bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4690: Next-generation screen for integrative subtyping and target discovery for KRAS-mutant cancer
Authors: Yuan Tina L. , Bagni Rachel , Yi Ming , Amzallag Arnaud , Afghani Shervin , Beam Katie , Burgan William , Fer Nicole , Garvey Leslie , Smith Brian , Waters Andrew , Stephens Robert , Benes Cyril , McCormick Frank 
Published: August 2015

Abstract
Mutations in the small GTPase, KRAS, are found in ∼140,000 new cases of cancer every year in the United States. This heterogeneous class of cancers manifests primarily as adenocarcinomas of the lung, colon and pancreas. These cancers display a wide spectrum of KRAS-dependency and differentially activate downstream effector signaling. The tumors further diverge in their array of co-occurring secondary mutations, expression signatures and KRAS mutant allele. Ultimately, the sole trait these cancers share in common is an obstinate resistance to chemo- and targeted-therapies, making identification of effective treatments an urgent need. To identify treatments for such a heterogeneous class of cancers, we developed a strategy to stratify KRAS-mutant cell lines into subtypes by integrating next-generation RNAi screening and “Omics” database mining. Each subtype is characterized by unique biomarkers and distinct patterns of effector dependency, both of which represent potential targets for personalized therapeutic strategies.
Our RNAi screen systematically evaluates sensitivity to siRNA-mediated knockdown of 40 KRAS effector nodes in a panel of 135 lung, colorectal and pancreatic cancer cell lines. Data is analyzed on the single cell level, through the simultaneous measurement of 5 functional parameters. This single-cell, multi-dimensional approach allows for a comprehensive assessment of cellular homeostasis, with unprecedented depth and dynamic range that allows robust classification of cell lines by similarity. We identify subtypes of KRAS-mutant cell lines that rely on particular effector pathways such as the RAL, RSK, MTOR and autophagy pathways, which are not engaged by all KRAS-mutant cell lines, and thus may represent targets for personalized treatment. We further identify widely shared dependencies such as on the RAF, glycolytic and cell cycle pathways. Through integrative data mining of exome, transcriptome and drug/siRNA sensitivity databases for each KRAS-mutant subtype, we can identify unique biomarkers that will serve to stratify patients in the clinic and recommend personalized treatment strategies.
Citation Format: Tina L. Yuan, Rachel Bagni, Ming Yi, Arnaud Amzallag, Shervin Afghani, Katie Beam, William Burgan, Nicole Fer, Leslie Garvey, Brian Smith, Andrew Waters, Robert Stephens, Cyril Benes, Frank McCormick. Next-generation screen for integrative subtyping and target discovery for KRAS-mutant cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4690. doi:10.1158/1538-7445.AM2015-4690
Abstract 470: Nicotine reduces survival via augmentation of paracrine HGF-MET signaling in the pancreatic cancer microenvironment
Authors: Delitto Daniel , Zhang Dongyu , Han Song , Black Brian S. , Knowlton Andrea E. , Vlada Adrian C. , Sarosi George A. , Behrns Kevin E. , Thomas Ryan M. , Lu Xiaomin , Liu Chen , George Thomas J. , Hughes Steven J. , Wallet Shannon M. , Trevino Jose G. 
Published: August 2015

