrate's ubiquitylation status, thus regulating its fate. In most instances, DUBs moderate the absolute level of a substrate, its locality or activity, rather than being an "all-or-none" phenomenon. Yet, disruption of this quantitative regulation can produce dramatic qualitative differences. The ubiquitin-specific protease 9X (USP9X/FAM) is a substrate-specific DUB, which displays an extraordinarily high level of sequence conservation from Drosophila to mammals. It is primarily the recent revelations of USP9X's pivotal role in human cancers, both as oncogene or tumour suppressor, in developmental disorders including intellectual disability, epilepsy, autism and developmental delay that has led to a subsequent re-examination of its molecular and cellular functions. Results from experimental animal models have implicated USP9X in neurodegeneration, including Parkinson's and Alzheimer's disease, as well as autoimmune diseases. In this review, we describe the current and accumulated knowledge on the molecular, cellular and developmental aspects of USP9X function within the context of the biological consequences during normal development and disease.

Casorzo L, Dell'Aglio C, Sarotto I, Risio M
Aurora kinase A gene copy number is associated with the malignant transformation of colorectal adenomas but not with the serrated neoplasia progression.
Hum Pathol. 2015; 46(3):411-8 [PubMed] Related Publications
A crucial role for Aurora Kinase A (AURKA) gene has been demonstrated in the advanced steps of colorectal tumor progression. Little is known, however, about its role in the early phases of the adenoma-carcinoma sequence. Moreover, no data are currently available concerning AURKA involvement in the serrated tumorigenesis. Fluorescence in situ hybridization analysis and immunohistochemistry were used to assess gene copy number and protein expression in 40 colorectal adenomas, 20 cancerized adenomas, and 20 serrated polyps. An increased copy number was found either in adenomatous tissue or in early cancer in the vast majority of cancerized adenomas, but only in 5% of adenomas (P < .001). Protein expression strictly paralleled fluorescence in situ hybridization results. No changes in the gene copy number were observed in serrated polyps, regardless of their histotype and the presence of dysplasia, even if high percentages of immunostained cells were detected in all the subgroups. AURKA gene is associated with progressive colorectal adenomas but is uninvolved in the development of nonprogressive adenomas. The diploid status of the gene is maintained along the progression of serrated neoplasia. AURKA protein expression in serrated polyps is uncoupled from gene status and is likely to reflect apoptotic dysregulation.

Hyoda T, Tsujioka T, Nakahara T, et al.
Rigosertib induces cell death of a myelodysplastic syndrome-derived cell line by DNA damage-induced G2/M arrest.
Cancer Sci. 2015; 106(3):287-93 [PubMed] Related Publications
A multi-kinase inhibitor, rigosertib (ON 01910.Na) has recently been highlighted as a novel type of anti-cancer agent for the treatment of the myelodysplastic syndromes (MDS), but its action mechanisms remain to be clarified. We investigated the in vitro effects of rigosertib on an MDS-derived cell line MDS-L and a myeloid leukemia cell line HL-60. Rigosertib suppressed the proliferation of both HL-60 and MDS-L cells and induced apoptosis by inhibition of the PI3 kinase/Akt pathway. As the effects on cell cycle, rigosertib treatment promoted the phosphorylation of histone H2AX and led to the DNA damage-induced G2/M arrest. In addition, an immunofluorescence staining study demonstrated the abnormal localization of aurora A kinase, suggesting that rigosertib causes perturbation of spindle assembly and deregulated mitotic patterns towards cell cycle arrest and apoptosis. We also found that rigosertib exerted growth inhibitory effects on two lymphoid cell lines, Jurkat and Ramos. We further examined the molecular pathways influenced by rigosertib from the gene expression profiling data of MDS-L cells and found a possible involvement of rigosertib treatment in the upregulation of the genes related to microtubule kinetics and the downregulation of the mRNA degradation system. The gene set enrichment analysis showed the suppression of "nonsense-mediated mRNA decay (NMD)" as the most significantly affected gene set. These data provide a new aspect and a potential utility of rigosertib for the treatment of refractory hematopoietic malignancies.

