tbuckley/cabot-search huggingface dataset:
Abstract 5215: Time dependent blood-brain barrier modulation by vascular endothelial growth factor to improve CNS drug delivery
Authors: Matthew McCord
Journal: Cancer Research (2017)

Abstract Introduction: Efforts to transiently increase blood brain barrier permeability would facilitate improved CNS delivery of chemotherapy agents. Previous studies demonstrated that vascular endothelial factor (VEGF) increases permeability in traumatic brain injury and ischemic brain disease. Exogenously administered VEGF increases barrier permeability in the non-diseased CNS. In our study, we investigated the role for exogenous VEGF therapy to modulate blood-brain barrier permeability Methods: For in vitro studies, confluent mouse brain endothelial cells (BEND.3) were treated with VEGF165. Trans-endothelial electrical resistance measured cell impedance changes and immunofluorescence was used to assess qualitative expression of tight and adherens junction proteins at key time points. Western blotting and qPCR were done to evaluate the effect of VEGF on expression of protein and RNA associated with tight and adherens junctions. Results: Confluent endothelial cells treated with rVEGF165 (200ng/mL) evaluated by TEER show a significant drop in cell impedance approximately 6 hours post treatment, compared to control (more than 10-fold) reflecting increased permeability of the monolayer. Treatment with progressively higher doses of VEGF (200, 400, and 600ng/mL) showed a progressively greater drop in cell impedance. Immunofluorescence of endothelial cells treated with rVEGF165 (200ng/mL) shows disassembly of both tight junctions and adherens junctions between 4 and 8 hours post-treatment compared to controls. Western blots and qPCR demonstrate that rVEGF165 treatment induces down-regulation of genes associated with tight junctions, such as Claudin5, beginning as early as 4 hours post treatment and continuing up to 24 hours post treatment. Conclusion: Our results suggest that VEGF is capable of inducing transient breakdown of the blood-brain barrier, which may facilitate improved CNS delivery of chemotherapeutic agents. Our in vitro data warrants further investigations of the applicability of VEGF therapy to induce endothelial cell permeability in animal tumor models, potentially improving delivery of chemotherapeutic drugs. Citation Format: Matthew McCord. Time dependent blood-brain barrier modulation by vascular endothelial growth factor to improve CNS drug delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5215. doi:10.1158/1538-7445.AM2017-5215
Abstract 980: BAY-299, a novel chemical probe for in-depth analysis of the function of the bromodomain proteins BRPF2 and TAF1
Authors: Lea Bouche, Clara D. Christ, Stephan Siegel, Cynthia Tallant, Amaury E. Fernández-Montalván, Kilian V. Huber, Verra Pütter, Susanne Müller, Oleg Fedorov, Antonius ter Laak, Tatsuo Sugawara, Detlef Stöckigt, Julia Meier, Simon J. Holton, Ingo V. Hartung, Bernard Haendler
Journal: Cancer Research (2017)

Abstract With the exception of the bromodomain and extra-terminal domain BET subgroup, little is known about the role of bromodomain (BD) containing proteins in cancer so that there is a dire need for chemical probes addressing other family members. The bromodomain and PHD-finger (BRPF) family encompasses three paralogs, BRPF1, BRPF2 and BRPF3, which are all found in histone acetyltransferase (HAT) complexes. BRPF2 is a scaffold protein and its knock-out leads to embryonic lethality at E15.5, potentially due to its role in embryonic stem cell differentiation. Here we present the structure-activity relationship (SAR) and characterization of the first selective BRPF2 chemical probe BAY-299, with additionnal strong activity at TAF1, a major component of the basal transcription initiation complex TFIID. BAY-299 shows in vitro activity for BRPF2 (IC50 = 67 nM) and TAF1 second bromodomain (BD2; IC50 = 8 nM) in the TR-FRET assay, as well as in the cellular NanoBRET assay [IC50 (BRPF2) = 575 nM; IC50 (TAF1 BD2) = 825 nM]. To the best of our knowledge BAY-299 is the only disclosed inhibitor showing BRPF2 selectivity over its two paralogues BRPF1 and BRPF3. It belongs to the 1,3-benzimidazolone scaffold and bears a novel substitution which is responsible for its high BRPF2 selectivity and also for its inactivity on BET BDs. The dual inhibitory properties of BAY-299 against BRPF2 and TAF1 make it an ideal research tool for further investigation of these two proteins in physiological and pathological processes. Citation Format: Lea Bouche, Clara D. Christ, Stephan Siegel, Cynthia Tallant, Amaury E. Fernández-Montalván, Kilian V. Huber, Verra Pütter, Susanne Müller, Oleg Fedorov, Antonius ter Laak, Tatsuo Sugawara, Detlef Stöckigt, Julia Meier, Simon J. Holton, Ingo V. Hartung, Bernard Haendler. BAY-299, a novel chemical probe for in-depth analysis of the function of the bromodomain proteins BRPF2 and TAF1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 980. doi:10.1158/1538-7445.AM2017-980
Abstract 4063: Design and synthesis of indole derivatives as ABCG2 mediated resistance reversal agents
Authors: Chao-Yun Cai, Hong Zhai, Zi-Ning Lei, Bao-Li Chen, Zhao-Yi Du, Yun-Kai Zhang, Yi-Jun Wang, Bo Wang, Zhe-Sheng Chen
Journal: Cancer Research (2017)

