bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA09: Therapy of lymphoma inspired by functional and structural genomics
Authors: Staudt Louis M. 
Published: November 2015

Abstract
Diffuse large B cell lymphoma (DLBCL) is a heterogeneous diagnostic category that is comprised of two prominent molecular subtypes, termed activated B cell-like (ABC) and germinal center B cell-like (GCB). These DLBCL subtypes are now viewed as molecularly distinct diseases since they arise from distinct stages of normal B cell development, require distinct recurrent genetic abnormalities to become malignant, have distinct cure rates with current chemotherapy regimens, and respond differentially to targeting agents. We defined a chronic active form of B cell receptor (BCR) signaling that activates NF-kB in ABC DLBCLs. Such ABC DLBCLs are killed by knockdown of BCR signaling components, such as the kinase BTK or components of the BCR itself. Over one fifth of ABC DLBCLs have mutations affecting the CD79B or CD79A subunits of the BCR that augment BCR signaling. To attack chronic active BCR signaling therapeutically, we initiated clinical trials in relapsed/refractory DLBCL of ibrutinib, an irreversible and highly selective inhibitor of BTK. Ibrutinib monotherapy induced a high rate of complete and partial responses in ABC DLBCL, while GCB DLBCL tumors rarely responded. Genetic analysis of responding tumors demonstrated an enrichment for those with CD79B mutations, but most responses were observed in tumors with wild type BCR subunits. This observation allowed us to define a non-genetic mechanism of BCR activation that depends on reactivity of the lymphoma BCR to self antigens. In addition to chronic active BCR signaling, the signaling adapter MyD88 is activated by oncogenic mutations in 40% of ABC DLBCL cases. Since these mutant MyD88 isoforms act in parallel to BCR signaling to activate the NF-kB pathway in ABC DLBCL, they might have been predicted to mitigate the clinical effects of ibrutinib. On the contrary, ABC DLBCL tumors with both CD79B and MYD88 mutations were highly responsive to ibrutinib, leading us to demonstrate that the BCR and MyD88 pathways positively regulate one another. To extend the efficacy of ibrutinib, we have identified additional therapeutic targets in the oncogenic signaling pathways in ABC DLBCL including: 1) ubiquitin ligases, such as LUBAC, that are required to assemble active signaling complexes downstream of the BCR; 2) the kinase IRAK4, which mediates oncogenic MyD88 signaling; 3) the PI3 kinase pathway, which is activated by chronic active BCR signaling; 4) BCL2, which is expressed highly in most ABC DLBCL tumors and is the target of recurrent amplifications. Several synergistic, mechanism-based drug combinations that exploit these redundant survival pathways will be presented.
Citation Format: Louis M. Staudt. Therapy of lymphoma inspired by functional and structural genomics. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA09.
Abstract IA13: Deconvoluting the molecular circuitry of cancerous cells with high-throughput experimentation
Authors: Lum Lawrence 
Published: November 2015

Abstract
Developmentally important signal transduction pathways such as those controlled by the secreted Wnt and Hedgehog (Hh) ligands are frequently exploited in cancerous cells to promote unfettered growth. We describe functional and chemical genomics-based efforts to recover actionable mechanisms sustaining cancer-associated Wnt and Hh signaling. Our findings extend the portfolio of druggable enzymes with anti-cancer relevance and reveal novel prosurvival mechanisms in cancerous cells.
Citation Format: Lawrence Lum. Deconvoluting the molecular circuitry of cancerous cells with high-throughput experimentation. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA13.
Abstract PR01: Identifying clinically important somatic mutations through a knowledge-based approach
Authors: Ainscough Benjamin J. , Griffith Malachi , Kunisaki Jason , Coffman Adam , McMichael Joshua F. , Eldred James M. , Walker Jason R. , Fulton Robert S. , Wilson Richard K. , Griffith Obi L. , Mardis Elaine R. 
Published: November 2015

