bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY32-04: Defects in T cell migration within tumors: a role for extracellular matrix architecture
Authors: Donnadieu Emmanuel 
Published: May 2015

Abstract
T cell-based immunotherapies have given promising results in patients with metastatic melanoma. However, a significant proportion of cancer patients did not respond to these therapeutic interventions for reasons that are not understood. To attack a tumor, T cells need to be correctly primed in the tumor-draining lymph nodes, enter into the tumor, navigate within the tumor environment and then mediate their effector functions to cause destruction of cancer cells. All of these criteria that rely on proper migration of T cells must be met for a treatment to be effective. By using fluorescence imaging techniques, we have made significant progress in the understanding of how T cells are blocked in their migratory activities and have identified several obstacles. The first occurs in tumor-draining lymph nodes as our data reveal the existence of marked cellular and structural changes that limit T cells from migrating and performing their surveillance activity. Another alteration concerns the poor ability of T cells to contact malignant cells within tumors. Indeed, in several human carcinomas, T cells are far from malignant cells but enriched in the stroma composed of non-tumors cells along with the extracellular matrix. We have identified the matrix structure as an important stromal component in controlling the ability of T cell to migrate and mount antitumor immune response. Whereas reticular fiber networks favor T cell navigation, dense and aligned matrix fibers act as unfavorable migration zones for T cells. Such fibrotic structures, which are frequently observed around tumor islets, contribute to the poor capacity of T cells to contact and kill tumor cells.
Thus, abnormal extracellular matrix, as observed in solid tumors, can be considered another important player of the tumor stroma involved in blocking T cells in their antitumor activities. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma rendering it more permissive to antitumor T cells.
Citation Format: Emmanuel Donnadieu. Defects in T cell migration within tumors: a role for extracellular matrix architecture. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY32-04. doi:10.1158/1538-7445.AM2014-SY32-04
Abstract SY36-01: Functional genomics and cancer dependencies
Authors: Hahn William C. 
Published: May 2015

Abstract
Recent advances in genomics continue to elucidate the genetic lesions that occur in specific cancers and are increasingly being applied prospectively to patient samples in the clinic. These efforts have already identified a large number of mutations that occur at low frequency. Systematic approaches to identify cancer vulnerabilities will provide critical information about the function of these low frequency mutations and will allow the identification of cancer co-dependencies and synthetic lethal interactions. Over the past several years, we have developed genome scale RNAi libraries and open reading frame expression libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. Using these libraries, we have now performed screens in a large panel of human cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several new oncogenes that contribute to cancer development as well as co-dependencies that are required for the survival of cancers harboring specific mutations. The ability to systematically manipulate gene expression at genome scale now provides opportunities to investigate the function of genes involved in cancer initiation and maintenance, which will provide a framework for therapeutic strategies.
Citation Format: William C. Hahn. Functional genomics and cancer dependencies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY36-01. doi:10.1158/1538-7445.AM2014-SY36-01
Abstract SY36-03: How aneuploidy drives tumorigenesis
Authors: Davoli Teresa , Xu Wei , Park Peter , Elledge Stephen J. 
Published: May 2015

Abstract
Aneuploidy has been recognized as a hallmark of cancer for over 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here we describe the development of Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing &gt;8200 tumor-normal pairs we provide statistical evidence suggesting many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and the potency of TSGs (STOP genes), OGs and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.
Citation Format: Teresa Davoli, Wei Xu, Peter Park, Stephen J. Elledge. How aneuploidy drives tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY36-03. doi:10.1158/1538-7445.AM2014-SY36-03
Abstract SY42-02: Sensitization to chemoradiation by inhibition of cell cycle checkpoints
Authors: Morgan Meredith Ann 
Published: May 2015

