bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY18-01: Hypoxia, metabolism, and tumor progression
Authors: Simon M. Celeste 
Published: August 2012

Abstract
Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O2), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mTORC1 activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O2. Specifically, we demonstrate that hypoxic Tsc2-/- cells deprived of serum lipids undergo mTORC1-dependent apoptosis associated with elevated reactive oxygen species (ROS), a persistent unfolded protein response (UPR), and a failure to fully activate autophagy. Of note, UPR activation and cell death can be reversed by the addition of unsaturated fatty acids or ROS inhibitors. Our data suggest that cancer cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance protein and lipid synthesis due to a critical limitation in desaturated fatty acids.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY18-01. doi:1538-7445.AM2012-SY18-01
Abstract SY19-01: Integrating proteomic, transcriptional, epigenomic, and interactome data reveals the signaling changes induced by oncogenic mutations
Authors: Fraenkel Ernest 
Published: August 2012

Abstract
Proteomic technologies, next-generation sequencing and RNAi screens are providing increasingly detailed descriptions of the molecular changes that occur in diseases. However, it is difficult to assemble these data into a coherent picture that could lead to new therapeutic insights for several reasons. Despite their power, each of these methods still only captures a small fraction of the cellular response. Moreover, when different assays are applied to the same problem, they often provide apparently conflicting answers. We have developed powerful new approaches to integrate these data to identify small, functionally coherent pathways that underlie cellular behavior. In this talk, I will demonstrate how these methods can be applied to understand how oncogenic mutations alter signaling and transcription.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY19-01. doi:1538-7445.AM2012-SY19-01
Abstract SY19-02: Novel models and treatments targeting the HER-AKT pathway in cancers that overexpress HER2
Authors: Itani Soulaiman , Korkola James , Gray Joe , Tomlin Claire 
Published: August 2012

Abstract
Dynamic treatments targeting the HER-AKT pathway in cancers that overexpress HER2 Soulaiman Itani*, James Korkola**, Joe Gray**, Claire Tomlin* The mixed performance of TKI treatment for HER2-amplified breast cancers has inspired further research of the HER-PI3K signaling pathway. This in turn has produced new insight into the feedback that allows this pathway to survive the inhibition of HER2, and the role of additional mutations in the pathway. Based on this insight, we created an Ordinary Differential Equation (ODE) model for the pathway. The model was based on mass action kinetics, catalytic, and Michaelis-Menten models of chemical reactions, and was able to give several correct predictions about the response of different cell lines to overstimulation, their sensitivity to treatment, and their basal activity levels. The modeling also emphasized the importance of dynamic treatments, where the dosing and mixture of the drugs changes over time to drive the cancer first to susceptible states and then to death. Dynamic treatments are inspired by the steering of dynamic systems: To make a wide left turn, you go right first. Our novel dynamic treatment scheme was designed, tested, and was shown in experiment to increase the apoptosis of HER2 amplified cancers from 11% to 50%. The experiments tested the treatment on five cell lines, SKBR3, BT747, HCC1954, JIMT1, and MDAMB361. The cell lines were serum starved, then pretreated for two days with a drug that activates AKT, and then treated with Lapatinib. The pretreatment increased the efficacy of Lapatinib, which is nonintuitive since these drugs have opposite effects on AKT. Dynamic treatments focus on the idea of using the cancer's strongest asset, its adaptability, against it. *UC Berkeley **Oregon Health and Science University
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY19-02. doi:1538-7445.AM2012-SY19-02
Abstract SY22-02: Mammalian functional genetic signatures identify efficacy landscapes of combination chemotherapy
Authors: Lauffenburger Douglas A. , Pritchard Justin R. , Hemann Michael T. 
Published: August 2012

Abstract
Many current cancer treatments involve the administration of multi-drug regimens. However, no clear consensus exists to explain how drugs interact to create combinatorial effects. Here we will describe recent studies using RNAi-based functional signatures in mammalian cells to test specific hypotheses underlying combination drug mechanisms. We find that while potently synergistic drug combinations reinforce the cytotoxic action of one component in a manner that highlights drug-specific genetic dependencies, clinically used multi-drug regimens minimize the effect of genetic diversity and thus homogenize response across distinct subpopulations. We confirmed this finding in spontaneously arising lymphomas, where standard combination therapy reduced the variation in drug response between different tumors. Thus, we suggest that commonly used chemotherapeutic drug combinations are intrinsically “de-personalized” and function by homogenizing therapeutic response across randomized patient cohorts.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY22-02. doi:1538-7445.AM2012-SY22-02
Abstract SY23-01: Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues
Authors: Shibata Yoshiyuki , Kumar Pankaj , Layer Ryan , Willcox Smaranda , Gagan Jeffrey R. , Griffith Jack D. , Dutta Anindya 
Published: August 2012

