bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA27: A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma
Authors: Fan QiWen , Aksoy Ozlem , Wong Robyn , Ilkhanizadeh Shirin , Novotny Chris , Gustafson William , Tuong Albert , Cayanan Geraldine , Simonds Erin , Haas-Kogan Daphne , Phillips Joanna , Nicolaides Theo , Nicolaides Theo , Okaniwa Masanori , Shokat Kevan , Weiss William A.
Published: May 2017

San Francisco, San Francisco, CA.

Glioblastoma (GBM), the most common primary brain tumor, numbers among the most aggressive of cancers. Although signaling from PI3K and AKT to mTOR is dysregulated prominently, we show here that blockade of these upstream targets affects mTOR activity minimally in glioma. Direct targeting using allosteric inhibitors (rapamycin) blocked mTORC1 incompletely, while we also show here that mTOR active site inhibitors (TORKi) have short residence times, limiting their efficacy preclinically. We therefore tested the third-generation mTOR inhbitior RapaLink-1 a TORKi to the mTORC1-specific binding domain of rapamycin, for activity in GBM. RapaLink-1 interacted with FKBP12, an abundant mTOR interacting protein, enabling accumulation of RapaLink-1 in tumor cells. RapaLink-1 showed better efficacy and durability than rapamycin or a TORKi, potently blocking cancer-derived, activating mutants of mTOR. RapaLink-1 drove regression of intracranial xenografts in-vivo, improving survival compared with earlier-generation inhibitors. Our studies re-establish mTOR as a central target in glioma, trace the failure of existing drugs to incomplete/nondurable inhibition of mTORC1, and offer a new class of mTORC1 inhibitors with improved potency and durability.

Citation Format: QiWen Fan, Ozlem Aksoy, Robyn Wong, Shirin Ilkhanizadeh, Chris Novotny, William Gustafson, Albert Tuong, Geraldine Cayanan, Erin Simonds, Daphne Haas-Kogan, Joanna Phillips, Theo Nicolaides, Theo Nicolaides, Masanori Okaniwa, Kevan Shokat, William A. Weiss. A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. [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 IA27.
Abstract PR04: Translational control of human colon tumor cell survival
Authors: Lemma Eyerusalem M. , McCall Jamie L. , Clymer Beth K. , Kelly David L. , White Michael A. , Lewis Robert E.
Published: May 2017

Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK kinase cascade, is required for transformation and survival of cells bearing oncogenic Ras, but is not required for normal cell survival. KSR1 knockout mice are phenotypically normal, and depletion of KSR1 by RNAi does not kill immortalized, non-transformed human colon epithelial cells (HCECs), suggesting that KSR1 or KSR1-dependent effectors may serve as highly selective therapeutic targets. Our previous work showed that KSR1 regulates expression of the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1β), whose expression is critical to colon cancer cell survival. Using RNAi and pharmacological inhibition, we observed that KSR1 and ERK drive both cap-dependent and cap-independent translation of Myc in human colon tumor cell lines, which increases PGC1β mRNA expression (McCall et al. MCB, 2016). This effect is mediated through the KSR1 and ERK-dependent phosphorylation of 4E-PB1 and phosphorylation-dependent loss of PDCD4 that reverses their inhibitory effect on eIF4E and eIF4A, respectively. Treatment with ERK inhibitor SCH772984 showed that ERK regulates PDCD4 protein expression and 4EBP1 phosphorylation to promote Myc expression in four of the seven colon cancer cell lines. These observations suggest that KSR1-dependent regulation of translation may be a common mechanism used to support tumor cell survival. Using KSR1 as a reference standard, Functional Signature Ontology (FUSION, Potts et al. Sci. Signaling 2013) was used to identify genetic vulnerabilities in human colon tumor cells that are absent in HCECs. Comparison of results from this screen to genome-wide polysome profiling data from cells transformed with Ras and Myc (Truitt et al. Cell 2015) identified 25 candidate mRNAs with altered translational efficiency that are predicted to support the survival of human colon tumor cells. These data suggest that KSR1 and ERK-dependent alteration of the translational landscape is a common strategy used to support colon tumor cell survival. Identification of mRNAs preferentially translated in colon tumor cells may yield novel targets for therapeutic manipulation and may provide unique markers with which to classify colon tumors, predict patient outcome, and select effective treatment.

This abstract is also being presented as Poster B36.

Citation Format: Eyerusalem M. Lemma, Jamie L. McCall, Beth K. Clymer, David L. Kelly, Michael A. White, Robert E. Lewis. Translational control of human colon tumor cell survival. [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 PR04.
Abstract IA02: Mcl-1 inhibitors for the treatment of cancer
Authors: Fesik Stephen W.
Published: May 2017

Myeloid cell leukemia 1 (Mcl-1) is a member of the Bcl-2 family of proteins that is overexpressed and amplified in a wide variety of cancers and causes resistance to many chemotherapies. Although a very promising cancer target, it exerts its activity through protein-protein interactions and is very challenging to drug with small molecules. In this presentation, I will describe the discovery of picomolar Mcl-1 inhibitors using fragment-based methods and structure-based design that show promise as therapeutic agents for the treatment of heme malignancies and solid tumors.

