bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR06: PTEN-mTOR pathway serves as a guardian of ribosomal DNA
Authors: Xu Baoshan , Li Hua , Perry John , Harris Bethany , Slaughter Brian , Unruh Jay , Singh Vijay Pratap , Zakari Musinu , McDowell William , Li Linheng , Gerton Jennifer L. 
Published: May 2017

Abstract
Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number, yet we know virtually nothing about what governs its copy number, stability, and sequence. Ribosomal DNA is present in many tandem repeats that are incredibly important because 1) they encode the template for the RNA component of ribosomes, 2) they organize large parts of nearly every human chromosome and 3) they can titrate factors involved in chromosomal processes, with profound impact on DNA replication, repair, and gene expression. We applied computational and droplet digital PCR approaches to explore rDNA copy number in normal and cancer states in human and mouse genomes. We find that the copy number is similar between tissues from the same mouse, and is similar within inbred mouse strains, but can vary widely between individuals in an outbred strain. PTEN is a tumor suppressor and negative regulator of mTOR activity that is critical for genome stability. We find that hematopoietic stem cells from a PTEN-/- mouse model for leukemia have lower rDNA copy number than normal tissue, associated with hypersensitivity to DNA damage. Remarkably, analysis of three human cancer genome projects reveals low rDNA copy number relative to matched normal tissue. Our analysis reveals a genomic signature associated with hyperactive mTOR in osteosarcoma that includes loss of rDNA copies accompanied by an increase in sequence heterogeneity, as well as additional genes that co-vary in copy number. PTEN-mTOR may normally contribute to maintenance of ribosomal DNA.
This abstract is also being presented as Poster A38.
Citation Format: Baoshan Xu, Hua Li, John Perry, Bethany Harris, Brian Slaughter, Jay Unruh, Vijay Pratap Singh, Musinu Zakari, William McDowell, Linheng Li, Jennifer L. Gerton. PTEN-mTOR pathway serves as a guardian of ribosomal DNA. [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 PR06.
Abstract B44: Emerging targets from Cancer Dependency Map v0.1
Authors: Vazquez Francisca , Tsherniak Aviad , Weir Barbara , Montgomery Phil , 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
Precision Cancer Medicine requires the identification of vulnerabilities linked to genetic features of tumors. Recent studies utilizing highly annotated small molecule collections to assess dependencies across hundreds of genomically annotated cell lines have demonstrated the potential for such large-scale preclinical “Dependency Map” projects. We have undertaken a complementary approach using genetic perturbation tools (RNAi and CRISPR-Cas9 based loss-of-function viability screens), to systematically catalog preferential genetic dependencies and markers that predict response. These efforts are providing a foundation for the discovery of novel targets poised for early therapeutic discovery projects together with patient populations that may be enriched for responders to such therapies.
Here, we present results from our initial Cancer Dependency Map consisting of RNAi loss-of-function screens across 503 cell lines, including both solid and hematopoietic tumors. We discovered 43 genes whose mutation or copy number creates a cancer dependency (oncogene addiction) including a novel dependency on the small GTPase, GNAI2 in Diffuse large B-cell Lymphoma. We discovered 142 genes in which elevated levels of expression create a dependency (gene addiction), a group of genes highly enriched for master regulator transcription factors such as SOX10, SPDEF, PAX8 and HNF1B. We discovered 474 genes for which hemizygous copy number creates a dependency (CYCLOPS genes), a group of genes highly enriched for members of macromolecular protein complexes including the spliceosome and proteasome. Finally, we discovered 171 genes that become a dependency when a redundant functional paralog is lost in cancer cells (redundant essentials). We demonstrate the mechanistic basis behind one such redundant essential dependency relationship in which promoter methylation of the UBB ubiquitin gene eliminates a compensatory mechanism leading to a novel vulnerability on the suppression of the UBC ubiquitin gene.
These observations begin to provide an initial census, categorization and prioritization of robust cancer dependencies and support the potential impact for expanding early efforts to develop dependency maps of cancer.
Citation Format: Francisca Vazquez, Aviad Tsherniak, Barbara Weir, Phil 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. Emerging targets from Cancer Dependency Map v0.1. [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 B44.
Abstract IA07: Addiction of prostate cancer to androgen receptor
Authors: Dong Yan 
Published: May 2017

