tbuckley/cabot-search huggingface dataset:
Abstract 3571: Precise somatic mutation prediction in the absence of matching normal DNA
Authors: Irina Kalatskaya, Quang Trinh, Melanie Spears, John Bartlett, Lincoln Stein
Journal: Cancer Research (2017)

Abstract Accurate identification of somatic mutations is an essential first step for many cancer studies. It is usually done by comparing the genome of the tumour to the reference genome sequence derived from a normal tissue taken from the same donor. However, there are a number of possible scenarios in which matched normal tissues might be not available for comparisons. It is most commonly encountered when performing analysis on retrospective studies with human tissues from clinical trials or pathology archives when normal samples were not collected in the first place or patient consent precludes examination of normal tissue or germline variants. Another common scenario is the use of a cancer cell line as an experimental model, many of which have no information on the donor’s normal genome. In this work, we describe an algorithm to identify somatic single nucleotide variants (SNVs) in Next Generation Sequencing (NGS) data in the absence of normal samples using a machine learning approach. Our algorithm was evaluated using a family of supervised learning classifications across six different cancer types and ~1,600 samples, including cell lines, fresh frozen tissues, and formalin-fixed paraffin-embedded (FFPE) tissues. In addition, our algorithm was tested with both deep targeted sequencing and whole exome sequencing strategies. The algorithm correctly classified between 95% and 98% of somatic mutations with F1-measure ranges from 75.9% to 98.6% depending on the tumour type. We have released the algorithm as a software package called ISOWN (Identification of SOmatic mutations Without matching Normal tissues), which is available as Open Source under Apache License 2.0 from https://github.com/ikalatskaya/ISOWN. Citation Format: Irina Kalatskaya, Quang Trinh, Melanie Spears, John Bartlett, Lincoln Stein. Precise somatic mutation prediction in the absence of matching normal DNA [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 3571. doi:10.1158/1538-7445.AM2017-3571
Race/Ethnicity, Socioeconomic Status, Residential Segregation, and Spatial Variation in Noise Exposure in the Contiguous United States
Authors: Joan A. Casey, Rachel Morello-Frosch, Daniel J. Mennitt, Kurt Fristrup, Elizabeth L. Ogburn, Peter James
Journal: Environmental Health Perspectives (2017)

Prior research has reported disparities in environmental exposures in the United States, but, to our knowledge, no nationwide studies have assessed inequality in noise pollution.We aimed to a) assess racial/ethnic and socioeconomic inequalities in noise pollution in the contiguous United States; and b) consider the modifying role of metropolitan level racial residential segregation.We used a geospatial sound model to estimate census block group–level median (L50) nighttime and daytime noise exposure and 90th percentile (L10) daytime noise exposure. Block group variables from the 2006–2010 American Community Survey (ACS) included race/ethnicity, education, income, poverty, unemployment, homeownership, and linguistic isolation. We estimated associations using polynomial terms in spatial error models adjusted for total population and population density. We also evaluated the relationship between race/ethnicity and noise, stratified by levels of metropolitan area racial residential segregation, classified using a multigroup dissimilarity index.Generally, estimated nighttime and daytime noise levels were higher for census block groups with higher proportions of nonwhite and lower-socioeconomic status (SES) residents. For example, estimated nighttime noise levels in urban block groups with 75% vs. 0% black residents were 46.3 A-weighted decibels (dBA) [interquartile range (IQR): 44.3–47.8 dBA] and 42.3 dBA (IQR: 40.4–45.5 dBA), respectively. In urban block groups with 50% vs. 0% of residents living below poverty, estimated nighttime noise levels were 46.9 dBA (IQR: 44.7–48.5 dBA) and 44.0 dBA (IQR: 42.2–45.5 dBA), respectively. Block groups with the highest metropolitan area segregation had the highest estimated noise exposures, regardless of racial composition. Results were generally consistent between urban and suburban/rural census block groups, and for daytime and nighttime noise and robust to different spatial weight and neighbor definitions.We found evidence of racial/ethnic and socioeconomic differences in model-based estimates of noise exposure throughout the United States. Additional research is needed to determine if differences in noise exposure may contribute to health disparities in the United States. https://doi.org/10.1289/EHP898
Abstract 5626: Investigation of T cell activation by anti-human PD-1 antibodies Nivolumab, Pembrolizumab and BGB-A317 using tumor-infiltrating lymphocytes (TILs) from colorectal cancer and colorectal liver metastasis patients
Authors: Lusong Luo, Xiaoran Wu, Tong Zhang, Chunyan Fu, Yanjuan Zhang, Amy Guo, Dongping Zhou, Lianhai Zhang, Kun Wang, Baocai Xing, Jiafu Ji, Lai Wang, Kang Li
Journal: Cancer Research (2017)