Majewski IJ, Nuciforo P, Mittempergher L, et al.
PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer.
J Clin Oncol. 2015; 33(12):1334-9 [PubMed] Related Publications
PURPOSE: We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer.
PATIENTS AND METHODS: Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO). Activating mutations in PIK3CA were identified using mass spectrometry-based genotyping.
RESULTS: PIK3CA mutations were identified in 23% of HER2-positive breast tumors, and these mutations were associated with poorer outcome in all of the treatment arms. Patients treated with a combination of trastuzumab and lapatinib who had wild-type PIK3CA obtained a total pathologic complete response (pCR) rate of 53.1%, which decreased to 28.6% in patients with tumors that carried PIK3CA activating mutations (P = .012).
CONCLUSION: Activating mutations in PIK3CA predicted poor pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapies that target HER2. Consequently, the combination of anti-HER2 agents and PI3K inhibitors is being investigated.

Li Y, Zhang J
AURKA is a predictor of chemotherapy response and prognosis for patients with advanced oral squamous cell carcinoma.
Tumour Biol. 2015; 36(5):3557-64 [PubMed] Related Publications
Increasing evidence proposes the benefits of cisplatin-based chemotherapy in a subpopulation of patients with oral squamous cell carcinoma (OSCC), yet reliable indicators for this subpopulation are poorly explored. AURKA, also known as aurora kinase A, playing important functions in cell mitosis and making cells resistant to cisplatin through dysregulation of DNA damage repair networks, has been reported to be upregulated in OSCC, making AURKA a promising indicator. In this study, we recruited 78 patients with advanced OSCC to examine the expression of AURKA and the correlation with chemotherapy response and clinical outcomes. We found that AURKA was strongly expressed in 31 (39.74 %) of the 78 advanced OSCC samples and its expression was significantly associated with cisplatin resistance (P = 0.023), clinical recurrence (P = 0.021), and 5-year survival (P = 0.019). Chemotherapy increased AURKA expression in post-chemotherapy samples, yet with no significance (P = 0.101). Multivariate Cox proportional hazards regression model analysis demonstrated that lymph node samples with positive, strong AURKA staining, and poor chemotherapy response were independently associated with the 5-year survival and disease-free survival. Inhibiting AURKA expression in OSCC cell lines remarkably increased their sensitivity to cisplatin treatment by 2.5-fold difference. Our results imply that the overexpression of AURKA in advanced OSCC not only plays a role in the disease course but also shows an involvement in cisplatin treatment response. AURKA level may be a valuable predictor for patients with advanced OSCC, with downregulation of AURKA being a promising adjuvant therapy in this patient population.

Caputo E, Wang E, Valentino A, et al.
Ran signaling in melanoma: implications for the development of alternative therapeutic strategies.
Cancer Lett. 2015; 357(1):286-96 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over-represented (p ≤ 0.001) and up-regulated in melanoma cells. A melanoma-associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down-regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down-regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma.

Rashid NN, Yusof R, Watson RJ
A B-myb--DREAM complex is not critical to regulate the G2/M genes in HPV-transformed cell lines.
Anticancer Res. 2014; 34(11):6557-63 [PubMed] Related Publications
BACKGROUND/AIM: It is well-established that HPV E7 proteins, encoded by human papillomavirus (HPV) genes, frequently associated with cervical cancers bind avidly to the retinoblastoma (RB) family of pocket proteins and disrupt their association with members of the E2F transcription factor family. Our previous study showed that the repressive p130-dimerization partner, RB-like, E2F and multi-vulval class (DREAM) complex was disrupted by HPV16 E7 proteins in order to maintain the viral replication in CaSki cells. However, we would like to address whether the activator B-myb-DREAM complex is critical in regulating the replication and mitosis phase since our previous study showed increased B-myb-DREAM expression in HPV-transformed cell lines when compared to control cells.
RESULTS: The association of B-myb with both LIN-54 and LIN-9 was equally decreased by depleting LIN-54 in CaSki cells. Flow cytometry analysis showed that LIN-54 depletion caused an increased proportion of G2/M cells in T98G, SiHa and CaSki cells. The mRNA levels of certain S/G2 genes such as cyclin B, aurora kinase A and Polo-like kinase 1 have demonstrated a marginal increased in CaSki-Lin-54-depleted cells when compared to SiHa- and T98G-Lin-54-depleted cells. We further confirmed this experiment by depleting the B-myb itself in CaSki cells and the results showed the same pattern of cell cycle and mRNA levels for S/G2 genes when compared to LIN-54- and LIN-9-depleted cells.
CONCLUSION: The B-myb-DREAM complex might not be vital for progression through mitosis in cells lacking a G1/S checkpoint and not as crucial as the p130-DREAM complex for the survival of the HPV virus.

