bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2490: R2: Genomics analysis and visualization platform
Authors: Koster Jan , Volckmann Richard , Zwijnenburg Danny , Molenaar Piet , Versteeg Rogier 
Published: August 2019

Abstract
Given the complexity, omics data like RNA-seq are often analyzed by bioinformaticians, and not the wetlab researchers that performed the experiments. With the biomedical researcher (with limited or no bioinformatics skills) in mind as the end-user, we developed the user-friendly, publicly accessible R2 platform (http://r2.amc.nl), enabling biomedical scientists to work with their own data from anywhere at any time. R2 (cited in &gt;850 peer-reviewed scientific publications) consists of an omics database, coupled to an extensive set of interactive tools to analyze/visualize the datasets. Interactive analyses within the software are highly connected, allowing quick navigation between various aspects of the datamining process. Besides password protected private data, R2 also contains an extensive body of publicly available omics data, enabling users to relate their findings to other diseases / tissues, or as validation in integrative analyses. Next to gene expression (bulk as well as single cell), R2 is also being employed for the integration, analysis and visualization of copynumber, SNP, methylation, miRNA, drug response, ChIP-seq, and NGS exome/WGS DNA sequencing data. Analyses include correlation, differential expression, gene sets, gene ontology, transcription factor binding sites, tSNE, PCA, k-means, Kaplan Meier survival scans, signature creation etc. Visualizations include various gene oriented plots, heatmaps, Circos plots, embedded genome browser, Venn diagrams, etc. The real power of the platform lies in the chaining of results of analyses; e.g. the results of a differential expression analysis can be further trimmed down using a Kaplan Meier analysis that in turn can be used for a Gene Ontology over-representation analysis. Furthermore, the webserver allows for overviews across different datasets (such as MegaSampler and 2D distribution), where a user can harness the power of thousands of measurements. Recently, integrated analyses for personalized medicine, where copy number, mRNA expression, methylation and mutation data are combined into a comprehensive overview, occasionally supplemented with PDX/organoid drug response data. These serve clinical decision making for a patient, but as growing cohorts also form a treasure trove for scientific discovery. R2 provides a central starting point from where data mining and analysis paths can be followed within one environment. Data/analyses can be shared between R2-users via our community options, making R2 an outstanding environment for discovery, hypothesis testing and scientific collaboration.
Citation Format: Jan Koster, Richard Volckmann, Danny Zwijnenburg, Piet Molenaar, Rogier Versteeg. R2: Genomics analysis and visualization platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2490.
Abstract 252: Tumor treating fields (TTFields) affect blood brain barrier (BBB) integrity in vitro and in vivo
Authors: Kessler Almuth F. , Schaeffer Clara M. , Burek Malgorzata , Ruschig Ursula , Tempel-Brami Catherine , Voloshin Tali , Giladi Moshe , Salvador Ellaine , Ernestus Ralf-Ingo , Löhr Mario , Förster Carola , Hagemann Carsten 
Published: August 2019

Abstract
Background: The blood-brain barrier (BBB) may impede application of drugs to the brain for treatment of malignant brain tumors, in particular glioblastoma multiforme (GBM). Alternating electric fields with intermediate frequency and low intensity, called Tumor Treating Fields (TTFields), are an established novel adjuvant treatment modality for GBM. Here, the effect of TTFields on BBB permeability is analyzed.
Material and Methods: After TTFields treatment with a frequency of 100-300 kHz for up to 72 h, immortalized murine brain capillary endothelial cells (cerebEND) grown on cover slips and transwell inserts were stained for immunofluorescent assessment of the tight junction proteins Claudin-5 and ZO-1. Transendothelial electrical resistance (TEER) was applied to investigate BBB integrity. Moreover, BBB permeability was determined by fluorescein isothiocyanate (FITC) staining followed by flow cytometry. For in vivo analysis, the increase in vessel permeability was quantified by utilizing i.v. injected Evans Blue (EB) in rats during TTFields application to the brain (100 kHz, 72 h).
Results: The BBB was disturbed by treatment with TTFields as tight junction proteins were delocalized from the cell boundaries to the cytoplasm with maximal effects at 100 kHz. TTFields application significantly reduced the BBB integrity by 65% and significantly increased the BBB permeability for 4 kDa large molecules. Initial recovery of the cell morphology was observed 48 h post-treatment and a complete recovery could be detected after 96 h, indicating a reversibility of the TTFields effect on the BBB. Average accumulation of EB in the rat brain was significantly increased by TTFields application to the rats head.
Conclusion: In the future, TTFields could be utilized to deliver drugs generally unable to cross the BBB to the central nervous system as TTFields at a frequency of 100 kHz are potentially able to disrupt the BBB. The data presented on in vitro and in vivo application of TTFields to permeabilize the BBB may be a rationale for a phase I clinical trial and clinical application in the future.
Citation Format: Almuth F. Kessler, Clara M. Schaeffer, Malgorzata Burek, Ursula Ruschig, Catherine Tempel-Brami, Tali Voloshin, Moshe Giladi, Ellaine Salvador, Ralf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann. Tumor treating fields (TTFields) affect blood brain barrier (BBB) integrity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 252.
Abstract 253: Protein-tyrosine phosphatase 1B (PTP1B) as a therapeutic target in glioblastoma
Authors: Bartolomé Ruben , Jaén Marta , Burdiel Miranda , Balyasnikova Irina V. , Casal Ignacio 
Published: August 2019