Abstract Blockade of the PD-1 pathway with anti-PD-1 antibody, such as nivolumab (nivo) and pembrolizumab (pembro), has led to remarkable clinical responses in patients with many different cancer types. In this study, we investigated the activation of tumor-infiltrating lymphocytes (TILs) from patients with colorectal cancer (CRC) and colorectal liver metastasis (CLM) by nivo, pembro and BGB-A317, a novel humanized IgG4 anti-PD-1 antibody under clinical development. BGB-A317 has a unique binding signature to PD-1 with high affinity. Additionally, it is engineered to remove Fc gamma receptor (FcγR) binding, including FcγRI, FcγRIIA, FcγRIIB and FcγRIIIA. In our studies, all three anti-PD-1 antibodies showed significant increases in IFN-γ and TILs proliferation in a 3D tumor spheroid model. In both CRC and CLM patients, BGB-A317 treatment at concentration levels of 0.1, 1 and 10 μg/mL led to higher IFN-γ production than that in nivo and pembro treated groups. The enhanced TILs function was associated with a high density of CD8+ T cells, but inversely correlated with the percentage of CD11b+ myeloid cells in CRC tumors. Of interest, BGB-A317 showed better activation of TILs in the liver metastasis tumor microenvironment (TME) where macrophages were more abundant. This observation is consistent with the hypothesis that removal of FcγR binding might offer advantage to PD-1 mAbs in tumor microenvironment enriched with macrophages. Citation Format: Lusong Luo, Xiaoran Wu, Tong Zhang, Chunyan Fu, Yanjuan Zhang, Amy Guo, Dongping Zhou, Lianhai Zhang, Kun Wang, Baocai Xing, Jiafu Ji, Lai Wang, Kang Li. Investigation of T cell activation by anti-human PD-1 antibodies Nivolumab, Pembrolizumab and BGB-A317 using tumor-infiltrating lymphocytes (TILs) from colorectal cancer and colorectal liver metastasis patients [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 5626. doi:10.1158/1538-7445.AM2017-5626
Abstract 3429: Genome and epigenome profiling of high stage neuroblastoma
Authors: Miki Ohira-Ichikawa, Ryuichi P. Sugino, Hisanori Takenobu, Zhenghao Li, Masayuki Haruta, Genta Nagae, Claire Renard-Guillet, Akira Nakagawara, Hiroyuki Aburatani, Takehiko Kamijo
Journal: Cancer Research (2018)