Cigoli MS, Avemaria F, De Benedetti S, et al.
PDCD10 gene mutations in multiple cerebral cavernous malformations.
PLoS One. 2014; 9(10):e110438 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.

Dere R, Perkins AL, Bawa-Khalfe T, et al.
β-catenin links von Hippel-Lindau to aurora kinase A and loss of primary cilia in renal cell carcinoma.
J Am Soc Nephrol. 2015; 26(3):553-64 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
von Hippel-Lindau (VHL) gene mutations are associated with clear cell renal cell carcinoma (ccRCC). A hallmark of ccRCC is loss of the primary cilium. Loss of this key organelle in ccRCC is caused by loss of VHL and associated with increased Aurora kinase A (AURKA) and histone deacetylase 6 (HDAC6) activities, which drive disassembly of the primary cilium. However, the underlying mechanism by which VHL loss increases AURKA levels has not been clearly elucidated, although it has been suggested that hypoxia-inducible factor-1α (HIF-1α) mediates increased AURKA expression in VHL-null cells. By contrast, we found that elevated AURKA expression is not increased by HIF-1α, suggesting an alternate mechanism for AURKA dysregulation in VHL-null cells. We report here that AURKA expression is driven by β-catenin transcription in VHL-null cells. In a panel of RCC cell lines, we observed nuclear accumulation of β-catenin and increased AURKA signaling to HDAC6. Moreover, HIF-1α inhibited AURKA expression by inhibiting β-catenin transcription. VHL knockdown activated β-catenin and elevated AURKA expression, decreased primary cilia formation, and caused significant shortening of cilia length in cells that did form cilia. The β-catenin responsive transcription inhibitor iCRT14 reduced AURKA levels and rescued ciliary defects, inducing a significant increase in primary cilia formation in VHL-deficient cells. These data define a role for β-catenin in regulating AURKA and formation of primary cilia in the setting of VHL deficiency, opening new avenues for treatment with β-catenin inhibitors to rescue ciliogenesis in ccRCC.

Fan X, Wang YY, Zhang CB, et al.
Expression of RINT1 predicts seizure occurrence and outcomes in patients with low-grade gliomas.
J Cancer Res Clin Oncol. 2015; 141(4):729-34 [PubMed] Related Publications
PURPOSE: Most patients with low-grade gliomas (LGGs) experience epileptic seizures as an initial symptom. However, the mechanism of LGG-related epilepsy is poorly understood. Genetic changes in brain tumors influence epileptic seizures, but few biomarkers have been associated with LGG-related seizures. We investigated the association between LGG-related epilepsy and tumor-specific molecular changes.
METHODS: Clinical characteristics, RNA sequence data, and case follow-up data were reviewed for 76 patients with histologically confirmed LGG. Gene expression (n = 21,469) was compared between patients with preoperative epileptic seizures and those without preoperative epileptic seizures. The Engel classification was used at 6 months after surgery to evaluate the prognostic role of genes that passed the screen.
RESULTS: Expression of RAD50 interactor 1 (RINT1) significantly differed between LGG patients with and without preoperative epileptic seizures (p = 0.003). This result was validated by applying the same analysis to RNA sequence data from The Cancer Genome Atlas (p = 0.048). Patients with high RINT1 expression were at increased risk of LGG-related seizures compared to those with low expression (p = 0.044). RINT1 was also identified as a predictor of seizure outcomes in patients with LGG at 6 months after tumor resection (p = 0.022).
CONCLUSIONS: Our results suggest that high RINT1 expression may represent a risk factor for LGG-related seizures and may be associated with seizure outcomes.