Abstract
New targeted therapies are urgently needed in glioblastoma (GBM). IL13Rα2 receptor is considered a highly specific receptor for GBM cells and has been proposed for therapeutic purposes. Here, we aimed to identify the protein interaction network of IL13Rα2 and its mediators in GBM searching for novel associated therapeutic targets.
We investigated the IL13Rα2 protein interaction network in U251 GBM cells using immunoprecipitation followed by mass spectrometry. Different cell lines were used for validation. Two glioblastoma cell lines were used for testing proliferation, adhesion, migration and invasion. Claramine, a PTP1B inhibitor, was tested to study inhibition of GBM cells growth in cultured cells and in animal experiments. In vivo experiments with NSG mice were performed after treatment with PTP1B inhibitors.
Using a proteomic approach, we identified the association of the PTP1B phosphatase with IL13Rα2 in U251 GBM cells. Although GBM cell lines were positive for PTP1B, the highest PTP1B expression was found in GBM clinical samples. Moreover, “in silico” dataset analysis showed PTP1B association with poor outcome in GBM patients. PTP1B silencing inhibited the IL-13-promoted activation of Src (Tyr419), AKT and ERK1/2 in all the cell lines tested causing a significant effect on IL-13-mediated migration and invasion, and proliferation at a lower extent, of GBM cells. Therefore, PTP1B-silencing reverted most of the pro-metastatic capacities of the IL-13/ IL13Rα2 signaling axis. Further immunoprecipitation of PTP1B showed its association with a large number of NF-κB and NOTCH-related proteins in GBM cells. Both pathways are highly relevant for cancer proliferation and invasion. Claramine, a selective inhibitor of PTP1B, caused similar results to PTP1B silencing, inhibiting the dephosphorylation of Src Tyr527, migration and invasion in GBM. Moreover, treatment with Claramine caused a complete regression of GBM xenografts in NSG mice and total inhibition of liver metastatic growth in nude mice inoculated with colorectal cancer cells.
In conclusion, our results provide new insights into the mechanisms underlying IL13Rα2-driven GBM aggressiveness after identifying PTP1B as a critical mediator of IL-13/IL13Rα2 signaling. A PTP1B inhibitor such as Claramine showed a great value as a therapeutic candidate in GBM. PTP1B inhibitors might be highly effective to prevent GBM progression and invasion.
Citation Format: Ruben Bartolomé, Marta Jaén, Miranda Burdiel, Irina V. Balyasnikova, Ignacio Casal. Protein-tyrosine phosphatase 1B (PTP1B) as a therapeutic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 253.
Abstract 2531: Genomic landscape of breast cancer patients in Korea: Early data from K-MASTER project
Authors: Sung Jae Sook , Chung Hee-Joon , Choi Yoon Ji , Chang Won Jin , Choi Jung Yoon , Kim Ju Won , Park Kyong Hwa , Kim Yeul Hong 
Published: August 2019