Abstract Neuroblastoma (NB) is the most common pediatric extracranial solid tumor with a wide range of clinical phenotypes from spontaneous regression to highly resistant to chemotherapy. Loss of 1p and 11q and genomic alterations of MYCN, ALK, ATRX and TERT have been known to be involved in oncogenesis and unfavorable phenotype of NB, however, only small numbers of recurrent driver mutations have been observed by NGS-based studies. This implies epigenetic alterations also influence the pathogenesis of NB. In this study, to elucidate the molecular basis of malignant subtype of NB, we conducted methylome analysis for 145 primary NBs (stage 1:3; stage 2:8; stage 3:16; stage 4:105; stage 4s:13) by Infinium Human Methylation 450 BeadChip. By hierarchical clustering of methylome signature, the tumors were classified into four clusters. Cluster-1 shows good similarity with nerve cell controls and, together with cluster-3 (very young, early tumor stage), exhibited favorable prognosis. Unfavorable cluster-2 and -4 exhibited hyper-methylation phenotypes in CpG islands (CGI) and the former was enriched by MYCN-amplified tumors. These two clusters (n=73) showed strong correlation with poor patient prognosis (p=0.0055). 1400 hyper-methylated CGI locus which corresponded 550 genes were picked up and annotated by GO database. The term “cell adhesion”, “cell-cell signaling”, “transmission of nerve impulse” and “cellular component morphogenesis” were enriched. No 1p or 11q genes were enriched in hyper-methylated genes but several genes such as ANKK1 on chr11q whose lower expression levels are strongly correlated with unfavorable prognosis of the patient (p=4.0e-07) were included. Further analyses by comparing the influences in gene expression profiles by methylation and by histone modification of PRC2 are ongoing. Our recent data indicated that NTRK1, whose higher expression is a strong favorable marker, is transcriptionally downregulated in MYCN-amplified tumors by both methylation and H3K27me3 on distinct promoter regions (Li Z et al). Since application of epigenetic drugs are one of the possible therapeutic choices for NB, transcriptional regulation by the epigenetic alterations are needed to be intensively studied. Citation Format: Miki Ohira-Ichikawa, Ryuichi P. Sugino, Hisanori Takenobu, Zhenghao Li, Masayuki Haruta, Genta Nagae, Claire Renard-Guillet, Akira Nakagawara, Hiroyuki Aburatani, Takehiko Kamijo. Genome and epigenome profiling of high stage neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3429.
Abstract 5853: Peroxiredoxin I-targeted AMRI-59 has a role of radiosensitizer by promoting induction of ROS/γH2AX/caspase pathway and suppression of ERK
Authors: Wan Gi Hong, Jeong Hyun Cho, Ju Yeon Kim, EunAh Lee, Sang-Gu Hwang, Tong-Shin Chang, Hong-Duck Um, Jong Kuk Park
Journal: Cancer Research (2017)

Abstract We have identified AMRI-59, one of small molecule, is specific pharmaceutical inhibitor of peroxiredoxin (PRX) I enzyme activity in our previous study. In this study, we tried to prove whether AMRI-59 has role of radiosensitizer against non-small cell lung cancer cells - NCI-H460 and NCI-H1299. The radiosensitizer effects of AMRI-59 were tested with clonogenic assays. The intracellular mechanism underlying this effect was determined by performing immunoblotting and measuring ROS generation, mitochondrial potential and cell death. The radiosensitizer activity of AMRI-59 in vivo was tested in nude mice by treating with AMRI-59 and IR, and measuring tumor volume and assessing apoptosis. Dose-enhancement ratios of 30 μM AMRI-59 in NCI-H460 and NCI-H1299 are 1.57 or 3.38, respectively. Combination with AMRI-59 and IR also increased the production of ROS and disruption of mitochondrial potential via enhancement of PrxI oxidation, which subsequently induced one of DNA damage markers - phospho-γH2AX, and suppressed phosphorylation of ERK, and, finally, activated caspase-3. Notably, inhibition of ROS production prevented ERK suppression, and inhibition of ERK in addition of combination with AMRI-59 and IR increased caspase activation and apoptosis. In a xenograft assay, combination with AMRI-59 and IR delayed tumor growth by 11.4 days compared with controls, yielding an enhancement factor of 1.48. Collectively, these results indicate that AMRI-59 functions as a Prx I - targeted radiosensitizer by induction of apoptosis through activation of a ROS/γH2AX/caspase pathway and suppression of ERK. Citation Format: Wan Gi Hong, Jeong Hyun Cho, Ju Yeon Kim, EunAh Lee, Sang-Gu Hwang, Tong-Shin Chang, Hong-Duck Um, Jong Kuk Park. Peroxiredoxin I-targeted AMRI-59 has a role of radiosensitizer by promoting induction of ROS/γH2AX/caspase pathway and suppression of ERK [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 5853. doi:10.1158/1538-7445.AM2017-5853
Abstract 5664: PLAG prevents the loss of circulating neutrophils in the chemotherapy induced neutropenia model
Authors: Yong-Jae Kim, Jinseon Jung, Ha-Reum Lee, Ki-Young Sohn, Heung-Jae Kim, Sun Young Yoon, Jae Wha Kim
Journal: Cancer Research (2017)