Citation Format: Stephen W. Fesik. Mcl-1 inhibitors for the treatment of 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 IA02.
Abstract IA05: Autophagy prevents fatal nucleotide pool depletion in Ras-driven cancer cells
Authors: White Eileen
Published: May 2017

Autophagy degrades and recycles proteins and organelles essential for quality control and survival in starvation. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes tumor growth and malignancy. Autophagy-deficient tumor-derived cell lines (TDCLs) are respiration impaired, starvation sensitive, and glutamine-dependent. To survive starvation, autophagy may eliminate defective mitochondria or supply mitochondrial substrates. Here, we sequenced the mitochondrial genome from Kras-driven lung tumors and found higher mutant allele frequencies without autophagy-related-7 (Atg7). But the low pathogenic allele frequency was insufficient to account for metabolic defects. In starvation, Atg7 deficiency attenuated substrate supply for mitochondrial oxygen consumption and increased nucleotide degradation. The resulting nucleotide pool depletion and energy crisis in starvation was rescued by nucleoside supplementation. Thus the role for autophagy in Kras-driven tumor cells is to provide substrates to mitochondria to maintain nucleotide pools and energy homeostasis, which promotes survival to nutrient limitation.

Citation Format: Eileen White. Autophagy prevents fatal nucleotide pool depletion in Ras-driven cancer cells. [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 IA05.
Abstract IA06: Genomic approaches to drug discovery
Authors: Golub Todd R.
Published: May 2017

The principles of genomics (systematic, high throughput approaches to biology) can increasingly be brought to bear on drug discovery. Our group is developing two new approaches: Connectivity Map and PRISM.

The concept of the Connectivity Map (CMap) is that disease states, cellular states and the action of pharmacologic or genetic perturbation can be captured by gene expression profiling. In order to make large-scale perturbational profiling feasible, we developed a high-throughput, ultra-low cost profiling method (named L1000) whereby the abundance of 1000 transcripts are quantified by hybridization to Luminex microspheres. As part of the NIH LINCS program, we have now generated over 2 million such L1000 profiles representing knock-down and over-expression of over 3000 genes and perturbation with over 4000 small molecules in more than 15 cell types. Examples of discoveries emanating from this next generation Connectivity Map will be presented.

The PRISM method takes inspiration from recent large-scale drug sensitivity profiling studies demonstrating the value of determining the pattern of compound killing across a large panel of genetically characterized cancer cell lines. In order to increase the scale at which such studies can be performed, we inserted unique molecular barcodes (24-mer oligonucleotides) into the genomes of cancer cell lines, such that the lines could then be pooled and the pooled lines exposed to a compound of interest. Drug sensitivity is then quantified by changes in abundance of the molecular barcodes. We have demonstrated feasibility of pooling more than 500 cancer cell lines in a single pool, and have demonstrated feasibility of high throughput screening using the PRISM method. These experiments suggest that PRISM can be used as a starting point for oncology drug discovery and for the characterization of lead compounds for the genotype-specific patterns of cancer cell killing. Examples of recent PRISM discoveries will be presented.

Citation Format: Todd R. Golub. Genomic approaches to drug discovery. [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 IA06.
Abstract IA23: Enhancing anti-tumor immunity through selective inhibition of IDO1
Authors: Huber Reid
Published: May 2017

Tryptophan catabolism serves as an important metabolic immunoregulatory checkpoint, functioning in anti-inflammatory, immunosuppressive and tolerance-inducing processes. Three distinct heme-containing enzymes—indoleamine 2,3-dioxygenase (IDO) 1, IDO2 and tryptophan 2,3-dioxygenase (TDO)—have the capacity to initiate the first and rate-limiting step in this metabolic process, catalyzing the conversion of tryptophan to kynurenine. A growing body of scientific evidence indicates that this pathway, and more specifically, the IDO1 enzyme, may be of fundamental importance to tumor immune evasion. Through the depletion of local tryptophan and the production of kynurenine and other downstream metabolites, IDO1 activity has been shown to have an anti-proliferative effect on T cells, to promote Treg differentiation and to bias dendritic cells and macrophages toward an immunosuppressive phenotype. Further, IDO1 expression is a negative prognostic factor across numerous cancer histologies. Therefore, the selective inhibition of IDO1 has emerged as an attractive therapeutic approach to enhance anti-tumor immunity. This presentation will review the immunologic basis for targeting tryptophan catabolism in cancer, describe the emerging preclinical and clinical data on epacadostat, a novel first-in-class selective IDO1 inhibitor, and discuss the therapeutic rationales for epacadostat-based combination immunotherapies.