Chen JM, Chiu SC, Wei TY, et al.
The involvement of nuclear factor-κappaB in the nuclear targeting and cyclin E1 upregulating activities of hepatoma upregulated protein.
Cell Signal. 2015; 27(1):26-36 [PubMed] Related Publications
Hepatoma upregulated protein (HURP) is originally isolated during the search for the genes associated with hepatoma. HURP is upregulated in many human cancers. Culture cells exhibit transformed and invasive phenotype when ectopic HURP is introduced, revealing HURP as an oncogene candidate. Our previous studies demonstrated that Aurora-A regulated the cell transforming activities of HURP by phosphorylating HURP at four serines. To unravel how the Aurora-A/HURP cascade contributes to cell transformation, we firstly noticed that HURP shuttled between cytoplasm and nucleus. The nuclear localization activity of HURP was promoted or abolished by overexpression or knockdown of Aurora-A. Similarly, the HURP phosphorylation mimicking mutant 4E had higher nuclear targeting activity than the phosphorylation deficient mutant 4A. The HURP 4E accelerated G1 progression and upregulated cyclin E1, and the cyclin E1 upregulating and cell transforming activities of HURP were diminished when the nuclear localization signal (NLS) was removed from HURP. Furthermore, HURP employed p38/nuclear factor-κB (NF-κB) cascade to stimulate cell growth. Interestingly, NF-κB trapped HURP in nucleus by interacting with HURP 4E. At last, the HURP/NF-κB complex activated the cyclin E1 promoter. Collectively, Aurora-A/HURP relays cell transforming signal to NF-κB, and the HURP/NF-κB complex is engaged in the regulation of cyclin E1 expression.

Roylance R, Endesfelder D, Jamal-Hanjani M, et al.
Expression of regulators of mitotic fidelity are associated with intercellular heterogeneity and chromosomal instability in primary breast cancer.
Breast Cancer Res Treat. 2014; 148(1):221-9 [PubMed] Related Publications
Regulators of transition through mitosis such as SURVIVIN and Aurora kinase A (AURKA) have been previously implicated in the initiation of chromosomal instability (CIN), a driver of intratumour heterogeneity. We investigate the relationship between protein expression of these genes and directly quantified CIN, and their prognostic utility in breast cancer. The expression of SURVIVIN and AURKA was determined by immunohistochemistry in a cohort of 426 patients with primary breast cancer. The association between protein expression and histopathological characteristics, clinical outcome and CIN status, as determined by centromeric FISH and defined by modal centromere deviation, was analysed. Significantly poorer clinical outcome was observed in patients with high AURKA expression levels. Expression of SURVIVIN was elevated in ER-negative relative to ER-positive breast cancer. Both AURKA and SURVIVIN increased expression were significantly associated with breast cancer grade. There was a significant association between increased CIN and both increased AURKA and SURVIVIN expression. AURKA gene amplification was also associated with increased CIN. To our knowledge this is the largest study assessing CIN status in parallel with the expression of the mitotic regulators AURKA and SURVIVIN. These data suggest that elevated expression of AURKA and SURVIVIN, together with AURKA gene amplification, are associated with increased CIN in breast cancer, and may be used as a proxy for CIN in breast cancer samples in the absence of more advanced molecular measurements.

Michaelis M, Selt F, Rothweiler F, et al.
Aurora kinases as targets in drug-resistant neuroblastoma cells.
PLoS One. 2014; 9(9):e108758 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.

Kalinsky K, Lim EA, Andreopoulou E, et al.
Increased expression of tumor proliferation genes in Hispanic women with early-stage breast cancer.
Cancer Invest. 2014; 32(9):439-44 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Hispanic women have higher breast cancer mortality compared to non-Hispanic whites. We evaluated for Proliferation Axis Score differences, as determined by Oncotype Dx, in Hispanic and non-Hispanic white women with newly diagnosed breast cancer. We matched 219 women, based upon age, stage, and nodal status. Compared to non-Hispanic whites, Hispanic women with hormone-sensitive, HER2-negative early-stage breast cancer had a higher Proliferation Axis Score. No differences were seen in Recurrence Score, ER, PR, or HER2 by Oncotype DX. CCNB1 and AURKA were significantly higher in Hispanic women. These tumor differences may help explain breast cancer outcome differences between the two ethnicities.