Abstract
Large-scale tumor sequencing projects, like The Cancer Genome Atlas (TCGA), have implicated thousands of somatic mutations in cancer. These initiatives have incentivized many improvements in somatic variant detection. However, we have observed that important pathogenic variants are often missed due to stringent filtering, tumor heterogeneity, tumor contamination of normal, low tumor purity, alignment challenges, and other issues. These idiosyncrasies can impede variant detection algorithms from reliably calling even the most clinically relevant variants. To rescue this missed variation we devised a knowledge based variant identification strategy. We mined the literature and other variant databases for pathogenic variation and assembled them into an integrated Database of Curated Mutations (DoCM - www.docm.info). The DoCM contains 488 variants across 63 genes implicated in 34 cancer types. We developed an algorithm to identify any pathogenic variant signal, for all variants in the DoCM, in aligned sequence data. As a proof of principle, we applied this approach to four cancer types sequenced by TCGA: acute myeloid leukemia (AML), breast cancer, ovarian carcinoma, and uterine corpus endometrial carcinoma. Obvious sequencing and alignment errors, like variants in homopolymer runs, were excluded from subsequent analysis by manual review. Across these four TCGA projects, which includes 1,840 individuals, 1,757 clinically relevant variants were identified, 1,223 of which had not been previously reported in TCGA studies. To validate this approach, custom capture probes were designed for all of the DoCM variants, new libraries constructed and deep sequencing performed on 96 tumor and matched normal samples from the AML and breast cancer TCGA projects. Following this strategy, we were able to confirm the rescue of clinically relevant somatic mutations that were missed in the original TCGA analysis. We propose a knowledge-driven variant detection approach be considered as standard practice to avoid false-negative calls of events likely to be clinically relevant
Citation Format: Benjamin J. Ainscough, Malachi Griffith, Jason Kunisaki, Adam Coffman, Joshua F. McMichael, James M. Eldred, Jason R. Walker, Robert S. Fulton, Richard K. Wilson, Obi L. Griffith, Elaine R. Mardis. Identifying clinically important somatic mutations through a knowledge-based approach. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR01.
Abstract PR04: Cancer drug response networks built for comparative cancer pharmacogenomics identifies combination therapies for repositioning
Authors: Brubaker Doug , Elena Svenson , Smith Kai , Monroe Maya , Ryu Christopher , Chance Mark R. , Narla Goutham , Bebek Gurkan 
Published: November 2015

Abstract
We present an integrative framework for classifying drug response: CAncer Drug Response nEtworks (CADREs). We built CADREs for drugs with differential sensitivity profiles in cancer cell lines by integrating baseline copy number, gene expression, and drug sensitivity data for the cell lines. The nodes in the network are drugs and the edges are weighted according to the number of shared copy number variations, differentially expressed genes, and dysregulated pathways present in sensitive cell lines at baseline. These baseline features were mapped into pathways to generate a Pathway CADRE, and were also integrated into a differential gene expression and copy number Feature CADRE. CADREs were built for breast, ovarian, and endometrial cancers individually and combined to assess shared and unique features of drug sensitivity. Analyzing CADRE clusters associated multiple gene features and pathways with sensitivity to frontline therapies used in combination in these cancers. We identified four clusters of breast cancer drugs whose effectiveness is driven by a shared core of pathways. Compounds that were used in combination in clinical trials tended to not share an edge or are completely disconnected in networks. Specifically, ten such drug pairs in our breast CADREs have been found to work in combination in breast cancer and an additional five have been used in combination in other cancers, representing opportunities for repositioning these combinations in breast cancer. Examining highly interconnected CADRE nodes gave us an understanding for compounds that might work best together.
Citation Format: Doug Brubaker, Svenson Elena, Kai Smith, Maya Monroe, Christopher Ryu, Mark R. Chance, Goutham Narla, Gurkan Bebek. Cancer drug response networks built for comparative cancer pharmacogenomics identifies combination therapies for repositioning. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR04.
Abstract PR05: Using genome-scale CRISPR-mediated loss-of-function and gain-of-function screens to analyze gene-drug interactions in cancer
Authors: Gilbert Luke A. , Tanenbaum Marvin E. , Horlbeck Max A. , Adamson Britt , Villalta Jacqueline E. , Vale Ronald D. , Kampmann Martin , Weissman Jonathan S. 
Published: November 2015

