scholarly journals EPEN-20. EZHIP/CATACOMB COOPERATES WITH PDGF-A AND p53 LOSS TO GENERATE A GENETICALLY ENGINEERED MOUSE MODEL FOR POSTERIOR FOSSA A EPENDYMOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii311-iii311
Author(s):  
Emily Kagan ◽  
Daniel Brat ◽  
Ali Shilatifard ◽  
Andrea Piunti ◽  
Oren Becher
Keyword(s):  
Median Survival ◽  
Critical Role ◽  
Pediatric Brain Tumor ◽  
Genetically Engineered ◽  
Rank Test ◽  
Loss Of Function ◽  
Wild Type ◽  
Term Survival ◽  
Log Rank Test ◽  
Genetically Engineered Mouse Model

Abstract BACKGROUND PFA ependymoma is a pediatric brain tumor with only 30% long-term survival. Recently a gene called CXORF67/EZHIP/CATACOMB (henceforward: CATACOMB) was found to be overexpressed in PFA ependymoma. CATACOMB’s mechanism of action has been found to be analogous to that of the H3K27M mutation as its expression reduces H3K27me3 via inhibition of PRC2 catalytic activity. METHODS We infected NESTIN- or GFAP-expressing neonatal hindbrain progenitors with wild-type CATACOMB or a loss of function (LOF) point mutant (M406K), alone, with PDGFA, and with and without p53 deletion. RESULTS CATACOMB overexpression alone or with p53 loss was insufficient to induce tumorigenesis. CATACOMB overexpression with PDGFA and p53 loss was sufficient to induce tumorigenesis using either the LOF mutant (M406K) or the wild-type CATACOMB in both cells-of-origin. The histology appeared more ependymoma-like when CATACOMB was expressed in GFAP-expressing progenitors. Median survival for the model initiated in NESTIN progenitors was 99.5 days for the CATACOMB mutant (n=26) group and 61 days for the CATACOMB wild-type (n=28; log-rank test p=0.0033). Median survival for the model initiated in GFAP progenitors were 144 days for the CATACOMB mutant (n=19) group and 65 days for the CATACOMB wild-type (n=21; log-rank test is P<0.0013). Immunohistochemistry for H3K27me3 demonstrated that CATACOMB wild-type tumors had reduced H3K27me3 compared to CATACOMB mutant tumors. CONCLUSIONS Disrupting CATACOMB inhibitory activity toward PRC2 significantly increases survival in mice in both models, suggesting this activity plays a critical role in accelerating tumorigenesis. Ependymoma-like histology was more commonly observed in the model initiated in the GFAP-expressing progenitors.

scholarly journals DIPG-68. ALPHA-THALASSEMIA X-LINKED MENTAL RETARDATION PROTEIN (ATRX) LOSS-OF-FUNCTION IN A MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii300-iii300
Author(s):  
Chen Shen ◽  
David Picketts ◽  
Oren Becher
Keyword(s):  
Mouse Model ◽  
Pediatric Brain Tumor ◽  
High Grade Glioma ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Tumor Incidence ◽  
Loss Of Function ◽  
Nestin Expression ◽  
Genetically Engineered Mouse Model ◽  
Clinical Cases

Abstract Diffuse Intrinsic Potine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Previous discoveries have revealed that, DIPG harbors distinct genetic alterations, when compared with adult high-grade glioma (HGG) or even with non-DIPG pediatric HGGs. ATRX alteration is found in 9% of clinical cases of DIPG, and significantly overlaps with H3.3K27M mutation and p53 loss, the two most common genetic changes in DIPG, found in 80% and 77% clinical cases, respectively. Here we developed genetically engineered mouse model of brainstem glioma using the RCAS-Tv-a system by targeting PDGF-B overexpression, p53 loss, H3.3K27M mutation and ATRX loss-of function to Nestin-expression brainstem progenitor cells of the neonatal mouse. Specifically, we used Nestin-Tv-a; p53 floxed; ATRX heterozygous female and Nestin-Tv-a; p53 floxed; ATRX floxed male breeders, generated offsprings with ATRX loss of function (n=18), ATRX heterozygous females (n=6), and ATRX WT (n=10). Median survial of the three groups are 65 days, 88 days and 51 days, respectively. Also, ATRX null mice is lower in tumor incidence (44.4%), compared with ATRX WT (80%). We evaluated the pathological features of DIPG with or without ATRX alteration, RNA-seq is performed to identify differentially expressed genes between ATRX WT and loss-of-function. In conclution, this study generated the first genetically modified mouse model studying ATRX loss-of-function in DIPG, and suggested that ATRX loss-of-function in DIPG may slow down tumorigenesis and decrease tumor incidence.

