bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA06: Oncogenic translation programs
Authors: Wendel Hans-Guido 
Published: May 2017

Abstract
New York, NY.
I will provide an overview of the lab's contribution to deciphering the role of aberrant mRNA translation in cancer. We initially reported that aberrant eIF4E expression can drive lymphomagenesis in vivo. Next, we noticed that eIF4E's oncogenic activity strictly required phosphorylation at S209 by MNK1/2 kinases. The latter is the basis of ongoing efforts to develop and test MNK kinase inhibitors for cancer applications. More recently, we dissected the molecular basis of the anti-cancer action of eIF4A inhibitors like silvestrol. Using the ribosome footprinting technology developed by the Weissman lab we noticed that eIF4A inhibition acutely and preferentially suppressed a select group of ~200 mRNAs. These are marked by repeated 5' UTR sequences that are predicted to fold into energetically favorable G-quadruplex structures. Notably, many of these eIF4A–dependent transcripts encode oncogenic transcription factors (e.g. MYC and MYB), a number of cell cycle regulators (e.g. CDK6, CCND3), and anti-apoptotic BCL2 family genes. These findings also begin to shed light on the overarching question of how aberrant translation may lead to cancer. We speculate that it is not simply a global increase in protein production but instead the activation of oncogenic translation programs. We will discuss these findings also in light of recent work proposing an additional mechanism of eIF4A action that emphasizes binding to ubiquitous RNA sequence elements over the enzymatic activity of eIF4A.
Citation Format: Hans-Guido Wendel. Oncogenic translation programs. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA06.
Abstract IA09: Translational control of the tumor microenvironment
Authors: Robichaud Nathaniel , Guo Qianyu , Rincon Sonia del , Miller Wilson H. , Siegel Peter , Hsu Brian , Sonenberg Nahum 
Published: May 2017

Abstract
Translational control has emerged as a critical determinant in tumorigenesis. The mRNA cap-binding protein eIF4E is an oncoprotein that plays an important role in cancer initiation and progression. We recently demonstrated that eIF4E phosphorylation on serine 209 by the Map Kinase Integrating Kinases (MNK1/2) promotes epithelial to mesenchymal transition, invasion and metastasis. We recently discovered a critical importance of eIF4E phosphorylation in the tumor microenvironment (TME) for the metastatic process. To investigate the role of eIF4E phosphorylation in the TME, we utilized a syngeneic model in which a murine mammary tumor cell line (66cl4) was orthotopically injected into mice bearing the non-phosphorylatable eIF4E ^S209A mutation and their WT counterparts. Tumor growth was monitored by caliper measurements, and tissues were collected for histological assessment and immunohistochemistry. The onset of tumor formation was significantly delayed in eIF4E ^S209A mice. However, established tumors showed no differences in growth, proliferation, apoptosis, vascularization or immune infiltration. Strikingly, eIF4E ^S209A mice were nearly completely resistant to the formation of lung metastases from primary mammary tumors. Metastatic potential in this model was correlated with neutrophil accumulation in the spleen, blood and lungs of WT mice, which was significantly reduced in eIF4E ^S209A mice. Furthermore, treatment of tumor-bearing WT mice with an inhibitor of MNK1/2 significantly reduced lung metastasis without affecting primary tumor growth. Considering that eIF4E phosphorylation in both the TME and cancer cells promotes metastasis, our findings support the development of MNK inhibitors for metastasis prevention.
Citation Format: Nathaniel Robichaud, Qianyu Guo, Sonia del Rincon, Wilson H. Miller, Peter Siegel, Brian Hsu, Nahum Sonenberg. Translational control of the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA09.
Abstract IA12: Low rates of protein synthesis in hematopoietic stem cells are determined partly by relatively high levels of hypophosphorylated eIF4E-BP
Authors: Signer Robert A. J. , Qi Le , Morrison Sean J. 
Published: May 2017

