tbuckley/cabot-search huggingface dataset:
Abstract 427: A path towards determining tumor mutation burden and identifying neoantigens using next-generation sequencing (NGS)
Authors: Alex So, Shannon Kaplan, Nai-yu Wang, Shile Zhang, Aaron Wise, Kristina Kruglyak, Karen Gutekunst
Journal: Cancer Research (2017)

Abstract Introduction: The recent clinical demonstrations that cancer immunotherapy is effective for some patients, but not others has led to widespread interest in identifying cancer genetic factors that can predict positive response. Importantly, it has been shown by various studies that tumor mutation burden (TMB) and predicted neoantigen load correlate with patient response to checkpoint inhibitors. This project aims to develop a clinical next-generation sequencing (NGS) assay that utilizes TMB and neoantigen information to guide cancer immunotherapy selection. Experimental Procedures: Whole exome sequencing (WES) and whole transcriptome sequencing (WTS) libraries were generated using Illumina’s TruSeq® Exome and RNA Access library preparation kits, respectively. The samples were pair-end sequenced (2x75bp) using HiSeq® 2000 and 2500 instruments. Data Summary: Here, we demonstrate a workflow using tumor/normal WES and tumor-only WTS to determine expressed TMB. Using the WES data, we were also able to accurately identify human leukocyte antigen (HLA) major histocompatibility complex (MHC) Class I genes at four-digit resolution. We then identified putative neoantigens, defined as peptides with mutated amino acids, that were expressed in the tumor samples and predicted to bind to the respective HLA sequences. In addition, as a path towards developing a clinical assay for TMB and neoantigen determination, we tested the ability of reagents developed for Illumina’s Trusight® Tumor 170 panel to be used for an exome panel. With workflow modifications, we achieved comparable quality of sequencing metrics as compared to the TruSeq® Exome kit. Conclusion: Our data demonstrate a path towards developing a clinical assay that can be used to assess TMB and neoantigen candidates. Citation Format: Alex So, Shannon Kaplan, Nai-yu Wang, Shile Zhang, Aaron Wise, Kristina Kruglyak, Karen Gutekunst. A path towards determining tumor mutation burden and identifying neoantigens using next-generation sequencing (NGS) [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 427. doi:10.1158/1538-7445.AM2017-427
Abstract 4639: HLA and NKG2D ligand abnormalities and IFN-γ unnresponsiveness in human colorectal carcinoma cell lines
Authors: Yi-Hsin Liang, Yen-Cheng Lin, Kuo-Hsin Chen, Chiu-Hwa Kao, Ann-Lii Cheng, Kun-Huei Yeh, Chien-Chung Chang
Journal: Cancer Research (2017)

Abstract Background: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has shown promising efficacy on wild-type RAS metastatic colorectal cancer (CRC) patients. Cetuximab demonstrates anti-cancer effect via NK cells and subsequent immunogenic cell death. Chemotherapy or targeted therapy may change immune surface markers. Methods: We characterized a panel of 6 CRC cell lines with different genetic features. The impacts of interferon-γ (IFN-γ) on cell surface expressions of major histocompatibility complex (MHC) class I (including subtypes), MHC class II (including subtypes), MHC class 1 related molecule A (MICA, the NK cell ligand), Intercellular Adhesion Molecule 1 (ICAM-1, the immunoglobulin superfamily), EGFR, and Chondroitin Sulfate Proteoglycan 4 (CSPG-4, pericyte attaching marker) before and after treatment with IFN-γ (100 U/ml, 48 h) were explored in selected cell lines Results: Among six human colon cancer cell lines analyzed, DLD-1, HCT15, and LoVo exhibited no expression of HLA-A and HLA-B,C. Colo-320 demonstrated both low HLA-A and HLA-B,C expression and irresponsive to IFN-γ stimulation. In contrast, both HT-29 and SW-480 showed low HLA-A and HLA-B,C expression, but the expression of both HLA-A and HLA-B,C was corrected after IFN-γ stimulation. All six cell lines possessed low MHC class II expression and irresponsive to IFN-γ stimulation. All six cell lines possessed low MIC expression and irresponsive to IFN-γ stimulation. All six cell lines showed low ICAM-1 expression, but only HT-29 and SW-480 were responsive to IFN-γ stimulation. LOVO and SW-480 demonstrated high EGFR expression and irresponsive to IFN-γ stimulation. Only HT-29 possessed high CSPG-4 expression. Conclusion: These findings reveal that regardless of their genetic features, all six CRC cell lines possess a phenotype that may allow them to escape cytotoxic T and NK cell attack. Table Cell LineMSICIMPKRASBRAFPI3KCATP53DLD-1MSI+G13DWTE545KS241FHCT-15MSI+G13DWTE545KS241FLOVOMSI-G13DWTWTWTCOLO-320MSS-WTWTWTR248WHT-29MSS+WTV600EP449TR273HSW-480MSS-G12VWTWTR273H Citation Format: Yi-Hsin Liang, Yen-Cheng Lin, Kuo-Hsin Chen, Chiu-Hwa Kao, Ann-Lii Cheng, Kun-Huei Yeh, Chien-Chung Chang. HLA and NKG2D ligand abnormalities and IFN-γ unnresponsiveness in human colorectal carcinoma cell lines [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 4639. doi:10.1158/1538-7445.AM2017-4639
Abstract 4349: Adverse & anticancer activities of 5-azaCdR & DNA methyltransferase (DNMT) isoform specific inhibitors: therapeutic implications
Authors: David Cheishvili, Moshe Szyf
Journal: Cancer Research (2017)

