bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL01-01: The genetic basis for cancer therapeutics
Authors: Sellers William R. 
Published: August 2012

Abstract
Cancer is a disease driven by the acquisition and clonal selection of gain- and loss-of-function genetic alterations. While a fuller understanding of the pattern, specificity and biological consequences of such genetic events remains for us to elucidate, it is now clear that therapeutics directed against the genetic underpinnings of cancer have had a marked clinical impact. The growing list of therapeutics with efficacy in defined genetic settings includes imatinib in BCR-ABL driven CML, trastuzumab in HER2+ breast cancer, and erlotinib and gefitinib in EGFR mutated lung cancer among others. Indeed, the efficacy of small molecule inhibitors of KIT, PDGFR, HER2, EGFR, BRAF and ALK in a diversity of malignances including GIST, lung cancer and melanoma support the notion that a new generation of efficacious drugs is emerging. Nonetheless, we can articulate 5 key road-blocks to the more rapid and widespread application of the “genetic paradigm” including 1) an incomplete understanding of the genetic alterations characteristic of human cancer; 2) the difficulty in developing therapeutics that reverse the activity of non-kinase oncogenes (e.g. RAS and MYC) or reverse the consequences of tumor suppressor mutations (e.g. p53, RB1); 3) the development of resistance to genetic targeted therapy; 4) the need to identify highly active novel combination therapy regimens and 5) the lack of a robust pre-clinical translational infrastructure allowing for the more accurate prediction of human clinical trial results. This lecture will discuss strategic approaches to these 5 problems in the context of novel emerging therapeutics.
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 PL01-01. doi:1538-7445.AM2012-PL01-01
Abstract SY03-01: Revealing new metabolic networks in cancer
Authors: Gottlieb Eyal 
Published: August 2012

Abstract
The extent to which metabolism plays a role in tumorigenesis cannot be overstated and drugs that selectively target these processes are likely to at least delay, if not halt tumour progression. Our work utilizes analytical chemistry and system biology approaches to study metabolic transformation. We investigated cells deficient in the mitochondrial tumour suppressor fumarate hydratase (FH) and using extensive metabolomics data we applied a computer model, generated to study their unique metabolome. We identified several important metabolic pathways which are specific and crucial for the survival of cancer cells deficient in FH. These include the heme biosynthesis and degradation pathway as well as mechanisms of alleviating the tricarboxylic acid (TCA) cycle carbon stress. These technologies are not only important for understanding the basic biochemistry of cancer cells but they can inform us on future clinical management of cancer and may lead to new therapeutic approaches to target cancer-specific metabolic pathways.
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 SY03-01. doi:1538-7445.AM2012-SY03-01
Abstract SY06-01: Intracellular antibody therapy: Specific delivery of synthetic antibodies to cytoplasmic targets in cancer cells
Authors: Kossiakoff Anthony A. 
Published: August 2012

Abstract
Synthetic Antigen Binders (sABs) are a new class of antibody-based reagents engineered using novel phage display libraries and selection strategies. These attributes provide for the ability to generate sABs that are customized to: 1) target specific regions on the surface of the protein, 2) recognize specific conformational or oligomeric states, 3) induce conformational changes, and 4) capture and stabilize multi-protein complexes. As such, they have the potential to outperform traditional monoclonal antibodies as therapeutic modalities for biomedical applications. However, a critical limitation is that antibodies can only be directed at extracellular targets because they cannot penetrate the cell membrane. This eliminates a rich set of potential cytoplasmic targets that function as crucial components of signaling pathways or structural networks. To overcome this limitation we have developed receptor-mediated delivery systems that have proven effective in internalizing a novel class of synthetic antigen binders in their fully functional form. Further, this delivery system inherently seeks out certain types of cancer cells, while being inert towards cells on normal tissue.
As a demonstration of the power of the approach, we have generated a set of sABs that have been tailored to induce conformational changes in F-actin filaments that substantially alter actin cytoskeletal structure by mechanisms involving depolymerizing, severing, bundling and capping of actin filaments. We introduce these sABs into cancer cells using receptor-mediated delivery and show the properties selected for in the in vitro phage display sorting are exactly recapitulated in the live cells. The effects of actin filament bundling are shown to be particularly detrimental to the cancer cells suggesting that sABs performing this function may be useful therapeutic agents. This approach is being expanded to make agents that target nuclear components to alter cell function at the DNA level.
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 SY06-01. doi:1538-7445.AM2012-SY06-01
Abstract SY07-01: Functions of ubiquitin and SUMO in DNA damage bypass
Authors: Ulrich Helle D. 
Published: August 2012