Abstract Multidrug resistance is a phenomenon that cancer cells become resistant to anticancer drugs. Multidrug resistance has been shown to be related with the overexpression of ATP-binding (ABC) transporters, including ABCG2. Therefore, ABCG2 is a therapeutic target for the development of multidrug resistance reversal agents. Fumitremorgin C, with an indole group which is an important pharmacophore in many drugs, is a known ABCG2 inhibitor. Inspired by this, we synthesized two series of indole derivatives as ABCG2 mediated resistance reversal agents. With MTT assay, we found that two compounds from the two series of indole derivatives respectively exhibited good reversal activity against ABCG2. The two compounds did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines and they stimulated the basal ATP hydrolysis of ABCG2. Citation Format: Chao-Yun Cai, Hong Zhai, Zi-Ning Lei, Bao-Li Chen, Zhao-Yi Du, Yun-Kai Zhang, Yi-Jun Wang, Bo Wang, Zhe-Sheng Chen. Design and synthesis of indole derivatives as ABCG2 mediated resistance reversal agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4063. doi:10.1158/1538-7445.AM2017-4063
Matuzumab and cetuximab activate the epidermal growth factor receptor but fail to trigger downstream signaling by akt or erk
Authors: Takeshi Yoshida, Isamu Okamoto, Takafumi Okabe, Tsutomu Iwasa, Taroh Satoh, Kazuto Nishio, Masahiro Fukuoka, Kazuhiko Nakagawa
Journal: Cancer Research (2008)

2749  The effectiveness of treatment with monoclonal antibodies (mAbs) to epidermal growth factor receptor (EGFR) has been thought to be based on prevention of ligand binding to EGFR. However, the detailed effects of anti-EGFR mAbs on EGFR signaling have remained unclear. We have examined the effects of two anti-EGFR mAbs, matuzumab (EMD72000) and cetuximab (Erbitux), on EGFR signal transduction and cell survival. Similar to EGF, matuzumab and cetuximab each induced phosphorylation of EGFR at several tyrosine phosphorylation sites. EGFR phosphorylation induced by these antibodies was completely blocked by gefitinib, the specific EGFR-tyrosine kinase inhibitor (TKI). Furthermore, matuzumab and cetuximab each induced EGFR dimerization in the cross-linking reaction. These results suggested that matuzumab and cetuximab activated EGFR as a result of receptor dimerization and activation of the receptor tyrosine kinase. In contrast to the effects of EGF, however, EGFR activation induced by these antibodies was not accompanied by activation of downstream signaling pathways that are mediated by Akt and Erk and are important for regulation of cell proliferation and survival. In addition, matuzumab and cetuximab prevented EGFR internalization important for the activation of EGFR downstream signaling, likely explaining the failure of these antibodies to activate Akt and Erk pathways. Our clonogenic survival assays revealed that matuzumab and cetuximab reduced the survival rate of H292 cells, in which they also inhibited the EGF-induced activation of Akt and Erk. Our findings provide new insight into the antitumor effects of anti-EGFR mAbs which depend on inhibition of EGFR downstream signaling by blocking EGFR turn-over rather than on inhibition of EGFR itself.
Infographic. Golf spectating and health
Authors: Andrew Murray, Hilary Scott, Daryll Archibald, Kieran Turner, Steffan Arthur Griffin, Chloe Schiphorst, Roger Hawkes, Paul Kelly, Liz Grant, Nanette Mutrie
Journal: British Journal of Sports Medicine (2017)

