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  • 1
    Publication Date: 2018-01-04
    Description: Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non–small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor ( EGFR ) mutation-positive NSCLC patients with LM. Results: The status of EGFR -activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development. Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. Clin Cancer Res; 24(1); 209–16. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2018-02-01
    Description: The transcription factor nuclear factor erythroid 2-like 1 (NFE2L1 or NRF1) is involved in various critical cell processes such as maintenance of ubiquitin-proteasome system and regulation of the cellular antioxidant response. We previously determined that pancreatic β-cell-specific Nfe2l1 -knockout mice had hyperinsulinemia and that silencing of Nfe2l1 in mouse islets or MIN6 insulinoma β-cells induced elevated basal insulin release and altered glucose metabolism. Hypoglycemia is a major issue with aggressive insulinomas, although a role of NFE2L1 in this pathology is not defined. In the present work, we studied the tumorigenicity of Nfe2l1- deficient insulinoma MIN6 cells ( Nfe2l1 -KD) and sensitivity to chemotherapy. Nfe2l1 -KD cells grew faster and were more aggressive than Scramble cells in vitro . In a mouse allograft transplantation model, insulinomas arising from Nfe2l1 -KD cells were more aggressive and chemoresistant. The conclusion was amplified using streptozotocin (STZ) administration in an allograft transplantation model in diabetic Akita background mice. Furthermore, Nfe2l1 -KD cells were resistant to damage by the chemotherapeutic drugs STZ and 5-fluorouracil, which was linked to binding of hexokinase 1 with mitochondria, enhanced mitochondrial membrane potential and closed mitochondrial potential transition pore. Overall, both in vitro and in vivo data from Nfe2l1 -KD insulinoma cells provided evidence of a previously un-appreciated action of NFE2L1 in suppression of tumorigenesis. Nfe2l1 silencing desensitizes insulinoma cells and derived tumors to chemotherapeutic-induced damage, likely via metabolic reprograming. These data indicate that NFE2L1 could potentially play an important role in the carcinogenic process and impact chemosensitivity, at least within a subset of pancreatic endocrine tumors.
    Print ISSN: 1351-0088
    Electronic ISSN: 1479-6821
    Topics: Medicine
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  • 3
  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; CELL ; human ; GENE ; GENES ; transcription ; MICE ; radiation ; ACTIVATION ; RESPONSES ; DNA ; recombination ; fibroblasts ; PHOSPHORYLATION ; TARGET ; DELETION ; MOUSE ; STRESS ; MUTATION ; CELL-LINE ; LINE ; p53 ; DAMAGE ; DNA-DAMAGE ; STABILITY ; ONCOGENIC RAS ; EMBRYONIC STEM-CELLS ; HOMOLOGOUS RECOMBINATION ; THYMOCYTES ; WILD-TYPE P53 ; TUMOR SUPPRESSION ; ESCAPE ; DNA damage ; ROLES ; MISSENSE MUTATION ; REPLICATIVE SENESCENCE ; senescence ; PREMATURE SENESCENCE ; homologous ; genotoxic ; CELLULAR SENESCENCE ; GENOTOXIC STRESS ; LIGASE ; PROMOTES
    Abstract: Posttranslational modification such as phosphorylation of p53 plays important roles in activating p53 responses to various cellular and genotoxic stresses. Cell line studies have shown that phosphorylation of Ser46 is correlated with the activation of p53 apoptotic activity. To address the physiological roles of Ser46 phosphorylation, we employed homologous recombination and LoxP/Cre-mediated deletion to introduce Ser46 to Ala missense mutation into the human p53 knock-in (HUPKI) allele in mice (p53hki(S46A)). p53 stabilization in response to various types of DNA damage is modestly reduced in p53hki(S46A) embryonic stem (ES) cells, mouse embryonic fibroblasts (MEFs) and thymocytes. In addition, p53-dependent apoptosis is partially impaired in p53hki(S46A) thymocytes and E1A/Ras-expressing mouse embryonic fibroblasts (MEFs) after DNA damage. Consistent with this finding, transcription of p53 target apoptotic genes is preferentially affected by S46A mutation after DNA damage. p53hki(S46A) MEFs proliferate and reach senescence normally but can be spontaneously immortalized more easily than wild type MEFs. In addition, p53hki(S46A) MEFs more readily escapes from Ras-induced senescence. Therefore, Ser46 phosphorylation activates p53-dependent apoptosis induced by DNA damage and cellular senescence induced by oncogenic stress
    Type of Publication: Journal article published
    PubMed ID: 17172844
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  • 5
    Keywords: SIMULATION ; DESIGN ; STRESS ; REPAIR ; ARTERY ; PLACEMENT ; FINITE-ELEMENT-ANALYSIS ; INTERNATIONAL REGISTRY ; WALL STIFFNESS ; IRAD
    Abstract: Aortic dissection is the result of blood intruding into the layers of the aortic wall creating a duplicate channel along the aortic course. This considerably changes aortic morphology and thereby alters blood flow, inducing severe pathological conditions. Endovascular stent-graft placement has become an accepted treatment option for complicated Stanford type B aortic dissection. Stent-graft deployment aims to cover the primary entry, preventing most of the inflow to the false lumen, thereby promoting false lumen thrombosis and true lumen expansion. In recent years the application of this treatment has increased continuously. However, a fast and reasonable prediction for the released stent-graft and the resulting aortic remodelling prior to intervention is still lacking. In this paper, we propose a preliminary study on the fast virtual stent-graft deployment algorithm based on contact mechanics, spring analogy and deformable meshes. By virtually releasing a stent-graft in a patient-specific model of an aortic dissection type Stanford B, we simulate the interaction between the expanding stent-graft and the vessel wall (with low computational cost), and estimate the post-interventional configuration of the true lumen. This preliminary study can be finished within minutes and the results present good consistency with the post-interventional computed tomography angiography. It therefore confirms the feasibility and rationality of this algorithm, encouraging further research on this topic, which may provide more accurate results and could assist in medical decision-making.