Guo XG, Zheng L, Feng WB, Xia Y
The AURKA gene rs2273535 polymorphism contributes to breast carcinoma risk - meta-analysis of eleven studies.
Asian Pac J Cancer Prev. 2014; 15(16):6709-14 [PubMed] Related Publications
The rs2273535 polymorphism in the AURKA gene had proven to be associated with breast carcinoma susceptibility. Nevertheless, the results of different studies remain contradictory. A meta-analysis covering 28, 789 subjects from eleven different studies was here carried out in order to investigate the association in detail. The random effects model was used to analyze the pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). A significant relationship between the rs2273535 polymorphism and breast tumors was found in an allelic genetic model (OR: 1.076, 95% CI: 1.004-1.153, p=0.040, Pheterogeneity=0.002). No significant association was detected in a homozygote model (OR: 1.186, 95% CI: 0.990-1.423, P=0.065, Pheterogeneity=0.002), a heterozygote model (OR: 1.016, 95% CI: 0.959-1.076, p=0.064, Pheterogeneity=0.000), a dominant genetic model (OR: 1.147, 95% CI: 0.992-1.325, p=0.217, Pheterogeneity=0.294) and a recessive genetic model (OR: 1.093, 95% CI: 0.878- 1.361, p=0.425, Pheterogeneity=0.707). A significant relationship between the rs2273535 polymorphism in the AURKA gene and breast tumor in Asian group was found in an allelic genetic model (OR: 1.124, 95% CI: 1.003-1.29, p=0.044, Pheterogeneity=0.034), a homozygote model (OR: 1.229, 95% CI: 1.038-1.455, p=0.016, Pheterogeneity=0.266) and a recessive genetic model (OR: 1.227, 95% CI: 1.001-1.504, p=0.049, Pheterogeneity=0.006). A significant association was thus observed between the rs2273535 polymorphism in the AURKA gene and breast cancer risk. Individuals with the rs2273535 polymorphism in the AURKA gene have a higher risk of breast cancer in Asian populations, but not in Caucasians.

Park K, Chen Z, MacDonald TY, et al.
Prostate cancer with Paneth cell-like neuroendocrine differentiation has recognizable histomorphology and harbors AURKA gene amplification.
Hum Pathol. 2014; 45(10):2136-43 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Aurora kinase A (AURKA) gene amplification has been documented in 67% of hormone-naive prostate cancer cases that progress to a highly aggressive variant of castrate-resistant disease, clinically referred to as "neuroendocrine" prostate cancer, "small cell" prostate carcinoma, or "anaplastic" prostate cancer. Therefore, AURKA amplification is a potential prognostic biomarker that may help to identify patients with prostate cancer who are at high risk for developing castrate-resistant disease with clinical features of small cell carcinoma. Furthermore, AURKA inhibitors are currently being tested in clinical trials. In a previous study, we found AURKA amplification in 6 cases of prostate cancer with Paneth cell-like cells. This morphologic pattern has been suggested to represent low-grade neuroendocrine differentiation (NED) with generally favorable prognosis. We sought to investigate the frequency of AURKA amplification and the histologic characteristics of prostate cancer with Paneth cell-like NED. Twenty-five cases from 172 prostatectomies were evaluated for the presence of 18 morphologic features and AURKA amplification. Most prostate cancers with Paneth cell-like NED had macronucleoli (92%), basophilic appearance (88%), perineural invasion (72%), and nuclear stratification (76%). The frequency of AURKA amplification was 45%, present throughout the examined tumor nodule including areas without Paneth cell-like cells. When histologically similar cases with and without AURKA amplification were compared, this gene alteration was associated with larger extent of Paneth cell-like NED identified at magnification ×20 (P = .015), higher percentage of Paneth cell-like NED throughout the tumor nodule (P = .033), ductal features (P = .02), and higher overall Gleason grade (P = .039). AURKA amplification was not associated with age, serum prostate specific antigen, or tumor stage. The high frequency of AURKA amplification (45%) in localized prostate cancer with Paneth cell-like NED and its potential prognostic significance warrant further investigation.