Abstract
DNA in normal mammalian somatic cells is either in long chromosomes or in mitochondria. Furthermore, other than in specialized tissues like B and T cells, the genomic DNA in normal tissues is usually considered to be an exact copy of germ-line DNA. We hypothesized that errors in DNA replication may lead to the production of extra-chromosomal DNA and/or changes in copy number of segments of the DNA in normal somatic tissue. We have identified tens of thousands of short double-stranded and single-stranded extrachromosomal circular DNA (microDNA) that are derived from unique, non-repetitive sequences of chromosomes in normal mouse brain, heart and liver as well as mouse and human cell lines. MicroDNAs are 200-400 bases long and high in GC content. Short direct repeats are often present at the start and end of the corresponding chromosomal sequence suggesting that microDNAs are produced by replication slippage, homologous recombination or microhomology mediated repair. Several of the microDNAs overlap with nucleosome-occupied DNA, explaining how such short double-stranded DNA can be bent into a circle. The genomic sources of the microDNAs are enriched in the 5′ region of genes, exons and CpG islands. Ultrahighthroughput sequencing of adult brain DNA targeted to chromosomal loci that are enriched sources of microDNA, reveals a small fraction of genomic DNA molecules with micro-deletions that may be generated by the excision of microDNAs. We have thus identified a new DNA entity in somatic cells and provide evidence that deletions may occur in different genomic loci in somatic tissues, leading to genetic variability between normal somatic cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY23-01. doi:1538-7445.AM2012-SY23-01
Abstract SY27-01: Cutting both ways: Why FADD, FLIP, and Caspase-8 are required for embryonic development
Authors: Green Douglas R. 
Published: August 2012

Abstract
Caspase-8 has two opposing biological functions - it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T lymphocyte activation, and resistance to necrosis induced by Tumor Necrosis Factor-α (TNF) and related family ligands. We found that development of caspase-8-deficient mice is completely rescued by ablation of Receptor Interacting Protein Kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand, and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-Like Inhibitory Protein Long (FLIPL), and this complex is required for the protective function.
Caspase-8 homodimers and caspase-8-FLIP heterodimers are activated on the oligomerized adapter molecule, FADD. Therefore, while the FADD-caspase-8-FLIP complex protects against RIPK3-dependent necrosis, the FADD-caspase-8 complex does not, and necrosis ensues. In the absence of RIPK3, FADD-caspase-8 instead induces apoptosis. This idea has several ramifications. Knock-outs of FADD, or FLIP show identical embryonic lethality, but while the FADD KO is fully rescued by ablation of RIPK3, the FLIP KO is not. Our in vitro studies suggest that in the FLIP, RIPK3 DKO mouse, sensitive cell populations die by apoptosis rather than necrosis. Indeed, we found that unlike caspase-8 or FADD KO embryos, FLIP RIPK3 DKO embryos at e9.5 show focal regions of apoptosis.
Another prediction from the in vitro studies is even more striking_that lethality in the FLIP RIPK3 DKO mouse should be rescued by ablation of FADD. We have now generated the FADD FLIP RIPK3 TKO mouse, and these animals are developmentally normal. In addition to providing strong genetic evidence for a model of FADD-caspase-8-FLIP interaction with RIPK1-RIPK3, these studies involve an effect that has not been previously seen to our knowledge_two lethal genotypes (one KO, one DKO) when combined into a TKO, result in normal development. We think that's pretty cool.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY27-01. doi:1538-7445.AM2012-SY27-01
Abstract SY27-04: The signaling pathway of necrosome
Authors: Wang Xiaodong 
Published: August 2012

Abstract
Understanding Cell Death Xiaodong Wang, Ph.D. National Institute of Biological Sciences, Beijing Programmed cell death is a critical part of normal being in metazoan animals. Program cell death happens in two forms, apoptosis and necrosis. Apoptotic death is executed by a group of intracellular cysteine proteases, caspases, which are activated by apoptosis trigger. In contrast to apoptosis, the molecular mechanism of necrosis execution is poorly understood. Our laboratory has been using necrosis induced by TNF-α to study the biochemical pathway of necrosis. The programmed necrosis induced by TNF-α family of cytokines requires the activities of the receptor interacting serine-threonine kinases RIP1 and RIP3. Such form of cell death has now recognized to have important roles in animal development, tissue damage response, and innate immunity against microbes. How RIP kinases cause cell death is not known. In this meeting, I plan to discuss our recent progress in dissecting the molecular pathway downstream of RIP3 activation using a combination of tools from chemical biology, biochemistry and live cell imaging. We are able to map a necrotic pathway with discrete biochemical steps leading to the characteristic changes associated with necrosis. Moreover, we have identified a necrosis execution step that seems to be the convergent point of multiple necrosis pathways including necrosis induced by reactive oxygen species (ROS) and calcium overload.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY27-04. doi:1538-7445.AM2012-SY27-04
Abstract SY28-04: Targeting the tumor extracellular matrix with armed antibodies
Authors: Neri Dario 
Published: August 2012