Abstract
Hematopoietic stem cells (HSCs) synthesize less protein per hour, on average, than other hematopoietic progenitors. Limited protein synthesis appears to be a widely shared feature of adult stem cells. The low rate of protein synthesis is necessary for HSC maintenance as genetic changes that modestly increase or decrease protein synthesis each impair HSC function. However, the mechanisms that suppress protein synthesis in adult stem cells remain unexplored. We assessed a number of potential mechanisms and found that the reduced rate of protein synthesis in HSCs as compared to other hematopoietic progenitors is not explained by differences in proteasome activity, cell division rate, or mRNA content. However, adult bone marrow HSCs had increased amounts of hypophosphorylated eukaryotic initiation factor 4E binding protein1 (eIF4E-BP1) and eIF4E-BP2 as compared to other hematopoietic progenitors. Since unphosphorylated eIF4E-BP negatively regulates protein synthesis, this raised the possibility that eIF4E-BPs hypophosphorylation suppresses protein synthesis in HSCs. Consistent with this, genetic inactivation of eIF4E-BP1 and eIF4E-BP2 increased protein synthesis in HSCs and impaired their reconstituting activity. These findings provide insight into the mechanisms that promote adult tissue regenerative capacity by attenuating protein synthesis in stem cells.
Citation Format: Robert A. J. Signer, Le Qi, Sean J. Morrison. Low rates of protein synthesis in hematopoietic stem cells are determined partly by relatively high levels of hypophosphorylated eIF4E-BP. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA12.
Abstract IA18: The post-transcriptional response to bulky-adduct DNA damage
Authors: Willis Anne E. 
Published: May 2017

Abstract
Under conditions of physiological cell stress, including those that are found within a tumor cell and following treatment with chemotoxic drugs that cause DNA damage, post-transcriptional control pathways are initiated to aid cell survival. Global rates of protein synthesis are reduced by altering the phosphorylation status of eukaryotic initiation factors (eIFs), leading to decreases in the levels of ternary complex (required to bring the initiator Met-tRNAi to the 40S ribosomal subunit) and eIF4F complex (which binds to the 7methyl G cap). In parallel with protein synthesis shut down there is reprogramming of the translatome to allow the translation of “survival” mRNAs, which is mediated by RNA motifs within their 5' and 3' untranslated regions (UTRs) and their interaction with RNA binding proteins. Interestingly, the data show that this re-programming of the translatome is dependent upon the type of DNA damage initiated. For example, we have shown that following treatment with agents that cause bulky-adduct DNA damage, such a platinum-based compounds (cisplatin, oxaliplatin) or mitomycin C, the polysomes are enriched with mRNAs that encode enzymes that function in nucleotide excision repair. We have shown that these mRNAs contain regulatory upstream open reading frames (uORFs). Importantly, we have identified a common polymorphism in an uORF in the 5' UTR of the critical DNA repair enzyme ERCC5 and show that this determines sensitivity to platinum-based chemotherapy by controlling ERCC5 translation. Signaling from DNA-PKcs to eIF2 is required as part of this response, and modulation of this pathway alters the synthesis of critical repair enzymes and can chemosensitize cells to treatment with platinum-based compounds. We have used RNA-interactome capture to examine changes in the interactions of RNA binding proteins with their target mRNAs following bulky adduct-DNA damage and have identified a cytoplasmic RNA-BP complex that responds specifically to this type of DNA damage.
Citation Format: Anne E. Willis. The post-transcriptional response to bulky-adduct DNA damage. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA18.
Abstract IA23: eIF4E as anti-cancer target
Authors: Wagner Gerhard , Papadopoulos Evangelos , Yi Tingfang , Leger-Abraham Melissa , Sekiyama Naotaka 
Published: May 2017

