tbuckley/cabot-search huggingface dataset:
Abstract 2284: Effects of smoking on breast tumor pathology
Authors: Nicholas Costantino, Craig D. Shriver, Rachel E. Ellsworth
Journal: Cancer Research (2017)

Abstract Background Although smoking is not a well-established breast cancer risk factor, proximity of lungs to the breasts and findings that tobacco smoke constituents serve as mammary carcinogens in animal models suggests that smoking may alter the breast microenvironment and affect breast tumorigenesis. To determine how smoking influences tumor pathogenesis, the relationships between smoking and pathological characteristics and outcome were evaluated in 1,707 women with invasive breast cancer. Methods Patients enrolled in the Clinical Breast Care Project 2001-2013 filled out a questionnaire that included answers to current smoking status, current and previous pack use/day, number of years smoked, and length since last smoked. Patients were classified as never, former or current smokers. Pack years was calculated as years smoked x pack use/day. Logistic regression was performed to determine whether smoking was associated with any characteristics. Significance was defined as P&amp;lt;0.05 Results 55.7% of women never smoked, 31.5% were former smokers and 12.8% were current smokers. The average number or pack years was 14.5 in former smokers and 25.5 in current smokers. Current smoking status was associated with lymph node metastasis (OR 1.44; 95% CI 1.03-2.01), positive HER2 status (OR 1.54, 95% CI 1.04-2.25), larger tumor size (OR 1.55; 95% CI 1.14-2.11) and higher tumor stage (OR 1.54, 95% CI 1.16-2.04) when compared to never smokers. Former smokers were less likely to be diagnosed with later stage tumors (OR 0.77, 95% CI 0.62-0.96) compared to never smokers. No significant associations were detected when pack years were considered as a continuous variable; when categorized as 0, &amp;lt;20, 20-34 or &amp;gt;35 pack years, &amp;gt;35 pack years was associated with positive HER2 status (OR 1.80, 95% CI 1.06-3.03) and tumors of the ER+HER2+ subtype (OR 1.99, 95% CI 1.07-3.7). Overall survival was significantly lower for former and current smokers compared to never smokers (P=0.014); however, breast cancer specific survival did not differ significantly between groups (P=0.226). Conclusions Current smokers are at increased risk for having larger and later stage tumors with positive lymph node and HER2 status. Tumor size, stage and lymph node status are temporal factors, thus suggest that current smokers may have delayed diagnosis compared to never and former smokers. In contrast, HER2 status reflects a biological phenomenon and the risk of HER2 positivity increases with pack years, suggesting that carcinogens found in tobacco smoke may promote overexpression of HER2. Citation Format: Nicholas Costantino, Craig D. Shriver, Rachel E. Ellsworth. Effects of smoking on breast tumor pathology [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 2284. doi:10.1158/1538-7445.AM2017-2284
Abstract 1464: miR-6734 induces cell cycle arrest and apoptosis via up-regulation of p21 expression in colon cancer cells
Authors: Jong Soon Kang, Moo Rim Kang
Journal: Cancer Research (2017)

Abstract Recently, microRNAs have been implicated in the regulation of gene expression in terms of both gene silencing and gene activation. Here, we investigated the effects of miR-6734, which has a sequence homology with a specific region of p21WAF1/CIP1 (p21) promoter, on cancer cell growth and the mechanisms involved in this effect. miR-6734 up-regulated p21 expression at both mRNA and protein levels and chromatin immunoprecipitation analysis using biotin-labeled miR-6734 confirmed the association of miR-6734 with p21 promoter. Moreover, miR-6734 inhibited cancer cell growth and induced cell cycle arrest and apoptosis in HCT-116 cells, which was abolished by knockdown of p21. The phosphorylation of Rb and the cleavage of caspase 3 and PARP were suppressed by miR-6734 transfection in HCT-116 cells and these effects were also reversed by p21 knockdown. In addition, miR-6734 transfection caused prolonged induction of p21 gene and modification of histones in p21 promoter, which are typical aspects of a phenomenon referred to as RNA activation (RNAa). Collectively, our results demonstrated that miR-6734 inhibits the growth of colon cancer cells by up-regulating p21 gene expression and subsequent induction of cell cycle arrest and apoptosis, suggesting its role as an important endogenous regulator of cancer cell proliferation and survival. Citation Format: Jong Soon Kang, Moo Rim Kang. miR-6734 induces cell cycle arrest and apoptosis via up-regulation of p21 expression in colon cancer 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 1464. doi:10.1158/1538-7445.AM2017-1464
Abstract 1988: Exosome-mediated ovarian cancer tumorigenesis mediated by miR1246/Rb/Cav1 axis
Authors: Pinar Kanlikilicer, Recep Bayraktar, Mohammed Rashed, Burcu Aslan, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein
Journal: Cancer Research (2017)