Abstract Activation of methylated and silenced promoters of genes that suppress tumorigenesis has been the rationale behind the clinical use of DNMT family inhibitor 5aza for treating cancer. However, the adverse effects of general DNA methylation inhibition on tumors through activation of tumor promoting and prometastatic genes as well adverse effects on normal cells have not been comprehensively assessed, nor is it known which particular DNMT is responsible for regulating these adverse effects. A related critical question is whether such potential toxicity could be reduced by targeting a specific isoform of DNMT. We, therefore, performed a comprehensive molecular characterization of the effects of the pan DNMT inhibitor 5aza and isoform-specific inhibition of DNMT1, DNMT3a and DNMT3b by shRNA on cell growth and invasiveness, the methylome and transcriptome of the breast, liver and lung cancer cells as well as their normal primary cell counterparts. Our results suggest that 5aza causes general DNA methylation inhibition both as far as genomic features as well as the genes that are affected. This results in activation of genes involved in promoting cancer and metastasis in both cancer and normal cells. 5aza also induces rampant activation of retroviral elements and ectopic transcription initiation in gene bodies and intergenic regions. Second, isoform-specific exhibit a more limited and specific profile of activity on promoter methylation and gene expression. Third, the adverse profile of 5aza corresponds to the effects of specific inhibition of DNMT3a suggesting that the adverse effects of 5aza are partly mediated through inhibition of DNMT3a. Fourth, specific inhibition of DNMT1 results in an enriched inhibition of DNA methylation in promoters and inhibition of growth without triggering activation of tumor suppressor genes and a more favorable molecular footprint on cancer cells. Our data provide a comprehensive assessment of the impact of DNA methylation inhibition on normal and cancer cells and points to the potential adverse effects of such an approach. However, since the different DNMTs have a different molecular footprint, these adverse effects might be inhibited using isoform-specific DNMT inhibitors. Our data needs to be considered for further clinical development of DNMT inhibitors. Note: This abstract was not presented at the meeting. Citation Format: David Cheishvili, Moshe Szyf. Adverse &amp; anticancer activities of 5-azaCdR &amp; DNA methyltransferase (DNMT) isoform specific inhibitors: therapeutic implications [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 4349. doi:10.1158/1538-7445.AM2017-4349
Abstract 1328: Mechanism of transcriptional regulation of metabotropic glutamate recepter-5 induced by the CXCR4 signaling pathway
Authors: Nobuyuki Kuribayashi, Daisuke Uchida, Makoto Kinouchi, Sayaka Izumi, Kyoko Kuribayashi, Hitoshi Kawamata
Journal: Cancer Research (2017)