The authors wish to thank Paths for All, the European Tour Golf, and 4sports for their input and collaboration at the Paul Lawrie Matchplay tournament. Tournament host Paul Lawrie, as a player provided …
Abstract 2587: VCF2CNA: a tool for efficiently detecting copy number alteration using VCF genotype data
Authors: Daniel K. Putnam, Xiaotu Ma, Stephen V. Rice, Yu Liu, Jinghui Zhang, Xiang Chen
Journal: Cancer Research (2017)

Abstract Whole genome sequencing (WGS) is increasingly used in both research and clinical settings. The Variant Call Format (VCF) specification is a widely adopted file format for genetic variation data exchange partially due to its smaller file size compared to raw WGS BAMs. Each variant in a typical VCF file contains its chromosome position, reference/alternative alleles and corresponding allele counts. This makes it possible to identify copy number alterations (CNAs). To this end, we developed VCF2CNA (http://vcf2cna.stjude.org), a web interface tool for CNA analysis from VCF files. A user of VCF2CNA, uploads a VCF file via the provided web interface. The entire analysis runs remotely with an average run time of 23 minutes. Results are emailed to the user as either a downloadable link or file attachments. VCF2CNA also accepts input in the Mutation Annotation Format (MAF) and the variant file format produced by the Bambino program. We analyzed 22 TCGA glioblastoma tumor/normal pairs by Illumina technology to evaluate VCF2CNA’s performance. It achieved high consistency (average F1-score: 0.952 ± 0.082) with CONSERTING, a tool that incorporated read-depth and SV data from raw BAMs for CNA detection. A segment-by-segment comparison between results from CONSERTING and VCF2CNA indicated that the latter was less sensitive to focal CNAs. This is expected because there is less information in the VCF input than in raw BAMs. Further analysis using samples with a “fractured genome” pattern revealed that VCF2CNA was more robust to library artifacts and produced relatively clean CNA profiles (on average 76.2-fold reduction compared to the number of segments reported by CONSERTING). Finally, we analyzed 137 pediatric neuroblastoma samples from the TARGET project, sequenced by Complete Genomics, Inc. (CGI) technology. MYCN amplification has been clinically validated in 33 samples. VCF2CNA identified high amplitude MYCN gains in 32 samples and the remaining sample carried a low-level broad gain covering MYCN. For comparison, CGI’s HMM-based method reported MYCN gains in only 15 out of the 33 samples. VCF2CNA further identified two additional MYCN amplifications among the remaining samples. Collectively, our analysis suggests that VCF2CNA is a platform-independent, efficient, robust and accurate tool for general WGS-based CNA analysis. It further complements CONSERTING, which produces more accurate result in focal CNAs at the cost of significantly higher computational burden. Citation Format: Daniel K. Putnam, Xiaotu Ma, Stephen V. Rice, Yu Liu, Jinghui Zhang, Xiang Chen. VCF2CNA: a tool for efficiently detecting copy number alteration using VCF genotype data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2587. doi:10.1158/1538-7445.AM2017-2587
Abstract 916: Asymmetric cell division regulator prevents hyperproliferation in glioma cell-of-origin
Authors: Mathieu Daynac, Claudia K. Petritsch
Journal: Cancer Research (2017)