    Type of Publication: Journal article published
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  • 6
    Keywords: GROWTH-FACTOR ; WHITE-MATTER ; GENE-THERAPY ; MALIGNANT GLIOMAS ; NEURAL STEM-CELLS ; neurogenesis ; SUBVENTRICULAR ZONE ; ADULT HUMAN BRAIN ; PRECURSOR CELLS ; CELLULAR COMPOSITION
    Abstract: Data from transgenic mouse models show that neuronal progenitor cells (NPCs) migrate toward experimental brain tumors and modulate the course of pathology. However, the pathways whereby NPCs are attracted to CNS neoplasms are not fully understood and it is unexplored if NPCs migrate toward brain tumors (high-grade astrocytomas) in humans. We analyzed the tumor-parenchyma interface of neurosurgical resections for the presence of (NPCs) and distinguished these physiological cells from the tumor mass. We observed that polysialic acid neural cell adhesion molecule-positive NPCs accumulate at the border of high-grade astrocytomas and display a marker profile consistent with immature migratory NPCs. Importantly, these high-grade astrocytoma-associated NPCs did not carry genetic aberrations that are indicative of the tumor. Additionally, we observed NPCs accumulating in CNS metastases. These metastatic tumors are distinguished from neural cells by defined sets of markers. Transplanting murine glioma cells embedded in a cell-impermeable hollow fiber capsule into the brains of nestin-gfp reporter mice showed that diffusible factors are sufficient to induce a neurogenic reaction. In vitro, vascular endothelial growth factor (VEGF) secreted from glioma cells increases the migratory and proliferative behavior of adult human brain-derived neural stem and progenitor cells via stimulation of VEGF receptor-2 (VEGFR-2). In vivo, inhibiting VEGFR-2 signaling with a function-blocking antibody led to a reduction in NPC migration toward tumors. Overall, our data reveal a mechanism by which NPCs are attracted to CNS tumors and suggest that NPCs accumulate in human high-grade astrocytomas.
    Type of Publication: Journal article published
    PubMed ID: 24170295
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  • 7
    Abstract: Importance: The current staging system of gastric cancer is not adequate for defining a prognosis and predicting the patients most likely to benefit from chemotherapy. Objective: To construct a survival prediction model based on specific tumor and patient characteristics that enables individualized predictions of the net survival benefit of adjuvant chemotherapy for patients with stage II or stage III gastric cancer. Design, Setting, and Participants: In this multicenter retrospective analysis, a survival prediction model was constructed using data from a training cohort of 746 patients with stage II or stage III gastric cancer who satisfied the study's inclusion criteria and underwent surgery between January 1, 2004, and December 31, 2012, at Nanfang Hospital in Guangzhou, China. Patient and tumor characteristics were included as covariates, and their association with overall survival and disease-free survival with and without adjuvant chemotherapy was assessed. The model was internally validated for discrimination and calibration using bootstrap resampling. To externally validate the model, data were included from a validation cohort of 973 patients with stage II or stage III gastric cancer who met the inclusion criteria and underwent surgery at First Affiliated Hospital in Guangzhou, China, and at West China Hospital of Sichuan Hospital in Chendu, China, between January 1, 2000, and June 30, 2009. Data were analyzed from July 10, 2016, to September 1, 2016. Main Outcomes and Measures: Concordance index and decision curve analysis for each measure associated with postoperative overall survival and disease-free survival. Results: Of the 1719 patients analyzed, 1183 (68.8%) were men and 536 (31.2%) were women and the median (interquartile range) age was 57 (49-66) years. Age, location, differentiation, carcinoembryonic antigen, cancer antigen 19-9, depth of invasion, lymph node metastasis, and adjuvant chemotherapy were significantly associated with overall survival and disease-free survival, with P 〈 .05. The survival prediction model demonstrated good calibration and discrimination, with relatively high bootstrap-corrected concordance indexes in the training and validation cohorts. In the validation cohort, the concordance index for overall survival was 0.693 (95% CI, 0.671-0.715) and for disease-free survival was 0.704 (95% CI, 0.681-0.728). Two nomograms and a calculating tool were built on the basis of specific input variables to estimate an individual's net survival gain attributable to adjuvant chemotherapy. Conclusions and Relevance: The survival prediction model can be used to make individualized predictions of the expected survival benefit from the addition of adjuvant chemotherapy for patients with stage II or stage III gastric cancer.