Abstract
Smoking is an established risk factor for the development of pancreatic adenocarcinoma (PC). However, the relationship between smoking and PC tumor biology is incompletely defined. We report reduced overall survival (OS) in PC patients who continued smoking after surgical resection with curative intention (HR 1.93; P = .040). We further demonstrate augmented paracrine signaling via the hepatocyte growth factor (HGF)/c-Met pathway as a result of nicotine exposure in the PC microenvironment. Specifically, HGF, secreted by patient-derived PC tumor associated stroma (TAS), activates the c-Met receptor in PC cells. This paracrine activation subsequently leads to downstream induction of inhibitor of differentiation-1 (Id1) in PC cells, previously established as a mediator of chemoresistance. Further delineation of the signaling pathway demonstrates HGF-induced Id1 expression is abrogated by silencing of c-Met or pharmacologic inhibition. In patient-derived PC xenografts, nicotine treatment augmented tumor growth and metastasis; tumor lysates from nicotine-treated mice demonstrated elevated HGF expression and phospho-Met levels. Additionally, patients with high intratumoral phospho-Met levels exhibited reduced overall survival compared to those with low phospho-Met levels (Median OS 6.1 vs. 15.2 months, respectively; P = .028). Taken together, our data reveal that nicotine promotes the progression of PC via a microenvironment-dependent, paracrine signaling mechanism.
Citation Format: Daniel Delitto, Dongyu Zhang, Song Han, Brian S. Black, Andrea E. Knowlton, Adrian C. Vlada, George A. Sarosi, Kevin E. Behrns, Ryan M. Thomas, Xiaomin Lu, Chen Liu, Thomas J. George, Steven J. Hughes, Shannon M. Wallet, Jose G. Trevino. Nicotine reduces survival via augmentation of paracrine HGF-MET signaling in the pancreatic cancer microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 470. doi:10.1158/1538-7445.AM2015-470
Abstract 4704: Neo-antigen enriched TIL therapy mediates superior tumor eradication in a patient-derived xenograft model of human melanoma
Authors: Kelderman Sander , Bies Laura , Van Buuren Marit M. , Van Rooij Nienke , Haanen John , Kvistborg Pia , Schumacher Ton 
Published: August 2015

Abstract
The mutational load in melanoma is high relative to that in most other human malignancies, resulting in the possible expression of large numbers of patient-specific mutated antigens. This may, in part, explain the immunogenicity of this disease and the high rate of responsiveness to immunotherapeutic strategies such as tumor-infiltrating lymphocyte (TIL) therapy. Indeed, recent data have shown that cytotoxic T-cell reactivity targeting neo antigens may be common in human melanoma TILs. Importantly though, the clinical relevance of neo-antigen specific T cell populations remains uncertain.
To directly address the tumoricidal potential of defined neo-antigen specific T cell populations, we first identified two neo-antigen specific T-cell populations within a bulk melanoma TIL culture by the combination of exome sequencing and MHC multimer-based T cell screens. Subsequently, we generated TIL products that are highly enriched for these neo-antigen reactivities and we compared the anti-tumor activity of these neo-antigen enriched TIL with that of ‘standard’ bulk TIL in NSG mice bearing the autologous tumor. We observed outgrowth of the tumors in mice treated with standard TIL. In contrast, tumors in mice treated with enriched TILs were controlled long-term. Additional experiments showed that this superior activity of neo-antigen enriched TIL was caused by the increased numbers of T cells with a high anti-tumor activity, rather than the depletion of cell populations with inhibitory activity. Furthermore, once tumors eventually recurred these were still recognized in vitro by cells from the initially infused TIL culture.
Together, these preclinical data demonstrate that neo-antigen reactive T cells within bulk TIL cultures form a critical component of anti-tumor reactivity and provide a further basis to target mutated antigens with cancer immunotherapy.
Citation Format: Sander Kelderman, Laura Bies, Marit M. Van Buuren, Nienke Van Rooij, John Haanen, Pia Kvistborg, Ton Schumacher. Neo-antigen enriched TIL therapy mediates superior tumor eradication in a patient-derived xenograft model of human melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4704. doi:10.1158/1538-7445.AM2015-4704
Abstract 4709: Compartmental flexibility in mammalian folate metabolism
Authors: Ducker Gregory S. , Chen Li , Teng Xin , Rabinowitz Joshua D. 
Published: August 2015