Abstract We have previously demonstrated that stromal cell-derived factor (SDF)-1/CXCR4 system enhances the metastases of oral cancer cells via induction of mGluR5. In this study, we examined the transcriptional regulation of mGluR5 induced by the SDF-1/CXCR4 system, using oral cancer cells, B88, which express functional CXCR4 and have highly metastatic potentials. mGluR5 was markedly induced both by the exogenous SDF-1 addition and overexpression of SDF-1 in B88 cells. These induction was completely inhibited by a MEK inhibitor, U0126, and partially inhibited by a PI3K inhibitor, wortmannin. Furthermore, these inhibitors significantly inhibited the SDF-1/CXCR4 dependent cell-migration in the presence or absence of mGluR5 agonist, DHPG. Recently, several investigators demonstrated that activation of the ERK1/2 pathway is responsible for the transcription of several cancer-associated microRNAs (miRNAs). Thus, we performed miRNA microarray in SDF-1 stimulated B88 cells. we isolated miR-30 family which has predictive binding sites in 3'-UTR of mGluR5 mRNA in silico analysis. We now analyze the regulation of these miRNA by MEK/ERK1/2 and PI3K/Akt pathway. Citation Format: Nobuyuki Kuribayashi, Daisuke Uchida, Makoto Kinouchi, Sayaka Izumi, Kyoko Kuribayashi, Hitoshi Kawamata. Mechanism of transcriptional regulation of metabotropic glutamate recepter-5 induced by the CXCR4 signaling pathway [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 1328. doi:10.1158/1538-7445.AM2017-1328
Abstract 2113: Mechanism of action of pixantrone in non-Hodgkin's lymphoma cells
Authors: Serina Ng, Ruben Muñoz, Daniel Von Hoff, Haiyong Han
Journal: Cancer Research (2017)

Abstract Background: Pixantrone (PIX), an anthracenedione analog, has shown promising results with reduced cardiotoxicity as compared to structurally similar mitoxantrone and doxorubicin (DOX) in early phase clinical trials in patients with non-Hodgkin’s lymphoma (NHL). The exact mechanisms of action on how PIX induce cell death by targeting DNA replication through intercalating DNA and/or inhibiting Topoisomerase II has not been clearly illustrated. Methods: A short-term cell proliferation assay (3 days treatment) and a long-term clonogenic assay (cells were treated with the drugs for 24 hours and then allowed to grow into colonies for 10-14 days) were used to assess and compare the effects of PIX and DOX on cell growth in three NHL cell lines, OCI-Ly8, Z138, and Raji. Immunofluorescent assays using γH2AX antibodies, and DAPI staining were used to examine the effect of PIX and DOX on the formation of double-strand breaks and micronuclei. Results: In the short-term cell proliferation assay, PIX was not as potent as DOX (IC50 values ranging from 22 nM to 2737 nM for PIX and 2.8 nM to 67 nM for DOX). The two drugs were significantly more potent in the long-term clonogenic assay with IC50 values in low nanomolar range (5.1 nM to 82.8 nM) and the difference between PIX and DOX was much smaller. Cells treated with PIX displayed less increases in DNA double-strand breaks compared to those of DOX as quantified by the number of γH2AX positive foci formed in the cells. Furthermore, PIX treatment significantly increased the formation of micronuclei in a drug concentration and time dependent manner. Conclusions: The findings from the current study indicate that PIX induces DNA damages that impair the chromosomal segregation but do not significantly trigger double-strand breakage checkpoint response. Overall, our results suggest that PIX may exert its antitumor activity via mechanisms that are different from those of DOX. Citation Format: Serina Ng, Ruben Muñoz, Daniel Von Hoff, Haiyong Han. Mechanism of action of pixantrone in non-Hodgkin's lymphoma cells [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 2113. doi:10.1158/1538-7445.AM2017-2113
WHAT ARE THE RISK FACTORS FOR INJURY TO SKIERS AND SNOWBOARDERS IN TERRAIN PARKS AND WHICH STRATEGIES ARE EFFECTIVE IN REDUCING THE RISK OF INJURY? A SYSTEMATIC REVIEW
Authors: Olivier Audet, Tatum Priyambada Mitra, Carolyn A. Emery, Brent E. Hagel, Alison Macpherson, Claude Goulet
Journal: British Journal of Sports Medicine (2017)

