bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2181: Functionalizing intratumoral signaling heterogeneity in triple negative breast cancer
Authors: Rinkenbaugh Amanda L. , Sinha Vidya C. , Zhang Xiaomei , Piwnica-Worms Helen 
Published: August 2018

Abstract
Tumors are highly heterogeneous populations of cells, and measures of intratumoral heterogeneity (ITH) and diversity correlate with worse prognosis in many cancers, including breast cancer. Emerging studies are highlighting functional interactions between subclones, as well as among subclones and components of the tumor microenvironment. However, these studies have largely focused on soluble factors without interrogating the spatial distribution of subclones defined by activated signaling pathways. Previous work in this area has been severely limited by technical restrictions – existing techniques allowing measurement of many biomarkers simultaneously lose all information about the tissue architecture, while those that do retain spatial information can only assay a handful of markers at once. We will circumvent these limitations by undertaking imaging mass cytometry (IMC), which allows for simultaneous measurement of 30-40 antigens while retaining the spatial organization of the sample. Our objective is to dissect the signaling heterogeneity in tumors from patients and patient-derived xenograft (PDX) models of triple negative breast cancer (TNBC), through two main approaches: (1) characterization of signaling heterogeneity in human tumors and PDX models of TNBC through the use of imaging mass cytometry (IMC) and (2) modeling cell signaling heterogeneity in cell line-based models to determine mechanisms of cell-cell interaction and communication. We have constructed an IMC panel of antibodies that combines markers for tissue architecture, cell phenotyping, and signaling pathway activation. Profiling of a panel of TNBC PDX models, including matched sets of pre- and post-chemotherapy treatment, indicates emerging patterns of pathway activation. We will utilize these results to inform functional studies in our isogenic cell line models. As it is becoming more clear that tumors are composed of heterogeneous subclones, it is crucial that we understand the communication between subclones and with components of the microenvironment. Ultimately, we plan to use these results to identify novel vulnerabilities in subclonal interactions that can be targeted therapeutically in TNBC.
Citation Format: Amanda L. Rinkenbaugh, Vidya C. Sinha, Xiaomei Zhang, Helen Piwnica-Worms. Functionalizing intratumoral signaling heterogeneity in triple negative breast cancer [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 2181.
Abstract 2184: Enrichment and isolation of tumor cells using a unique flow-sorting approach to decrypt intratumoral heterogeneity in matched samples of squamous cell carcinoma of the lung
Authors: Krause Arthur , Lorber Thomas , Perrina Valeria , Barrett Michael T. , Ruiz Christian , Bubendorf Lukas 
Published: August 2018

Abstract
Background:
Genomic intratumoral heterogeneity in cancers is a driving force for progression or recurrence. Availability of pure tumor cell material is critical for studying clonal evolution. In general, tumors are highly mixed with benign cells with a mean tumor cell purity of only 49%1 shown in lung squamous cell carcinoma (LSCC). Using a unique flow-sorting based approach enables us to overcome this limitation by highly enriching for tumor cells. Here, we aimed at precisely identifying different tumor populations in primary LSCC and matched distant metastases from 18 patients.
Methods:
Nuclei from snap-frozen and FFPE tumor specimens were extracted and subjected to flow-sorting using DNA content/ploidy as a parameter. Pan-cytokeratin (pCK) was used to differentiate diploid tumor cell populations from benign diploid stromal cells. DNA has been extracted from these individual tumor cell populations and the mutational profile and copy number status are currently being analyzed using whole exome seqeuencing (WES).
Results:
We successfully enriched for tumor cells with a purity of higher than 95% using the multi parameter flow-sorting approach. Besides the aneuploid tumors with higher ploidies, we discovered near-diploid tumor populations after enrichment with the pCK antibody. The pCK negative fraction consisting of stromal cells can serve as a germ line control in further downstream analysis as WES.
Conclusion:
The present study illustrates a unique method that allows high enrichment for tumor cells. Avoiding the dilution of DNA by benign stromal cells, together with the purity of aneuploid tumor cells, the precision of genomic analysis highly increases. At the same time, the diploid and pCK negative stromal cells can serve as a germ line control. Comprehensive genomic profiling of flow-sorted aneuploid and pCK positive diploid tumor populations represent a powerful technique to study intratumoral heterogeneity.
References:
1. Zack, T. I. Pan-cancer patterns of somatic copy number alteration. Nature Genetics. 45, 10 (2013).
Citation Format: Arthur Krause, Thomas Lorber, Valeria Perrina, Michael T. Barrett, Christian Ruiz, Lukas Bubendorf. Enrichment and isolation of tumor cells using a unique flow-sorting approach to decrypt intratumoral heterogeneity in matched samples of squamous cell carcinoma of the lung [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 2184.
Abstract 2217: Concordance of PIK3CA mutations in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer: A systematic literature review
Authors: Aguilar Alejandra , Dean Joni , Anderson Elizabeth , Mollon Lea , Davis Lisa , Warholak Terri , Aizer Ayal , Platt Emma , Bardiya Aditya , Tang Derek 
Published: August 2018