Abstract In the past, we demonstrated that adult oligodendrocyte progenitor cells (OPC) undergo asymmetric cell division (ACD) to self-renew and generate functional cells by unequally distributing active EGFR and the OPC-specific marker NG2. Moreover, premalignant OPC switch from an asymmetric to symmetric, self-renewing division mode at premalignant stages, and exhibit aberrant proliferation and impaired differentiation (Sugiarto S et al Cancer Cell 2011). OPC are the cell-of-origin of glioma in genetically engineered mouse models (Persson A et al Cancer Cell 2010) and OPC-like glioma cells have high tumor-initiating potential in some glioma types. These data contribute to the emerging evidence that asymmetric cell division (ACD) has tumor suppressive activity. Whether the loss of ACD directly promotes tumor initiation is unclear, because the detailed mechanisms of mammalian ACD have not been elucidated (Gomez-Lopez S et al. Cell Mol Life Sci 2014). Lethal giant larvae 1 (Lgl1) was initially identified as a tumor suppressor in Drosophila and has been implicated in the asymmetric localization of cell fate determinants in mammalian neural progenitor cells (Klezovitch et al., Genes Dev, 2004). Others have shown also that human Lgl1 is inhibited by PTEN loss, which is common in glioblastoma, and Lgl1 depletion in human glioblastoma cells increases their invasive properties (Gont et al, Oncotarget, 2013 and 2014). Whether Lgl1 restricts proliferation, promotes differentiation and prevents neoplastic transformation of OPC, by regulating their asymmetric division, is unknown. We developed a flow cytometry method to isolate proliferative and differentiation-committed OPC (COP) and showed that Lgl1 expression is elevated in differentiation. Using a Cre-conditional knock-out allele (Klezovitch et al., Genes Dev, 2004), we show that Lgl1 knockout OPC proliferate more and differentiate less when compared with Lgl1 wildtype OPC. Lgl1 depletion increases symmetric, self-renewing divisions and reduces the frequency of ACD. Lgl1 appears to control the expression of several conserved ACD regulators, as revealed by comparative Taqman expression analyses of Lgl1 knockout versus control OPC. Ongoing studies are aimed to investigate the link of Lgl1 depletion, altered ACD regulator expression and observed OPC phenotypes. Data derived from this work are expected to provide further insights into the extent to which defective ACD contributes to neoplastic transformation in all cancers. Citation Format: Mathieu Daynac, Claudia K. Petritsch. Asymmetric cell division regulator prevents hyperproliferation in glioma cell-of-origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 916. doi:10.1158/1538-7445.AM2017-916
Abstract 2394: Subpopulation of infiltrating lymphocyte and MGMT methylation in brain tumor prognosis
Authors: Carlos Castaneda, Miluska Castillo, Carolina Belmar-Lopez, Sandro Casavilca, Luis Angel Bernabe, Tatiana Vidaurre
Journal: Cancer Research (2017)

Abstract Background: Clinicopathological features including MGMT methylation have been correlated to prognosis in Glioblastoma (GBM). Tumor infiltrating lymphocytes (TILs) are predictive of clinical outcome in different malignancies. We evaluated association between clinicopathological features including MGMT methylation and IHC infiltrating immune cell subpopulations in 43 resected GBM cases who came from 2008 to 2013. Methods: A prospective evaluation of TIL (CD3, CD4, CD8 and CD20) and macrophages (CD68 and CD163) through H&amp;E was performed by a pathologist and evaluated Immune cell subpopulations was evaluated through scanning, and software analysis (BX63 Olympus and TissueMorph-Visionpharm) with pathologist support. MGMT evaluation was prospectively performed by bisulphyte PCR test in paraffin samples. Results: Median age was 47.9 y, men (51.2%), Karnofsky scale 90% (62.8%), median tumor size of 5.1 cm, and partial/ complete tumor resection (22/21). Methylation MGMT test was performed in 31 cases and 17 showed un- methylated, 4 partial methylated and 10 methylated. TILs evaluation by HE showed low- intensity (29 cases), middle- intensity (1) and high- intensity level (9). Pattern of distribution was focal (9 cases), multi- focal (13) and diffuse (17). Median CD3, CD4, CD8, CD20, CD68 and CD163 were 1.6%, 0.032%, 1.6%, 0.03%, 9.1% and 2.2% (regarding total cells), respectively. Higher CD163 level was associated to male (p=0.03) and larger size (p=0.05). Higher levels of CD8 was associated to larger size (p=0.05). Higher CD8 and CD20 was associated to unmethylated MGMT (p=0.041 and 0.013). Median follow- up was 14 months. Only total resection (p&amp;lt;0.05) and MGMT methylation (p&amp;lt;0.05) was associated to outcome. Lymphocyte infiltration (H&amp;E) was not associated to outcome: Lymphocyte intensity (p=0.703), distribution (p=0.61). Longer OS was associated to lower CD4 levels (p=0.01). Conclusion: Tumor Infiltrating immune cell are not common in GBM, CD8 and CD20 was associated to unmethylation, and CD4 and MGMT methylation were associated to prognosis. Citation Format: Carlos Castaneda, Miluska Castillo, Carolina Belmar-Lopez, Sandro Casavilca, Luis Angel Bernabe, Tatiana Vidaurre. Subpopulation of infiltrating lymphocyte and MGMT methylation in brain tumor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2394. doi:10.1158/1538-7445.AM2017-2394
Abstract 1377: Set7 is a novel histone methyltransferase inSchizosaccharomyces Pombe
Authors: Eric Di Luccio, Yunpeng Shen, Damiaan E.H.F Mevius, Yeon Jeong Noh, Jihyeon Kim, Masayo Morishita
Journal: Cancer Research (2017)