Abstract
Background: Folate metabolism occurs in parallel cytosolic and mitochondrial pathways. Increased mitochondrial, but not cytosolic, folate dependent serine catabolism is among the most consistent metabolic alterations in human tumors. This study employs genetics coupled with quantitative metabolic analysis to determine the respective requirements for compartmentalized folate metabolism in proliferating human cells.
Methods: Using CRISPR-Cas9 technology, we created a library of deletion mutant cell lines for enzymes in folate metabolism. Cellular metabolites from these cells were quantified by liquid chromatography mass spectrometry (LC-MS). Compartmental specific folate metabolic fluxes were assayed by labeling experiments using isotopic tracers of serine, glycine and formate.
Results: We show that in HEK 293T cells, as well as in many but not all human cancer cell lines, folate dependent serine catabolism occurs predominantly in the mitochondria. In mutant cell lines deficient for mitochondrial folate genes, the reversal of the direction of cytosolic one-carbon flux enables cell growth, albeit at a reduced rate and with metabolic hallmarks of 10-formyltetrahydrofolate deficiency. Addition of exogenous formate rescued the 10-formyltetrahydrofolate deficiency in all mutants, but the growth defect in only a subset. The growth defect persisted in cell lines mutant for enzymes required for the generation of mitochondrial one-carbon units and folate dependent generation of NAD(P)H but not for the production of formate.
Conclusions: This study finds that folate metabolism is flexible with respect to compartmentalization. Cytosolic folate metabolism can provide sufficient one-carbon flux to fuel cell growth even in the complete absence of mitochondrial activity. High expression of mitochondrial folate genes in cancer may function to meet biosynthetic requirements under the stressful conditions of the tumor or to provide necessary compartmentalized one-carbon units and/or reducing equivalents.
Citation Format: Gregory S. Ducker, Li Chen, Xin Teng, Joshua D. Rabinowitz. Compartmental flexibility in mammalian folate metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4709. doi:10.1158/1538-7445.AM2015-4709
Abstract 4713: Targeting the mitochondria for the treatment of MLH1-deficient disease
Authors: Rashid Sukaina , Bridge Gemma , Yao Zhi , Szabadkai Gyorgy , Martin Sarah A. 
Published: August 2015

Abstract
The DNA Mismatch repair (MMR) pathway is responsible for the repair of base-base mismatches and insertion/deletion loops that arise during DNA replication. MMR deficiency is currently estimated to be present in 15-17% of colorectal cancer cases and 30% of endometrial cancers. MLH1 is one of the key proteins involved in the MMR pathway. MMR deficient tumours are often resistant to standard chemotherapies, therefore there is a critical need to identify new therapeutic strategies to treat MMR deficient disease.
We have performed synthetic lethal compound and RNAi screens to identify potential therapeutic targets for the treatment of MLH1 deficient tumours. Strikingly, upon analysis, a number of the hit compounds have been shown to target mitochondrial function. Our previous work has shown that MLH1 can localize to the mitochondria and silencing of the mitochondrial genes, POLG and PINK1 are synthetically lethal with MLH1 deficiency.
We demonstrate that MLH1 deficient tumours are synthetically lethal with mitochondrial targeted agents (Menadione, Parthenolide) which are known to induce reactive oxygen species and cause oxidative stress as one of their main mechanisms of action. Upon functional analysis we show that loss of MLH1 is associated with a reduction in Complex I activity, reduced basal oxygen consumption rate, reduced spare respiratory capacity and reactive mitochondrial biogenesis (upregulation of pgc1β), suggesting that mitochondrial function is deregulated upon loss of MLH1.
Taken together, our results thus far suggest that targeting the mitochondria may be a potential therapeutic strategy for the treatment of MLH1 deficient disease.
Citation Format: Sukaina Rashid, Gemma Bridge, Zhi Yao, Gyorgy Szabadkai, Sarah A. Martin. Targeting the mitochondria for the treatment of MLH1-deficient disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4713. doi:10.1158/1538-7445.AM2015-4713
Abstract 4718: Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells
Authors: Jiang Chen Chen , Chi Meng Na , Guo Su Tang , Wilmott James S. , Guo Xiang Yun , Yan Xu Guang , Wang Chun Yan , Liu Xiao Ying , Jin Lei , Tseng Hsin-Yi , Croft Amanda , Hondermarck Hubert , Liu Tao , Scolyer Richard A. , Zhang Xu Dong 
Published: August 2015