Abstract
Chemoradiation is uniquely effective at generating DNA DSBs (double-strand breaks) in the environment of chemotherapy-induced DNA damage and replication stress producing complex, difficult-to-repair DNA DSBs. However, chemoradiation therapy also initiates robust cell cycle checkpoint responses in tumor cells which promote repair of DNA damage and thus contribute to therapy resistance. Thus, inhibition of cell cycle checkpoints by inhibitors of kinases such as Wee1 or Chk1 is an especially effective strategy for sensitizing tumor cells to chemoradiation. In addition to abrogating cell cycle checkpoints, inhibitors of Wee1 and Chk1 inhibit homologous recombination repair of DNA DSBs. Furthermore, the efficacy of PARP1/2 [poly (ADP- ribose) polymerase1/2] inhibitors in homologous recombination repair defective tumor cells provides a rationale for the combination of Wee1 or Chk1 inhibitors with PARP1/2 inhibitors and radiation. Clinical investigation of Wee1 inhibitors with chemoradiation has recently been initiated. Novel combinations of targeted agents such as Wee1 and PARP1/2 inhibitors with radiation are an important area of emphasis for future clinical studies. Preclinical studies to define optimal agent combinations and scheduling, mechanisms of tumor cell selectivity, and biomarkers will improve the likelihood of clinical success for these combinations.
Citation Format: Meredith Ann Morgan. Sensitization to chemoradiation by inhibition of cell cycle checkpoints. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY42-02. doi:10.1158/1538-7445.AM2014-SY42-02
Abstract SY44-02: Insights into pro-survival signaling by PERK
Authors: Diehl J. Alan 
Published: May 2015

Abstract
PERK, one of three key signal transducers localized to the Endoplasmic Reticulum (ER), regulates cell fate in response to proteotoxic stress. PERK activation can be triggered by exposure of cells to physiological stresses such as low energy (glucose deprivation), low oxygen (hypoxia), or by chemical that inhibit protein degradation (bortezomib) or deplete ER calcium stores (thapsigargin). Since tumor survival and progression requires bypass of many of the same stresses that are known to activate PERK, extensive efforts have been undertaken to ascertain whether targeted inhibition of PERK would have therapeutic benefit. Indeed, genetic abrogation of PERK signaling has a profound influence on tumor progression and metastasis supporting the development of small molecule PERK inhibitors. Importantly, the successful use of such small molecules in a clinical setting requires knowledge of both the potential tissue toxicities associated with acute PERK inhibition and a detailed understanding of downstream PERK effectors that contribute to cell growth and survival. To definitively establish the functional role of PERK in the adult tissue, we have generated mice harboring a conditional PERK allele where excision is regulated by tamoxifen administration. In contrast to previous reports, PERK deletion has a profound impact on pancreata regardless of age. This result has profound implications for the utility of small molecule PERK inhibitors and highlights the need to clearly delineate downstream PERK-dependent regulatory pathways. With this in mind, we have set out to define additional pro-survival PERK effector and effector pathways in an effort to develop a more complete understanding of PERK function and ascertain whether any novel effectors might represent opportunities for therapeutic development. The identification and contribution of novel PERK effectors will be discussed.
Citation Format: J. Alan Diehl. Insights into pro-survival signaling by PERK. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY44-02. doi:10.1158/1538-7445.AM2014-SY44-02
Abstract 10: DNA repair and nutritional risk models of triple-negative breast cancer
Authors: Hu Jennifer , Lee Eunkyung , Allen Glenn 
Published: May 2015