Abstract Exosomes are secreted from many cell types and play an important role in the tumor microenvironment. The most impressive breakthrough in exosomes research was that they contain the genetic material of the host cell. However, whether cancer cells use their exosomes to transfer their oncogenic material to recipient cells, or to get rid of their tumor suppressor material is not well understood. We previously identified that miR-1246 was hundreds of folds higher expressed in six different ovarian cancer exosomes compared to their originating cells. Here, we showed that miR-1246 co-localized in the exosomes in ovarian cancer cells. miR-1246 act as an oncogenic miRNA and the levels were elevated in ovarian cancer patients compared to health donors. We also demonstrated that miR-1246 inhibitor treatment in combination with paclitaxel was significantly inhibited tumor burden in SKOV3-ip1 orthotopic ovarian cancer model. Our results suggest that miR-1246 inhibited RB tumor suppressor protein and regulate Cav-1 and platelet-derived growth factor receptor beta precursor signaling in ovarian cancer. In addition Inhibiting miR-1246 led a significant decrease in exosome release. Together, our findings provide strong evidence that oncogenic miR-1246 can be targeted as a potential novel therapeutic approach in the treatment of ovarian cancer. . Note: This abstract was not presented at the meeting. Citation Format: Pinar Kanlikilicer, Recep Bayraktar, Mohammed Rashed, Burcu Aslan, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein. Exosome-mediated ovarian cancer tumorigenesis mediated by miR1246/Rb/Cav1 axis [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 1988. doi:10.1158/1538-7445.AM2017-1988
Abstract 5347: Molecular barcoding improves confidence in variant calling with low input FFPE tissue samples
Authors: Bahram Arezi, Bilan Hsue, Keith Chen, Brenda Rogers, Christian Lecocq, Ashutosh Ashutosh, Jayati Ghosh, Gilbert Amparo, Madhuvanthi Ramaiah, Carlos Pabon, Holly Hogrefe
Journal: Cancer Research (2017)

Abstract FFPE tissue archiving is the most widely used method for clinical sample preservation, and provides a valuable source of diverse genetic information for cancer biomarker discovery. NGS library preparation is often challenging, however, as FFPE-derived DNAs exhibit varying degrees of fragmentation and chemical modification depending on how tissues were handled and processed. Moreover, the presence of low allele frequency variants because of tumor heterogeneity, sample degradation, and high rate of formalin-induced mutations make SNV calling a challenging task. To improve variant calling and consistency across FFPE samples of varying quality, we developed a complete workflow solution that features DNA pre-qualification, molecular barcodes for uniquely tagging each DNA fragment, pre-capture indexing for tracking up to 192 samples, accelerated hybrid capture, and one-tube library prep, to enable the preparation of complex enriched libraries in less than 8 hours from 10-200ng of FFPE-derived DNA. We incorporate molecular barcodes at the ligation step to enable de-duplication and generation of consensus reads using SureCall software, which significantly improves confidence of variant calling (99% of calls &amp;gt;150 variant call quality threshold) at low allelic frequencies. Using ClearSeq Comprehensive Cancer Panel which targets 151 genes frequently mutated in solid and hematological cancers, we routinely obtain high quality libraries (with 1000X sequencing depth and after deduplication) with &amp;gt;99% of the targeted region covered at 20X for high quality gDNA (FF tissue), and greater than 95% and 90% covered at 20X for medium and low quality FFPE samples, respectively. Using multiplex reference samples, we demonstrate detection of low frequency variants (at 1-5%) including SNVs, small indels, and RET and ROS1 translocations. As we will further show, FFPE integrity scores determined by qPCR and TapeStation (ddCq and DIN) enable researchers to choose the appropriate quantification method, PCR cycling, and sequencing depth for optimal sequencing coverage. Citation Format: Bahram Arezi, Bilan Hsue, Keith Chen, Brenda Rogers, Christian Lecocq, Ashutosh Ashutosh, Jayati Ghosh, Gilbert Amparo, Madhuvanthi Ramaiah, Carlos Pabon, Holly Hogrefe. Molecular barcoding improves confidence in variant calling with low input FFPE tissue samples [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 5347. doi:10.1158/1538-7445.AM2017-5347
Abstract 5400: Accurate identification of single nucleotide variants in whole genome amplified single cells
Authors: Xiao Dong, Lei Zhang, Brandon Milholland, Moonsook Lee, Alexander Y. Maslov, Tao Wang, Jan Vijg
Journal: Cancer Research (2017)