Abstract
The K-MASTER cancer precision medicine diagnosis and treatment enterprise (K-MASTER project) is a precision medicine cancer treatment clinical trial platform, which uses NGS assay to screen the actionable mutations in 10,000 patients with refractory solid tumors and assigns the patients to matched treatment. K-MASTER project was initiated in Korea since June 2017. From October 2017, we have analyzed next-generation (NGS)-based cancer panel to detect cancer genomic variations in breast cancer. This study is ongoing with 36 sites. Tumor DNA was analyzed by CancerSCAN (Samsung Genomic Institute) which allows to detect variations of 375 genes. As of October 31 in 2018, total 164 breast cancer patients were submitted and 95 samples were analyzed. The failure rate of sequencing was 4.1% of patients with samples submitted. The mean depth of CancerSCAN was 701x. Average turn-around time (TAT) of CancerSCAN was 3 weeks.In Korean breast cancer patients, variations were mainly identified in TP53 (63.6%), PIK3CA (35.2%), BRCA1 (25.0%), BRCA2 (23.9%), ERBB2 (23.9%), PTCH1 (21.6%), NOTCH1 (19.3%), FGFR1 (12.5%), PTEN (11.4%) and MET (9.1%). Further analysis will confirm amplification and deletion in breast cancer. Until March 2019, we will finish the genomic profiling of 350 breast cancer patients and will be reported. In conclusion, this project is efficient to detect actionable variations in breast cancer. This novel knowledge provides an intriguing background to investigate new target approaches and to progress precision medicine. (This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206).)
Citation Format: Jae Sook Sung, Hee-Joon Chung, Yoon Ji Choi, Won Jin Chang, Jung Yoon Choi, Ju Won Kim, Kyong Hwa Park, Yeul Hong Kim. Genomic landscape of breast cancer patients in Korea: Early data from K-MASTER project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2531.
Abstract 2533: The genomic and transcriptomic landscape of left versus right sided breast cancer in 410 cases
Authors: Newton Yulia , Szeto Christopher , Vaske Charles , Reddy Leia , Reddy Sandeep 
Published: August 2019

Abstract
Background: Studies have shown that unilateral breast cancer is more common on the left (L) than right (R) and that the L breast is often larger than the R. No clear explanation for this finding has been described in the literature. Hypotheses range from complex genomic effects to environmental, hormonal, and anatomical causes.
Methods: We performed a retrospective analysis of data from the NantHealth database of 410 commercial cases where WGS (35x germline, 75x somatic) or WES (∼150x). Primary and metastatic breast tumors were included in the analysis. Of these 410 cases, 39.3% were R, 38.5% were L, and 22% were unspecified. Bases adjacent to variant sites were used to determine genomic context (i.e. mutation signatures) as previously reported. Additionally, paired deep whole transcriptomic sequencing (RNA-Seq; ∼200x106 reads per tumor) was performed on 376 of the 410 cases. Nant Breast Cancer Intrinsic Subtypes sorting based on RNAseq assay classified breast tumors into 4 subtypes (LumA/B, Basal-like, and HER2-enriched).
Results: Luminal A subtype was significantly overrepresented in R v L (OR=0.53, p=0.015). Similarly, R-side cases were significantly enriched for estrogen response gene expression by GSEA. However, only slight differential expression of ESR1 and MKI67 was observed specifically in individuals between 40 and 50 years old. Germline variants in the following genes were associated with sidedness: MEN1, KIT, JAK2, TET2, EP300, MET, FLCN, and KMT2D, and somatic variants within the following genes were associated with sidedness: CACNA1E, AGRN, RIMS2, TTYH3, KRTAP10-6, and DDX60L. However, significance of the variant frequency differences was lost after multiple-hypothesis correction. No significant differences between L and R were noted in tumor stage, HER2, ER, PR, somatic CNV, and mutation signatures, including signature 3 (BRCAness).
Conclusions: Despite performing WGS/WES a paucity of differentially mutated genes were seen between left and right sided breast tumors. RNAseq analysis reveals that right sided breast cancers may be more likely to involve ESR1-signaling and be Luminal A subtype. Right-sided ESR1-signaling may be especially relevant in perimenopausal cases, however the current cohort is underpowered to achieve significance in this analysis.
Citation Format: Yulia Newton, Christopher Szeto, Charles Vaske, Leia Reddy, Sandeep Reddy. The genomic and transcriptomic landscape of left versus right sided breast cancer in 410 cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2533.
Abstract 2538: p53 activation induces cell cycle arrest by promoting DREAM and RB repression of cell cycle genes
Authors: Schade Amy E. , Fischer Martin , DeCaprio James A. 
Published: August 2019