Abstract
The interaction of the cap-binding protein eIF4E with eIF4G is central for recruiting the small ribosomal subunit to the 5' end of mRNA. This interaction is regulated by the competitive interaction with the 4E-binding proteins (4E-BPs). Genome analyses have shown that mRNAs coding for proto-oncogenes, transcription factors, translation factors, growth factors and their receptors have statistically long 5' UTRs with large negative free energies estimated with mfold. Translation of these genes thus, depends heavily on an efficient translation-initiation machinery. This is in contrast to 5' TOP mRNAs and highly expressed genes with expression controlled at the transcription level that have small negative free estimated with mfold. Consistently, overexpression of 4E-BP1 has been shown to suppress tumor growth in mouse xenografts. In a high-throughput screen of compound libraries we discovered a small molecule that mimics the action of 4E-BP1 by displacing eIF4G from eIF4E. Surprisingly, the compound does not displace 4E-BP1 but rather stabilizes its binding both in vitro and in vivo. To understand this effect we have solved crystal structures of complexes between eIF4E and several inhibitor analogs. In addition, we determined the structure of eIF4E in complex with a long fragment of 4E-BP1. These data revealed the dual mechanism of the compound displacing the tumor promoter eIF4G while stabilizing the tumor suppressor 4E-BP1. Furthermore, we investigated the activities of 4EGI-1 aggressive breast cancer cells that have properties of cancer stem cells and find that the compound specifically suppresses the aggressive properties of these cancer cells. In addition, we discovered that eIF4E is transcriptionally upregulated in hypoxia as it promoter contains hypoxia response elements utilized by Hif1a. Finally, we tested 4EGI-1 against a panel of ~1000 cancer cell lines and tested the global impact on Jurkat cells in a proteomics approach.
Citation Format: Gerhard Wagner, Evangelos Papadopoulos, Tingfang Yi, Melissa Leger-Abraham, Naotaka Sekiyama. eIF4E as anti-cancer target. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA23.
Abstract IA25: Third-generation inhibitors of mTOR
Authors: Shokat Kevan M. 
Published: May 2017

Abstract
Precision medicines exert selective pressure on tumor cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA–AKT–mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in “N-of-1” cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials. Here we seek to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumors with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.
Citation Format: Kevan M. Shokat. Third-generation inhibitors of mTOR. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA25.
Abstract B43: Towards a Cancer Dependency Map
Authors: Tsherniak Aviad , Vazquez Francisca , Weir Barbara , Montgomery Philip , Cowley Glenn , Gill Stanley , Kryukov Gregory , Pantel Sasha , Harrington Will , Burger Mike , Meyers Robin , Ali Levi , Goodale Amy , Lee Yenarae , Garraway Levi , Boehm Jesse , Root David , Golub Todd , Hahn William 
Published: May 2017

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR02) of the Conference Proceedings.
Citation Format: Aviad Tsherniak, Francisca Vazquez, Barbara Weir, Philip Montgomery, Glenn Cowley, Stanley Gill, Gregory Kryukov, Sasha Pantel, Will Harrington, Mike Burger, Robin Meyers, Levi Ali, Amy Goodale, Yenarae Lee, Levi Garraway, Jesse Boehm, David Root, Todd Golub, William Hahn. Towards a Cancer Dependency Map. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B43.
Sources of Sodium in US Adults From 3 Geographic Regions
Authors: Harnack Lisa J. , Cogswell Mary E. , Shikany James M. , Gardner Christopher D. , Gillespie Cathleen , Loria Catherine M. , Zhou Xia , Yuan Keming , Steffen Lyn M. 
Published: May 2017

Background:
Most US adults consume excess sodium. Knowledge about the dietary sources of sodium intake is critical to the development of effective reduction strategies.

Methods:
A total of 450 adults were recruited from 3 geographic locations: Birmingham, AL (n=150); Palo Alto, CA (n=150); and the Minneapolis–St. Paul, MN (n=150), metropolitan areas. Equal numbers of women and men from each of 4 race/ethnic groups (blacks, Asians, Hispanics, and non-Hispanic whites) were targeted for recruitment. Four record-assisted 24-hour dietary recalls were collected from each participant with special procedures, which included the collection of duplicate samples of salt added to food at the table and in home food preparation.