Abstract
Antibodies can be used to deliver bioactive molecules (drugs, cytokines, photosensitizers, radionuclides, etc.) to the tumor environment, thus sparing normal tissues.
The targeting of modified sub-endothelial extracellular matrix components using armed antibodies is particularly attractive, because of:
(i) the abundance and stability of some of these antigens (e.g., splice isoforms of fibronectin and tenascin-C); (ii) the dependence of cancer on new blood vessels (iii) accessibility of these structures from the blood-stream (iv) the fact that some of these antigens are very aboundant in many different cancer types, while being virtually undetectable in most normal adult tissues.
Advanced preclinical and clinical data on armed antibodies will be presented in this lecture.
References:
Neri & Bicknell (2005) Nature Rev. Cancer, 5: 436-446
Neri & Supuran (2011) Nature Rev. Drug Discov.: 10: 767-777
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY28-04. doi:1538-7445.AM2012-SY28-04
Abstract SY29-01: mTOR, metabolism, and cell growth control
Authors: Blenis John , Csibi Alfredo , Kim Sang Gyun , Choo Andrew , Buel Gwen , Jang Young Jin , Hoffman Gregory 
Published: August 2012

Abstract
The mTOR complex 1 (mTORC1) is a ser/thr protein kinase complex and critical regulator of cellular metabolism, protein synthesis, autophagy and cell growth. This signaling system is normally carefully controlled by the integration of inputs from growth factors, nutrients, cellular energy status, oxygen availability and stress. A variety of loss-of-function or gain-of-function alterations in key mTORC1 regulatory proteins, very often results in inappropriate regulation of this signaling system. Uncontrolled mTORC1 activation contributes on its own or in combination with other pathways to metabolic diseases ranging from diabetes and obesity, cardiac hypertrophy, neurodegeneration, aging, benign tumor syndromes to highly malignant cancers. Mechanistically, uncontrolled mTORC1 activation leads to a constant positive input into anabolic processes and suppression of many catabolic processes. As a result, these cells require increased energy and carbon sources to meet their high metabolic needs for cell growth. To meet this demand, we have found in cells that are PTEN or TSC1/2 null, that activated mTORC1 uses distinct mechanisms to increase glutamine consumption (glutaminolysis) by elevating the expression of glutaminase and the activity of glutamate dehydrogenase. Furthermore, under nutrient-rich conditions, these tumor cells sense the increased energy production and in a positive feedback loop, promote more mTORC1 assembly via an AMP kinase (AMPK)-dependent, and a novel AMPK-independent mechanism. This acquired addiction to glutamine provides a novel therapeutic strategy for treating patients with activated mTORC1. Indeed, by acutely blocking the ability of energetically stressed cells with hyperactive mTORC1 to metabolize glutamine, we can selectively kill some tumor cells without damaging normal cells. We anticipate that these studies will lead to the development of “synthetic-lethal” drugs useful in the treatment of patients with diseases linked to inappropriate activation of mTORC1. Research supported by NIH RO1-GM51405 and the LAM Foundation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY29-01. doi:1538-7445.AM2012-SY29-01
Abstract SY31-03: Inflammatory mechanisms of cancer-related fatigue
Authors: Bower Julienne 
Published: August 2012