Sheng Y, Li W, Zhu F, et al.
3,6,2',4',5'-Pentahydroxyflavone, an orally bioavailable multiple protein kinase inhibitor, overcomes gefitinib resistance in non-small cell lung cancer.
J Biol Chem. 2014; 289(41):28192-201 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
Non-small cell lung cancer (NSCLC) is the most lethal cancer, causing more than 150,000 deaths in the United States in 2013. The receptor tyrosine kinase inhibitors such as gefitinib are not perfect clinical therapeutic agents for NSCLC treatment due to primary or acquired tyrosine kinase inhibitor resistance. Herein, 3,6,2',4',5'-pentahydroxyflavone (36245-PHF) was identified as a multiple kinase inhibitor for NSCLC treatment based on the computational screening of a natural products database. 36245-PHF was shown to inhibit PI3K and Aurora A and B kinases and overcome gefitinib-resistant NSCLC growth. Our data clearly showed that 36245-PHF markedly inhibited anchorage-independent growth of gefitinib-resistant NSCLC cell lines and exerted a substantial chemotherapeutic effect following oral administration in a gefitinib-resistant NSCLC xenograft model. The evidence from three different subsequent methodological approaches, in vitro, ex vivo, and in vivo, all confirmed that 36245-PHF as a multiple protein kinase inhibitor. Overall, we identified 36245-PHF as a multiple protein kinase inhibitor and as a novel therapeutic agent to overcome gefitinib-resistant NSCLC growth, which could provide a new option for clinical NSCLC oral treatment.

Xu LZ, Long ZJ, Peng F, et al.
Aurora kinase a suppresses metabolic stress-induced autophagic cell death by activating mTOR signaling in breast cancer cells.
Oncotarget. 2014; 5(17):7498-511 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
Aberrant Aur-A signaling is associated with tumor malignant behaviors. However, its involvement in tumor metabolic stress is not fully elucidated. In the present study, prolonged nutrient deprivation was conducted into breast cancer cells to mimic metabolic stress in tumors. In these cells, autophagy was induced, leading to caspase-independent cell death, which was blocked by either targeted knockdown of autophagic gene ATG5 or autophagy inhibitor 3-Methyladenine (3-MA). Aur-A overexpression mediated resistance to autophagic cell death and promoted breast cancer cells survival when exposed to metabolic stress. Moreover, we provided evidence that Aur-A suppressed autophagy in a kinase-dependent manner. Furthermore, we revealed that Aur-A overexpression enhanced the mammalian target of rapamycin (mTOR) activity under metabolic stress by inhibiting glycogen synthase kinase 3β (GSK3β). Inhibition of mTOR activity by rapamycin sensitized Aur-A-overexpressed breast cancer cells to metabolic stress-induced cell death. Consistently, we presented an inverse correlation between Aur-A expression (high) and autophagic levels (low) in clinical breast cancer samples. In conclusion, our data provided a novel insight into the cyto-protective role of Aur-A against metabolic stress by suppressing autophagic cell death, which might help to develop alternative cell death avenues for breast cancer therapy.

Jia L, Lee HS, Wu CF, et al.
SMAD4 suppresses AURKA-induced metastatic phenotypes via degradation of AURKA in a TGFβ-independent manner.
Mol Cancer Res. 2014; 12(12):1779-95 [PubMed] Related Publications
UNLABELLED: SMAD4 has been suggested to inhibit the activity of the WNT/β-catenin signaling pathway in cancer. However, the mechanism by which SMAD4 antagonizes WNT/β-catenin signaling in cancer remains largely unknown. Aurora A kinase (AURKA), which is frequently overexpressed in cancer, increases the transcriptional activity of β-catenin/T-cell factor (TCF) complex by stabilizing β-catenin through the inhibition of GSK-3β. Here, SMAD4 modulated AURKA in a TGFβ-independent manner. Overexpression of SMAD4 significantly suppressed AURKA function, including colony formation, migration, and invasion of cell lines. In addition, SMAD4 bound to AURKA induced degradation of AURKA by the proteasome. A luciferase activity assay revealed that the transcriptional activity of the β-catenin/TCF complex was elevated by AURKA, but decreased by SMAD4 overexpression. Moreover, target gene analysis showed that SMAD4 abrogated the AURKA-mediated increase of β-catenin target genes. However, this inhibitory effect of SMAD4 was abolished by overexpression of AURKA or silencing of AURKA in SMAD4-overexpressed cells. Meanwhile, the SMAD4-mediated repression of AURKA and β-catenin was independent of TGFβ signaling because blockage of TGFβR1 or restoration of TGFβ signaling did not prevent suppression of AURKA and β-catenin signaling by SMAD4. These results indicate that the tumor-suppressive function of SMAD4 is mediated by downregulation of β-catenin transcriptional activity via AURKA degradation in a TGFβ-independent manner.
IMPLICATIONS: SMAD4 interacts with AURKA and antagonizes its tumor-promoting potential, thus demonstrating a novel mechanism of tumor suppression.