Abstract
Introduction: This systematic literature review sought to determine the concordance of PIK3CA mutations in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) patients.
Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts was performed by two independent researchers that included, but was not limited to, keywords: “breast neoplasm,” “PIK3CA protein,” “hormone receptor positive,” and “metastases.” Databases were searched for English-language publications in HR+, HER2- mBC published between January 1993 through August 2017. Studies were included if results reported were specific to patients with HR+, HER2- mBC and reported data comparing PIK3CA mutations from liquid biopsies versus tumor biopsies or primary tumor samples versus metastatic lesion samples. Concordance was assessed between tissue samples (mutations found in primary tumors versus those from metastatic lesions) and between biopsy methods (i.e., tumor biopsy versus liquid biopsy) when the assessment was done at a variety of time points including time of initial diagnosis and time of diagnosis at disease progression. Content analysis was employed to quantify collected data elements.
Results: Of 558 studies included for full-text review, four met inclusion criteria (number of patient samples [n]=358). One study (n = 9) found the concordance between the mutation status of primary breast tumors to the mutation status of metastatic lesions to be 100%. Three studies (n = 47; n = 55; n = 247) determined the concordance of PIK3CA mutations between tumor biopsies and liquid biopsies with concordance ranging from 70.4% to 94%. One study found that the concordance of circulating tumor DNA (ctDNA) against tumor biopsy was higher among metastatic lesions only (81.6%) relative to using all tumor samples (either primary or metastatic lesions) (70.4%).
Conclusions: Available evidence suggested high level of concordance across sampling methods as well as across time. However, additional evidence is needed to increase study generalizability as well as to assess other possible confounding factors, such as differential timing between tumor and liquid biopsies.
Citation Format: Alejandra Aguilar, Joni Dean, Elizabeth Anderson, Lea Mollon, Lisa Davis, Terri Warholak, Ayal Aizer, Emma Platt, Aditya Bardiya, Derek Tang. Concordance of PIK3CA mutations in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer: A systematic literature review [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 2217.
Abstract 2218: Trim29 regulates hemangiomas neovascularization through targeting HMOX1
Authors: Huang Qiang , Li Wei , Ge Xin , Li Peng , Gao Ya 
Published: August 2018

Abstract
Infantile hemangiomas is the most common benign vascular tumors of childhood, characterized by rapid proliferation after birth and slow involution thereafter. Although several signaling pathways have been implicated in hemangiomas neovascularization, the mechanism is still unrevealed especially the initiative factor. Here we used gene microarray to profile proliferating and involuting phases of infantile hemangiomas and bioinformatic methods to find the distinguished genes. Log2FC&gt;0.585 or &lt;-0.585 and a nominal P value of 0.05 were used as the filtering criteria. A total of 354 significant genes were identified including 262 upregulated genes. 20 genes were selected for screening according to the microarray results. Trim29 was certified to be responsible for the proliferation of IH using Celigo cytometer method, which were reinforced in patient lesions. By overexpression of Trim29, proteomics was used to detect the downstream proteins.After comparing with the microarray results, HMOX1 was identified and selected for further study after reidentification in patient lesions. Through overexpression and knockdown assay in vitro, we found Trim29 could regulate the expression of HMOX1 and affect hemangiomas neovascularization. Propranolol could block this potential pathway to inhibit proliferation of IH in vivo. These results indicated Trim29 could regulate hemangiomas neovascularization through targeting HMOX1. This innovative pathway could be blocked by propranolol and gave a potential target gene for further investigation to find new drug treatment for IH.
Citation Format: Qiang Huang, Wei Li, Xin Ge, Peng Li, Ya Gao. Trim29 regulates hemangiomas neovascularization through targeting HMOX1 [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 2218.
Abstract 2228: Differential expression of MT-ATPase and COXIV genes in colorectal adenopolyps
Authors: Wallace Lashanale , Cherian Anju , Aikhionbare Felix 
Published: August 2018