Abstract
Recurrence with lethal castration-resistant prostate cancer after endocrine therapy remains the major challenge in treatment of advanced prostate cancer. Significant advances in our understanding of continued androgen receptor signaling in castration-resistant prostate cancer have led to the development and FDA approval of two next-generation endocrine therapy drugs, the androgen biosynthesis inhibitor abiraterone and the potent androgen receptor antagonist enzalutamide. These drugs heralded a new era of prostate cancer therapy. However, some patients present with therapy-resistant disease, and most initial responders develop acquired resistance within months of therapy initiation. Recent studies indicate that these resistant tumors commonly remain androgen receptor driven. This presentation will describe how the androgen receptor signal pathway evades endocrine therapies and how our understanding of endocrine treatment resistance is providing insights into novel therapeutic strategies for improving outcome from this disease.
Citation Format: Yan Dong. Addiction of prostate cancer to androgen receptor. [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 IA07.
Abstract IA09: Non-mutational resistance to anti-cancer drugs
Authors: Settleman Jeff 
Published: May 2017

Abstract
“Rationally-targeted” oncology drugs can deliver significant therapeutic benefit in genomically-defined subsets of cancer patients. However, the clinical benefit associated with these agents is substantially limited by the nearly invariable emergence of drug resistance over time. In many cases, specific mutational mechanisms of resistance have been elucidated, presumably reflecting the clonal selection of stochastically-generated mutations that were present prior to treatment; however, additional pre-clinical and clinical findings implicate non-mutational mechanisms as well. We have identified and characterized a small subpopulation of reversibly “drug-tolerant” cells. The drug-tolerant phenotype is associated with a distinct chromatin state, and is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity. The drug-tolerant subpopulation can be selectively ablated by treatment with certain chromatin-modifying agents, potentially yielding a therapeutic opportunity. Furthermore, this subpopulation appears to contain the precursors of drug-resistant clones that acquire mutations during, rather than prior to, drug treatment. Additional studies of non-mutational drug resistance mechanisms implicate the rewiring of growth factor-responsive cellular signaling pathways as a common survival mechanism within tumor cell populations. These findings suggest that cancer cell populations employ various epigenetically-determined survival strategies to establish sufficient phenotypic variation among cells in order to protect the population from eradication by potentially lethal exposures.
Citation Format: Jeff Settleman. Non-mutational resistance to anti-cancer drugs. [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 IA09.
Abstract IA14: Targeting Ras
Authors: McCormick Frank 
Published: May 2017

Abstract
We are exploring multiple ways of targeting Ras proteins and Ras-driven cancers. We have identified compounds that covalently bind to cysteine-185 on K-Ras 4B, and to the G-domain of K-Ras 4A and 4B. We are also screening for compounds that bind directly to K-Ras using a new technique referred to as Second Harmonic Generation and are developing compounds that promote phosphorylation of K-Ras4B on serine-181. In addition, we are attempting to solve novel structures of oncogenic Ras proteins on their own, or complexed with effectors, regulators and chaperones, in an attempt to identify new targeting opportunities. For example, we have solved the structure of fully processed K-Ras 4B bound to PDE-delta. This co-structure suggests several new approaches to targeting K-Ras processing.
In addition to targeting K-Ras directly, we are validating downstream dependencies that are specific for K-Ras cancers, including the cytokine LIF, which is expressed at high levels in K-Ras transformed cells and plays a major role in stem-like properties of K-Ras cancers. Suppressing LIF expression using shRNA, CRISPR or monoclonal antibodies has profound effects on K-Ras tumor initiation and maintenance, and suggests new therapeutic opportunities. We are also analyzing signaling pathways that differ between Ras mutants and between Ras isoforms. These results, and their opportunities for intervention, will be discussed.
Citation Format: Frank McCormick. Targeting Ras. [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 IA14.
Abstract IA30: Targeting hormone receptors for degradation: Nuclear receptor downregulation as a therapeutic approach in cancer
Authors: McDonnell Donald , Cocce Kimberly , Wardell Suzanne , Norris John 
Published: May 2017

Abstract
Durable clinical responses to endocrine therapies in breast cancer are limited by the development of resistance that can occur as a consequence of estrogen receptor–alpha (ERα) mutations, the production of non-canonical ER ligands, or to the reprogramming of ER signaling pathways. This contemporary view of resistance has driven the search for Selective Estrogen Receptor Degraders (SERDs), compounds that target the receptor for proteasomal degradation. The clinical activity of fulvestrant, the first drug in this class, confirmed the utility of SERDs in late stage disease; however the poor pharmaceutical properties of this drug have limited its use. Previously, we reported the discovery and early clinical development of the first orally bioavailable SERD (GW5638) and although its development was discontinued, the early positive signals from clinical studies of this drug provided others with the impetus to develop additional molecules that function using the same mechanism of action (GDC810 and AZ9694). These latter drugs, if approved, will be significant additions to the breast cancer armamentarium. Anticipating that acquired resistance is likely to be a response to SERD treatment, we have recently embarked on an effort to identify targets/pathways that are required for the maintenance of the receptor expression. It is anticipated that combined treatment with SERDs and agents that inhibit ERα expression would result in more durable clinical responses. These efforts have led to the discovery that the AGR2/LYPD3 signaling axis within cancer cells is required for ERα expression and that its inhibition achieves a quantitative downregulation of this receptor in tumor models. The impact of targeting ERα expression, directly (SERDs) and/or indirectly (AGR2 blocking antibodies) in breast cancer will be the focus of this presentation.
Citation Format: Donald McDonnell, Kimberly Cocce, Suzanne Wardell, John Norris. Targeting hormone receptors for degradation: Nuclear receptor downregulation as a therapeutic approach in cancer. [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 IA30.
Abstract PR04: Small molecule-mediated activation of Ras elicits inhibition of MAPK and PI3K signaling though pathway feedback
Authors: Howes Jennifer E. , Akan Denis T. , Alicie Bethany M. , Waterson Alex G. , Rossanese Olivia W. , Fesik Stephen W. 
Published: May 2017

