bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY09-02: Can sitruin activation treat cancer
Authors: Guarente Leonard P. 
Published: May 2019

Abstract
SIR2 and related genes are NAD-dependent deacetylases that slow aging in yeast, C. elegans, and Drosophila. In yeast and flies, SIR2 genes are also involved in the longevity conferred by dietary or calorie restriction (CR). The mammalian SIR2 homologs termed SIRT genes, or sirtuins, are involved in changes in stress resistance and metabolism and are known to be associated with CR. Critically, the CR diet in rodents not only extends life span, but also protects against many diseases of aging. In this talk, I will describe recent findings in the field regarding SIRT1 function in specific mammalian tissues in relation to murine disease models, with an emphasis on cancer. Our findings indicate that SIRT1 can influence many of the major diseases of aging, including metabolic diseases like diabetes, neurodegenerative diseases (Alzheimer's and Huntington's), cancer and osteoporosis. Therefore small molecules that alter the activity of SIRT1 (i.e. CR mimetic drugs) offer a new approach to prevent and possibly treat the major diseases of aging.
Supported by NIA, The Glenn Foundation, and The AAF. Guarente consults for Sirtris/GSK
Guarente, L. (2007). Sirtuins in aging and disease. CSH Symp. Quant. Biol. 72, 483-488.
Guarente, L. (2008). Mitochondria - a nexus for aging, calorie restriction and sirtuins?. Cell 132, 171-175.
Citation Format: Leonard P. Guarente. Can sitruin activation treat cancer [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY09-02
Abstract SY11-03: Turning enzymes on with small molecules
Authors: Wells James A. , Wolan Dennis , Zorn Julie , Datta Debajyoti , Gray Daniel , Sadowsky Jack 
Published: May 2019

Abstract
Most drug discovery efforts focus on generating inhibitors leading to loss-of-function phenotypes. My lab has been focusing on discovering ways to activate enzymes leading to gain-of-function phenotypes. Many enzymes such as proteases and kinases are stored in dormant “off” forms that are subsequently activated through post-translational modification. Work will be presented for discovery of small molecule activators for the apoptotic proteases known as caspases, as well a Ser-Thr kinase PDK-1. Our group is also developing split-proteins that can be activated by orthogonal small molecule dimerizers to phenocopy the effects seen from the small molecule activators. Such protein activators allow one to ignite signaling from specific nodes and thus probe the sufficiency of enzyme activity to drive a cellular response. Protein activation, as opposed to inhibition, expands the landscape for drug discovery.
Citation Format: James A. Wells, Dennis Wolan, Julie Zorn, Debajyoti Datta, Daniel Gray, Jack Sadowsky. Turning enzymes on with small molecules [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY11-03
Abstract SY13-02: Transcriptional control of tumor-induced myeloid-derived suppressor cells
Authors: Bronte Vincenzo 
Published: May 2019

Abstract
We have generated myeloid-derived suppressor cells (MDSCs) from bone marrow precursors (BM-MDSCs) as a tool to investigate the molecular pathways involved in their immunosuppressive program. BM-MDSCs suppress in vitro both antigen-specific and unspecific CD8+ T cells. The tolerogenic properties of BM-MDSC were further confirmed in vivo following their adoptive transfer in a setting of allogeneic pancreatic insulae transplantation in pharmacologically-induced diabetic mice. The cytokines leading to generation of MDSCs are normally produced during an inflammatory response and act on a common transcription factor which is considered a master regulator of the emergency granulopoyesis. We investigated the effect of genetic knock out of this transcription factor in vivo by creating mice lacking it in myelomonocytic cells. In these mice tumor growth did not cause dysfunction in CD8+ T cells, suggesting that this transcription factor is crucial for their tolerogenic activity and a potential target for new approaches aimed at controlling tumor-induced tolerance.
Citation Format: Vincenzo Bronte. Transcriptional control of tumor-induced myeloid-derived suppressor cells [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY13-02
Abstract SY14-03: Anaplastic lymphoma kinase (ALK): Normal biology and role in hematopoietic malignancies
Authors: Morris Stephan W. 
Published: May 2019

Abstract
Citation Format: Stephan W. Morris. Anaplastic lymphoma kinase (ALK): Normal biology and role in hematopoietic malignancies [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY14-03
Abstract SY15-04: Systematic reconstruction of regulatory networks in mammalian cells: Lessons from the pathogen response
Authors: Regev Aviv 
Published: May 2019