scholarly journals MBRS-24. FUNCTIONAL CHARACTERIZATION OF IKBKAP/ELP1 AS A NOVEL SHH MEDULLOBLASTOMA PREDISPOSITION GENE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii402-iii403
Author(s):  
Jesus Garcia Lopez ◽  
Lena Kutscher ◽  
Marija Kojic ◽  
Brian Gudenas ◽  
Kyle Smith ◽  
...  
Keyword(s):  
Critical Role ◽  
Functional Characterization ◽  
Pediatric Brain Tumor ◽  
Genetically Engineered ◽  
Loss Of Function ◽  
Cell Degeneration ◽  
Functional Studies ◽  
Shh Pathway ◽  
Group 4 ◽  
Ribosome Pausing

Abstract Medulloblastoma (MB), a common malignant pediatric brain tumor, comprises at least four distinct molecular entities: WNT, SHH, Group 3, and Group 4. SHH-MB is driven by aberrant activation of the Sonic hedgehog (SHH) pathway in granule neuron progenitors (GNPs) and is associated with hereditary cancer predisposition syndromes including Li Fraumeni and Gorlin. We recently identified germline loss of function (LoF) mutations affecting IKBKAP/ELP1, the primary scaffolding subunit of the Elongator complex in a subset of SHH-MB patients. Germline ELP1 mutations account for ~15% of all pediatric SHH-MBs and position ELP1 as the most prevalent hereditary predisposition gene in MB. We genetically engineered Elp1 LoF in mouse GNPs to determine Elp1 function in cerebellar development and SHH-MB. Results of both mechanistic and phenotypic experiments demonstrate that GNPs harboring Elp1 loss exhibit ribosome pausing and protein aggregation, reinforcing the critical role of Elp1 in translational elongation and protein homeostasis. Further, we generated new transgenic mouse models mimicking germline ELP1 LoF mutations observed in SHH-MB patients. Elp1+/- transgenic mice exhibit purkinje cell degeneration and an increased DNA damage response. These mice are currently being evaluated for their capacity to recapitulate ELP1-associated SHH-MB. Additional analyses carried out on SHH-MB patient-derived xenografts showed that ELP1-mutant tumor cells specifically exhibit defects in tRNA biogenesis. Therefore, the function of ELP1 as a translational regulator is severely impaired in ELP1-mutant SHH-MBs. Our ongoing molecular and functional studies will provide important insights into the most common MB predisposition gene and will lay the foundation for future preclinical studies.

scholarly journals Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma

2021 ◽  
Author(s):  
Rebecca K Marcus ◽  
Sammy Ferri-Borgogno ◽  
Abdel Hosein ◽  
Wai Chin Foo ◽  
Bidyut Ghosh ◽  
...  
Keyword(s):  
Median Survival ◽  
Intrahepatic Cholangiocarcinoma ◽  
Genetically Engineered ◽  
Primary Hepatocellular Carcinoma ◽  
Allelic Loss ◽  
Loss Of Function ◽  
Hepatic Expression ◽  
Dismal Prognosis ◽  
Genetically Engineered Mouse Model

Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss of function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing Albumin-Cre mice bearing conditional alleles of mutant Kras and/or floxed Bap1, Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant KrasG12D alone (KA), bi-allelic loss of hepatic Bap1 (BhomoA), and heterozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhetKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhomoKA) devel-oped discrete foci of HCC and ICC. Further, the median survival of BhomoKA mice was significantly shorter at 24 weeks, when compared to median survival of ≥40 weeks in BhetKA mice and approximately 50 weeks in BhomoA and KA mice (p <0.001). Microarray analysis performed on liver tissue from KA and BhomoKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.

scholarly journals Management trends for anaplastic meningioma with adjuvant radiotherapy and predictors of long-term survival

2019 ◽  
Vol 46 (6) ◽  
pp. E4 ◽  
Author(s):  
Ahmad Alhourani ◽  
Zaid Aljuboori ◽  
Mehran Yusuf ◽  
Shiao Y. Woo ◽  
Eyas M. Hattab ◽  
...  
Keyword(s):  
Median Survival ◽  
Adjuvant Radiotherapy ◽  
Rank Test ◽  
Outcome Analysis ◽  
Adjuvant Radiation ◽  
Survival Curves ◽  
Term Survival ◽  
Long Term Survival ◽  
Log Rank Test

OBJECTIVEThe purpose of this study was to describe effects of adjuvant radiotherapy (RT) for anaplastic meningiomas (AMs) on long-term survival, and to analyze patient and RT characteristics associated with long-term survival.METHODSThe authors queried a retrospective cohort of patients with AM from the National Cancer Database (NCDB) diagnosed between 2004 and 2015 to describe treatment trends. For outcome analysis, patients with at least 10 years of follow-up were included, and they were stratified based on adjuvant RT status and propensity matched to controls for covariates. Survival curves were compared. A data-driven approach was used to find a biologically effective dose (BED) of RT with the largest difference between survival curves. Factors associated with long-term survival were quantified.RESULTSThe authors identified 2170 cases of AM in the NCDB between 2004 and 2015. They observed increased use of adjuvant RT in patients treated with higher doses. A total of 178 cases met the inclusion criteria for outcome analysis. Forty-five percent (n = 80) received adjuvant RT. Patients received a BED of 80.23 ± 16.6 Gy (mean ± IQR). The median survival time was not significantly different (32.8 months for adjuvant RT vs 38.5 months for no RT; p = 0.57, log-rank test). Dichotomizing the patients at a BED of 81 Gy showed maximal difference in survival distribution with a decrease in median survival in favor of no adjuvant RT (31.2 months for adjuvant RT vs 49.7 months for no RT; p = 0.03, log-rank test), but this difference was not significant after false discovery rate correction. Age was a significant predictor for long-term survival.CONCLUSIONSAMs are aggressive tumors that carry a poor prognosis. Conventional adjuvant RT improves local control. However, the effect of adjuvant radiation on overall survival is unclear. Further investigation into this area is warranted.

scholarly journals Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5709
Author(s):  
Rebecca Marcus ◽  
Sammy Ferri-Borgogno ◽  
Abdel Hosein ◽  
Wai Chin Foo ◽  
Bidyut Ghosh ◽  
...  
Keyword(s):  
Median Survival ◽  
Intrahepatic Cholangiocarcinoma ◽  
Genetically Engineered ◽  
Primary Hepatocellular Carcinoma ◽  
Allelic Loss ◽  
Loss Of Function ◽  
Hepatic Expression ◽  
Dismal Prognosis ◽  
Genetically Engineered Mouse Model

Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss-of-function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing Albumin-Cre mice bearing conditional alleles of mutant Kras and/or floxed Bap1, Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant KrasG12D alone (KA), bi-allelic loss of hepatic Bap1 (BhomoA), and heterozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhetKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhomoKA) developed discrete foci of HCC and ICC. Further, the median survival of BhomoKA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in BhetKA mice and approximately 50 weeks in BhomoA and KA mice (p < 0.001). Microarray analysis performed on liver tissue from KA and BhomoKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.

Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis

2021 ◽  
Author(s):  
Khoa Pham ◽  
Micah J Maxwell ◽  
Heather Sweeney ◽  
Jesse Alt ◽  
Rana Rais ◽  
...  
Keyword(s):  
Pediatric Brain Tumor ◽  
Glutamine Metabolism ◽  
Rank Test ◽  
Cell Penetration ◽  
Plasma Ratio ◽  
Log Rank Test ◽  
Naturally Occurring ◽  
Ongoing Development ◽  
Orthotopic Xenografts ◽  
Pediatric Brain

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Amplification of c-MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism across many types of cancer. We modified the naturally occurring glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) by adding 2 promoeities to increase its lipophilicity and brain penetration creating the prodrug isopropyl 6-diazo-5-oxo-2-(((phenyl (pivaloyloxy) methoxy) - carbonyl) amino) hexanoate, termed JHU395. This prodrug was shown to have a 10-fold improved CSF-to-plasma ratio and brain-to-plasma ratio relative to DON. We hypothesized that JHU395 would have superior cell penetration compared with DON and would effectively and more potently kill MYC-expressing medulloblastoma. JHU395 treatment caused decreased growth and increased apoptosis in multiple human high-MYC medulloblastoma cell lines at lower concentrations than DON. Parenteral administration of JHU395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain. Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p &lt; 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.

scholarly journals Oncological and functional outcomes of supratotal resection of IDH1 wild-type glioblastoma based on 11C-methionine PET: a retrospective, single-center study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Seiichiro Hirono ◽  
Ko Ozaki ◽  
Masayoshi Kobayashi ◽  
Ayaka Hara ◽  
Tomohiro Yamaki ◽  
...  
Keyword(s):  
Functional Outcomes ◽  
Awake Craniotomy ◽  
Rank Test ◽  
Wild Type ◽  
Log Rank Test ◽  
Positron Emission ◽  
Single Center Study ◽  
Supratotal Resection ◽  
Subcortical Mapping

AbstractThe oncological and functional outcomes in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-met positron emission tomography (Met-PET), are unknown. We conducted a retrospective review in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was resected. All patients underwent standard radiotherapy and temozolomide treatment, and were followed for tumor recurrence and overall survival (OS). Among the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median OS in the GTR and SupTR groups was 18.5 months (95% confidence interval [CI] 14.2–35.1) and not reached (95% CI 30.5-not estimable), respectively; this difference was statistically significant (p = 0.03 by log-rank test). No postoperative neurocognitive decline was evident in patients who underwent SupTR. Compared to GTR alone, aggressive resection of both CE tumors and areas with Met uptake (SupTR) under awake craniotomy with functional mapping results in a survival benefit associated with better local control and neurocognitive preservation.

scholarly journals Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer

PLoS ONE ◽  
2015 ◽  
Vol 10 (10) ◽  
pp. e0140253 ◽  
Author(s):  
Jamie D. Weyandt ◽  
Benjamin L. Lampson ◽  
Sherry Tang ◽  
Matthew Mastrodomenico ◽  
Diana M. Cardona ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Genetically Engineered ◽  
Wild Type ◽  
Genetically Engineered Mouse Model

Bioinformatics Analysis of The Expression of ATP Binding Cassette Transporters and The Screening of Regulatory Genes in PTEN/PI3K/Akt/mTOR Signaling Pathway in The Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Tingdan Zheng ◽  
Wuqi Song ◽  
Aiying Yang
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Bioinformatics Analysis ◽  
Wilcoxon Test ◽  
Rank Test ◽  
Short Term ◽  
Term Survival ◽  
Log Rank Test ◽  
Short Term Survival