Abstract
Oncogenic mutation or hyper-activation of Ras results in aberrant cellular signaling and is responsible for approximately 30% of all human tumors. Therefore, Ras is an outstanding candidate for therapeutic inhibition. However, the discovery of potent inhibitors has been challenging. Our laboratory has recently discovered small molecules that perturb Son of Sevenless (SOS) -catalyzed nucleotide exchange on Ras (Burns et al. PNAS 2014). Here we describe experiments conducted to determine the mechanism of compound action. SOS activator compound 4 (C4) induces signaling flux through the MAPK pathway in response to elevated Ras-GTP levels, reminiscent of epidermal growth factor signaling. We used mass spectrometry to show that in response to C4 stimulation, phospho-modifications on SOS1 increased at ERK phosphorylation consensus sequences. We hypothesize that these phospho-modifications can cause delocalization of SOS and membrane bound Ras, and we are currently using proximity-ligation to assess whether the interaction between SOS1 and Ras is affected by C4 treatment.
Cross-talk between the MAPK and PI3K signaling pathways may be responsible for the inhibition of phospho-AKT Ser473 levels in response to MAPK signaling flux, or vice versa. Here we show, using MEK and PI3K inhibitor pre-treatments, that events in both pathways are independent after C4 treatment. As both SOS1 and PI3K bind to Ras at a similar site, we are currently testing the hypothesis that C4 disrupts the interaction between Ras and PI3K, whilst allowing signaling flux through the MAPK pathway.
Overall, we have discovered small-molecule activators of SOS that modulate Ras-GTP levels, resulting in signaling flux through the MAPK pathway and eventual downstream inhibition of both the MAPK and PI3K pathways in cancer cells.
This abstract is also being presented as Poster A15.
Citation Format: Jennifer E. Howes, Denis T. Akan, Bethany M. Alicie, Alex G. Waterson, Olivia W. Rossanese, Stephen W. Fesik. Small molecule-mediated activation of Ras elicits inhibition of MAPK and PI3K signaling though pathway feedback. [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 PR04.
Bitter Melon Enhances Natural Killer–Mediated Toxicity against Head and Neck Cancer Cells
Authors: Bhattacharya Sourav , Muhammad Naoshad , Steele Robert , Kornbluth Jacki , Ray Ratna B. 
Published: May 2017

AbstractNatural killer (NK) cells are one of the major components of innate immunity, with the ability to mediate antitumor activity. Understanding the role of NK-cell–mediated tumor killing in controlling of solid tumor growth is still in the developmental stage. We have shown recently that bitter melon extract (BME) modulates the regulatory T cell (Treg) population in head and neck squamous cell carcinoma (HNSCC). However, the role of BME in NK-cell modulation against HNSCC remains unknown. In this study, we investigated whether BME can enhance the NK-cell killing activity against HNSCC cells. Our results indicated that treatment of human NK-cell line (NK3.3) with BME enhances ability to kill HNSCC cells. BME increases granzyme B accumulation and translocation/accumulation of CD107a/LAMP1 in NK3.3 cells exposed to BME. Furthermore, an increase in cell surface expression of CD16 and NKp30 in BME-treated NK3.3 cells was observed when cocultured with HNSCC cells. Collectively, our results demonstrated for the first time that BME augments NK-cell–mediated HNSCC killing activity, implicating an immunomodulatory role of BME. Cancer Prev Res; 10(6); 337–44. ©2017 AACR.
Socioeconomic Status and the Risk of Stroke Recurrence
Authors: Pennlert Johanna , Asplund Kjell , Glader Eva-Lotta , Norrving Bo , Eriksson Marie 
Published: May 2017

Background and Purpose—
This nationwide observational study aimed to investigate how socioeconomic status is associated with risk of stroke recurrence and how possible associations change over time.