Abstract
Deciphering the regulatory networks that control dynamic and specific gene expression responses in mammalian cells remains a major challenge. While models inferred from genomic data have identified candidate regulatory mechanisms, such models remain largely unvalidated. Here, we present an unbiased strategy based on systematic gene perturbation and innovative multiplex detection to derive regulatory networks in mammalian cells. We apply this approach to decipher the network that controls the transcriptional response to pathogens in primary dendritic cells (DCs), testing the regulatory function of 125 transcription factors, chromatin modifiers, and RNA binding proteins. Our approach accurately assigned 32 known regulators (e.g. NFκB, IRFs, and STATs) to their target genes and discovered 68 additional functional regulators that were not previously implicated in this response. We quantify the contribution of each regulator to two major transcriptional programs (inflammatory and antiviral), identifying a core network of two dozen key regulators and 76 fine-tuners, that uses a combination of coherent feed-forward circuits, dominant activation, and cross-inhibition to control response specificity. Among these we discover a tier of chromatin modifiers that specifically repress interferon beta 1 (IFNβ1) expression upon bacterial but not viral stimulation, and a large circuit of cell cycle regulators that was co-opted to regulate the viral response. Our work establishes a broadly-applicable, comprehensive and unbiased approach to identifying the wiring and function of a regulatory network controlling a major transcriptional response in primary mammalian cells.
Citation Format: Aviv Regev. Systematic reconstruction of regulatory networks in mammalian cells: Lessons from the pathogen response [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY15-04
Abstract SY19-03: Single-cell signaling and pathology in primary cell cancers for mechanism and diagnostics
Authors: Nolan Garry P. 
Published: May 2019

Abstract
Intracellular assays of signaling systems has been limited by an inability to correlate functional subsets of cells in complex populations based on active kinase states or other nodal signaling junctions. Such correlations could be important to distinguish changes in signaling status that arise in rare cell subsets during functional activation or in disease manifestation. We have demonstrated the ability to simultaneously detect activated kinases and phosphoproteins in simultaneous pathways in subpopulations of complex cell populations by multi-parameter flow cytometric analysis, and now via high throughput mass spectrometry at the single cell level.
The focus of the presentation will be our mechanistic studies of human Follicular Lymphoma, as well as signaling of “stem cell” like cell subsets in Acute Myelogenous Leukemia and other myeloid dysplasias. The detailed, correlated datasets generated via single cell phospho-flow allows for ready representation via automated signaling network determination using Bayesian analysis. Our pursuit of deep analysis of these datasets, and the limitations of cloud computing or standard multi-CPU systems, has stimulated our development of unique computational approach using field programmable gate arrays and GPU multiprocessor architectures in the development of a ‘bioinformatics supercomputer’ and associated algorithms.
By analyzing the immune system, or cancer, as individual cells we now observe structured network interactions within these tissues at a new level of clarity. I will present our initial generations of comprehensive network topology maps of signaling within, and between, primary immune subsets in normal and pathologic disease tissues in cancer. My emphasis will be on the application of these approaches directly to human samples in near-patient settings for the development of point-of-care mechanistic referencing of disease and drug action.
Citation Format: Garry P. Nolan. Single-cell signaling and pathology in primary cell cancers for mechanism and diagnostics [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY19-03
Abstract SY19-04: A systems biology approach reveals master regulators of the mesenchymal phenotype of glioblastoma
Authors: Califano Andrea 
Published: May 2019

Abstract
A key challenge in cancer research is the identification of master regulators associated with oncogenesis and tumor progression, i.e., gene products that are necessary and/or sufficient to induce these events. We show that this problem can be successfully tackled by reverse-engineering and unbiased interrogation of context-specific maps of molecular interactions, commonly known as Interactomes.
Specifically, it has been shown that a mesenchymal phenotype is the hallmark of tumor aggressiveness in human malignant glioma. Yet, the regulatory programs determining the associated signature are unknown. We used the ARACNe reverse-engineering algorithm to infer a genome-wide transcriptional interactome, from a large collection of high-grade glioma samples. Interactome-based analysis of the mesenchymal signature of high-grade gliomas revealed a regulatory module causally related to its transcriptional activation.
Two transcription factors (C/EBP and Stat3) emerged as synergistic initiators and master regulators of mesenchymal transformation. Indeed, ectopic co-expression of C/EBPβ and Stat3 was sufficient to reprograms neural stem cells along an aberrant mesenchymal lineage. Conversely, co-silencing of these transcription factors in high-grade glioma cells led to collapse of the mesenchymal signature and systematic reduction in tumor aggressiveness. In human glioma, expression of C/EBPβ and Stat3 correlates with mesenchymal differentiation and predicts poor clinical outcome.
Citation Format: Andrea Califano. A systems biology approach reveals master regulators of the mesenchymal phenotype of glioblastoma [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY19-04
Abstract SY24-03: The signaling landscape of oncogenic ras
Authors: Bar-Sagi Dafna 
Published: May 2019