Abstract Objective Here we performed the Bioinformatics analysis on the data from The Cancer Genome Atlas (TCGA), in order to find the correlation between the expression of ATP Binding Cassette (ABC) Transporters’ genes and hepatocellular carcinoma (HCC) prognosis; Methods Transcriptome profiles and clinical data of HCC were obtained from TCGA database. Package edgeR was used to analyze differential gene expression. Patients were divided into low-ABC expression and high-ABC expression groups based on the median expression level of ABC genes in cancer. The overall survival and short-term survival (n= 341) of the two groups was analyzed using the log-rank test and Wilcoxon test; Results We found that ABC gene expression was correlated with the expression of PIK3C2B (p<0.001, ABCC1: r=0.27; ABCC10: r=0.57; ABCC4: r=0.20; ABCC5: r=0.28; ABCB9: r=0.17; ABCD1: r=0.21). All patients with low-ABC expression showed significantly increased overall survival. Significantly decreased overall survival (Log-rank test: p<0.05, Wilcoxon test: p<0.05) was found in patients with high expression of ABCC1 (HR=1.58), ABCD1 (HR=1.45), ABCC4 (HR=1.56), and ABCC5 (HR=1.64), while decreased short-term survival (Log-rank test: p>0.05, Wilcoxon test: p<0.05) was correlated with the increased expression of ABCC10 (HR=1.29), PIK3C2B (HR=1.29) and ABCB9 (HR=1.23); Conclusions Our findings indicate that the specific ABC gene expression correlates with the prognosis of HCC. Therefore, ABC expression profile could be a potential indicator for HCC patients.

scholarly journals The relationship of the prolonged PR interval with the long-term survival in patients with heart failure undergoing cardiac resynchronization therapy

2020 ◽  
Vol 25 (1) ◽  
pp. 33-38
Author(s):  
A. M. Soldatova ◽  
V. A. Kuznetsov ◽  
T. P. Gizatulina ◽  
L. M. Malishevsky ◽  
S. M. Dyachkov
Keyword(s):  
Cardiac Resynchronization ◽  
Rank Test ◽  
Term Survival ◽  
Log Rank Test ◽  
Group I ◽  
Pr Interval ◽  
Qrs Duration ◽  
Group Ii ◽  
The Relationship

Aim. To assess the relationship between the prolonged PR interval (≥200 ms) and the long-term survival of patients undergoing cardiac resynchronization therapy (CRT).Material and methods. A total of 85 patients (mean age — 55,1Ѓ}9,9 years; men — 81,2%) with NYHA class II-IV heart failure (HF) were examined. The mean follow-up was 34,0Ѓ}21,2 months. Patients with PR<200 ms (n=52) made up group I, with PR≥200 ms (n=33) — group II. Then the patients were divided into subgroups depending on the QRS duration: ≥150 ms (n=33 in group I and n=14 in group II, respectively) <150 ms (n=19 in group I and n=19 in group II, respectively).Results. In patients of group II, a history of myocardial infarction (MI) was more often registered (p=0,005), left ventricular ejection fraction (LVEF) was lower (p=0,032). In a multivariate analysis, MI (OR 3,217; CI 95% 1,188-8,712; p=0,022) and LVEF value (OR 0,869; CI 95% 0,780-0,968; p=0,011) had a significant relationship with the PR interval prolongation (≥200 ms). The survival of patients of group I was 59,6%, group II — 18,2% (Log-rank test p<0,001). According to Cox regression model, the initial left ventricle end-systolic volume (OR 1,012; 95% CI 1,006-1,017; p<0,001), inferior wall MI (OR 1,690; 95% CI 1,131-2,527; p=0,011) and PR interval ≥200 ms (OR 2,179; 95% CI 1,213–3,915; p=0,009) were associated with long-term mortality. In patients with PR≥200 ms, survival rate was low, regardless of the QRS duration (21,4% in patients with QRS≥150 ms, 15,8% in patients with QRS<150 ms; Log-rank test p=0,698) In patients with PR<200 ms, the survival rate of patients with QRS≥150 ms was 72,7%, and for patients with QRS<150 ms — 36,8% (Log-rank test p=0,031).Conclusion. In HF patients, PR interval prolongation (≥200 ms) is associated with long-term mortality increase. The highest survival rates were observed in patients with PR<200 ms and QRS≥150 ms. In patients with QRS≥150 ms, the presence of PR≥200 ms should be considered as an additional criterion for CRT.

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