Abstract
Therapeutic decisions in colorectal cancer (CRC) will be enhanced if guided by more accurate prognostic and predictive biomarkers during the progression of adenomas to CRC. Given that most CRCs develop from adenopolyps via the adenoma-carcinoma sequence, a mechanism for the inhibition of this sequence in patients with a high risk of developing CRC is a pressing need. Variants in mitochondrial (mt) protein expressions have been correlated with several clinico-pathological features of cancers as the majority of energy for tumor transformation are of mitochondrial origin. Differences in mitochondrial efficiency may be reflected as in adenoma-carcinoma sequence. Reports have shown that cytochrome c oxidase (COX) is a key player in oxidative phosphorylation and reactive oxygen species (ROS) formation. In addition ATPase subunits are also associated with ROS formation and mtDNA maintenance. Here, we specifically searched for differentially expressed ATPase and COX subunits in early adenomas of CRC tissues as compared to late stages of CRC tissues. In addition mitochondria variants were analyzed in mitochondrial encoded subunits of complexes IV and V of the electron transport chain. Direct sequencing, high resolution restriction digestion, RT-qPCR and western blot techniques were used to assess differences in colorectal tumors. Tissue samples used included early adenomas classified as tubular adenoma (TA), tubulovillous adenoma (TV), and villous adenomas (v); cancer tissues, and normal surrounding tissues. Results suggest that most variants of complex IV were found in mitochondrial encoded cytochrome c oxidase subunit III (9207-9990). Of these variants 9414delC found in 60% TA and 20% CA samples was predicted to be disease causing. Furthermore, ATPase6 variant G9055A found abundantly in TA and V samples was confirmed using high resolution restriction digestion. Expression levels of ATPase6 progressively increased from early adenomas to late stage adenomas and cytochrome c oxidase mitochondrial subunits also varied within the adenoma carcinoma sequence. Interestingly, COX subunit 4 isoform 1 protein expression decreased by five-fold in cancer samples when compared to normal tissue and by three-fold when compared to TA. Therefore, this study suggest an important role of ATPase and COX IV-1 in tumor CRC progression in respect to the impact on mitochondrial ROS production and oxidative phosphorylation regulation.
Citation Format: Lashanale Wallace, Anju Cherian, Felix Aikhionbare. Differential expression of MT-ATPase and COXIV genes in colorectal adenopolyps [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 2228.
Abstract 2230: Low frequency variant detection in cell free DNA by applying molecular identifiers to targeted NGS
Authors: Wood Ashley , Sandhu Sukhinder , Pezeshkian Mida , Kelchner Vanessa , RoseFigura Jordan , Lenhart Justin , Kurihara Laurie , Makarov Vladimir 
Published: August 2018

Abstract
The growing use of liquid biopsy for early detection and monitoring of disease necessitates accurate variant detection at &lt;1% allele frequencies due to a low population of disease DNA within circulating, cell-free DNA (cfDNA). Reliable, low-frequency variant detection by next-generation sequencing (NGS) is challenging due to background noise from PCR and sequencing errors. We employed molecular identifiers (MIDs) to uniquely label individual DNA molecules prior to amplification, facilitating the distinction of true variants from PCR and sequencing errors. We incorporated MIDs in both our amplicon library prep that uses multiplex PCR for targeted NGS and our whole genome library prep followed by targeting with hybridization capture using an 800kb pan-cancer panel. We performed low frequency spike-in experiments at &lt;1% allele frequencies. We prepared MID libraries with various amplicon panels including a 17 amplicon EGFR pathway panel and a 104 amplicon SNP panel. Deep sequencing to &gt;30,000x was done to maximize MID family size (number of PCR duplicates) and optimize generation of a consensus sequence. This analysis identified all known variants present at 1%, 0.5%, and 0.25% allele frequencies. Next, the hybridization capture libraries were prepared with low-frequency spike-in samples, sequenced to &gt;8000x, and all known variants at 1% and 0.5% allele frequencies were maintained in the consensus data. In both cases, the number of false positives was reduced, resulting in improved specificity. Further, EGFR amplicon libraries and hybridization capture libraries were prepared using cfDNA samples from lung, ovarian, liver, stomach, and colon cancers. Variant calling based on MID generated consensus sequences identified mutations in cfDNA samples as well as corresponding tumor and normal samples when available. This study highlights the ability of MID technology to enable low frequency variant detection, critical to track known variants and identify novel pathogenic mutations in cfDNA samples.
Citation Format: Ashley Wood, Sukhinder Sandhu, Mida Pezeshkian, Vanessa Kelchner, Jordan RoseFigura, Justin Lenhart, Laurie Kurihara, Vladimir Makarov. Low frequency variant detection in cell free DNA by applying molecular identifiers to targeted NGS [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 2230.
Abstract 2236: Metformin and pancreatic cancer risk in Taiwanese patients with type 2 diabetes
Authors: Tseng Chin-Hsiao 
Published: August 2018