Abstract Single cell sequencing for analyzing DNA mutations across the genome in somatic tissues is critically important for studying development, cancer and aging. However, current procedures are prone to artifacts and to date a reliable protocol for single-cell somatic mutation analysis remains to be developed. Here we address the two largest sources of artifacts, i.e., DNA denaturation-related cytosine deamination and allelic bias-driven whole genome amplification errors. We first reconfigured multiple displacement amplification (MDA) into an efficient protocol for whole genome amplification of single cells without cytosine deamination artifacts, i.e., Single Cell MDA (SCMDA). We then developed a new single-cell SNV caller (SCcaller) that distinguishes real somatic mutations and amplification errors by utilizing a SNP-based localized estimate of allelic amplification bias. The procedure was validated by comparing SCMDA-amplified single cells with unamplified clones derived from single cells from the same population. Together with SCcaller, SCMDA provides a firm foundation for analyzing cellular heterogeneity in somatic mutational landscapes in tumor and surrounding, normal tissues. Citation Format: Xiao Dong, Lei Zhang, Brandon Milholland, Moonsook Lee, Alexander Y. Maslov, Tao Wang, Jan Vijg. Accurate identification of single nucleotide variants in whole genome amplified single 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 5400. doi:10.1158/1538-7445.AM2017-5400
Abstract 4967: RAF kinase inhibition synergizes with MEK inhibitors in KRAS mutant tumors
Authors: Ivana Yen, Christiaan Klijn, Frances Shanahan, Mark Merchant, Christine Orr, Thomas Hunsaker, Matthew Durk, Hank La, Xiaolin Zhang, Scott Martin, Eva Lin, John Chan, Yihong Yu, Amy Gustafson, Joachim Rudolph, Shiva Malek
Journal: Cancer Research (2017)

Abstract While activating mutations in the KRAS oncogene frequently drive tumorigenesis in human cancers (40% CRC, 20% NSCLC) through constitutive activation of the MAPK pathway, there are currently no targeted treatments available for KRAS mutant cancers. Inhibitors of the individual nodes of the MAPK pathway have been developed, but these molecules have been largely ineffective against KRAS mutant tumors in the clinic. Multiple studies have shown rational combinations of MAPK inhibitors may have anti-tumor activity in KRAS mutant models. In order to understand the versatility of combining RAF inhibitors in this context, we conducted a library screen consisting of 430 small molecule tool compounds in combination with RAF inhibitor AZ-628. Here we show: RAF inhibitors combine especially well with other MAPK pathway inhibitors in KRAS mutant tumor cells. In particular, Type II RAF inhibitors are synergistic with the MEK inhibitor Cobimetinib in vitro and exhibit tumor regressing efficacy in xenograft mouse model studies in vivo. Mechanistically, we have found the MEK inhibitor disables ERK induced negative feedback on the MAPK pathway resulting in activation of CRAF in a KRAS dependent manner. The combination of RAF with MEK inhibition blunts KRAS-dependent activation of CRAF kinase activity and robustly inhibits MAPK signaling, thereby driving efficacy in KRAS mutant tumors. Broad cell line profiling with the combination of RAF and MEK inhibitors demonstrates that a majority of KRAS mutant lung and colorectal tumor lines exhibit synergy with the combination. Therefore, combining a Type II pan-RAF inhibitor with a MEK inhibitor has the potential to improve the therapeutic outcome in KRAS mutant cancers. Citation Format: Ivana Yen, Christiaan Klijn, Frances Shanahan, Mark Merchant, Christine Orr, Thomas Hunsaker, Matthew Durk, Hank La, Xiaolin Zhang, Scott Martin, Eva Lin, John Chan, Yihong Yu, Amy Gustafson, Joachim Rudolph, Shiva Malek. RAF kinase inhibition synergizes with MEK inhibitors in KRAS mutant tumors [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 4967. doi:10.1158/1538-7445.AM2017-4967
Graphene Quantum Dots Downregulate Multiple Multidrug‐Resistant Genes via Interacting with Their C‐Rich Promoters
Authors: Chao Luo, Yanfang Li, Lijuan Guo, Fangwei Zhang, Hui Liu, Jiali Zhang, Jing Zheng, Jingyan Zhang, Shouwu Guo
Journal: Advanced Healthcare Materials (2017)