Abstract Chemotherapy-induced neutropenia (CIN) is a common dose-limiting toxicity in cancer patients undergoing cytotoxic chemotherapy. It is generally understood that myelosuppression is the major mechanism resulting in CIN. However, an excessive extravasation (diapedesis) of neutrophils in response to tissue damage-caused by anti-cancer agents is also a possible mechanism. In this study, we have investigated the effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) for the maintenance of circulating neutrophil in the gemcitabine induced neutropenia. In CIN mouse model using anticancer drugs, PLAG effectively protected the loss of circulating neutrophils as similar to CXCR2 antagonist, reparixin. And succeeded in vitro neutrophil migration assay also revealed that chemo-attractive activity of neutrophil induced by treatment of anticancer drugs was completely interrupted by PLAG addition. Chemokine (C-X-C motif) ligand 2 (CXCL2) and CXCL8 were effectively induced by treatment of gemcitabine with dose dependent manner in monocyte cell lines and mainly mediated via the signal transducer and activator of transcription 3 (STAT3) signaling pathway. PLAG effectively attenuated gemcitabine induced CXCL2 and CXCL8 expression via interrupting STAT3 activity and also regulated gemcitabine induced macrophage 1 antigen (MAC-1) and L-selectin expression, which means that PLAG interrupted the acceleration of neutrophil extravasation under CIN. Also we have verified that PLAG analogues and metabolites were not affected on neutrophil migration unlike PLAG, suggesting that acetylated diacylglycerol has a key role to regulate on neutrophil migration. Collectively, modulating effect of PLAG on excessive neutrophil extravasation by chemotherapy via attenuating STAT3/CXCL2(8) pathway could be used as very powerful regimen for preventing of neutropenia during diverse chemotherapy. Citation Format: Yong-Jae Kim, Jinseon Jung, Ha-Reum Lee, Ki-Young Sohn, Heung-Jae Kim, Sun Young Yoon, Jae Wha Kim. PLAG prevents the loss of circulating neutrophils in the chemotherapy induced neutropenia model [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 5664. doi:10.1158/1538-7445.AM2017-5664
Abstract 903: CXCR4 and CXCR7 play distinct and overlapping roles in prostate cancer dissemination to bone
Authors: Sounak Roy, Kenneth C. Valkenburg, Kenneth J. Pienta
Journal: Cancer Research (2017)

Abstract Approximately 28,000 men die of prostate cancer (PCa) each year in the US, and 90-100% of them will be due to bone metastasis. It has been demonstrated that PCa cells detach from the primary tumor and “home” to bone. Osteoblasts (bone-forming cells) secrete the chemoattractant stromal-derived factor 1 (SDF-1, also known as CXCL12), and PCa cells express the receptors for SDF-1, C-X-C chemokine receptors 4 and 7 (CXCR4 and CXCR7). PCa cells use these receptors to enter the chemoprotective bone microenvironment, specifically, the hematopoietic stem cell (HSC) niche in the endosteum. While small molecule inhibition of CXCR4 can mobilize PCa cells from the bone marrow microenvironment, it is unknown whether CXCR7 plays a compensatory role when CXCR4 is antagonized. SDF-1 is known to bind with greater affinity to CXCR7 compared to CXCR4 indicating a possible role of CXCR7 in tumor migration to the endosteal niche. Therefore, it is crucial to determine the individual and combined roles of CXCR4 and CXCR7 in the formation and treatment of PCa bone metastases. To answer these questions, first we assessed CXCR4 and CXCR7 expression across a panel of prostate cancer cell lines. We then transiently overexpressed and knocked down CXCR4 and CXCR7 in PCa cells and found CXCR4 and CXCR7 expression in vitro to directly correlate to cell viability and migration in PC3 PCa cells. To further test dissemination and metastasis in bone, we are making stable overexpression and knockout cells and will perform in vivo metastasis experiments. We have developed a novel immunofluorescence protocol for detecting and quantifying tumor cells in murine blood and bone marrow and will use this technique to determine the ability of PCa cells to disseminate to bone in the presence or absence of CXCR4 and/or CXCR7. This will be quickly translatable because we are currently running a first-in-prostate cancer clinical trial to determine whether small molecule inhibition of CXCR4 to mobilize PCa tumor cells from the bone marrow, combined with docetaxel, will benefit metastatic PCa patients. If we determine that CXCR7 plays a compensatory role in dissemination and/or metastasis, we will need to add CXCR7 inhibition to our treatment strategy to obtain the most efficient benefit for patients. Citation Format: Sounak Roy, Kenneth C. Valkenburg, Kenneth J. Pienta. CXCR4 and CXCR7 play distinct and overlapping roles in prostate cancer dissemination to bone [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 903. doi:10.1158/1538-7445.AM2017-903
Abstract 5842: Therapeutic enhancement of aminolevulinic acid-mediate tumor fluorescence and photodynamic therapy with kinase inhibitors
Authors: Bin Chen, Pratheeba Palasuberniam
Journal: Cancer Research (2017)

