bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4179: A novel approach for antimetastatic therapies against TNBC utilizing a physiologic suppressor
Authors: Yesilkanal Ali Ekrem , Rabe Daniel C. , Tiwari Payal , Frankenberger Casey , Johnson Gary L. , Rosner Marsha 
Published: August 2018

Abstract
Metastatic progression of tumors is the major cause of death in patients with triple-negative breast cancer (TNBC). However, since metastasis is a multistep process, unraveling its complexity is a major challenge. One effective way of tackling this question is to study natural blockers of the metastatic process, metastasis suppressors, and identify the mechanisms by which they regulate metastasis. Raf kinase inhibitory protein (RKIP), a protein that regulates kinase activity, is a suppressor of TNBC metastasis. Although RKIP inhibits the activity of key kinases such as Raf-1, GRK2, NIK/IKK in cultured cells, the kinase targets of RKIP in tumors are not known. To address this question, we used a mass spectrometry approach involving inhibitor-conjugated beads to identify kinases that are downregulated by RKIP in human TNBC xenograft tumors. Our results identified a network of stress kinases targeted by RKIP, including kinases that have not been previously reported as RKIP targets. In order to unravel the effect of this stress network on metastatic gene expression, we investigated genes that correlate with RKIP expression in TCGA breast cancer patient data set. We identified prometastatic genes such as APC and DOCK4 as novel RKIP targets in in vitro and in vivo models of TNBC. We also demonstrated these genes are downstream of the RKIP-stress network. Finally, by using a high-throughput invasion assay, we developed a low-dose multidrug cocktail of small-molecule kinase inhibitors that mimic RKIP's antimetastatic role in TNBCs. Elucidating RKIP function at a systems level reveals the interplay between key metastatic signaling cascades, particularly in relation to cell motility and invasion. Our findings suggest that the low-dose multidrug combination that targets a network of stress kinases is a viable antimetastatic therapy for TNBC patients.
Citation Format: Ali Ekrem Yesilkanal, Daniel C. Rabe, Payal Tiwari, Casey Frankenberger, Gary L. Johnson, Marsha Rosner. A novel approach for antimetastatic therapies against TNBC utilizing a physiologic suppressor [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 4179.
Abstract 4183: Gold nanorods-assisted photothermal therapy inhibits metastasis by decreasing the mammary tumors bleeding in canine and felines
Authors: Ali Moustafa Ragab Khalil 
Published: August 2018

Abstract
Metastasis enables cancer cells to migration, which is responsible for most cancer-related deaths. It usually begins with local invasion to the surrounding tissues, followed by intravasation into the lymph and blood microvasculature before the cancer cells finally colonize within the microenvironment of other locations in the patient's body. Recently, we discovered that gold nanorods assisted photothermal therapy (AuNRs-PPTT) inhibits cancer cell migration and prevent metastasis. AuNRs-PPTT is a therapy in which AuNRs are injected to a tumor before near-infrared light is transiently applied to the tumor producing localized heat. However, AuNRs-PPTT has great potential in replacing the current ineffective anti-metastasis treatments but most of the studies has been performed in vitro. The objectives of this study to understand the AuNRs-PPTT impacting blood and blood vessels in naturally occurring mammary glands tumor in cats and dogs. Our histopathology results showed AuNRs-PPTT caused infiltration of neoplastic cells into lymphatic vessels. Furthermore, we observed that AuNRs-PPTT significantly cause blood coagulation around the tumor, which could be incorporated in the surgery to decrease the bleeding and potentially avoiding the risk of metastasis caused by the surgery. This observation might explain why AuNRs-PPTT inhibited metastasis for mammary gland metastasis upon AuNRs-PPTT. After 24 months, the optimized doses of 2.5 nm of AuNRs irradiated by near-Infrared laser with 0.5 w/cm2 intensity for 2 minutes, have shown no any toxicity signs in liver and kidney functions.
Citation Format: Moustafa Ragab Khalil Ali. Gold nanorods-assisted photothermal therapy inhibits metastasis by decreasing the mammary tumors bleeding in canine and felines [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 4183.