Abstract
Ubiquitin and SUMO are members of a conserved family of proteins that exert their functions by being covalently attached to intracellular substrate proteins. Ubiquitin is best known for targeting its substrates to the 26S proteasome, but it mediates many non-proteolytic functions, mainly by modulating protein-protein interactions. Similarly, SUMO controls a variety of biological processes by changing the properties of its substrates. Both ubiquitin and SUMO play a prominent role in the maintenance of genome stability, and our lab is interested in elucidating the mechanisms by which the two modifiers affect DNA replication, repair and mutagenesis.
An important focus of our research is the investigation of DNA damage tolerance, a highly conserved mechanism that protects cells from the harmful effects of genotoxic agents by allowing the replication machinery to pass over DNA lesions. Although beneficial in terms of promoting cell survival, bypass of DNA damage can result in unwanted mutations that may ultimately lead to genetic instability and cancer. The activity of lesion bypass is carefully controlled through posttranslational modifications of PCNA, an essential processivity factor for DNA polymerases, by monoubiquitin, polyubiquitin chains and SUMO. Here I will discuss the effects of these modifications on the replication of damaged DNA, the interplay between the different conjugation systems and the mechanisms by which the relevant modifying enzymes are activated in response to the appropriate cellular signals.
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 SY07-01. doi:1538-7445.AM2012-SY07-01
Abstract SY35-03: Gene expression and epigenetic programs in leukemia stem cell development
Authors: Armstrong Scott A. 
Published: August 2012

Abstract
Acute myelogenous leukemia stem cells (LSC) are the subset of leukemia cells capable of extensive self-renewal and maintenance of leukemia. We are interested in the mechanisms of leukemia development as they relate to activation and maintenance of gene expression programs by epigenetic pathways responsible for deregulated self-renewal in leukemia. We have demonstrated that oncogenic fusion proteins can activate a self-renewal associated gene expression program when expressed in myeloid progenitor cells that normally have limited self-renewal capabilities. Detailed characterization of LSC from multiple different mouse leukemias has shown that LSC are most similar to differentiating myeloid cells that express a limited hematopoietic stem cell (HSC) associated signature. Detailed analysis of the gene expression data from normal HSC and progenitors as compared to LSC identified the Wnt/β-catenin pathway as potentially important for acute myeloid leukemia LSC, and we have subsequently validated this pathway as critical using conditional mouse models. We are continuing to assess the gene expression programs subverted during the transition from normal HSC and progenitor cells to LSC and are comparing these data to genome wide epigenomic analyses to determine which specific epigenetic programs are required for leukemia stem cell maintenance. Identification of epigenetic pathways required to maintain leukemia self-renewal should provide new targets for novel therapeutic approaches.
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 SY35-03. doi:1538-7445.AM2012-SY35-03
Abstract SY38-03: Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukemia
Authors: Huntly Brian 
Published: August 2012

Abstract
Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukemia Recurrent chromosomal translocations involving the mixed lineage leukemia (MLL) gene initiate aggressive forms of leukemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process plays an important role in leukemia induction. Here we will describe a global proteomic strategy to demonstrate that MLL-fusions, as part of SEC and the polymerase associated factor (PAFc) complex are associated with the BET family of acetyl-lysine recognising, chromatin “adaptor” proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukemia, via the displacement of the BET family of proteins from chromatin. We will show that a novel small molecule inhibitor of the BET family GSK1210151A (I-BET151) has profound efficacy against human and murine MLL-fusion leukemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukemia cell lines with different MLL-fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies will demonstrate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukemia. In addition, the efficacy of I-BET151 against human leukemia stem cells (LSC) will be shown, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukemias.
To extend the applications of our work, we will also present preliminary data to demonstrate that inhibition of BET proteins has therapeutic promise in a larger number of AML subtypes. We will speculate on potential mechanisms for this, the investigation of which is ongoing. Finally, we will discuss extension of the paradigm of BET inhibition to the numerous other epigenetic “readers” implicated in the induction and progression of cancer.
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 SY38-03. doi:1538-7445.AM2012-SY38-03
Abstract SY38-04: Altered metabolic enzymes and metabolites in cancer
Authors: Xiong Yue 
Published: August 2012