Abstract Multidrug resistance (MDR) is the major factor in the failure of many forms of chemotherapy, mostly due to the increased efflux of anticancer drugs that mediated by ATP‐binding cassette (ABC) transporters. Therefore, inhibiting ABC transporters is one of effective methods of overcoming MDR. However, high enrichment of ABC transporters in cells and their broad substrate spectra made to circumvent MDR are almost insurmountable by a single specific ABC transporter inhibitor. Here, this study demonstrates that graphene quantum dots (GQDs) could downregulate the expressions of P‐glycoprotein, multidrug resistance protein MRP1, and breast cancer resistance protein genes via interacting with C‐rich regions of their promoters. This is the first example that a single reagent could suppress multiple MDR genes, suggesting that it will be possible to target multiple ABC transporters simultaneously with a single reagent. The inhibitory ability of the GQDs to these drug‐resistant genes is validated further by reversing the doxorubicin resistance of MCF‐7/ADR cells. Notably, GQDs have superb chemical and physical properties, unique structure, low toxicity, and high biocompatibility; hence, their capability of inhibiting multiple drug‐resistant genes holds great potential in cancer therapy.
Abstract 5462: GTP cyclohydrolase in brain tumor stem cells is implicated in glioblastoma growth
Authors: Anh N. Tran, Kiera Walker, David Harisson, Wei Chen, James Mobley, Lauren Hocevar, James R. Hackney, Randee S. Sedaka, Jennifer S. Pollock, Sara J. Cooper, George Y. Gillespie, Anita B. Hjelmeland
Journal: Cancer Research (2017)

Abstract Glioblastomas (GBMs) are the most common primary brain tumors in adults and one of the most aggressive cancers with high rates of recurrence and therapeutic resistance. In GBMs, subpopulations of highly tumorigenic cells called brain tumor initiating cells (BTICs) have been characterized by their unique capacity to promote tumor maintenance, therapeutic resistance, and angiogenesis. BTIC maintenance is known to be regulated by reactive oxygen and nitrogen species. GTP cyclohydrolase, or GCH1, is a critical molecule regulating reactive species levels. We found that expression of GCH1 RNA and protein were upregulated in BTICs in comparison to non-BTICs. Overexpression of GCH1 in glioma cells increased cell growth in vitro and increased tumor formation and decreased survival in an intracranial GBM mouse model. In contrast, GCH1 depletion with short hairpin RNA in GBM cells led to growth inhibition in vitro as well as increased survival in animal orthotopic models. Furthermore, genetic modulation of GCH1 led to altered ROS levels in GBM xenolines. In silico analyses demonstrate that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence and worse survival. Together, our data suggest that upregulation of GCH1 in BTICs promotes tumor maintenance and is a key regulator of reactive oxygen species in glioblastoma. Citation Format: Anh N. Tran, Kiera Walker, David Harisson, Wei Chen, James Mobley, Lauren Hocevar, James R. Hackney, Randee S. Sedaka, Jennifer S. Pollock, Sara J. Cooper, George Y. Gillespie, Anita B. Hjelmeland. GTP cyclohydrolase in brain tumor stem cells is implicated in glioblastoma growth [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 5462. doi:10.1158/1538-7445.AM2017-5462
Abstract LB-252: Single-cell mRNA profiling reveal transcriptional heterogeneity among pancreatic circulating tumor cells
Authors: Morten Lapin, Kjersti Tjensvoll, Satu Oltedal, Milind Javle, Rune Smaaland, Bjørnar Gilje, Oddmund Nordgård
Journal: Cancer Research (2017)