Abstract
Purpose: Triple negative breast cancer (TNBC), which lacks treatment targets for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), has been associated with African-American race, BRCA1/2 mutations, TP53 mutations, and poor prognosis. However, the etiology of TNBC remained unknown, which represents a critical barrier in reducing breast cancer mortality. Therefore, we designed a case-only study to test combined genetic and nutritional risk models of TNBC.
Methods: In 354 breast cancer patients diagnosed between 1998 and 2004, we evaluated 18 DNA-repair non-synonymous single nucleotide polymorphisms (nsSNPs) using the Sequenom MassARRAY system. The 110-item Block 1998 food frequency questionnaire was used to evaluate dietary/nutritional intakes. The Multivariate Adaptive Regression Splines (MARS)-logit models were used to define nutritional intakes cut-offs for their associations with TNBC.
Results: TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or 3 micronutrients (zinc, folate, and β-carotene). Combined DNA-repair risk genotypes and lower micronutrient intakes had a significant dosage-dependent association with TNBC (p&lt;0.001): ORs=2.77 (95%CI=1.01-7.64), 9.57 (95%CI=2.87-31.84), and 20.78 (95%CI=2.46-175.71) for 2, 3, and at least 4 risk factors combined, respectively.
Conclusion: To the best of our knowledge, this is the first study to demonstrate multiple DNA repair nsSNPs and nutritional factors are associated with TNBC. Our results suggest that dietary modulation and micronutrient supplementation may have implication in preventing or reversing TNBC, particularly in genetically susceptible women.
Citation Format: Jennifer Hu, Eunkyung Lee, Glenn Allen. DNA repair and nutritional risk models of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 10. doi:10.1158/1538-7445.CANSUSC14-10
Abstract 21: Quantitative FRET technology for SUMOylation cascade and high-throughput screening assay for SUMOylation inhibitor in cancer drug discovery
Authors: Liao Jiayu , Wiryawan Hilda , Li Yang , Song Yang , Liu Yan , You Jiacong , Jiang Ling , Malik Harbani Kaur , Saavedra Amanda N. , Qu Sophie 
Published: May 2015

Abstract
The ubiquitin–proteasome system and ubiquitin-like protein pathways, such as SUMOylation, are critical in protein homeostasis and activities in vivo and are emerging as a new strategy to treat many acute and chronic human diseases, such as cancers. Although various kinase inhibitors have been developed as target-based therapy, solid tumors are still challenges in clinical therapy because various resistant are developed after kinase inhibitor treatments, and therapeutic agents with novel mechanisms are urgently needed. SUMO has been shown to modify various critical proteins, such as p53, MDM2, Estrogen receptor and androgen receptors. More recently, a genome-wide siRNA screening shown that inhibition of SUMO E1 ligases can lead to synergistically lethality of c-Myc overexpressed breast cancer cells. However, so far, specific inhibitor of SUMOylation is still not available for the community.
Fig. 1. SUMOylation in human diseases and quantitative systems biology approach for basic and translational research of SUMOylation. We developed a novel quantitative Förster resonance energy transfer (FRET) technology platform for both basic kinetics parameter determinations and high-through screening(HTS) assays for SUMOylation cascade. The novel theoretical and experimental procedures for protein interactions affinity(Kd) determinations in the SUMOylation cascade, including the interaction between SUMO1 and its E2 ligase, Ubc9, E1 heterodimers(Aos1 and Uba2), E1 and E2 interactions(Uba2 and Ubc9), and E2 and substrate interactions(Ubc9 and RanGap1c) and protease kinetics, Kcat/KM of SENP1 endopeptidase activity have been developed in a systems biology manner. The data are in good agreement with traditional methods. Multiple FRET-based HTS assays have also been developed and HTS campaigns have led to very promising hit that can preferentially kill Non-small cell lung cancer cells. The novel SUMOylation inhibitor can be used for cancer treatments by synergistically lethality strategy.
Citation Format: Jiayu Liao, Hilda Wiryawan, Yang Li, Yang Song, Yan Liu, Jiacong You, Ling Jiang, Harbani Kaur Malik, Amanda N. Saavedra, Sophie Qu. Quantitative FRET technology for SUMOylation cascade and high-throughput screening assay for SUMOylation inhibitor in cancer drug discovery. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 21. doi:10.1158/1538-7445.CANSUSC14-21
Abstract 28: Chemoprevention strategies to target abnormal imprinting in high-risk African American women who do or do not carry a BRCA1 mutation
Authors: Seewaldt Victoria , Skaar David , Dietze Eric , Desai Shraddha , Jirtle Randy 
Published: May 2015