Abstract
Fatigue is one of the most common and disabling side effects of cancer treatment and may persist for months or years after successful treatment completion, causing significant impairment in quality of life. Basic research on neural-immune signaling has demonstrated that proinflammatory cytokines signal the central nervous system to trigger a constellation of behavioral changes that include fatigue as well depression, sleep disturbance, and cognitive impairment. This presentation will review the evidence linking proinflammatory cytokines and fatigue in cancer patients and survivors. In addition, we will consider host factors that influence inflammation and associated symptoms of fatigue, focusing on genetic mechanisms. There is considerable variability in the experience of post-treatment fatigue that cannot be explained by treatment exposure, suggesting that host factors play an important role in symptom severity and persistence. Single nucleotide polymorphisms (SNPs) that influence quantitative gene expression have been identified in the promoter regions of several genes that encode proinflammatory cytokines and examined individually in relation to breast cancer susceptibility and prognosis as well as behavioral symptoms. Here, we will present findings linking SNPs in the promoter regions of three proinflammatory cytokine genes (IL-1β -511 C&gt;T (rs16944), IL6 -174 G&gt;C (rs1800795), and TNF -308 G&gt;A (rs1800629)) to fatigue in breast cancer survivors. Further, we will consider how alterations in glucocorticoid signaling pathways may contribute to persistent cancer-related fatigue.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY31-03. doi:1538-7445.AM2012-SY31-03
Abstract SY31-04: Impact of cytokines on neurocircuits relevant to anxiety, depression, and fatigue in cancer patients
Authors: Miller Andrew 
Published: August 2012

Abstract
Clues have been revealed regarding the brain regions that may be targeted by cytokines to change behavior and cognition. Mounting data indicate that activation of the inflammatory response and the release of inflammatory cytokines can lead to changes in behavior including depression, anxiety, fatigue and cognitive dysfunction. Given the association of immune system activation with a host of medical illnesses including cancer, such cytokine-induced behavioral changes may contribute to the high rate of depression, anxiety, fatigue and other behavioral alterations observed in cancer patients. Using the anti-viral cytokine, interferon (IFN)-alpha, work by our group and others has demonstrated that cytokines can access the brain and alter the function of the basal ganglia as measured by brain imaging techniques including both functional magnetic resonance imaging (fMRI) and positron emission tomography as well as in vivo microdialysis in non-human primates. The basal ganglia are key brain structures involved in the regulation of motor activity and motivation. Cytokine-induced alterations in basal ganglia function in turn have been associated with motor slowing and fatigue and appear to involve fundamental alterations in presynaptic dopamine function. In addition, cytokines appear to activate areas of the brain including the dorsal anterior cingulate cortex that are triggered in behavioral states of anxiety, arousal and alarm. Thus, the constellation of effects of cytokines on the brain includes the inhibition of brain circuits involved in exploratory behavior in addition to the activation of circuits that lead to a sense of danger. Taken together, these cytokine effects on behavior and cognition may subserve competing evolutionary survival priorities during infection and/or wounding to conserve energy resources for fighting pathogens while at the same time increasing vigilance against predators who may attack during states of vulnerability. Chronic or excessive inflammation and activation of these brain circuits during illnesses such as cancer, however, may lead to the development of behavioral pathologies in vulnerable individuals. Such behavioral alterations may be uniquely targeted by therapies focused on the immune system.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY31-04. doi:1538-7445.AM2012-SY31-04
WRF-Fire: Coupled Weather–Wildland Fire Modeling with the Weather Research and Forecasting Model
Authors: Coen Janice L. , Cameron Marques , Michalakes John , Patton Edward G. , Riggan Philip J. , Yedinak Kara M. 
Published: August 2012

AbstractA wildland fire-behavior module, named WRF-Fire, was integrated into the Weather Research and Forecasting (WRF) public domain numerical weather prediction model. The fire module is a surface fire-behavior model that is two-way coupled with the atmospheric model. Near-surface winds from the atmospheric model are interpolated to a finer fire grid and are used, with fuel properties and local terrain gradients, to determine the fire’s spread rate and direction. Fuel consumption releases sensible and latent heat fluxes into the atmospheric model’s lowest layers, driving boundary layer circulations. The atmospheric model, configured in turbulence-resolving large-eddy-simulation mode, was used to explore the sensitivity of simulated fire characteristics such as perimeter shape, fire intensity, and spread rate to external factors known to influence fires, such as fuel characteristics and wind speed, and to explain how these external parameters affect the overall fire properties. Through the use of theoretical environmental vertical profiles, a suite of experiments using conditions typical of the daytime convective boundary layer was conducted in which these external parameters were varied around a control experiment. Results showed that simulated fires evolved into the expected bowed shape because of fire–atmosphere feedbacks that control airflow in and near fires. The coupled model reproduced expected differences in fire shapes and heading-region fire intensity among grass, shrub, and forest-litter fuel types; reproduced the expected narrow, rapid spread in higher wind speeds; and reproduced the moderate inhibition of fire spread in higher fuel moistures. The effects of fuel load were more complex: higher fuel loads increased the heat flux and fire-plume strength and thus the inferred fire effects but had limited impact on spread rate.