bluuebunny/crossref_metadata_2025_split huggingface dataset:
On Crowdsourcing Relevance Magnitudes for Information Retrieval Evaluation
Authors: Maddalena Eddy , Mizzaro Stefano , Scholer Falk , Turpin Andrew 
Published: January 2017

Magnitude estimation is a psychophysical scaling technique for the measurement of sensation, where observers assign numbers to stimuli in response to their perceived intensity. We investigate the use of magnitude estimation for judging the relevance of documents for information retrieval evaluation, carrying out a large-scale user study across 18 TREC topics and collecting over 50,000 magnitude estimation judgments using crowdsourcing. Our analysis shows that magnitude estimation judgments can be reliably collected using crowdsourcing, are competitive in terms of assessor cost, and are, on average, rank-aligned with ordinal judgments made by expert relevance assessors.
We explore the application of magnitude estimation for IR evaluation, calibrating two gain-based effectiveness metrics, nDCG and ERR, directly from user-reported perceptions of relevance. A comparison of TREC system effectiveness rankings based on binary, ordinal, and magnitude estimation relevance shows substantial variation; in particular, the top systems ranked using magnitude estimation and ordinal judgments differ substantially. Analysis of the magnitude estimation scores shows that this effect is due in part to varying perceptions of relevance: different users have different perceptions of the impact of relative differences in document relevance. These results have direct implications for IR evaluation, suggesting that current assumptions about a single view of relevance being sufficient to represent a population of users are unlikely to hold.
Nitric oxide promotes GABA release by activating a voltage-independent Ca2+ influx pathway in retinal amacrine cells
Authors: Maddox J. Wesley , Gleason Evanna 
Published: January 2017

Retinal amacrine cells express nitric oxide (NO) synthase and produce NO, making NO available to regulate the function of amacrine cells. Here we test the hypothesis that NO can alter the GABAergic synaptic output of amacrine cells. We investigate this using whole cell voltage clamp recordings and Ca2+ imaging of cultured chick retinal amacrine cells. When recording from amacrine cells receiving synaptic input from other amacrine cells, we find that NO increases GABAergic spontaneous postsynaptic current (sPSC) frequency. This increase in sPSC frequency does not require the canonical NO receptor, soluble guanylate cyclase, or presynaptic action potentials. However, removal of extracellular Ca2+ and buffering of cytosolic Ca2+ both inhibit the response to NO. In Ca2+ imaging experiments, we confirm that NO increases cytosolic Ca2+ in amacrine cell processes by activating a Ca2+ influx pathway. Neither the increase in sPSC frequency nor the cytosolic Ca2+ elevations are dependent upon Ca2+ release from stores. NO also enhances evoked GABAergic responses. Because voltage-gated Ca2+ channel function is not altered by NO, the increased evoked response is likely due to the combined effect of voltage-dependent Ca2+ influx adding to the NO-dependent, voltage-independent, Ca2+ influx. Insight into the identity of the Ca2+ influx pathway is provided by the transient receptor potential canonical (TRPC) channel inhibitor clemizole, which prevents the NO-dependent increase in sPSC frequency and cytosolic Ca2+ elevations. These data suggest that NO production in the inner retina will enhance Ca2+-dependent GABA release from amacrine cells by activating TRPC channel(s). NEW & NOTEWORTHY Our research provides evidence that nitric oxide (NO) promotes GABAergic output from retinal amacrine cells by activating a likely transient receptor potential canonical-mediated Ca2+ influx pathway. This NO-dependent mechanism promoting GABA release can be voltage independent, suggesting that, in the retina, local NO production can bypass the formal retinal circuitry and increase local inhibition.
Heterogeneous effects of norepinephrine on spontaneous and stimulus-driven activity in the male accessory olfactory bulb
Authors: Doyle Wayne I. , Meeks Julian P. 
Published: January 2017