Abstract Photodynamic therapy (PDT) involves the combination of a photosensitizer and light of a specific wavelength. Upon light activation in the presence of oxygen, photosensitizer molecules generate reactive oxygen species that cause cytotoxicity by inducing oxidative stress. Aminolevulinic acid (ALA) is a pro-drug used for the diagnosis and PDT treatment of various solid tumors based on endogenous production of heme precursor protoporphyrin IX (PpIX). Although all human cells express heme biosynthesis enzymes and produce PpIX, tumor cells are often found to have higher PpIX production and accumulation than normal cells, allowing for the detection and treatment of solid tumors. In exploring ALA-based tumor detection and therapy in breast cancer, we have reported that high ABCG2 transporter activity in triple negative breast cancer cells (TNBC) contributes to reduced PpIX levels in tumor cells, causing cell resistance to ALA-PDT. The administration of an ABCG2 inhibitor Ko143 was able to reverse cell resistance to ALA-PDT by increasing PpIX levels. In this study, we showed that some kinase inhibitors were able to increase ALA-mediated PpIX by inhibiting ABCG2 activity. Particularly, our results demonstrate that lapatinib, a dual inhibitor of EGFR and Her2, increased the ALA-PpIX level and cell sensitivity to ALA-PDT in the MDA-MB-231 TNBC cells. Lapatinib treatment had little effect on MCF10A breast epithelial cells. These results indicate that small molecule kinase inhibitors such as lapatinib can be used for enhancing ALA-based tumor detection and PDT in tumors with high ABCG2 activity. Citation Format: Bin Chen, Pratheeba Palasuberniam. Therapeutic enhancement of aminolevulinic acid-mediate tumor fluorescence and photodynamic therapy with kinase inhibitors [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 5842. doi:10.1158/1538-7445.AM2017-5842
Abstract 4402: CHTM1, a novel protein linked to cellular metabolism and human malignancy
Authors: Mansi Babbar, Ying Huang, M Saeed Sheikh
Journal: Cancer Research (2017)

Abstract Several lines of emerging evidence indicate that alterations in metabolism are linked to pathogenesis of human malignancies. However, more studies are needed to completely understand the link between tumorigenesis and metabolism. In this context, we have characterized a novel protein named CHTM1 (Coiled-coil Helix Tumor and Metabolism 1) that appears to be associated with cancer and cellular metabolism. Per our findings, CHTM1 was present in cytosol as well as mitochondria. CHTM1 knockdown in human cancer cell lines caused oxidative stress, and decrease in cellular oxygen consumption and mitochondrial ATP levels, suggesting mitochondrial dysfunction. In view of the importance of mitochondria to nutrient stress, the effect of CHTM1 deficiency on human cancer cells in glucose-deprived conditions was also analyzed. The results indicated that CHTM1-deficient cells became more sensitive to glucose deprivation and exhibited altered cellular metabolism involving down regulation of PKC-CREB-PGC1 alpha signaling events. CHTM1 expression was also found to be increased in patient samples representing breast, colon and lung cancers when compared to their respective matching normal tissues. Based on our findings, we propose CHTM1 to be a valuable tumor marker that can also be developed as a target for novel therapeutics particularly those that exploit cellular metabolism to mediate their effects. Citation Format: Mansi Babbar, Ying Huang, M Saeed Sheikh. CHTM1, a novel protein linked to cellular metabolism and human malignancy [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 4402. doi:10.1158/1538-7445.AM2017-4402