Ribeiro-Varandas E, Ressurreição F, Viegas W, Delgado M
Cytotoxicity of Eupatorium cannabinum L. ethanolic extract against colon cancer cells and interactions with Bisphenol A and Doxorubicin.
BMC Complement Altern Med. 2014; 14:264 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
BACKGROUND: Eupatorium cannabinum L. has long been utilized in traditional medicine, however no information is available regarding cellular effects of full extracts. Here we assessed the effects of E. cannabinum ethanolic extract (EcEE) on the colon cancer line HT29. Potential interactions with bisphenol A (BPA) a synthetic phenolic compound to which humans are generally exposed and a commonly used chemotherapeutic agent, doxorubicin (DOX) were also evaluated.
METHODS: HT29 cells were exposed to different concentrations (0.5 to 50 μg/ml) of EcEE alone or in combination with BPA or DOX. Cell viability was analyzed through resazurin assay. Gene transcription levels for NCL, FOS, p21, AURKA and bcl-xl were determined through qRT-PCR. Cytological analysis included evaluation of nuclear and mitotic anomalies after DAPI staining, immunodetection of histone H3 lysine 9 acetylation (H3K9ac) and assessment of DNA damage by TUNEL assay.
RESULTS: Severe loss of HT29 cell viability was detected for 50 μg/ml EcEE immediately after 24 h exposure whereas the lower concentrations assayed (0.5, 5 and 25 μg/ml) resulted in significant viability decreases after 96 h. Exposure to 25 μg/ml EcEE for 48 h resulted in irreversible cell damage leading to a drastic decrease in cell viability after 72 h recovery in EcEE-free medium. 48 h 25 μg/ml EcEE treatment also induced alteration of colony morphology, H3K9 hyperacetylation, transcriptional up regulation of p21 and down regulation of NCL, FOS and AURKA, indicating reduced proliferation capacity. This treatment also resulted in drastic mitotic and nuclear disruption accompanied by up-regulation of bcl-xl, limited TUNEL labeling and nuclear size increase, suggestive of a non-apoptocic cell death pathway. EcEE/BPA co-exposure increased mitotic anomalies particularly for the lowest EcEE concentration, although without major effects on viability. Conversely, EcEE/DOX co-exposure decreased cell viability in relation to DOX for all EcEE concentrations, without affecting the DOX-induced cell cycle arrest.
CONCLUSIONS: EcEE has cytotoxic activity on HT29 cancer cells leading to mitotic disruption and non-apoptotic cell death without severe induction of DNA damage. Interaction experiments showed that EcEE can increase BPA aneugenic effects and EcEE synergistic effects with DOX supporting a potential use as adjuvant in chemotherapeutic approaches.

Licchetta L, Bisulli F, Naldi I, et al.
Limbic encephalitis with anti-GAD antibodies and Thomsen myotonia: a casual or causal association?
Epileptic Disord. 2014; 16(3):362-5 [PubMed] Related Publications
The association between hereditary myotonic disorders and epilepsy is seldom described in the literature. To date, few reports have dealt with dystrophic myotonias, whereas a single case demonstrating an association between sporadic congenital myotonia and epilepsy was recently reported in a patient carrying a de novo mutation of the CLCN1 gene. Additional evidence for a role of CLCN1 in the pathogenesis of epilepsy is derived from large-scale exome analysis of ion channel variants and expression studies. Here, we describe the first case of association between familial Thomsen myotonia and epilepsy. All the affected members of a two-generation family presented myotonia and disclosed a pathogenic mutation in CLCN1. In addition, one individual experienced epileptic seizures due to limbic encephalitis (LE) with anti-GAD antibodies. The occurrence of the two diseases in this patient could be a chance association, however, CLCN1 mutation, as a susceptibility factor for epilepsy through dysfunction of GABAA inhibitory signalling, cannot be ruled out as a possible influence.