Abstract
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599, USA. Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China Altered metabolic regulation was recognized as the first tumor phenotype and broadly used in the clinic for tumor detection. Recent findings of frequent mutations targeting gene encoding metabolic enzymes in cancer have renewed interest in cancer metabolism. Eight metabolic genes encoding for four metabolic enzymes, IDH1, IDH2, SDH and FH, have been found to be mutated in a wide range of human cancers. Our recent findings revealed that associated with the mutations of these four enzymes are the accumulation of three metabolites, 2-hydroxyglutarate (2-HG), succinate and fumarate, that act as antagonists of α-ketoglutarate (α-KG) and negatively regulate the activity of multiple α-KG-dependent dioxygenases, including both histone demethylases and newly discovered TET family of DNA hydroxylases. Consistent with these in vitro and cell culture studies, tumor with IDH1/2 mutation exhibit altered methylation on both histone and DNA. These findings suggest not only roles of these putative oncometabolites in epigenetic control and gene regulation, but also potential new targets for cancer therapy.
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 SY38-04. doi:1538-7445.AM2012-SY38-04
Abstract SY40-02: Interplay between microenvironment and cancers
Authors: Bhardwaj Nina , Godefroy Emmanuelle , Jotereau Francine , Manches Olivier , Gallois Anne , Goldberg Judith 
Published: August 2012

Abstract
Tumors are highly adept at evading the immune system through a multitude of mechanisms, including the secretion of factors that modulate both innate and adaptive immunity. Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme that degrades the extracellular matrix and is over expressed by many tumors, including melanoma. We recently documented the presence of MMP-2-specific CD4(+) T cells in tumor-infiltrating lymphocytes (TILs) in several melanoma patients (Cancer Cell 19:333, 2011). Strikingly, MMP-2-specific CD4(+) T cells displayed an inflammatory T(H)2 profile, mainly TNF-α, IL-4, and IL-13 and expressing GATA-3. When exposed to MMP-2, immature human dendritic cells (DCs) primed naïve CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 was subsequently found to degrade the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production, and the subsequent formation of bioactive IL-12. More recently we have explored the mechanisms underlying the up regulation of OX40L and have identified signaling pathways and potential receptors that lead to this modulation. Active MMP-2, therefore, acts as an endogenous type 2 “conditioner” providing an explanation for the observed prevalence of detrimental type 2 responses in melanoma. Novel properties of MMP-2 on other components of the immune system, and on tumor progression, will be discussed along with DC-based strategies to alleviate immune suppression.
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 SY40-02. doi:1538-7445.AM2012-SY40-02
Ultrasmall Superparamagnetic Particles of Iron Oxide in Patients With Acute Myocardial Infarction
Authors: Alam Shirjel R. , Shah Anoop S.V. , Richards Jennifer , Lang Ninian N. , Barnes Gareth , Joshi Nikhil , MacGillivray Tom , McKillop Graham , Mirsadraee Saeed , Payne John , Fox Keith A.A. , Henriksen Peter , Newby David E. , Semple Scott I.K. 
Published: August 2012

Background—
Inflammation following acute myocardial infarction (MI) has detrimental effects on reperfusion, myocardial remodelling, and ventricular function. Magnetic resonance imaging using ultrasmall superparamagnetic particles of iron oxide can detect cellular inflammation in tissues, and we therefore explored their role in acute MI in humans.

Methods and Results—

Sixteen patients with acute ST-segment elevation MI were recruited to undergo 3 sequential magnetic resonance scans within 5 days of admission at baseline, 24 and 48 hours following no infusion (controls; n=6) or intravenous infusion of ultrasmall superparamagnetic particles of iron oxide (n=10; 4 mg/kg). T2*-weighted multigradient-echo sequences were acquired and R2* values were calculated for specific regions of interest. In the control group, R2* values remained constant in all tissues across all scans with excellent repeatability (bias of −0.208 s
−1
, coefficient of repeatability of 26.96 s
−1
; intraclass coefficient 0.989). Consistent with uptake by the reticuloendothelial system, R2* value increased in the liver (84±49.5 to 319±70.0 s
−1
;
P
<0.001) but was unchanged in skeletal muscle (54±8.4 to 67.0±9.5 s
−1
;
P
>0.05) 24 hours after administration of ultrasmall superparamagnetic particles of iron oxide. In the myocardial infarct, R2* value increased from 41.0±12.0 s
−1
(baseline) to 155±45.0 s
−1
(
P
<0.001) and 124±35.0 s
−1
(
P
<0.05) at 24 and 48 hours, respectively. A similar but lower magnitude response was seen in the remote myocardium, where it increased from 39±3.2 s
−1
(baseline) to 80±14.9 s
−1
(
P
<0.001) and 67.0±15.7 s
−1
(
P
<0.05) at 24 and 48 hours, respectively.