Norepinephrine (NE) release has been linked to experience-dependent plasticity in many model systems and brain regions. Among these is the rodent accessory olfactory system (AOS), which is crucial for detecting and processing socially relevant environmental cues. The accessory olfactory bulb (AOB), the first site of chemosensory information processing in the AOS, receives dense centrifugal innervation by noradrenergic fibers originating in the locus coeruleus. Although NE release has been linked to behavioral plasticity through its actions in the AOB, the impacts of noradrenergic modulation on AOB information processing have not been thoroughly studied. We made extracellular single-unit recordings of AOB principal neurons in ex vivo preparations of the early AOS taken from adult male mice. We analyzed the impacts of bath-applied NE (10 μM) on spontaneous and stimulus-driven activity. In the presence of NE, we observed overall suppression of stimulus-driven neuronal activity with limited impact on spontaneous activity. NE-associated response suppression in the AOB came in two forms: one that was strong and immediate (21%) and one other that involved gradual, stimulus-dependent monotonic response suppression (47%). NE-associated changes in spontaneous activity were more modest, with an overall increase in spontaneous spike frequency observed in 25% of neurons. Neurons with increased spontaneous activity demonstrated a net decrease in chemosensory discriminability. These results reveal that noradrenergic signaling in the AOB causes cell-specific changes in chemosensory tuning, even among similar projection neurons. NEW & NOTEWORTHY Norepinephrine (NE) is released throughout the brain in many behavioral contexts, but its impacts on information processing are not well understood. We studied the impact of NE on chemosensory tuning in the mouse accessory olfactory bulb (AOB). Electrophysiological recordings from AOB neurons in ex vivo preparations revealed that NE, on balance, inhibited mitral cell responses to chemosensory cues. However, NE’s effects were heterogeneous, indicating that NE signaling reshapes AOB output in a cell- and stimulus-specific manner.
Abstract A10: Redox regulation of the Wnt/β-catenin pathway in colorectal cancer
Authors: Campos Alex , James Brian , Jong Petrus De , Powis Garth 
Published: January 2017

Abstract
Colorectal cancer (CRC) is the third most newly diagnosed cancer, and the third most frequent cause of cancer related death in the United States. Thus, there is an urgent unmet need for the development of new therapies for the treatment of CRC. Loss of function mutations in adenomatous polyposis coli (APC), a critical member of the β-catenin destruction complex, lead to elevated protein levels of β-Catenin, and are found in 85% of CRCs, where they are associated with decreased CRC patient survival. Increased levels of β-catenin protein augment the nuclear accumulation of β-catenin where it interacts with transcription factors to induce transcription of target genes promoting cell proliferation, survival, and migration. Currently, there is still no effective therapy targeting aberrant β-catenin transcriptional activity. Here we report on the redox dependency of the Wnt/β-catenin signaling pathway, identified through a forward genetic screen in Drosophila, and identify TxnR1 as a potential target for the inhibition of aberrant β-catenin transcriptional activity through in vivo studies with the APCmin/+ mouse model. Drosophila harboring a mutation in the thioredoxin reductase (txnr1) gene that have a partial lethality phenotype were used in an enhancer/suppressor forward genetic screen. Increased lethality was observed when the txnr1 mutation (Txnr1481) was combined with heterozygous mutations and deletions in dwnt2, while dwnt2 deletion and mutations alone had no effect (on lethality). In addition, β-Catenin mediated transcription, as measured by TOP Flash luciferase assay, was diminished when TxnR1 was silenced by siRNA. To test the translational value of these findings, APCmin/+ mice were treated with PX-12, a human TxnR1 inhibitor, daily by gavage from day 40 to time of death. We observed a dose dependent reduction in the number and size of intestinal polyps by PX-12 treatment, and an increased survival in treated mice. Also, human colorectal cancer cell lines treated with PX-12 displayed attenuated phosphorylation of β-catenin serine residues 552 and 675. These results suggest a conserved mechanism for the redox regulation of the Wnt/β-catenin pathway involving TxnR1; furthermore, inhibition of TxnR1 can inhibit intestinal neoplasia development in an experimental model of CRC.
Citation Format: Alex Campos, Brian James, Petrus De Jong, Garth Powis. Redox regulation of the Wnt/β-catenin pathway in colorectal 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 A10.
Abstract A12: Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide
Authors: Chen Wenshu , Padilla Mabel T. , Xu Xuling , Desai Dhimant , Krzeminski Jacek , Amin Shantu , Lin Yong 
Published: January 2017