Abstract
Background: Genomic imprinting is an inherited form of parent-of-origin-specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. KCNK9 gene amplification accounts for increased expression in &lt;10% of these breast cancers.
Methods/Results: Here we show that KCNK9 has imprinted expression in breast tissue and provide the first identification of the KCNK9 DMR and DMR-associated open chromatin. Our studies show that loss of KCNK9 regulatory methylation and imprinted expression occurs in 75% of triple-negative breast cancer (TNBC) and loss of methylation occurs in non-cancerous tissue from high-risk women. Functional studies show that TASK3 protein regulates mitochondrial membrane potential and apoptosis-sensitivity. In live TNBC cells and non-cancerous mammary epithelial cells from high-risk women, loss of KCNK9 DMR methylation predicts increased mitochondrial membrane potential (p=0.007). African American women have a significantly higher frequency of loss of KCNK9 imprinting than do risk-matched Caucasian women (p=0.005). African American women with BRCA1 mutation have the highest frequency of loss (p&lt;0.0001).
Clinical Prevention: This is the first identification of the KCNK9 DMR and demonstration that loss of methylation and overexpression of TASK3 increases mitochondrial membrane potential and promotes apoptosis resistance. Low-toxicity inhibitors of TASK3 are in clinical use and can be readily re-purposed to provide cost effective chemoprevention. These inhibitors include K+ inhibitors (developed for cardiac indications) and Schwann Pepper. Our studies identify TASK3 as a “drugable”, low-toxicity target that can be readily employed as a novel target for prevention and treatment of TNBC, particularly in high-risk African American women.
Citation Format: Victoria Seewaldt, David Skaar, Eric Dietze, Shraddha Desai, Randy Jirtle. Chemoprevention strategies to target abnormal imprinting in high-risk African American women who do or do not carry a BRCA1 mutation. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 28. doi:10.1158/1538-7445.CANSUSC14-28
Abstract 33: Interplay of DNA damage and cell cycle signaling on Replication Protein A in human cells
Authors: Brader Kerry , Mosel Adam , Liu Shengqin , Kremmer Elizabeth , Goettsch Kaitlin , Nasheuer Heinz-Peter , Oakley Greg , Borgstahl Gloria 
Published: May 2015

Abstract
Replication protein A (RPA) is the main human single-stranded DNA (ssDNA)-binding protein. It is essential for cellular DNA metabolism and has important functions in DNA damage signaling. RPA is indispensable for accurate homologous recombination (HR)-based DNA double-stranded break (DSB) repair and its activity is regulated by phosphorylation and other post-translational modifications. HR occurs only during S and G2 phase of the cell cycle and all three subunits of RPA contain phosphorylation sites. The exact set of HR-relevant phosphorylation sites of RPA is unknown. In this study, the phosphorylation sites of chromatin-bound RPA in S and G2 phase were identified. After DNA damage, phosphorylation included pSer4/8, pSer12, pThr21, pSer23 and pSer33 of RPA2. Phosphorylation of these sites increased with time after DNA damage. Using a general ATM/ATR phosphorylation antibody, only RPA2 had substantial pSer/pThr ATM/ATR signals. Additionally, pTyr was detected on RPA1 and RPA2 and was removed in response to DSBs, indicating the regulatory action of a phosphatase. A capillary isoelectric focusing immunoassay used under native conditions revealed in high resolution isoforms of the RPA heterotrimer in control and damaged cell lysates in G2. Strikingly, RPA is a phosphoprotein in control G2 cell lysates with up to 5 putative phospho-isoforms containing up to 7 phosphates. These isoforms include RPA2 pSer23 and pSer33 and RPA1 pTyr. DNA damaged lysates contained 9 isoforms, containing up to 14 phosphates. DNA damage isoforms contained RPA2 pSer4/8, pSer12, pThr21, pSer23, pSer33 and other not yet identified phosphorylation sites.
Citation Format: Kerry Brader, Adam Mosel, Shengqin Liu, Elizabeth Kremmer, Kaitlin Goettsch, Heinz-Peter Nasheuer, Greg Oakley, Gloria Borgstahl. Interplay of DNA damage and cell cycle signaling on Replication Protein A in human cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 33. doi:10.1158/1538-7445.CANSUSC14-33
Abstract 34: Investigating PIN1 as a genetic modifier in Li-Fraumeni syndrome
Authors: Villani Anita , Novokmet Ana , Malkin David 
Published: May 2015