Abstract
Ras proteins are highly conserved membrane-bound nucleotide binding proteins. They are essential for the transduction of diverse extracellular signals that control cell growth, and abnormal activation of Ras proteins is implicated in the development of several types of human cancers. It is now well established that Ras proteins control cell growth through the activation of multiple effector pathways. These pathways form a signaling network that enables the cell to interpret biological inputs in a context-dependent manner. I will describe our efforts to define a molecular framework for the regulation of Ras-dependent signal output and to understand how this output is modified in cancer cells.
Citation Format: Dafna Bar-Sagi. The signaling landscape of oncogenic ras [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY24-03
Abstract SY28-02: Connections in the BRCA1-BRCA2 pathway of homologous recombination: Implications for breast cancer development and treatment
Authors: Powell Simon N. 
Published: May 2019

Abstract
The breast cancer susceptibility gene, BRCA2, mediates homologous recombination (HR) via its direct interaction with the Rad51 recombinase. There is ample genetic and biological evidence that BRCA1 and BRCA2 are functioning in the same pathway of DNA repair, but the functional connection between the two proteins is poorly understood. Interestingly, a mutation of BRCA1 (S988A) localized normally to ionizing radiation induced nuclear foci (IRIF), but the BRCA2 protein could not be recruited to BRCA1 at the damage site. Phosphorylation of BRCA1 at the S988 site is carried out by Chk2, which was also required for BRCA2 to localize to sites of DNA damage and support homologous recombination. These observations suggest that CHK2-BRCA1-BRCA2-Rad51 function in a single pathway of homologous recombinational repair to prevent the development of breast cancer. In familial breast cancer, one allele of BRCA1 or BRCA2 is germline mutant and the second allele is inactivated to allow tumor development. Thus, loss of function of BRCA1/BRCA2 is a tumor-specific finding, making the role of alternative repair pathways in these cells critical for their survival. We show that loss of Rad52 function is synthetic lethal with BRCA2 deficiency, whereas there is no impact on cell growth in BRCA2-complemented cells. The frequency of both spontaneous and double-strand break-induced homologous recombination, and ionizing radiation induced Rad51 foci, decreased by greater than 50%, when Rad52 was depleted in BRCA2-deficient cells, with no effect in BRCA2-complemented cells. Ionizing radiation-induced and S-phase associated Rad52-Rad51 foci form equally well in the presence or absence of BRCA2, indicating that Rad52 can respond to DNA double strand breaks and replication stalling independently of BRCA2. The observation that Rad52-inactivation is synthetic lethal with BRCA2 and that Rad52 acts independently of BRCA2 makes Rad52 a target for therapy in these tumors. Finally, we have evidence that the BRCA1-BRCA2 pathway can be functionally inactivated in sporadic breast cancer, suggesting that the pool of patients with defects in homologous recombinational repair is larger than initially expected.
Citation Format: Simon N. Powell. Connections in the BRCA1-BRCA2 pathway of homologous recombination: Implications for breast cancer development and treatment [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY28-02
Abstract SY29-02: The Mdm2/Mdm4 complex: A rheostat for p53 activity
Authors: Lozano Guillermina 
Published: May 2019

Abstract
The activity of the p53 tumor suppressor is regulated by multiple factors. Two of these, Mdm2 and Mdm4, function as p53 inhibitors in vivo in multiple cell types. Loss of Mdm2 or Mdm4 in mice leads to embryo and cell lethal phenotypes that are rescued by deletion of p53. Additionally, haplo insufficiency at these loci results in elevated p53 activity, delayed lymphomagenesis, and developmental defects in some cases. On the other hand, over expression of Mdm2 and Mdm4 occurs in many tumors most of which retain wild type p53. Mdm2 and Mdm4 transgenic mice are tumor prone. Additionally, a single nucleotide polymorphism (SNP) in the human MDM2 promoter increases the levels of MDM2 expression is associated with increased cancer risk. A mouse model with this SNP shows increased Mdm2 levels, decreased p53 activity, and an enhanced tumor phenotype. These data emphasize the exquisite sensitivity of the p53 pathway to changes in Mdm2 and Mdm4 gene dosage, and the consequences of those effects on development and tumorigenesis.
Citation Format: Guillermina Lozano. The Mdm2/Mdm4 complex: A rheostat for p53 activity [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY29-02
Abstract SY31-01: The role of autophagy in cancer progression and therapy
Authors: White Eileen P. 
Published: May 2019