Abstract 4186: Monensin is selectively cytotoxic to cancer cells in an EMT-like state
Authors: Vanneste Marion , Qin Huang , Moose Devon , Li Mengshi , Schultz Michael , Wu Meng , Henry Michael 
Published: August 2018

Abstract
Metastatic, drug-resistant cancer is lethal. Epithelial-to-mesenchymal transition (EMT) is a type of phenotypic plasticity that has been implicated in cancer metastasis and drug resistance. One potential therapeutic approach is to specifically target cancer cells in an EMT-like state. In this study, we have developed a cell-based high-throughput screening (HTS) protocol using the high content Operetta imaging platform to identify EMT cytotoxic compounds. This screen was performed on epithelial (PC-3E) and mesenchymal-like (TEM 4-18) cell lines, both isolated from the parental PC-3 prostate cancer cell line based on their differential ability to invade an endothelial monolayer. A library of 2,640 compounds was screened on co-cultured PC-3E GFP cells and TEM 4-18 mCherry cells. After 72h exposure to compounds, relative numbers of GFP- and mCherry-positive cells were quantitated. Dose-response curves were established for each compound exhibiting a greater toxicity against EMT-like cells. The mechanisms of action of one of the most potent and selective compound against EMT-like cells, monensin, were further evaluated. Among the 2,640 compounds tested, salinomycin and monensin, both monovalent cation ionophores, displayed a potent and selective cytotoxic effect against EMT-like cells. A closely related compound absent from the compound library, nigericin, was also evaluated and appeared to be the most potent of the three compounds tested. Monensin (10nM) induced apoptosis, cell cycle arrest, and an increase in ROS production in TEM 4-18 cells. In addition, monensin rapidly induced swelling of Golgi apparatus, a previously known effect of monensin, in multiple cell lines most likely resulting in a blockage of intracellular protein trafficking and cell death. We then evaluated the toxicity of monensin in 24 human cancer cell lines and classified them as resistant or sensitive based on IC50 cutoff of 100nM. Supporting these findings, Gene Set Enrichment Analysis identified EMT as the top of the gene sets enriched in the sensitive group. Increased monensin sensitivity in EMT-like cells is associated with elevated uptake of H3-monensin compared to resistant cells. In conclusion, using a high-throughput screening approach, we identified monensin as a potent and specific inhibitor of cancer cells in an EMT-like state where it rapidly disrupts Golgi function. At least part of selectivity of monensin for EMT-like cells is due to increased uptake of this compound.
Citation Format: Marion Vanneste, Huang Qin, Devon Moose, Mengshi Li, Michael Schultz, Meng Wu, Michael Henry. Monensin is selectively cytotoxic to cancer cells in an EMT-like state [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 4186.
Abstract 4206: Pretreatment markers of cellular-mediated inflammation and association with survival vary significantly among cancers
Authors: Howard Rachel , Egan Kathleen , Kanetsky Peter 
Published: August 2018

Abstract
Background.
The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are established markers of systemic inflammation, and they are believed to have prognostic value in various diseases including many common cancers. These indicators of the cellular-mediated inflammatory response are easily obtained from patient blood samples and hold promise as simple and inexpensive tools for risk stratification.
Methods.
In the present study, 4509 patients spanning multiple cancer types (breast N=979; colorectal N=1024; esophageal N=594; hepatocellular N=287; melanoma N=349 and pancreatic N=1276) treated at Moffitt Cancer Center and with valid hematology lab values, demographic information, clinical disease characteristics, and outcome data were identified. We compared marker counts and ratios across all cancer types to identify disease-specific patterns in pre-treatment host immune response and evaluated the similarities with other established measures of disease-specific immunogenicity. An initial evaluation of the association between pre-treatment NLR, PLR (and corresponding absolute counts of lymphocytes (L), neutrophils (N) and platelets (P)) and disease-specific survival was conducted, controlling for age, sex, race, disease stage, treatment modality, and additionally for primary site and histological and molecular subtypes as appropriate.