Abstract
Background: Li-Fraumeni syndrome (LFS) is characterized by marked clinical heterogeneity in site and age of cancer onset. The prolyl-isomerase, Pin1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1), has been shown to serve a fundamental role in mutant TP53 oncogenic gain of function and the promotion of aggressive cancer phenotypes. We sought to determine whether alterations in PIN1 modify the phenotype of patients with germline mutations in TP53.
Methods: The PIN1 promoter and coding regions were sequenced from peripheral blood lymphocyte samples of 107 individuals with Li-Fraumeni syndrome and documented TP53 mutations. The expression and activity levels of PIN1 were determined in paired patient-derived lymphoblastoid cell lines.
Results: Multivariate analysis of PIN1 variants with TP53 mutation status and selected clinical parameters is in progress. A comprehensive summary of observed associations will be presented.
Conclusions: Demonstration of a modifying effect of PIN1 on the cancer phenotype conferred by a germline TP53 mutation may aid in the management of patients with Li-Fraumeni syndrome, including the implementation of patient-specific modifications of surveillance strategies for pre-symptomatic tumor detection.
Citation Format: Anita Villani, Ana Novokmet, David Malkin. Investigating PIN1 as a genetic modifier in Li-Fraumeni syndrome. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 34. doi:10.1158/1538-7445.CANSUSC14-34
Abstract 39: FANCA regulates MUS81-EME1 mediated DNA incision in a damage-dependent manner
Authors: Benitez Anaid , Yuan Fenghua , Nakajima Satoshi , Wei Leizhen , Qian Liangyue , Myers Richard , Hu Jennifer J. , Lan Li , Zhang Yanbin 
Published: May 2015

Abstract
MUS81-EME1 is a DNA endonuclease involved in replication-coupled repair of DNA interstrand crosslinks (ICL). A prevalent hypothetical role of MUS81-EME1 in ICL repair is to unhook the damage by incising the leading strand at the 3′ side of an ICL lesion. In this study, we report that purified MUS81-EME1 incises DNA at the 5′ side of a psoralen ICL residing in fork structures. Intriguingly, interstrand crosslink repair protein, FANCA, greatly enhances MUS81-EME1-mediated ICL incision. On the contrary, FANCA exhibits a two-phase incision regulation when DNA is undamaged or the damage affects only one DNA strand. Studies using truncated FANCA proteins indicate that both the N- and C-moieties of the protein are required for the incision regulation. Using laser-induced psoralen ICL formation in cells, we find that FANCA interacts with and recruits MUS81 to ICL lesions. This report clarifies the incision specificity of MUS81-EME1 on ICL damage and establishes that FANCA regulates the incision activity of MUS81-EME1 in a damage-dependent manner.
Citation Format: Anaid Benitez, Fenghua Yuan, Satoshi Nakajima, Leizhen Wei, Liangyue Qian, Richard Myers, Jennifer J. Hu, Li Lan, Yanbin Zhang. FANCA regulates MUS81-EME1 mediated DNA incision in a damage-dependent manner. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 39. doi:10.1158/1538-7445.CANSUSC14-39