Background The prevalence of terrain parks (TPs) in ski areas has grown over the past two decades. TPs are specific areas of the slopes where terrain is modified to accommodate acrobatic maneuvers. There is evidence that TP injuries are more severe than injuries sustained on regular slopes. However, injury prevention strategies in TPs still need to be explored. Objective To identify the risk factors for skiing and snowboarding injuries in TPs and assess the effectiveness of injury prevention strategies. Participants/population Recreational skiing or snowboarding injuries in a TP. Methods Searches in electronic literature databases and hand-searches in Skiing Trauma volumes and bibliographies were performed. A search strategy involving a combination of Subject Headings and keywords and related synonyms using OR, with the Boolean operator AND was performed. Reviewers independently performed an initial screen of all titles and published abstracts for inclusion criteria to determine full text required. Criteria were (1) original data; (2) injury sustained in terrain parks/half-pipes; (3) recreational ski or snowboard injury; (4) study design with comparison group. Authors reviewed included papers and extracted data into structured tables. Results The search strategy identified 62 relevant studies. Only 11 studies met inclusion criteria including one intervention study. Results suggest that removing man-made jumps reduces the risk of severe injury. According to preliminary results, type of slope, age, gender, and skill level are common risk factors. Critical appraisal of articles is in process. An overview suggests that risk factors studies in this area (n=10) are heterogeneous. With primarily cross-sectional and case-control study designs, the risk of associated bias is significant. Conclusions One intervention study suggests that removing man-made jumps from TPs reduces the risk of severe injuries. Further research is needed to better understand injury prevention strategies that are effective in reducing the risk of injury in TPs.
Appendix: Bantu Cultural Habits Possibly Leading to Use of Carcinogenic Foodstuffs&lt;xref ref-type="fn" rid="FN1"&gt;9&lt;/xref&gt;
Authors: R J Burrell
Journal: JNCI Journal of the National Cancer Institute (1966)

Journal Article Appendix: Bantu Cultural Habits Possibly Leading to Use of Carcinogenic Foodstuffs Get access R. J. W. Burrell R. J. W. Burrell Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 36, Issue 2, February 1966, Pages 211–214, https://doi.org/10.1093/jnci/36.2.211 Published: 01 February 1966
Abstract 4599: Antibody targeting PDZ domain of TIP-1 induces proliferation arrest through AKT/mTOR signaling inhibition in lung cancer and glioblastoma
Authors: Vaishali Kapoor, David Dadey, Kelly Hoye, Andrea Collins, Dinesh Thotala, Dennis Hallahan
Journal: Cancer Research (2017)

Abstract Antigens that are over-expressed in cancer in response to radiation are being used as novel targets. We showed tax interacting protein 1 (TIP-1) to be radiation-inducible that translocated to the surface of the cancer cell following irradiation. TIP-1, which consists of a single PDZ domain plays an important role in cell signaling, cancer development, and progression. TIP-1’s involvement in various survival pathways makes it an attractive target for anticancer therapeutics. We used antibodies specific to this PDZ domain to determine its role in cancer cell survival. We monitored proliferation in lung cancer (A549 and H460) and glioblastoma (D54 and U251) cells after 24, 48, 72 and 96h treatment with the anti-PDZ antibody. We observed a time-dependent proliferation arrest with anti-PDZ antibody treatment which was associated with increased apoptosis. The anti-PDZ antibody when combined with radiation (3Gy) led to reduced proliferation and colony formation. Anti-PDZ antibody had no effect on the proliferation of normal lung (MRC-5) and endothelial (HUVEC) cells. Cells treated with anti-PDZ antibody showed decreased levels of the phosphorylated forms of AKT, mTOR, and a downstream substrate of mTOR, 4EBP1. Anti-PDZ antibody treatment also led to an overall reduction in basal levels of AKT, mTOR, and 4EBP1. Further, we evaluated the effect of the anti-PDZ antibody on tumor growth in heterotopic mouse models of lung cancer (A549) and glioma (U251). We observed significant growth delay in mice treated with anti-PDZ antibody treatment when compared to mice treated with the isotype control. The combination of the anti-PDZ antibody with radiation showed an additive effect. Immunoblot analysis of tumor tissues also showed downregulation of phosphorylated and total levels of AKT, mTOR and 4EBP1 in the tumors treated with anti-PDZ antibody. Overall, our results suggest that TIP-1 is a promising therapeutic target for treatment of lung cancer and glioblastoma. Antibodies specific to the PDZ domain of TIP-1 enhance the efficacy of radiotherapy. The anti-PDZ antibodies need to be optimized further before translating it into the clinic. Citation Format: Vaishali Kapoor, David Dadey, Kelly Hoye, Andrea Collins, Dinesh Thotala, Dennis Hallahan. Antibody targeting PDZ domain of TIP-1 induces proliferation arrest through AKT/mTOR signaling inhibition in lung cancer and glioblastoma [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 4599. doi:10.1158/1538-7445.AM2017-4599
Abstract P220: Anthrax Receptor Regulation of FAK and JNK Activation in Cardiac Myocytes
Authors: Damir Nizamutdinov, Honey B Golden, FNU Gerilechaogetu, Hao Feng, Donald M Foster, Carl Tong, David E Dostal
Journal: Circulation Research (2011)