Results.
Mean levels of N, L, P, NLR, and PLR all demonstrated significant differences across cancer types. Pre-treatment NLR was significantly associated with disease-specific death in four of our six cancer sites (colorectal: hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.21-1.79; esophageal: HR = 1.38, 95% CI = 1.05-1.82; melanoma: HR = 1.87, 95% CI = 1.18-2.95; pancreatic: HR = 1.69, 95% CI = 1.43-1.99). Pre-treatment PLR was significantly associated with disease-specific death in two sites (colorectal: HR = 1.34, 95% CI = 1.10-1.64; pancreatic: HR = 1.53, 95% CI = 1.30-1.79). This suggests that the utilization of markers of the cellular-mediated inflammatory response for clinical prognosis and decision-making may require disease-specific risk classification criteria.
Citation Format: Rachel Howard, Kathleen Egan, Peter Kanetsky. Pretreatment markers of cellular-mediated inflammation and association with survival vary significantly among cancers [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 4206.
Abstract 4212: PD-L1 expression, EGFR and KRAS mutations in unresectable stage III non-small cell lung cancer (NSCLC) patients
Authors: Cronin-Fenton Deirdre , Dalvi Tapashi , Hedgeman Elizabeth , Norgaard Mette , Pedersen Lars , Hansen Hanh , Fryzek Jon , Walker Jill , Mellemgaard Anders , Rasmussen Torben , Shire Norah , Riggas James , Potter Danielle , Hamilton-Dutoit Stephen , Sørensen Henrik 
Published: August 2018

Abstract
Background: Anti-PD-L1 therapy may improve prognosis in advanced NSCLC. We examined the relation of PD-L1 expression, KRAS and EGFR mutations, with survival in unresectable stage III NSCLC patients.
Methods: We obtained data on unresectable stage III NSCLC patients (defined via TNM AJCC staging and without surgery up to 120 days after diagnosis) diagnosed 2001-2012. We retrieved medical data from Danish population-based registries and paraffin-embedded tumor tissue from pathology archives. We assessed PD-L1 expression using the Ventana IHC (SP263) validated assay. We genotyped KRAS and EGFR using PCR-based kits. Follow-up began at NSCLC diagnosis and continued to death, emigration, or 31/12/2014. We used Cox regression to compute hazard ratios (HRs) and associated 95% confidence intervals (95%CI) for PD-L1, EGFR, and KRAS.
Results: Among 305 patients, 183 (60%) were men, 167 (55%) were aged &gt;65 years at diagnosis and none used immunotherapy; 148 (49%) had adenocarcinoma, 117 (38%) squamous histology, 96 (31.5%) had PD-L1 positive tumors (&gt;=25%), 6 (2%) had EGFR mutations, and 69 (23%) had KRAS mutations. Among PD-L1 positive tumors, 55% had stage IIIA, 45% IIIB disease; 1% had EGFR and 34% had KRAS mutations. Among PD-L1 negative tumors, 54% had stage IIIA and 46% IIIB; 3% had EGFR and 16% had KRAS mutations. Median survival was similar in patients with KRAS wild-type and KRAS mutations (Hazards ratio (HR)=1.07; 95% CI=0.76-1.51). Patients with an EGFR mutation had a lower non-statistically significant risk of death (HR=0.75; 95% CI=0.28-2.06). Tumor cell positivity for PD-L1 (&gt;=25% versus &lt;25%) yielded an HR=0.80 (95%CI=0.60-1.07). Immune cell positivity for PD-L1 &gt;=1% and &gt;=25% yielded HRs of 0.50 (95%CI=0.39-0.66) and 0.45 (95%CI=0.30-0.67), respectively. Tumor infiltration by immune cells with PD-L1 measured as a continuous variable yielded an HR=0.96 (95%CI=0.93-0.99).
Conclusion: Our findings suggest that PD-L1 expression and EGFR mutations, but not KRAS mutations, are associated with survival in this real-world Danish study of unresectable Stage III NSCLC patients.