Karlinger K, Tárnoki ÁD, Tárnoki DL, et al.
Leukoencephalopathy, cerebral calcifications and cysts: a family study.
J Neurol. 2014; 261(10):1911-6 [PubMed] Related Publications
We present a clinical, neuro-radiological and genetic study on a family with members suffering from an autosomal dominantly inherited syndrome characterised by epilepsy, cerebral calcifications and cysts, bone abnormalities; progressive neuro-cognitive deterioration and paranasal sinusitis. This syndrome shares several features with leukoencephalopathy with calcifications and cysts also called Labrune syndrome and the condition of cerebroretinal microangiopathy with calcifications and cysts (CRMCC; Coats plus syndrome). Genetic studies in this family did not reveal mutations in the CTC1 gene defected in CRMCC. We interpret our results as those supporting recent findings that despite clinical similarities, late-onset Labrune and Coats plus syndrome might be distinct entities. This family may have Labrune syndrome or a yet unclassified entity; exploration of similar cases could help classifying this one, and related conditions.

Salvi S, Calistri D, Gurioli G, et al.
Copy number analysis of 24 oncogenes: MDM4 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer.
Int J Mol Sci. 2014; 15(7):12458-68 [PubMed] Article available free on PMC after 10/10/2015 Related Publications
Patients with non-muscle invasive bladder cancer (NMIBC) generally have a high risk of relapsing locally after primary tumor resection. The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease. We studied the copy number variations (CNVs) of 24 oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR and BRAF) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence. Formalin-fixed paraffin-embedded tissue samples from 43 patients who underwent transurethral resection of the bladder (TURB) were used; 23 patients had relapsed and 20 were disease-free after 5 years. Amplification frequencies were analyzed for all genes and MDM4 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones (0.65 vs. 0.3; Fisher's test p=0.023). Recurrence-free survival analysis confirmed the predictive role of MDM4 (log-rank test p=0.041). Our preliminary results indicate a putative role for the MDM4 gene in predicting local recurrence of bladder cancer. Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients.

De Mattos-Arruda L, Weigelt B, Cortes J, et al.
Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle.
Ann Oncol. 2014; 25(9):1729-35 [PubMed] Related Publications
BACKGROUND: Plasma-derived cell-free tumor DNA (ctDNA) constitutes a potential surrogate for tumor DNA obtained from tissue biopsies. We posit that massively parallel sequencing (MPS) analysis of ctDNA may help define the repertoire of mutations in breast cancer and monitor tumor somatic alterations during the course of targeted therapy.
PATIENT AND METHODS: A 66-year-old patient presented with synchronous estrogen receptor-positive/HER2-negative, highly proliferative, grade 2, mixed invasive ductal-lobular carcinoma with bone and liver metastases at diagnosis. DNA extracted from archival tumor material, plasma and peripheral blood leukocytes was subjected to targeted MPS using a platform comprising 300 cancer genes known to harbor actionable mutations. Multiple plasma samples were collected during the fourth line of treatment with an AKT inhibitor.
RESULTS: Average read depths of 287x were obtained from the archival primary tumor, 139x from the liver metastasis and between 200x and 900x from ctDNA samples. Sixteen somatic non-synonymous mutations were detected in the liver metastasis, of which 9 (CDKN2A, AKT1, TP53, JAK3, TSC1, NF1, CDH1, MML3 and CTNNB1) were also detected in >5% of the alleles found in the primary tumor sample. Not all mutations identified in the metastasis were reliably identified in the primary tumor (e.g. FLT4). Analysis of ctDNA, nevertheless, captured all mutations present in the primary tumor and/or liver metastasis. In the longitudinal monitoring of the patient, the mutant allele fractions identified in ctDNA samples varied over time and mirrored the pharmacodynamic response to the targeted therapy as assessed by positron emission tomography-computed tomography.
CONCLUSIONS: This proof-of-principle study is one of the first to demonstrate that high-depth targeted MPS of plasma-derived ctDNA constitutes a potential tool for de novo mutation identification and monitoring of somatic genetic alterations during the course of targeted therapy, and may be employed to overcome the challenges posed by intra-tumor genetic heterogeneity.
REGISTERED CLINICAL TRIAL: www.clinicaltrials.gov, NCT01090960.

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