    Type of Publication: Journal article published
    PubMed ID: 28538950
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  • 8
    Abstract: Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (alpha-KG) generating carbon dioxide and NADPH/NADH. Evidence suggests that the specific mutations in IDH1 are critical to the growth and reproduction of some tumor cells such as gliomas and acute myeloid leukemia, emerging as an attractive antitumor target. In order to discovery potent new mutant IDH1 inhibitors, we designed, synthesized and evaluated a series of allosteric mIDH1 inhibitors harboring the scaffold of 3-pyrazine-2-yl-oxazolidin-2-ones. All tested compounds effectively suppress the D-2-hydroxyglutarate (D-2-HG) production in cells transfected with IDH1-R132H and IDH1-R132C mutations at 10muM and 50muM. Importantly, compound 3g owns the similar inhibitory activity to the positive agent NI-1 and shows no significant toxicity at the two concentrations. The parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) identified 3g with a good ability to penetrate the blood-brain barrier (BBB). These findings indicate that 3g deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers.
    Type of Publication: Journal article published
    PubMed ID: 29089260
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  • 9
    Abstract: IDH1 mutation (mIDH1) occurs in 20-30% of gliomas and is a promising target for the cancer therapy. In this article, a cross docking-based virtual screening was employed to identify seven small molecules for the allosteric site of mIDH1. Compounds ZX01, ZX05 and ZX06 exhibited the potent inhibitory activity and the high selectivity against WT-IDH1, providing a good starting point for the further development of highly selective mIDH1 inhibitors. Importantly, the parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) identified ZX06 with a good ability to penetrate BBB. These findings indicate that ZX06 deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers.
    Type of Publication: Journal article published
    PubMed ID: 29290542
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  • 10
    Keywords: APOPTOSIS ; EXPRESSION ; IONIZING-RADIATION ; tumor ; CELL ; IN-VIVO ; PATHWAYS ; GENE ; GENES ; PROTEIN ; MICE ; radiation ; RESPONSES ; DNA ; BINDING ; BIOLOGY ; fibroblasts ; PHOSPHORYLATION ; TARGET ; MOUSE ; MUTATION ; p53 ; DAMAGE ; acetylation ; DNA-BINDING ; DNA-DAMAGE ; transactivation ; P53 PROTEIN ; DAMAGE-INDUCED PHOSPHORYLATION ; DEGRADATION ; KNOCK-IN MICE ; MDM2 ; RECRUITMENT ; SERINE-15
    Abstract: Phosphorylation of mouse p53 at Ser(18) occurs after DNA damage. To determine the physiological roles of this phosphorylation event in p53-dependent DNA damage responses, a Ser(18) to Ala missense mutation was introduced into the germline of mice. Thymocytes and fibroblasts from the knock-in mice show reduced transactivation of many p53 target genes following DNA damage. p53 protein stabilization and DNA binding are similar in knock-in and wild type mice, but C-terminal acetylation was defective, consistent with a role for Ser(18) in the recruitment of transcriptional co-activators. The apoptotic response of knock-in thymocytes to ionizing radiation is intermediate between that of wild type and p53 null thymocytes. Despite impaired transcriptional and apoptotic responses, the knock-in mice are not prone to spontaneous tumorigenesis. This indicates that neither phosphorylation of p53 on Ser(18) by ATM nor a full transcriptional response is essential to prevent spontaneous tumor formation in mice
    Type of Publication: Journal article published
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