Citation Format: Deirdre Cronin-Fenton, Tapashi Dalvi, Elizabeth Hedgeman, Mette Norgaard, Lars Pedersen, Hanh Hansen, Jon Fryzek, Jill Walker, Anders Mellemgaard, Torben Rasmussen, Norah Shire, James Riggas, Danielle Potter, Stephen Hamilton-Dutoit, Henrik Sørensen. PD-L1 expression, EGFR and KRAS mutations in unresectable stage III non-small cell lung cancer (NSCLC) patients [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 4212.
Abstract 4218: Breast cancer survival by age and subtype (ER/PR/HER2) in a nationwide population-based cohort
Authors: Johansson Anna L. , Trewin Cassia B. , Hjerkind Kirsti V. , Ellingjord-Dale Merete , Johannesen Tom B. , Sorlie Therese , Ursin Giske 
Published: August 2018

Abstract
Purpose: We assessed the effect of breast cancer subtype, as defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, on breast cancer survival among young (20-39y), middle-aged (40-49y), screen-aged (50-69y) and elderly (70-89y) women, to elucidate the role of tumor biology for differences in survival across age. Material and methods: A population-based cohort of 21,385 women with a breast cancer diagnosis at ages 20 to 89 between 2005 and 2015 was identified in the Cancer Register of Norway. Subtype was defined as luminal A-like (ER+ PR+ HER2-), luminal B-like HER2-negative (ER+ PR- HER2-), luminal B-like HER2-positive (ER+ PR+/PR- HER2+), HER2-positive (ER- PR- HER2+) and triple-negative (TRN) (ER- PR- HER2-). Cox regression models estimated hazard ratios (HR) for the association between age at diagnosis, subtype and breast cancer specific mortality, while adjusting for year, grade and TNM stage. Results: Young women had higher rates of HER2-positive and TRN tumors compared to middle-aged, screen-aged and elderly women who more often had luminal A-like tumors. Compared to women aged 50-59y, young women had doubled mortality rate (20-39y: HR=2.3 [95% CI 1.8-2.8]), while elderly had two to five times higher mortality rate (70-79y: HR=2.3 [1.9-2.7]; 80-89y: HR=5.2 [4.2-6.4]). After adjustment for subtype, grade and stage the association was reduced among young women (20-39y: HR=1.3 [1.1-1.6]) but less so among the elderly (70-79y: HR=2.1 [1.7-2.5]; 80-89y: HR=3.9 [3.2-4.9]). Among young women, luminal A-like and luminal B-like HER2-negative subtypes were still associated with increased mortality after adjustment for grade and stage. Among the elderly, all subtypes were associated with increased mortality after adjustment for grade and stage, with stronger effects for TRN, HER2-positive and luminal B-like HER2-positive subtypes. Conclusion: Tumor-associated factors, such as subtype, grade and stage, may explain a large part of the poorer survival among young patients, whereas comorbidities and less intensive treatment may explain the persisting poorer survival across subtypes among the elderly.
Citation Format: Anna L. Johansson, Cassia B. Trewin, Kirsti V. Hjerkind, Merete Ellingjord-Dale, Tom B. Johannesen, Therese Sorlie, Giske Ursin. Breast cancer survival by age and subtype (ER/PR/HER2) in a nationwide population-based cohort [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 4218.
Abstract 4219: Breast cancer distribution and survival among Buddhist and Muslim women in southern Thailand
Authors: Defever Kali , Rentschler Katie M. , Khazan Ana , Pinkerton Elizabeth , Virani Shama , Sriplung Hutcha , Pang Judy , Kleer Celina G. , Leon Carlos F. Mendes de , Colacino Justin A. , Rozek Laura S. 