Abstract
p53 activation results cell cycle arrest at the G1/S checkpoint and the repression of early (G1/S) and late (G2/M) cell cycle gene expression in a p21 dependent manner. The mechanism how p53 and p21 repress cell cycle gene expression is unclear. p21 is known to repress CDK2 which is a key inhibitor of the pocket protein family members RB and p130. During a normal cell cycle, p130 as part of the DREAM complex (DP1, RB-like p130, E2F4, and MuvB) and RB cooperate to repress expression of early (G1/S) and late (G2/M) cell cycle gene expression. DREAM binds and represses late (G2/M) cell cycle promoters through MuvB binding and early (G1/S) cell cycle promoters though repressor E2F binding. RB is only able to bind and repress early (G1/S) cell cycle promoters through its interaction with activator E2Fs. The requirement for DREAM and RB for control of cell cycle gene expression after p53 activation was unknown. We hypothesized that DREAM and RB would cooperate to repress cell cycle gene expression after DNA damage. Using primary human foreskin fibroblast cells lacking RB and/or p130, we found repression of early and late cell cycle gene expression is differentially regulated after p53 activation. We found that while RB is required for repression of early (G1/S) cell cycle genes after p53 activation, DREAM is required for repression of expression of late (G2/M) cell cycle genes. Surprisingly, DREAM was unable to repress early cell cycle genes after p53 activation, suggesting that RB is the key regulator of G1/S gene expression during cellular stress like DNA damage. Further, the requirement for DREAM to repress late cell cycle gene expression underlies the importance of DREAM to prevent expression of mitosis inducing genes in a state like DNA damage when mitosis could result in propagation of mutated DNA. We found that p107, a protein reported be able to replace p130 in DREAM, does not potently repress early cell cycle genes in HFFs under contact arrest and serum starvation. However, we found that p107 strongly represses expression of late cell cycle genes during G0 in cells lacking p130 alone or in combination with RB. These data provide evidence for a specific role for p107-DREAM not previously appreciated. Together, our data show that control of cell cycle gene expression after p53 activation is split in two: RB represses early cell cycle genes while DREAM represses late cell cycle genes.
Citation Format: Amy E. Schade, Martin Fischer, James A. DeCaprio. p53 activation induces cell cycle arrest by promoting DREAM and RB repression of cell cycle genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2538.
Abstract 254: Discovery of dual inhibitors of NQO1 and GSTP1 for malignant glioblastoma treatment
Authors: Lei Kecheng , Luo Shilin , Jin Lingjing , Ye Keqiang 
Published: August 2019

Abstract
Glioblastoma (GBM) is a highly aggressive form of neoplasia due to its frequently overexpressed or mutant epidermal growth factor receptor (EGFR). NADPH quinone Oxydoreductase1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 are enzymes with dual roles that decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and GBM cell proliferation. To search for a small molecule that blocks the malignant cancer proliferation, we conducted a high-throughput Screening (HTS) and identified a small molecule inhibitor (5-methyl-N-(nitro-1,3-thiazol-2-yl)-3-phenylisoxazole-4-carboxamide) as “HIT” that binds to both NQO1 and GSTP1 with high affinity and selectivity. The “HIT” blocks NQO1 and GSTP1 enzyme activity and mediates apoptosis in GBM via caspase activation. Inactivation of NQO1 and GSTP1 with siRNA or HIT resulted in imbalanced redox homeostasis, leading to mitigated cancer cell proliferation in vitro and in vivo. Thus, optimization of “HIT”, the dual NQO1 and GSTP1 inhibitor, may provide a novel strategy to antagonizing GBM.
Citation Format: Kecheng Lei, Shilin Luo, Lingjing Jin, Keqiang Ye. Discovery of dual inhibitors of NQO1 and GSTP1 for malignant glioblastoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 254.
Abstract 2544: Overexpression of the Polo-like kinase 4 (PLK4) contribute to tumor metastasis
Authors: Fung Yeung Sai , Ching Yick Pang 
Published: August 2019