Conclusions—
Following acute MI, uptake of ultrasmall superparamagnetic particles of iron oxide occurs with the infarcted and remote myocardium. This technique holds major promise as a potential method for assessing cellular myocardial inflammation and left ventricular remodelling, which may have a range of applications in patients with MI and other inflammatory cardiac conditions.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01323296.
Probabilistic Change of Wheat Productivity and Water Use in China for Global Mean Temperature Changes of 1°, 2°, and 3°C
Authors: Liu Yujie , Tao Fulu 
Published: August 2012

AbstractImpacts of climate change on agriculture are a major concern worldwide, but uncertainties of climate models and emission scenarios may hamper efforts to adapt to climate change. In this paper, a probabilistic approach is used to estimate the uncertainties and simulate impacts of global warming on wheat production and water use in the main wheat cultivation regions of China, with a global mean temperature (GMT) increase scale relative to 1961–90 values. From output of 20 climate scenarios of the Intergovernmental Panel on Climate Change Data Distribution Centre, median values of projected changes in monthly mean climate variables for representative stations are adapted. These are used to drive the Crop Environment Resource Synthesis (CERES)-Wheat model to simulate wheat production and water use under baseline and global warming scenarios, with and without consideration of carbon dioxide (CO2) fertilization effects. Results show that, because of temperature increase, projected wheat-growing periods for GMT changes of 1°, 2°, and 3°C would shorten, with averaged median values of 3.94%, 6.90%, and 9.67%, respectively. There is a high probability of decreasing (increasing) changes in yield and water-use efficiency under higher temperature scenarios without (with) consideration of CO2 fertilization effects. Elevated CO2 concentration generally compensates for the negative effects of warming temperatures on production. Moreover, positive effects of elevated CO2 concentration on grain yield increase with warming temperatures. The findings could be critical for climate-change-driven agricultural production that ensures global food security.
Impacts of Ice Clouds on GPS Radio Occultation Measurements
Authors: Zou X. , Yang S. , Ray P. S. 
Published: August 2012

Abstract
Mathematical solutions accounting for the effects of liquid and ice clouds on the propagation of the GPS radio signals are first derived. The percentage contribution of ice water content (IWC) to the total refractivity increases linearly with the amount of IWC at a rate of 0.6 (g m−3)−1. Measurements of coincident profiles of IWC from CloudSat in deep convection during 2007–10 are then used for estimating the ice-scattering effects on GPS radio occultation (RO) measurements from the Constellation Observing System for Meteorology, Ionosphere and Climate (COSMIC). The percentage contribution of IWC to the total refractivity from CloudSat measurements is consistent with the theoretical model, reaching about 0.6% at 1 g m−3 IWC.
The GPS RO refractivity observations in deep convective clouds are found to be systematically greater than the refractivity calculated from the ECMWF analysis. The fractional N bias (GPS minus ECMWF) can be as high as 1.8% within deep convective clouds. Compared with ECMWF analysis, the GPS RO retrievals have a negative temperature bias and a positive water vapor bias, which is consistent with a positive bias in refractivity. The relative humidity calculated from GPS retrievals is usually as high as 80%–90% right above the 0°C temperature level in deep convection and is about 15%–30% higher than the ECMWF analysis. The majority of the data points in deep convection are located on the negative side of temperature differences and the positive side of relative humidity differences between GPS RO retrievals and ECMWF analysis.
Tropical Stationary Wave Response to ENSO: Diabatic Heating Influence on the Indian Summer Monsoon
Authors: Jang Youkyoung , Straus David M. 
Published: August 2012

Abstract
The atmospheric response to boreal summer tropical diabatic heating is studied in the atmospheric model component of the Community Atmosphere Model [CAM, version 3 (CAM3)] of the National Center for Atmospheric Research. An idealized heating function (with broad vertical but localized horizontal structure) is added to CAM3 near the equator; the circulation response is studied as a function of the sign of the heating and its longitude (Indian Ocean to eastern Pacific Ocean). The atmospheric circulation forced by the added heating interacts with all the physical and dynamical processes in CAM3; the total heating is the sum of the added heating and that produced by CAM3. In experiments using climatological sea surface temperature, added cooling (heating) over the Maritime Continent induces asymmetric anticyclonic (cyclonic) circulation extending toward India, opposing (reinforcing) the climatological monsoon flow and weakening (strengthening) the Indian monsoon. The anchoring of the anticyclonic (cyclonic) circulation over India as the added cooling (heating) is moved eastward over warm SST regions is greatly reduced when a slab ocean model is used. A negative (positive) air–sea feedback over the Indian Ocean is identified when heating (cooling) is added in the Indonesian region. Experiments in which the total heating is similar to estimates of the observed heating for the summer of 1987 are examined.