Abstract
The interaction between epithelial and stromal cells through soluble factors such as cytokines plays an important role in carcinogenesis. Breaking this cancer-promoting interaction poses an opportunity for cancer prevention. The tumor-promoting function of interleukin 6 (IL-6) has been documented; however, the underlying mechanisms of this function in lung carcinogenesis are not well elucidated. Here, we show that benzo[a]pyrene diol epoxide (BPDE, the active metabolite of cigarette smoke carcinogen benzo[a]pyrene)-induced human bronchial epithelial cell (HBEC) transformation was enhanced by IL-6 in vitro. The carcinogen/IL-6-transformed cells exhibited higher expression of STAT3 (signal transducer and activator of transcription 3) when compared with cells transformed by BPDE alone. Constitutive STAT3 activation drove cell proliferation and survival through anti-apoptosis gene expression. We further show that quercetin, a dietary compound having preventive properties for lung cancer, decreased BPDE-stimulated IL-6 secretion from human lung fibroblasts through inhibition of the NF-κB and ERK pathways. The inhibition was accomplished at clinically achievable concentrations of the compound. Finally, quercetin blocked IL-6-induced STAT3 activation in HBECs, and IL-6 enhancement of HBEC transformation by BPDE was abolished by quercetin treatment. Altogether, our data reveal novel mechanisms for IL-6 in lung carcinogenesis and for the preventive role of quercetin in the process.
Citation Format: Wenshu Chen, Mabel T. Padilla, Xuling Xu, Dhimant Desai, Jacek Krzeminski, Shantu Amin, Yong Lin. Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide. [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 A12.
Abstract A17: Abiraterone metabolism and a novel therapeutic strategy for castration resistant prostate cancer
Authors: Li Zhenfei , Alyamani Mohammad , Li Jianneng , Taplin Mary-Ellen , Sharifi Nima 
Published: January 2017

Abstract
Prostate cancer is the most common cancer in men in the United States. Abiraterone (abi) is approved by the FDA for treatment of castration resistant prostate cancer (CRPC). However, ~30% of patients have limited or no response to abi. The underlying mechanism of resistance is elusive in these cases, and the best treatment plan for such patients is not clear. Thus we sought to determine a potential mechanism of resistance by analyzing abi metabolism. We found that abi undergoes metabolism catalyzed by steroidogenic enzymes. Abi is converted sequentially to delta-4-abi (D4A), then undergoes C5 reduction to produce several metabolites, including 5α-abi and 5 other metabolites. D4A has more potent anti-tumor activity than abi itself because it inhibits multiple enzymes and antagonizes the androgen receptor (AR) directly. D4A inhibits cell proliferation and xenograft growth better than Abi. However, 5α-Abi has more limited effects on steroidogenic enzymes and is a modest AR agonist, which might promote abi resistance. We suggest that abi metabolism could be a biomarker for abi response, and patients with limited or no response to abi might have less D4A or more 5α-Abi. Furthermore, we demonstrate that dutasteride, a 5α-reductase inhibitor, suppresses the conversion from D4A to 5α-Abi in both prostate cancer cell lines and patients, which might enhance the clinical response to abi. Taken together, these data reveal a novel metabolic pathway of abi that can be exploited for treatment, specifically as a biomarker. It is achievable in clinic to fine tune abi metabolism to obtain greater concentrations of D4A, the most potent anti-tumor abi metabolite, in patients by supplementing abi treatment with dutasteride.
Citation Format: Zhenfei Li, Mohammad Alyamani, Jianneng Li, Mary-Ellen Taplin, Nima Sharifi. Abiraterone metabolism and a novel therapeutic strategy for castration resistant prostate 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 A17.
Abstract A20: The DNA damage-induced phosphoproteome is modulated by inhibition of the MET receptor
Authors: Bensimon Ariel , Zimmer Yitzhak , Francica Paola , Koch Jonas P. , Glück Astrid A. , Aebersold Daniel M. , Aebersold Ruedi , Medova Michaela 
Published: January 2017