Published: August 2018

Abstract
Objective: Thailand is undergoing a period of rapid economic growth, which has led to an epidemiologic transition from infectious to chronic diseases such as cancer. Preliminary research shows a difference in rates of breast cancer incidence and mortality between Buddhist and Muslim women in southern Thailand. This study examines differences in breast cancer and potential explanations for this disparity. Methods: Demographic, diagnostic, and outcome data from breast cancer patients diagnosed from 2001-2015 were collected from a population-based cancer registry in southern Thailand and matched with formalin-fixed paraffin-embedded blocks from Songklanagarind Hospital. This region was selected due to the relatively high proportion of Muslim women. Of 424 cases selected, 369 were Buddhist and 55 were Muslim. Formalin-fixed paraffin-embedded blocks were sent to Michigan Medicine and histological and subtype analyses were performed by two pathologists. Statistical analysis was performed in RStudio using chi-square tests of independence, logistic regression, and Cox proportional hazards models. Results: Muslim women were generally diagnosed at a younger age than Buddhist women (Muslim mean: 46.6 years, Buddhist mean: 52.7 years) and with later stage cancers (Muslim: 36% stage 3 and 14% stage 4, Buddhist: 20% stage 3 and 8% stage 4). Buddhist and Muslim women had similar distributions of Luminal A and B subtypes, but Muslim women were more likely to be diagnosed with Triple Negative breast cancer (Muslim: 30%, Buddhist: 18%), the histological subtype with the worst prognosis. Invasive ductal carcinoma was most common in both groups, but Buddhists had more heterogeneity in subtypes. There were no significant differences in tumor histology or subtype by religion. Conclusions: These analyses show differences in the distribution of breast cancer between Buddhist and Muslim women. Muslim women are diagnosed younger with later stage breast cancers, and with histological differences, which generally lead to lower survival rates. Lack of statistical significance may be due to small sample size, necessitating further studies.
Citation Format: Kali Defever, Katie M. Rentschler, Ana Khazan, Elizabeth Pinkerton, Shama Virani, Hutcha Sriplung, Judy Pang, Celina G. Kleer, Carlos F. Mendes de Leon, Justin A. Colacino, Laura S. Rozek. Breast cancer distribution and survival among Buddhist and Muslim women in southern Thailand [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 4219.
Abstract 422: Single-stranded library preparation enables unbiased sequencing of damaged, FFPE-derived DNA for both targeted gene capture and WGS applications
Authors: Vilborg Anna 
Published: August 2018

Abstract
Next Generation Sequencing is increasingly used in translational cancer research and as a diagnostic test. Most tumor specimens available for testing are formalin-fixed, paraffin-embedded (FFPE) blocks. FFPE-derived DNA is typically damaged, causing difficulties for standard library preparation methods. Frayed ends prevent blunt-ended double-stranded adapter ligation, used for whole genome sequencing (WGS) and targeted bait hybridization library preparation. Fragmented DNA and modified bases interfere with PCR, which underlies amplification based targeted sequencing.
We present a single-stranded library preparation method especially forgiving for low quality FFPE-derived DNA. By excising damaged bases and using single-stranded adapter ligation, we omit repair aimed at generating blunt-ended double-stranded DNA, and eliminate the need for whole genome PCR. After ligation of the first adapter, libraries can either undergo second adapter ligation to generate WGS libraries, or be used as input to oligo-selective sequencing (OS-Seq) target capture.
We show that our FFPE-derived PCR-free WGS libraries exhibit coverage depth and uniformity highly similar to double-stranded PCR-free libraries of matched cell line (non-FFPE) materials. Additionally, we present performance of our WGS library preparation on clinical FFEP samples.
We further demonstrate reproducible high and uniform coverage for reference standards and clinical FFPE samples in targeted capture. We show a lack of correlation between DNA quality and sequencing metrics such as on-target rate (R2=0.005), uniformity (R2=0.0002), and coverage (R2=0.06), with successful removal of C&gt;T FFPE artifacts comparable to standard repair methods. We demonstrate sensitive copy number alteration detection through analysis of coverage depth, feasible due to the absence of pre-capture PCR.
In conclusion, our single-stranded library preparation method is forgiving for sample quality and provides uniform and high coverage as the basis for somatic variant calling.
Citation Format: Anna Vilborg. Single-stranded library preparation enables unbiased sequencing of damaged, FFPE-derived DNA for both targeted gene capture and WGS applications [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 422.