Methods—
This study included 168 295 patients, previously independent in activities of daily living, with a first-ever stroke in the Swedish Stroke Register (Riksstroke) 2001 to 2012. Riksstroke was linked with Statistics Sweden as to add individual information on education and income. Subdistribution hazard regression was used to analyze time from 28 days after first stroke to stroke recurrence, accounting for the competing risk of other causes of death.

Results—
Median time of follow-up was 3.0 years. During follow-up, 23 560 patients had a first recurrent stroke, and 53 867 died from other causes. The estimated cumulative incidence of stroke recurrence was 5.3% at 1 year, and 14.3% at 5 years. Corresponding incidence for other deaths were 10.3% and 30.2%. Higher education and income were associated with a reduced risk of stroke recurrence. After adjusting for confounding variables, university versus primary school education returned a hazard ratio of 0.902; 95% confidence interval, 0.864 to 0.942, and the highest versus the lowest income tertile a hazard ratio of 0.955; 95% confidence interval, 0.922 to 0.989. The risk of stroke recurrence decreased during the study period, but the inverse effect of socioeconomic status on risk of recurrence did not change significantly.

Conclusions—
Despite a declining risk of stroke recurrence over time, the differences in recurrence risk between different socioeconomic groups remained at a similar level in Sweden during 2001 to 2012.
Efficacy of Stent-Retriever Thrombectomy in Magnetic Resonance Imaging Versus Computed Tomographic Perfusion–Selected Patients in SWIFT PRIME Trial (Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke)
Authors: Menjot de Champfleur Nicolas , Saver Jeffrey L. , Goyal Mayank , Jahan Reza , Diener Hans-Christoph , Bonafe Alain , Levy Elad I. , Pereira Vitor M. , Cognard Christophe , Yavagal Dileep R. , Albers Gregory W. 
Published: May 2017

Background and Purpose—
The majority of patients enrolled in SWIFT PRIME trial (Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke) had computed tomographic perfusion (CTP) imaging before randomization; 34 patients were randomized after magnetic resonance imaging (MRI).

Methods—
Patients with middle cerebral artery and distal carotid occlusions were randomized to treatment with tPA (tissue-type plasminogen activator) alone or tPA+stentriever thrombectomy. The primary outcome was the distribution of the modified Rankin Scale score at 90 days. Patients with the target mismatch profile for enrollment were identified on MRI and CTP.

Results—

MRI selection was performed in 34 patients; CTP in 139 patients. Baseline National Institutes of Health Stroke Scale score was 17 in both groups. Target mismatch profile was present in 95% (MRI) versus 83% (CTP). A higher percentage of the MRI group was transferred from an outside hospital (
P
=0.02), and therefore, the time from stroke onset to randomization was longer in the MRI group (
P
=0.003). Time from emergency room arrival to randomization did not differ in CTP versus MRI-selected patients. Baseline ischemic core volumes were similar in both groups. Reperfusion rates (>90%/TICI [Thrombolysis in Cerebral Infarction] score 3) did not differ in the stentriever-treated patients in the MRI versus CTP groups. The primary efficacy analysis (90-day mRS score) demonstrated a statistically significant benefit in both subgroups (MRI,
P
=0.02; CTP,
P
=0.01). Infarct growth was reduced in the stentriever-treated group in both MRI and CTP groups.

Conclusions—
Time to randomization was significantly longer in MRI-selected patients; however, site arrival to randomization times were not prolonged, and the benefits of endovascular therapy were similar.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01657461.
Severe Convective Storms in Europe: Ten Years of Research and Education at the European Severe Storms Laboratory
Authors: Groenemeijer Pieter , Púčik Tomáš , Holzer Alois M. , Antonescu Bogdan , Riemann-Campe Kathrin , Schultz David M. , Kühne Thilo , Feuerstein Bernold , Brooks Harold E. , Doswell Charles A. , Koppert Hans-Joachim , Sausen Robert 
Published: May 2017

AbstractThe European Severe Storms Laboratory (ESSL) was founded in 2006 to advance the science and forecasting of severe convective storms in Europe. ESSL was a grassroots effort of individual scientists from various European countries. The purpose of this article is to describe the 10-yr history of ESSL and present a sampling of its successful activities. Specifically, ESSL developed and manages the only multinational database of severe weather reports in Europe: the European Severe Weather Database (ESWD). Despite efforts to eliminate biases, the ESWD still suffers from spatial inhomogeneities in data collection, which motivates ESSL’s research into modeling climatologies by combining ESWD data with reanalysis data. ESSL also established its ESSL Testbed to evaluate developmental forecast products and to provide training to forecasters. The testbed is organized in close collaboration with several of Europe’s national weather services. In addition, ESSL serves a central role among the European scientific and forecast communities for convective storms, specifically through its training activities and the series of European Conferences on Severe Storms. Finally, ESSL conducts wind and tornado damage assessments, highlighted by its recent survey of a violent tornado in northern Italy.