Abstract
Autophagy is induced by metabolic stress and can promote cell survival by maintaining energy homeostasis and by damage mitigation. Autophagy is negatively regulated by activation of mammalian target of rapamycin (mTOR) that links nutrient and growth factor availability to cell growth and catabolism. mTOR inhibitors have shown efficacy in renal cell carcinoma (RCC) but the role of autophagy stimulation and potentially counterproductive promotion of tumor cell stress tolerance was not known. We have found that the mTOR inhibitor CCI-779 (temsirolimus) promoted autophagy-mediated stress tolerance and that inhibition of autophagic degradation with chloroquine enhanced kidney tumor cell death in vitro and in vivo. Thus, autophagy inhibition may be a useful strategy to enhance the anti-tumor activity of mTOR inhibitors in RCC. Although therapeutic inhibitors of the mTOR pathway have been demonstrated to slow progression of advanced RCC in patients, and were approved by the FDA as a standard therapy for RCC, this beneficial effect is only temporary. One possible mechanism of resistance may be due to autophagy as a survival response. Additionally, metabolic stress caused by insufficient angiogenesis and the resulting mTOR inhibition activate tumor cell survival by autophagy, and tumor cells in these hypoxic regions respond most poorly to treatment. We reveal a new therapeutic paradigm of coordinate mTOR and autophagy inhibition to block the survival advantage and enhance tumor cell death to maximize therapeutic benefit.
Citation Format: Eileen P. White. The role of autophagy in cancer progression and therapy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY31-01
Abstract SY33-04: Role of shelterin in cancer and aging: Generation of conditional knockout mice for TRF1, TPP1, and RAP1
Authors: Blasco Maria 
Published: May 2019

Abstract
Shelterin is a highly conserved chromosome end-capping complex, which encompasses TRF1, TRF2, TPP1, POT1, TIN2 and RAP1. Although extensive cell culture studies suggest that shelterin is essential for telomere regulation, its role in telomere biology and disease in the context of the organism remained elusive due to lack of viable loss-of-function mouse models. I will report on mice and cells conditionally deleted for TRF1, TPP1 and RAP1. While deletion of TRF1 and TPP1 in mouse stratified epithelia results in perinatal mortality, severe skin atrophy and hyperpigmentation, and widespread epithelial dysplasia and tumors in the absence of p53, RAP1 deletion does not affect mouse viability and only leads to mild skin hyperpigmentation at aduldhood. This differential impact of TPP1 and TRF1 deletion compared to RAP1 deletion is in agreement with severe telomere uncapping produced by either TPP1 or TRF1 abrogation, which is not observed upon RAP1 deletion. These results argue that RAP1 is not an essential telomere capping protein in mammals. Instead, we show here that both TPP1 and RAP1 are important to recruit telomerase to telomeres and to maintain telomere length. In addition, we demonstrate that RAP1 is important for silencing of genes located near the telomeres, demonstrating a conserved role of RAP1 in subtelomeric gene silencing from yeast to mammals.
Citation Format: Maria Blasco. Role of shelterin in cancer and aging: Generation of conditional knockout mice for TRF1, TPP1, and RAP1 [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY33-04
Abstract SY34-04: Do we need to know what pO2 hypoxia is
Authors: Koch Cameron J. 
Published: May 2019

Abstract
Despite its widespread use in the literature, the word ‘hypoxia’ is often missing from dictionaries. It means “a deficiency of oxygen reaching the tissues of the body” (Encyclopaedia Britannica). Since many molecular, biological and chemical phenomena are related to the actual oxygen concentration (most commonly estimated in units of partial pressure for tissue) it seems reasonable to suggest that one must carefully define the precise nature of ‘hypoxia’ in tissue. In addition to many other possible applications, this first step is critical before attempting to overcome hypoxia's many deleterious effects by therapeutic intervention. Among its multiple complexities, and consistent with its vague definition, hypoxia in tumors can be caused by several distinct mechanisms. Although most of these mechanisms have been predicted to cause oxygen-deficits in isolated small volumes or thin inter-connected shells of tissue, we have recently described a new mechanism that leads to what we have termed ‘extended regional hypoxia’, whereby entire zones of hypoxic tissue, having multi-millimeter dimensions, may form.
In order to address the biological and/or therapeutic importance of the complexity described above, we clearly need to be able to distinguish between the causes of hypoxia, and then determine the relevance of this to either the biology or therapy of tumors and normal tissue. Unfortunately, the development of validated methods to determine the type and degree of hypoxia is far from complete. This talk will discuss various approaches to understanding tumor ‘hypoxia’ using the hypoxia marker EF5 (a 2-nitroimidazole), both from the point of view of invasive and non-invasive imaging. A novel modification of the EF5 binding technique has allowed an initial description of the mRNA transcriptional changes that accompany ‘hypoxia’ in a syngeneic rat tumor model.
Citation Format: Cameron J. Koch. Do we need to know what pO2 hypoxia is [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY34-04