Abstract
Inositol polyphosphate 4-phosphatase type II (INPP4B) inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling and is emerging as a tumor suppressor in a variety of tissues. Here we report that, conversely, it functions as an oncogenic regulator in human melanoma through activating PI3K/SGK3 signaling. While it was upregulated in a subset of melanomas, knockdown of INPP4B inhibited melanoma cell proliferation in vitro, and retarded melanoma growth in a xenograft model. In contrast, overexpression of INPP4B resulted in increased proliferation and anchorage-independent growth of melanocytes. Strikingly, INPP4B did not impinge on activation of Akt in melanocytic cells. Instead, it promoted PI3K/SGK3 signaling, in that INPP4B knockdown inhibited, whereas overexpression of INPP4B enhanced, activation of SGK3. Indeed, the effect of INPP4B on melanocytic cell proliferation was due to enhanced activation of SGK3, as co-introduction of an active form of SGK3 rescued melanocytes and melanoma cells from inhibition of proliferation triggered by INPP4B knockdown, and knockdown of SGK3 abolished enhancement in cell proliferation resulting from INPP4B overexpression. Upregulation of INPP4B appeared largely due to downregulation of microRNA-494 (miR-494) and/or miR-599 as a result of gene copy number reduction in melanoma cells. Collectively, these results reveal that INPP4B upregulation mediated by loss of miR-494 and/or miR-599 promotes melanoma cell proliferation through activation of PI3K/SGK3 signaling, and suggest that the role of INPP4B in the pathogenesis of cancers of different origins needs to be defined discretely.
Citation Format: Chen Chen Jiang, Meng Na Chi, Su Tang Guo, James S. Wilmott, Xiang Yun Guo, Xu Guang Yan, Chun Yan Wang, Xiao Ying Liu, Lei Jin, Hsin-Yi Tseng, Amanda Croft, Hubert Hondermarck, Tao Liu, Richard A. Scolyer, Xu Dong Zhang. Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4718. doi:10.1158/1538-7445.AM2015-4718
Abstract 473: Functional polarization of macrophage triggered by tumor-conditioned medium
Authors: Zhang Weina 
Published: August 2015

Abstract
Purpose: Macrophages are important components of leukocyte infiltrates in various tumor stroma. Macrophages that infiltrate into tumor tissues are called tumor-associated macrophages (TAMs). TAMs show anti-tumorigenesis(M1) or pro-tumorigenesis (M2) functions depending on the cytokine milieu of the tumor microenvironment. TAMs perform some key homeostatic functions that allow tumor maintenance and growth. However, the signals involved in communication between tumor cells and macrophages are poorly defined. The aim of this study is to explore the macrophage polarization treated with the tumor-conditioned medium.
Methods: Ana-1 macrophages, human THP-1 monocytes, and bone-marrow-derived macrophages (BMDMs) from C57BL/6J mice were incubated with HCT116-conditioned medium, respectively. Then we detected M1/M2 specific molecular markers by flow cytometry, Western blot and Real-time PCR. Flow cytometry was used to quantitatively assess the change of macrophage populations in macrophages treated with conditioned medium or normal medium. CD68(human) and CD11b(human), F4/80(mouse) and CD11b(mouse) were used as total-macrophage markers, CD206 as a marker of M2 macrophage. Secretory cytokine profile of the polarized macrophages was measured by cytokine array. Then, HCT116 cells were treated with conditioned medium of M2-like macrophage and applied to cell growth and colony formation assay.
Results: By Western blot, we found that HCT116-conditioned medium could induce BMDMs and Ana-1 cells to overexpress arginase1(Arg1), but Ana-1 cells to express low inducible nitric oxide synthase(iNOS). Flow cytometry showed high expression level of CD68(human) and CD11b(human), F4/80(mouse) and CD11b(mouse), CD206 in HCT116-conditioned medium induced macrophages. Additionally, mRNA level of Arg1 was higher and M2-related cytokines IL-10,IL13 were also significantly upregulated, while mRNA level of iNOS was lower and M1-related cytokines IL-12,IFN-γwere downregulated in HCT116-conditioned medium induced macrophages. Conditioned medium of M2-like macrophages promoted the HCT116 cell growth and proliferation.
Conclusions: HCT116 can secrete the soluble factors into conditioned medium, which would induce TAM polarization. Subsequently, conditioned medium of M2-like macrophages can promote tumor cells growth.
Citation Format: Weina Zhang. Functional polarization of macrophage triggered by tumor-conditioned medium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 473. doi:10.1158/1538-7445.AM2015-473
Abstract 4743: A population-based approach to address clinical cancer care: The national genomics platform
Authors: Abaan Ogan , Basu Amrita , Brown Noah , Light Bret , Deal David , Hultner Michael 
Published: August 2015