Abstract
Drug resistance remains a pressing problem in cancer therapy. One major mode of resistance involves altered gene expression in the cancer cell. Knowing which genes can promote resistance or sensitivity to a specific cancer drug could pave the way for the development of new treatment strategies that minimize cancer drug resistance. Genome-scale loss-of-function and gain-of-function screens can be used to discover novel gene-drug interactions in cancer. RNAi and cDNA/ORF overexpression libraries have previously been used to conduct such screens, but both have drawbacks. RNAi has off-target effects, which can lead to false-positive results. cDNAs/ORFs are usually kilobases long and can be challenging to clone, verify and maintain in an overexpression library. Our recently developed CRISPR-based screening methods address these shortcomings. The technology combines different catalytically inactive Cas9 (dCas9) fusion proteins and uniquely designed short guide RNAs (sgRNA) allowing us to repress (CRISPRi) or activate (CRISPRa) the transcription of specific genes.
CRISPRi uses KRAB, a repressive chromatin modifier domain, fused to dCas9. CRISPRa uses the sunCas9 system where a peptide epitope chain is fused to dCas9 and recruits multiple copies of VP64, a transcriptional activator, attached to an intracellular single-chain antibody directed against the epitope. The gene-specific region of sgRNAs is at most 25 bases, so with the help of massively parallel oligonucleotide synthesis and next-generation sequencing, we cloned and verified genome-scaled sgRNA libraries targeting 15,977 human protein-coding genes. When used for screening, we showed that CRISPRi has minimal off-target effects, one reason being that repression is highly sensitive to mismatches between sequences of the target DNA and the sgRNA.
Citation Format: Luke A. Gilbert, Marvin E. Tanenbaum, Max A. Horlbeck, Britt Adamson, Jacqueline E. Villalta, Ronald D. Vale, Martin Kampmann, Jonathan S. Weissman. Using genome-scale CRISPR-mediated loss-of-function and gain-of-function screens to analyze gene-drug interactions in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR05.
Abstract PR15: Functional analysis of diverse oncogenic driver mutations using an isogenic cell line library identifies novel drug responses and alterations in metabolism
Authors: Martins Maria M. , Zhou Alicia Y. , Corella Alexandra , Horiuchi Dai , Yau Christina , Rakshandehroo Taha , Gordan John D. , Levin Rebecca S. , Johnson Jeff , Jascur John , Shales Mike , Sorrentino Antonio , Cheah Jaime , Clemons Paul A. , Shamji Alykhan , Schreiber Stuart , Schreiber Stuart , Krogan Nevan J. , Shokat Kevan M. , Shokat Kevan M. , McCormick Frank , Nomura Daniel , Bandyopadhyay Sourav , Goga Andrei 
Published: November 2015

Abstract
There is an urgent need in oncology to link molecular aberrations in tumors with altered cellular behaviors, such as metabolic derangements, and to identify novel therapeutics for cancer treatment. We have sought to identify synthetic-lethal genetic interactions that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated an unbiased and quantitative chemical-genetic interaction map that measures the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model more complex cellular contexts. Applied to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene including resistance to PI3K/AKT pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic-lethal manner. These studies provide new drug and biomarker pairs for clinical investigation. We have also performed global metabolomics analysis in a subset of the isogenic cell lines demonstrating alterations in metabolic pathways that are shared across multiple oncogenes, as well as those that are distinct to specific oncogenic drivers. This scalable approach enables the prediction of drug responses from patient data and can be used to accelerate the development of new genotype-directed therapies.
Citation Format: Maria M. Martins, Alicia Y. Zhou, Alexandra Corella, Dai Horiuchi, Christina Yau, Taha Rakshandehroo, John D. Gordan, Rebecca S. Levin, Jeff Johnson, John Jascur, Mike Shales, Antonio Sorrentino, Jaime Cheah, Paul A. Clemons, Alykhan Shamji, Stuart Schreiber, Stuart Schreiber, Nevan J. Krogan, Kevan M. Shokat, Kevan M. Shokat, Frank McCormick, Daniel Nomura, Sourav Bandyopadhyay, Andrei Goga. Functional analysis of diverse oncogenic driver mutations using an isogenic cell line library identifies novel drug responses and alterations in metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR15.
The North American Soil Moisture Database: Development and Applications
Authors: Quiring Steven M. , Ford Trent W. , Wang Jessica K. , Khong Angela , Harris Elizabeth , Lindgren Terra , Goldberg Daniel W. , Li Zhongxia 
Published: November 2015

Abstract
Soil moisture is an important variable in the climate system that integrates the combined influence of the atmosphere, land surface, and soil. Soil moisture is frequently used for drought monitoring and climate forecasting. However, in situ soil moisture observations are not systematically archived and there are relatively few national soil moisture networks. The lack of observed soil moisture data makes it difficult to characterize long-term soil moisture variability and trends. The North American Soil Moisture Database (NASMD) is a new high-quality observational soil moisture database. It includes over 1,800 monitoring stations in the United States, Canada, and Mexico, making it the largest collections of in situ soil moisture observations in North America. Data are collected from multiple sources, quality controlled, and integrated into an online database (soilmoisture.tamu.edu). Here we describe the development of the database, including quality control/quality assurance, standardization, and collection of metadata. The utility of the NASMD is demonstrated through an analysis of the inter- and intraannual variability of soil moisture from multiple networks. The NASMD is a useful tool for drought monitoring and forecasting, calibrating/validating satellites and land surface models, and documenting how soil moisture influences the climate system on seasonal to interannual time scales.
The Dissipation of Trapped Lee Waves. Part II: The Relative Importance of the Boundary Layer and the Stratosphere
Authors: Hills Matthew O. G. , Durran Dale R. , Blossey Peter N. 
Published: November 2015