Abstract
Ionizing radiation (IR) is frequently used in the treatment of a variety of malignant tumors of different origins and stages. In recent years, numerous studies have demonstrated that interfering with signaling via growth factor receptor tyrosine kinases (RTKs) can increase the sensitivity of certain tumors to IR. The RTK for hepatocyte growth factor MET is aberrantly activated in numerous types of human malignancies. MET inhibition has been shown to synergize with DNA damaging agents in generation of DNA damage and to interfere with damage repair. In this study, we aimed to explore how the cellular response to ionizing radiation is modulated by MET inhibition.
We have conducted an immunoaffinity-based LC-MS/MS phosphoproteomics survey study to explore the cellular phosphoproteome following exposure of MET-addicted cancer cells to MET inhibition alone and in combination with IR. Phosphorylation sites of interest have been examined using selected reaction monitoring (SRM) and further validated in vitro and in vivo by Western blotting and immunohistochemistry, respectively.
Analysis of the survey data has identified more than 300 phosphopeptides which have changed in one experimental condition or more. Several of these phosphorylation changes have been confirmed and further investigated by targeted proteomics. These results have pointed to a sub-network of the DNA damage response (DDR) that is modulated in MET-addicted cancer cells upon DNA damage and MET inhibition. The resulting molecular signature present solely in MET-addicted systems could be responsible for the synergism observed between MET inhibition and DNA-damaging agents. We believe that these results will aid in understanding as how MET signaling crosstalks with the DDR with subsequent translational therapeutic clinical applications.
Citation Format: Ariel Bensimon, Yitzhak Zimmer, Paola Francica, Jonas P. Koch, Astrid A. Glück, Daniel M. Aebersold, Ruedi Aebersold, Michaela Medova. The DNA damage-induced phosphoproteome is modulated by inhibition of the MET 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 A20.
Abstract A32: Upregulation of the Notch signaling pathway is associated with mortality and in vitro cell invasion in squamous cell carcinoma of the oral cavity
Authors: Weaver Alice N. , Cooper Tiffiny S. , Manna Deborah Della , Wei Shi , Rosenthal Eben L. , Yang Eddy S. 
Published: January 2017

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with low survival rates, which have not significantly improved despite advances in surgery and radiotherapy. Although human papillomavirus is a strong predictor of outcomes in oropharyngeal tumors, other HNSCC subtypes lack reliable prognostic and therapeutic biomarkers. The purpose of this study was to identify molecular targets to improve the management of oral cavity SCC (OSCC). We isolated RNA from 19 OSCCs treated surgically at UAB and evaluated gene expression using the NanoString nCounter system and PanCancer Pathways analysis module. Results were confirmed using data from the oral cavity anatomic subdivision of the Head and Neck Squamous Cell Carcinoma cancer study generated by the TCGA Research Network. Associated in vitro phenotype was assessed in HNSCC cell lines UM-SCC1, UM-SCC6 and FaDu treated with the activating Notch ligand DLL4 and included evaluation of gene expression, proliferation, cell cycle, migration, invasion, and radiosensitivity. We identified a significant association between upregulation of the Notch pathway and mortality in both the UAB and TCGA OSCC sample sets. In vitro activation of Notch signaling altered transcription in a pattern similar to that found in patient samples from the mortality cohorts. HNSCC cells with Notch activation had increased expression of pro-invasive genes FGF1, IL1B, SIX1, and CCNA1. In addition, Notch activated cells displayed increased cell migration and invasion. Proliferation, cell cycle distribution, and radiosensitivity were unchanged in ligand-treated cells. Our results identify a subset of OSCC patients who have increased Notch pathway activity and worsened outcomes. These clinical findings may reflect a more invasive cell phenotype driven by Notch-mediated changes in transcription. Additional studies are needed to fully elucidate the mechanism underlying this association and to investigate the efficacy of therapies targeting Notch signaling in OSCC.
Citation Format: Alice N. Weaver, Tiffiny S. Cooper, Deborah Della Manna, Shi Wei, Eben L. Rosenthal, Eddy S. Yang. Upregulation of the Notch signaling pathway is associated with mortality and in vitro cell invasion in squamous cell carcinoma of the oral cavity. [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 A32.
Abstract A38: MTH1 Inhibition as an effective tumor-suppressive strategy in RAS-driven cancer
Authors: Samaranayake Govindi Jayanika , Troccoli Clara Issabella , Cunningham Tyler Andrew , Rai Priyamvada 
Published: January 2017