We previously demonstrated that anthrax lethal toxin (LT, protective antigen [PA] + lethal factor [LF]) produces acute systolic heart failure, characterized by increased left ventricular (LV) end-diastolic volume, reduced ejection fraction and decreased contractility in male Sprague-Dawley (SD) rats. The molecular basis for the cardiac dysfunction observed in either an animal model or clinical setting of anthrax toxicity remains to be examined. Previously, we tested LT dose-response effects on isolated neonatal rat ventricular myocytes (NRVM) at a dose of 0.05 ng/mL PA + 0.025 ng/mL LF diminished PLB and JNK phosphorylation from 1h to 4 h. During the LT+PA time-course, Akt phosphorylation at both Thr 308 and Ser 473 were also significantly reduced at all time points from 30 min to 4 h, accompanied by elevated B56α total protein and intracellular Ca 2+ , and reduced PLB phosphorylation. This response is mediated by translocation of LF into the cell through the anthrax receptors 1 and 2 (ATR1/2), which are structurally similar to integrins. In this study, we tested whether stimulation of ATR1/2 by PA alone can induce activation of the integrin effectors, FAK and JNK. Cardiac myocytes were treated time dependently (5 sec - 30 min) by PA at 0.25 ng/mL, and activation of FAK protein at different residues was determined. PA induced phosphorylation of FAK-Tyr 861 at 15 sec (p&lt;0.05), whereas there was no effect on FAK-Tyr 397 or FAK-Tyr 925 phosphorylation for any of the time points. Furthermore, we found that PA alone maximally increased JNK phosphorylation at 15 min of treatment (p&lt;0.05). This response was not blocked with either Losartan (10 µM) or AG1479 (100 nM) indicating that neither angiotensin type I receptor (AT1) or epidermal growth factor receptor (EGFR) transactivation was involved. In summary, this study suggests a key role of ATR1/2 in mediating of signal transduction across membrane of cardiac myocytes in response to B. anthracis PA stimulation and involvement in acute responses in regulation of FAK and JNK activation in independent of AT1 and EGFR pathway.
Abstract 4549: Identification of clinically relevant patterns in complex genomic interactions of glioblastoma multiforme
Authors: Nevenka Dimitrova, Konstantin Volyanskyy, Vlado Menkovski, Yee Him Cheung, Minghao Zhong, John T. Fallon, Eric Vail
Journal: Cancer Research (2017)

Abstract Background: In clinical practice of complex diseases such as cancer it is a challenging task to correctly identify driving factors and specific interactions between multitudes of genomic and clinical variables. In cancer where patterns are heterogeneous and involve highly complex interactions of biological pathways, this is by far a non-trivial task. Using novel approaches in machine learning, we demonstrate the ability to quantitatively and accurately reveal and describe patterns in genomic and clinical data. Method: We developed a computational framework based on a number of interacting learners performing extensive pattern search and data characterization. This framework is multilevel and involves steps of relevant data transformations. We formulate and apply contextually relevant criteria to distinguish and rank iteratively obtained findings and identify hidden relations between features and characteristic connections to the clinical outcome. Summary: We successfully tested our method on the public data of Glioblastoma Multiforme (GBM) from The Cancer Genome Atlas (TCGA). We identify interacting sets of genomic variables to represent clinically relevant subgroups of samples. We observe a dense presence of interacting known cellular processes in GBM such as EGFR, FGFR, ERK, RAS, MAPK, P53, as well as novel such as calcium signaling, kinesin motor and protein kinase pathways, tubulin and microtubule binding, phorbol esters/diacylglycerol binding domain (C1 domain), purine ribonucleoside triphosphate binding, positive regulation of phospholipase activity and others. The top ranking pathways recap the well-known and new biology. In addition, compared to known genes in the literature, we also observe involvement of novel genes in GBM subtype characterization. Finally, we propose two-fold solution: identification of distinctive patterns in the input genomic and output clinical data, and specific format of their interactions. Citation Format: Nevenka Dimitrova, Konstantin Volyanskyy, Vlado Menkovski, Yee Him Cheung, Minghao Zhong, John T. Fallon, Eric Vail. Identification of clinically relevant patterns in complex genomic interactions of glioblastoma multiforme [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 4549. doi:10.1158/1538-7445.AM2017-4549