Abstract
Our understanding of the genetic basis for cancer is advancing at a rapid rate due to the application of next generation sequencing (NGS) technologies. It is becoming common to sequence tumors and patients in an attempt to find actionable mutations that could offer the patient a more targeted and effective treatment. However, the genomics of cancer is very complex and only a handful of actionable mutations have been characterized. Larger-scale studies are needed to understand the pathogenic spectrum of cancer variants and deliver reliable clinical decision-making support to providers.
Several large-scale sequencing projects are underway to collect NGS data on tumors (e.g. TCGA, ICGC, and TARGET) but a national platform for analysis, interpretation, and reporting does not exist. We propose that a consolidated informatics platform for the collection of outcomes data with genomics and clinical data would accelerate research and provide patients with the opportunity for personalized cancer treatment. In addition, with 1,665,540 new cancer cases predicted in the US for 2014, a national-scale genomics platform is needed, capable of sequencing 3 million genomes per year, storing exabytes of data, while supporting over 20,000 oncologists, researchers, and analysts.
At Lockheed Martin, we deliver highly scalable and reliable information systems for a variety of missions and citizen services. Here, we will present our vision for a national cancer genomics platform to include NGS data collection, cost-efficient storage, scalable and modular processing pipelines, and collaborative analytics and data sharing capabilities, within a compliant privacy and security framework. In conclusion, by leveraging the scale of clinical cancer sequencing and capturing these data into a case management system for translational research, this platform provides data at-scale needed for finding actionable mutations, designing effective treatments and implementing prevention strategies, faster.
Citation Format: Ogan Abaan, Amrita Basu, Noah Brown, Bret Light, David Deal, Michael Hultner. A population-based approach to address clinical cancer care: The national genomics platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4743. doi:10.1158/1538-7445.AM2015-4743
Abstract 4752: Genomic cytometry: Single cell mutation analysis combining PCR with flow cytometry
Authors: Hyun William C. , Sciambi Adam , Pellegrino Maurizio , Eastburn Dennis 
Published: August 2015

Abstract
Genomic cytometry is a new technology field combining the high-throughput capabilities of flow cytometry and cell sorting with single-cell multiplex genomic analysis in microfluidic drops. The genomic cytometry method we will describe is PCR-activated cell sorting (PACS). PACS is analogous to Fluorescence-Activated Cell Sorting (FACS) in throughput and the ability to analyze single cells; however, unlike conventional flow cytometric immunophenotyping, PACS uses extremely sensitive microdroplet TaqMan PCR reactions to identify and, if needed, sort cells of interest for additional downstream molecular characterization. This unique approach enables PACS to identify cells based on the presence of transcripts, genomic DNA sequences, mRNA splice variants, SNPs, non-coding RNAs, and other biomarkers not amenable to antibody-based probe detection. PACS can be used to sort and enrich cells targeting single-copy genomic DNA for the analysis of circulating tumor cells (CTCs), intra-tumor heterogeneity, rare stem cells, viral or pathogen infections and genomic characterization of cancer immune system response and disorder. By analyzing individual cells within a population, it is possible to identify rare CTC populations or transient cell states, critical to human health and cancer progression, that are otherwise unobservable by ensemble measurements. With PACS, we identified and sorted prostate cancer cells from a heterogeneous population by performing &gt;132,000 simultaneous single-cell TaqMan RT-PCR reactions targeting vimentin mRNA. Following vimentin-positive droplet sorting and downstream analysis of recovered nucleic acids, we found that cancer-specific genomes and transcripts were significantly enriched.
Citation Format: William C. Hyun, Adam Sciambi, Maurizio Pellegrino, Dennis Eastburn. Genomic cytometry: Single cell mutation analysis combining PCR with flow cytometry. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4752. doi:10.1158/1538-7445.AM2015-4752