Abstract
Oncogenic RAS mutations confer multiple malignant traits to cancer cells, many of which are mediated by oncogene-induced reactive oxygen species (ROS). However, oncogenic ROS also create vulnerabilities in the cancer cells, sensitizing them to oxidative DNA damage and strand breaks which can trigger cellular senescence or cell death. Thus RAS-driven tumor cells require adaptive redox protective mechanisms to inhibit ROS-associated tumor suppression. We previously reported that MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase, comprises one such critical adaptation. We have shown MTH1 is important for facilitating the full gamut of RAS-driven malignancy by promoting evasion of the first barrier to transformation, viz. oncogene-induced senescence (OIS), enhancing RAS-mediated transformation and related pro-malignant traits, and maintaining proliferation and tumorigenicity in established RAS-driven tumor cells. Recently chemical inhibitors against MTH1 have been developed, although there is some controversy surrounding their efficacy and mode of action. Our work here discusses RAS regulation of MTH1 expression, and the molecular contexts under which MTH1 inhibition can synergize with oncogenic oxidative stress in RAS-driven tumor cells for optimal tumor suppressive response.
Citation Format: Govindi Jayanika Samaranayake, Clara Issabella Troccoli, Tyler Andrew Cunningham, Priyamvada Rai. MTH1 Inhibition as an effective tumor-suppressive strategy in RAS-driven 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 A38.
Abstract A41: Development of a risk analysis model for triple-negative breast cancer stages and treatment of African American women
Authors: Chowdhury Rupak , Nandy Shami , Tameru Berhanu 
Published: January 2017

Abstract
The main object of this study is to assess how different stages of triple-negative breast cancer (TNBC) influences treatment of triple negative breast cancer patient. The data was gathered from Alabama Department of Public Health. We developed a probabilistic pathway scenario tree based on the knowledge from the comprehensive literature review and organized the variables into twelve major parameter categories. We performed Monte Carlo simulations with the software @Risk 5.7 (Palisade Corporation) for the quantitative risk assessment to capture the uncertainty for the treatment of triple negative breast cancer and different stages of TNBC. The likelihood (LH) of having one of the treatments for Stage IV TNBC, Surgery and or Chemotherapy (CT) or none gave that the person is (African American women) AAW older than 50, TNBC ranges from a min. of 1.62 × 10−3 to a max. of 2.35 × 10−2 with the mean and standard deviation of 8.28 × 10−3 and 3.141 × 10−3 respectively. The LH of having one of the treatments for stage 1&2 of triple negative breast cancer, Surgery and or CT or none gave that the person is AAW older than 50, TNBC ranges from 1.78 × 10−5 to 1.053 × 10−1 with the mean and standard deviation of 2.74 × 10−2 and 2.06 × 10−2 respectively. However, there are no standard guidelines for Triple negative breast cancer patients, our study suggests that stage 1&2 triple negative breast cancer patients are most likely to be treated with either chemotherapy or surgery and stage 3, 4 triple negative breast cancer patient are most likely to be treated with combined surgery and chemotherapy.
Note: This abstract was not presented at the conference.
Citation Format: Rupak Chowdhury, Shami Nandy, Berhanu Tameru. Development of a risk analysis model for triple-negative breast cancer stages and treatment of African American women. [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 A41.