Abstract Dynamics and plasticity of chromatin regulation is mediated by a molecular ballet of writers, readers and erasers of epigenetic marks on both DNA and histones. The pattern of histone modifications may define a histone code, which is part of intricate networks that ultimately regulate transcriptional events. Dysfunction of histone methylation affects chromatin regulation and is involved in an increasing number of pathologies from cellular transformation to tumor progression and other diseases. However, histone methyltransferase (HMTase) pathways remain to be further explored and better understood. Fission yeast (Schizosaccharomyces pombe) is an ideal model organism to investigate the fundamental mechanisms of chromatin dynamics. Fission yeast possesses 13 SET-containing proteins (Set1 to 13), several of which methylate histones or ribosomes. The catalytic SET domain is highly conserved across eukaryotes (e.g. Set2, a homologue of the oncoprotein NSD2/MMSET/WHSC1 in human). Structure-function studies of HMTases are essential from basic science to translational research. However, full-length structures of fission yeast methyltransferases are still scarce. Here, in a bid to better understand histone methylation and to gain insight for drug-design, we report the identification and structural characterization of a novel histone methyltransferase Set7 (SPCC297.04c), in Schizosaccharomyces Pombe. In this study, we investigated Sp.Set7’s cellular localization and the effect of Sp.Set7 knock-out on the cell cycle and sporulation. Next, we elucidated Sp.Set7’s Lysine substrate specificity on histone H3 and H4 by biochemical assays and mass spectrometry. Finally, we solved the X-ray structure of the apo Sp.Set7 at 2.0 Å resolution. In summary, we report the biochemical and structural characterization of a novel histone methyltransferase in fission yeast, which has implications for better understanding the fundamental mechanism of HMTases. Citation Format: Eric Di Luccio, Yunpeng Shen, Damiaan E.H.F Mevius, Yeon Jeong Noh, Jihyeon Kim, Masayo Morishita. Set7 is a novel histone methyltransferase in Schizosaccharomyces Pombe [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1377. doi:10.1158/1538-7445.AM2017-1377
Abstract 5304: A serological biopsy using five stomach-specific circulating biomarkers for gastric cancer risk assessment: a multi-phase study
Authors: Huakang Tu, Liping Sun, Xiao Dong, Yuehua Gong, Qian Xu, Jingjing Jing, Roberd M. Bostick, Xifeng Wu, Yuan Yuan
Journal: Cancer Research (2017)

Abstract Objective: We aimed to assess a serological biopsy using five stomach-specific circulating biomarkers—pepsinogen I (PGI), PGII, PGI/II ratio, anti-Helicobacter pylori (H. pylori) antibody, and gastrin-17 (G-17)—for identifying high-risk individuals and predicting risk of developing gastric cancer (GC). Methods: Among 12112 participants with prospective follow-up from an ongoing population-based screening program using both serology and gastroscopy in China, we conducted a multi-phase study involving a cross-sectional analysis, a follow-up analysis, and an integrative risk prediction modeling analysis. Results: In the cross-sectional analysis, the five biomarkers (especially PGII, the PGI/II ratio, and H. pylori sero-positivity) were associated with the presence of precancerous gastric lesions or GC at enrollment. In the follow-up analysis, low PGI levels and PGI/II ratios were associated with higher risk of developing GC, and both low (&amp;lt;0.5 pmol/L) and high (2.0-4.7 or &amp;gt;4.7 pmol/L) G-17 levels were associated with higher risk of developing GC, suggesting a J-shaped association. In the risk prediction modeling analysis, the five biomarkers combined yielded a C statistic of 0.801 (95% CI=0.787-0.815) and improved prediction beyond traditional risk factors (C statistic from 0.580 to 0.811, P&amp;lt;0.001) for identifying precancerous lesions at enrollment, and higher serological biopsy score based on the five biomarkers at enrollment were associated with higher risk of developing GC during follow-up (P for trend &amp;lt;0.001). Conclusions: A serological biopsy composed of the five stomach-specific circulating biomarkers could be used to identify high-risk individuals for further diagnostic gastroscopy, and to stratify individuals’ risk of developing GC and thus to guide targeted screening/precision prevention. Citation Format: Huakang Tu, Liping Sun, Xiao Dong, Yuehua Gong, Qian Xu, Jingjing Jing, Roberd M. Bostick, Xifeng Wu, Yuan Yuan. A serological biopsy using five stomach-specific circulating biomarkers for gastric cancer risk assessment: a multi-phase study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5304. doi:10.1158/1538-7445.AM2017-5304