Abstract
The Polo-like kinase 4 (PLK4) is an important mitotic kinase that lies at the head of centriole duplication pathway. Aberration of PLK4's level in cancer cell often results in supernumery centrosome. PLK4 transcripts was upregulated in a number of cancers including breast, colon gastric and lung cancer, and PLK4 overexpression had been linked to chemoresistance and cancer metastasis. In our preliminary data, knocking down PLK4 in 97L and HLE Hepatocellular Carcinoma (HCC) cell reduced their migration and growth rate. Overexpression of PLK4 in well-differentiated hepatoma HepG2 and Huh7 cell showed enhancement in migration. Centrinone B, a highly potent PLK4 inhibitor, inhibits HCC cells' colony-forming ability and wound healing rate. To gain the insight into the mechanism how PLK4 contribute to cell migration, microtubule regrowth assay was carried out. The results indicating that PLK4 overexpressing cell had a higher rate of microtubule nucleation, which could contribute to directional movement of the cell. Further supporting that PLK4 contribute to HCC progression, we look into the clinical samples. Using qRT-PCR, we found PLK4 transcript is upregulated in a local cohort of HCC samples (n=48), we also confirmed that PLK4 is upregulated in the TCGA and two GEO available datasets. Data from the cancer dependency map showed PLK4 is a common essential gene in a panel of HCC cell line. Suggesting targeted therapy against PLK4 might be useful in reducing tumor growth or metastasis.
Citation Format: Yeung Sai Fung, Yick Pang Ching. Overexpression of the Polo-like kinase 4 (PLK4) contribute to tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2544.
Abstract 2545: Nek2 and other mitotic kinases are downstream of the E2F activators, and may modulate the epithelial-to-mesenchymal transition in breast cancer
Authors: Rivera-Rivera Yainyrette , Marina Mihaela , Saavedra Harold I. 
Published: August 2019

Abstract
The E2F transcription factors have been extensively studied in cancer since they are known for their role in the regulation of cell cycle progression, centrosome duplication, cell survival, and other functions. We recently demonstrated that the E2F activators (E2F1, E2F2, and E2F3) regulate mitosis through the elevated expression of multiple mitotic proteins including Sgo1, Nek2, Hec1, BubR1, and Mps1. We have shown that Mps1 triggers EMT through multiple mechanisms. NIMA-related kinase 2 (Nek2) is a centrosome-associated protein kinase particularly abundant in cells during the G2-M phase, which primary function is to phosphorylate centrosome linker proteins to cause centrosome disjunction and the formation of the bipolar mitotic spindle. Previous results from our lab showed that overexpression of Nek2 in HCC1954 (Her2+ breast cancer cell line) with a knock down for E2F3 rescued a high centrosome amplification pattern and enhances the formation of invasive protrusions. cBioportal analysis using the TCGA database showed Nek2 mRNA alterations in 9.1% of breast cancer patients and is predominantly present in tumors that are ER-, PR-, and Her2- (25%). Similarly, analysis using the METABRIC database showed Nek2 mRNA alterations in 6.1% of breast cancer patients and is predominantly present in tumors from basal (24%), Her2+ (10%), and luminal B (13.9%) subtypes. Based on these results, we hypothesize that Nek2 overexpression has a role in the epithelial-to-mesenchymal (EMT) pathway leading to cell migration and invasion as prelude to metastasis in breast cancer. To address this, we used MCF10A non-tumorigenic mammary cells with or without the overexpression of Nek2 (MCF10A/GFP and MCF10A/GFP-Nek2). Our preliminary data indicates that overexpression of GFP-Nek2 in mammary epithelial cells enhances levels of vimentin, whereas decreased the levels of E-cadherin, suggesting a role of Nek2 in a mesenchymal state. Likewise, siRNA-mediated silencing of Nek2 in mesenchymal breast cancer cells modulates markers of EMT. Because inhibitors are available for Nek2, it would be feasible to target this kinase to combat metastatic HR- breast cancers. Our work will allow the identification of mechanistic molecular pathways influenced by Nek2 role in driving invasion and metastasis to highlight this mitotic kinase as a potential prognostic marker for high-risk breast tumors.
Citation Format: Yainyrette Rivera-Rivera, Mihaela Marina, Harold I. Saavedra. Nek2 and other mitotic kinases are downstream of the E2F activators, and may modulate the epithelial-to-mesenchymal transition in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2545.