Abstract Background: Single-cell analysis of the transcriptional heterogeneity of circulating tumor cells have the prospect of better understanding the biology of these cells and their involvement in the metastatic process. In addition, such analyses may reveal new knowledge about the mechanisms leading to chemotherapy resistance and tumor progression in pancreatic cancer patients. Methods: Single circulating tumor cells were enriched from blood samples (n = 50) from patients with advanced pancreatic cancer using our previously established negative depletion strategy MINDEC, and detected by immuno-fluorescence microscopy. The single cells were isolated by micromanipulation, reverse transcribed, pre-amplified, and analyzed using single cell multiplex mRNA profiling to reveal transcriptional heterogeneity. Results: Circulating tumor cells were detected in 29 (58%) of the examined blood samples. A total of 48 potential circulating tumor cells were isolated, in which 17 cells had detectable mRNA levels and were identified as circulating tumor cells by expression of epithelial (KRT8, KRT19, EPCAM, E-Cadherin) or mesenchymal (Vimentin, N-Cadherin, ZEB1) markers. These pancreatic circulating tumor cells were revealed to heterogeneously express the examined transcripts, and also showed aberrant expression of cancer stem cell (CD24, CD44, ALDH1A1) markers and the extracellular matrix marker SPARC. Hierarchical clustering and principal component analyses revealed epithelial-like and mesenchymal-like circulating tumor cell subpopulations, which were distinct from white blood cells and cancer cell line cells. Further analyses of the transcript SPARC suggested a relation to epithelial-mesenchymal transition in pancreatic circulating tumor cells. Conclusion: The analysis of single pancreatic circulating tumor cells defines distinct subpopulations and reveals aberrant expression of transcripts relevant for the dissemination of circulating tumor cells to distant sites. Citation Format: Morten Lapin, Kjersti Tjensvoll, Satu Oltedal, Milind Javle, Rune Smaaland, Bjørnar Gilje, Oddmund Nordgård. Single-cell mRNA profiling reveal transcriptional heterogeneity among pancreatic circulating tumor 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 LB-252. doi:10.1158/1538-7445.AM2017-LB-252
Abstract 1690: Epitope-minigenes for optimal induction of the immune response against tumor associated antigens and neoantigens
Authors: Silvio Bandini, Laura Luberto, Fabio Palombo, Giuseppe Roscilli, Emanuele Marra, Gennaro Ciliberto, Luigi Aurisicchio
Journal: Cancer Research (2017)

Abstract We have recently established a workflow that allows the identification of T cell epitopes within Tumor Associated Antigens (TAAs) and the construction of genetic cancer vaccine based on the use of minigenes. The T-cell epitope in silico prediction approach is based on three criteria: 1) binding to MHC Class I alleles; 2) uniqueness to the antigen of interest; 3) increased likelihood of natural processing. The combination of in silico prediction and a biochemical binding/stability assay resulted in an accurate identification of novel TAA-derived epitopes. Predicted T cell epitopes were connected by furin sensitive linkers and linked to human tissue plasminogen activator (TPA) signal and E. Coli enterotoxin B subunit, to construct an optimal minigene scaffold used as vaccine candidate. The present study was aimed at evaluating HER2/neu and hTERT (telomerase) minigenes with the same technology platform. First of all, minigenes delivered via Electro Gene Transfer (DNA-EGT) were more immunogenic than genetic vectors encoding the full-length protein or peptides injected subcutaneously and they were able to break immune tolerance in wild type and HLA-A0201 transgenic mice. Moreover, this technology applied to epitopes selected within Mutated Tumor Antigens results in strong immunogenicity and significant antitumor effects in mouse models. In conclusion, we show that minigenes delivered via DNA-EGT and based on predicted and/or experimentally identified epitopes are powerful tools to induce immune responses and combat cancer. Combination studies of minigenes with peptide vaccination, chemotherapy and immune checkpoint blockade may define new therapeutic opportunities for cancer patients. Citation Format: Silvio Bandini, Laura Luberto, Fabio Palombo, Giuseppe Roscilli, Emanuele Marra, Gennaro Ciliberto, Luigi Aurisicchio. Epitope-minigenes for optimal induction of the immune response against tumor associated antigens and neoantigens [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 1690. doi:10.1158/1538-7445.AM2017-1690