Results:
Sodium added to food outside the home was the leading source of sodium, accounting for more than two thirds (70.9%) of total sodium intake in the sample. Although the proportion of sodium from this source was smaller in some subgroups, it was the leading contributor for all subgroups. Contribution ranged from 66.3% for those with a high school level of education or less to 75.0% for those 18 to 29 years of age. Sodium inherent to food was the next highest contributor (14.2%), followed by salt added in home food preparation (5.6%) and salt added to food at the table (4.9%). Home tap water consumed as a beverage and dietary supplement and nonprescription antacids contributed minimally to sodium intake (<0.5% each).

Conclusions:
Sodium added to food outside the home accounted for ≈70% of dietary sodium intake. This finding is consistent with the 2010 Institute of Medicine recommendation for reduction of sodium in commercially processed foods as the primary strategy to reduce sodium intake in the United States.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02474693.
Predicting the U.S. Drought Monitor Using Precipitation, Soil Moisture, and Evapotranspiration Anomalies. Part II: Intraseasonal Drought Intensification Forecasts
Authors: Lorenz David J. , Otkin Jason A. , Svoboda Mark , Hain Christopher R. , Anderson Martha C. , Zhong Yafang 
Published: May 2017

Abstract
Probabilistic forecasts of U.S. Drought Monitor (USDM) intensification over 2-, 4-, and 8-week time periods are developed based on recent anomalies in precipitation, evapotranspiration, and soil moisture. These statistical forecasts are computed using logistic regression with cross validation. While recent precipitation, evapotranspiration, and soil moisture do provide skillful forecasts, it is found that additional information on the current state of the USDM adds significant skill to the forecasts. The USDM state information takes the form of a metric that quantifies the “distance” from the next-higher drought category using a nondiscrete estimate of the current USDM state. This adds skill because USDM states that are close to the next-higher drought category are more likely to intensify than states that are farther from this threshold. The method shows skill over most of the United States but is most skillful over the north-central United States, where the cross-validated Brier skill score averages 0.20 for both 2- and 4-week forecasts. The 8-week forecasts are less skillful in most locations. The 2- and 4-week probabilities have very good reliability. The 8-week probabilities, on the other hand, are noticeably overconfident. For individual drought events, the method shows the most skill when forecasting high-amplitude flash droughts and when large regions of the United States are experiencing intensifying drought.
Vineyard Energy Partitioning Between Canopy and Soil Surface: Dynamics and Biophysical Controls
Authors: Zhao Peng , Zhang Xiaotao , Li Sien , Kang Shaozhong 
Published: May 2017

Abstract
For sparse planting crops, soil surface plays an important role in energy balance processes within the soil–canopy–atmosphere continuum; thus, it is necessary to partition field energy fluxes into soil surface and canopy to provide useful information to reduce agricultural water use and to develop evapotranspiration models. Field experiments were conducted in vineyards during four growing seasons to examine the energy partitioning among soil surface, canopy, and field separately. Vineyard energy fluxes including latent heat (LE) were measured by eddy covariance system and canopy latent heat LEc was obtained from sap flow. Then, soil surface latent heat LEs was calculated as the difference between LE and LEc. The Bowen ratio and the ratio of latent heat to available energy were used to examine energy partitioning. Results indicate daily and hourly LEs obtained from LE and LEc overestimated microlysimeter-derived values by 13.0% and 10.8%, respectively. Seasonal-average latent heat accounted for 59.0%–64.3%, 65.8%–77.8%, and 56.6%–62.5% of corresponding available energy for vineyard, canopy, and soil surface, respectively. Soil water content and canopy were the main controlling factors on energy partitioning. Surface soil moisture explained 32%, 11%, and 52% of the seasonal variability in energy partitioning at field, canopy, and soil surface, respectively. Leaf area index explained 41% and 26% of the seasonal variability in energy partitioning at field and soil surface. Air temperature was related to canopy and field energy partitioning. During wet periods, soil can absorb sensible heat from the canopy and LEs may exceed soil surface available energy, while during dry periods, the canopy may absorb sensible heat from the soil and LEc may exceed canopy available energy.
The Impact of Low-Level Moisture Errors on Model Forecasts of an MCS Observed during PECAN
Authors: Peters John M. , Nielsen Erik R. , Parker Matthew D. , Hitchcock Stacey M. , Schumacher Russ S. 
Published: May 2017