Abstract
Background: Whether metformin may reduce pancreatic cancer risk is controversial and has rarely been studied in Asian populations. This study evaluated pancreatic cancer risk in type 2 diabetes patients with and without metformin treatment. Methods: An original cohort of 16232 never users and 153408 ever users of metformin who were newly diagnosed of type 2 diabetes between 1999 and 2005 were enrolled from Taiwan's National Health Insurance. A propensity score matched cohort of 16232 ever users and 16232 never users were derived from this original cohort. The patients were followed up until December 31, 2011 and analyses were conducted in both the original cohort and the matched cohort. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Results: In the original cohort, the incidence rate of pancreatic cancer in never users and ever users were 43.59 and 28.85 per 100000 person-years, respectively, with an overall hazard ratio of 0.658 (95% confidence interval: 0.438-0.988, P=0.0436). While compared to never users, the hazard ratio (95% confidence interval) for cumulative duration of metformin use in the first (&lt;22.10 months), second (22.10-46.70 months) and third tertile (&gt;46.70 months) was 1.445 (0.950-2.196), 0.595 (0.384-0.922) and 0.157 (0.094-0.264), respectively. Results in the matched cohort were very similar, with an overall hazard ratio of 0.492 (0.252-0.961) and the hazard ratio in the respective tertile of cumulative duration was 0.900 (0.368-2.198), 0.648 (0.266-1.581) and 0.094 (0.013-0.692). Conclusions: Metformin significantly reduces pancreatic cancer risk in a dose-response pattern.
Citation Format: Chin-Hsiao Tseng. Metformin and pancreatic cancer risk in Taiwanese patients with type 2 diabetes [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 2236.
Abstract 2238: Self-microemulsifying drug delivery systems (SMEDDS) containing novel compounds for the chemoprevention of pancreatic cancer
Authors: Desai Preshita , Thakkar Arvind , Wang Jeffrey , Prabhu Sunil 
Published: August 2018

Abstract
Pancreatic cancer (PC) is the fourth leading cause of deaths in the United States, claiming approximately 43,000 lives every year. Existing trends suggest that it will be the second cause of death after lung cancer within the next 20 years. With mortality rates remaining high even after decades of research, scientists are now turning to develop chemopreventive strategies that may stop or delay the initiation and progression of the disease. Our study reports the chemoprevention potential of (1) a free drug combination of H1-receptor antagonist drug with Sulforaphane (SFN), a neutraceutical compound derived from broccoli and (2) lipid nanocarriers of H1-receptor antagonist drug (SP1 SMEDDS; formulation patent pending) with free SFN when administered at low doses in human pancreatic cancer cell lines (MIA PaCa-2 and Panc-1). IC50 concentrations were calculated for various treatment groups using MTS viability assay in accordance with published protocol, using 96-well microplates and incubation time of 72 h. The free drug combination revealed almost 70-fold and 20-fold enhancement in chemoprevention efficacy (based decrease in cancer cell viability) as compared to controls. Interestingly, the free drug combination (at 5µM) showed ~55 % (p&lt;0.001) inhibition in cell lines whereas no measurable response was observed with individual free drug treatments at the same concentration. This confirmed the synergistic chemoprevention potential of the free drug combination. SP1 SMEDDS were optimized for particle size, encapsulation efficiency and chemoprevention efficacy. SP1 SMEDDS (10µM) by itself exhibited 54% (p&lt;0.001) cell line inhibition whereas no measurable response was observed with free drug at that same concentration, confirming the potential of lipid nanocarriers in enhancing the chemoprevention activity. Moreover, the SP1 SMEDDS in combination with free SFN demonstrated synergistic activity with 500-fold, 140-fold and 7-fold enhancement in chemoprevention potential as compared to the free HI-receptor antagonist, SFN and the free drug combination, respectively. In conclusion, a novel lipid formulation of an H1-receptor antagonist in combination with free SFN was invented (provisional patent applied) to successfully elicit PC chemoprevention. Future studies will look into the efficacy of this novel formulation in in vivo PC models.
Citation Format: Preshita Desai, Arvind Thakkar, Jeffrey Wang, Sunil Prabhu. Self-microemulsifying drug delivery systems (SMEDDS) containing novel compounds for the chemoprevention of pancreatic cancer [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 2238.