Abstract
Decaying trapped waves exert a drag on the large-scale flow. The two most studied mechanisms for such decay are boundary layer dissipation and leakage into the stratosphere. If the waves dissipate in the boundary layer, they exert a drag near the surface, whereas, if they leak into the stratosphere, the drag is exerted at the level where the waves dissipate aloft. Although each of these decay mechanisms has been studied in isolation, their relative importance has not been previously assessed.
Here, numerical simulations are conducted showing that the relative strength of these two mechanisms depends on the details of the environment supporting the waves. During actual trapped-wave events, the environment often includes elevated inversions and strong winds aloft. Such conditions tend to favor leakage into the stratosphere, although boundary layer dissipation becomes nonnegligible in cases with shorter resonant wavelengths and higher tropopause heights. In contrast, idealized two-layer profiles with constant wind speeds and high static stability beneath a less stable upper troposphere support lee waves that are much more susceptible to boundary dissipation and relatively unaffected by the presence of a stratosphere. One reason that trapped waves in the two-layer case do not leak much energy upward is that the resonant wavelength is greatly reduced in the presence of surface friction. This reduction in wavelength is well predicted by the linear inviscid equations if the basic-state profile is modified a posteriori to include the shallow ground-based shear layer generated by surface friction.
Elusive ditrysian phylogeny: an account of combining systematized morphology with molecular data (Lepidoptera)
Authors: Heikkilä Maria , Mutanen Marko , Wahlberg Niklas , Sihvonen Pasi , Kaila Lauri 
Published: November 2015

Abstract
Background
Ditrysia comprise close to 99 % of all butterflies and moths. The evolutionary relationships among the ditrysian superfamilies have received considerable attention in phylogenetic studies based on DNA and transcriptomic data, but the deepest divergences remain for large parts unresolved or contradictory. To obtain complementary insight into the evolutionary history of the clade, and to test previous hypotheses on the subdivision of Ditrysia based on morphology, we examine the morphology of larvae, pupae and adult males and females of 318 taxa representing nearly all ditrysian superfamilies and families. We present the most comprehensive morphological dataset on Ditrysia to date, consisting of over 500 morphological characters. The data are analyzed alone and combined with sequence data (one mitochondrial and seven nuclear protein-coding gene regions, sequenced from 422 taxa). The full dataset consists of 473 exemplar species. Analyses are performed using maximum likelihood methods, and parsimony methods for the morphological dataset. We explore whether combining morphological data and DNA-data can stabilize taxa that are unstable in phylogenetic studies based on genetic data only.

Results
Morphological characters are found phylogenetically informative in resolving apical nodes (superfamilies and families), but characters serving as evidence of relatedness of larger assemblages are few. Results include the recovery of a monophyletic Tineoidea, Sesioidea and Cossoidea, and a stable position for some unstable taxa (e.g. Epipyropidae, Cyclotornidae, Urodoidea + Schreckensteinioidea). Several such taxa, however, remain unstable even though morphological characters indicate a position in the tree (e.g. Immidae). Evidence supporting affinities between clades are suggested, e.g. a novel larval synapomorphy for Tineidae. We also propose the synonymy of Tineodidae with Alucitidae, syn. nov.

Conclusions
The large morphological dataset provides information on the diversity and distribution of morphological traits in Ditrysia, and can be used in future research on the evolution of these traits, in identification keys and in identification of fossil Lepidoptera. The “backbone” of the phylogeny for Ditrysia remains largely unresolved. As previously proposed as an explanation for the scarcity of molecular signal in resolving the deeper nodes, this may be due to the rapid radiation of Ditrysia in the Cretaceous.
Jumps in High-Frequency Data: Spurious Detections, Dynamics, and News
Authors: Bajgrowicz Pierre , Scaillet Olivier , Treccani Adrien 
Published: November 2015

Applying tests for jumps to financial data sets can lead to an important number of spurious detections. Bursts of volatility are often incorrectly identified as jumps when the sampling is too sparse. At a higher frequency, methods robust to microstructure noise are required. We argue that whatever the jump detection test and the sampling frequency, a large number of spurious detections remain because of multiple testing issues. We propose a formal treatment based on an explicit thresholding on available test statistics. We prove that our method eliminates asymptotically all remaining spurious detections. In Dow Jones stocks between 2006 and 2008, spurious detections can represent up to 90% of the jumps detected initially. For the stocks considered, jumps are rare events, they do not cluster in time, and no cojump affects all stocks simultaneously, suggesting jump risk is diversifiable. We relate the remaining jumps to macroeconomic news, prescheduled company-specific announcements, and stories from news agencies that include a variety of unscheduled and uncategorized events. The vast majority of news does not cause jumps but may generate a market reaction in the form of bursts of volatility. This paper was accepted by Jérôme Detemple, finance.
Alteplase and Tenecteplase Confusion; Lack of E-Prescribing Interoperability Leads to Double Dosing; Accidental Overdoses Involving Fluorouracil Infusions
Authors: Cohen Michael R. , Smetzer Judy L. 
Published: November 2015

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