AbstractThis article investigates errors in forecasts of the environment near an elevated mesoscale convective system (MCS) in Iowa on 24–25 June 2015 during the Plains Elevated Convection at Night (PECAN) field campaign. The eastern flank of this MCS produced an outflow boundary (OFB) and moved southeastward along this OFB as a squall line. The western flank of the MCS remained quasi stationary approximately 100 km north of the system’s OFB and produced localized flooding. A total of 16 radiosondes were launched near the MCS’s eastern flank and 4 were launched near the MCS’s western flank.Convective available potential energy (CAPE) increased and convective inhibition (CIN) decreased substantially in observations during the 4 h prior to the arrival of the squall line. In contrast, the model analyses and forecasts substantially underpredicted CAPE and overpredicted CIN owing to their underrepresentation of moisture. Numerical simulations that placed the MCS at varying distances too far to the northeast were analyzed. MCS displacement error was strongly correlated with models’ underrepresentation of low-level moisture and their associated overrepresentation of the vertical distance between a parcel’s initial height and its level of free convection (, which is correlated with CIN). The overpredicted in models resulted in air parcels requiring unrealistically far northeastward travel in a region of gradual meso-α-scale lift before these parcels initiated convection. These results suggest that erroneous MCS predictions by NWP models may sometimes result from poorly analyzed low-level moisture fields.
The U.S. National Blend of Models for Statistical Postprocessing of Probability of Precipitation and Deterministic Precipitation Amount
Authors: Hamill Thomas M. , Engle Eric , Myrick David , Peroutka Matthew , Finan Christina , Scheuerer Michael 
Published: May 2017

AbstractThe U.S. National Blend of Models provides statistically postprocessed, high-resolution multimodel ensemble guidance, providing National Weather Service forecasters with a calibrated, downscaled starting point for producing digital forecasts.Forecasts of 12-hourly probability of precipitation (POP12) over the contiguous United States are produced as follows: 1) Populate the forecast and analyze cumulative distribution functions (CDFs) to be used later in quantile mapping. Were every grid point processed without benefit of data from other points, 60 days of training data would likely be insufficient for estimating CDFs and adjusting the errors in the forecast. Accordingly, “supplemental” locations were identified for each grid point, and data from the supplemental locations were used to populate the forecast and analyzed CDFs used in the quantile mapping. 2) Load the real-time U.S. and Environment Canada (now known as Environment and Climate Change Canada) global deterministic and ensemble forecasts, interpolated to ⅛°. 3) Using CDFs from the past 60 days of data, apply a deterministic quantile mapping to the ensemble forecasts. 4) Dress the resulting ensemble with random noise. 5) Generate probabilities from the ensemble relative frequency. 6) Spatially smooth the forecast using a Savitzky–Golay smoother, applying more smoothing in flatter areas.Forecasts of 6-hourly quantitative precipitation (QPF06) are more simply produced as follows: 1) Form a grand ensemble mean, again interpolated to ⅛°. 2) Quantile map the mean forecast using CDFs of the ensemble mean and analyzed distributions. 3) Spatially smooth the field, similar to POP12.Results for spring 2016 are provided, demonstrating that the postprocessing improves POP12 reliability and skill, as well as the deterministic forecast bias, while maintaining sharpness and spatial detail.