Citation Format: Reid Huber. Enhancing anti-tumor immunity through selective inhibition of IDO1. [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 IA23.
Abstract IA24: Transcriptional regulators as cancer dependencies
Authors: Vakoc Christopher
Published: May 2017

Broad alterations in the rate of gene transcription are necessary, and often sufficient, for cells to undergo malignant transformation. As a consequence, cancer cells are vulnerable to perturbations of individual transcription regulators, including DNA-binding transcription factors and general cofactors. Our laboratory has taken a functional-genomics approach to identify essential transcriptional regulators in cancer cells in an effort to expose opportunities for therapeutic intervention. Our initial efforts used shRNA screening to identify the BET bromodomain protein BRD4 as a targetable non-oncogene dependency in acute myeloid leukemia. More recently, we have pursued the use CRISPR-Cas9 genome editing as a tool for annotating essential transcriptional regulators in cancer. In my presentation, I will review our current understanding of BRD4 as a therapeutic target in leukemia, focusing on the upstream and downstream factors that support BRD4-dependent transcriptional activation. I will also present our use of CRISPR-Cas9 to identify and validate therapeutic targets in cancer, which exploits the heterogeneity of Cas9-induced indel mutations to infer structure-function relationships of individual protein domains.

Citation Format: Christopher Vakoc. Transcriptional regulators as cancer dependencies. [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 IA24.
Abstract IA25: Targeting cancers with deletion of the p16/p14 tumor suppressor locus
Authors: Marks Kevin
Published: May 2017

Mutations in tumor suppressor genes are a hallmark of cancer and contribute substantially to the molecular pathogenesis of the disease. Particularly prevalent are homozygous deletions of the CDKN2A tumor suppressor locus on chromosome 9p21, which occur in at least 15% of all cancer and lead to loss of the dual tumor suppressors p16(INK4A) and p14(ARF). Targeted therapies selective for loss of CDKN2A have proven elusive, and it may be necessary to identify alternate approaches to target tumors with this deletion. Notably, Chr9p21 deletions frequently involve co-deletion of genes proximal to CDKN2A. Foremost among these is the methylthioadenosine phosphorylase (MTAP) gene, which resides within 100 kb of CDKN2A, and is co-deleted in 80-90% of tumors with CDKN2A deletion. We sought therefore to evaluate whether the frequent co-deletion of the adjacent metabolic gene methylthioadenosine phosphorylase (MTAP) creates targetable vulnerabilities. We conducted an shRNA screen in isogenic cells that varied only in their MTAP-deletion status, and identified the metabolic enzyme, methionine adenosyltransferase II, alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss, and biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deletion leads to reduced basal PRMT5 methylation activity and increased sensitivity to PRMT5 targeting. MAT2A produces PRMT5 substrate S-adenosylmethionine (SAM), and targeting of MAT2A reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Further, this vulnerability extends to PRMT5 co-complex proteins such as the atypical kinase Rio Kinase 1 (RIOK1). Thus, MAT2A, PRMT5, and RIOK1 comprise an unappreciated axis of targets that is selectively vulnerable in CDKN2A/MTAP-deleted tumors. Unique biochemical features of PRMT5 create this vulnerability, which presents a promising new avenue for targeted therapy.

Citation Format: Kevin Marks. Targeting cancers with deletion of the p16/p14 tumor suppressor locus. [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 IA25.
Abstract IA29: Targeting undruggable proteins for degradation with small molecules
Authors: Kaelin William G.
Published: May 2017

Many well-studied oncoproteins are currently viewed to be “undruggable”. The infamous teratogen thalidomide was serendipitously discovered to be a potent antimyeloma drug in the 1990s but its mechanism of action was unknown. In 2010 thalidomide was shown by Handa and coworkers to bind to cereblon, which is the substrate-recognition subunit of a cullin-dependent ubiquitin ligase. Moreover, thalidomide was found to inhibit this ligase in vitro, suggesting that thalidomide is a cereblon antagonist. However, it soon became apparent that loss of cereblon rendered myeloma cells resistant to thalidomide (and related drugs such as lenalidomide, collectively referred to as IMiDs). This suggested to us that cereblon, once bound to an IMiD, acquires a new (neomorphic) ability to target a myeloma-relevant protein for destruction. To look for such a protein we built a bicistronic expression vector that encodes both a protein open reading frame (ORF)-firefly luciferase fusion protein and, from the same mRNA, renilla luciferase for normalization purposes, with both proteins under the control of an internal ribosomal entry site (IRES). We then made a library of ~12,000 such ORF-luciferase fusions and introduced them into 293T cells in quadruplicate in multiwell plate format (1 ORF/well), treated the cells with lenalidomide or vehicle, and monitored changes in firefly luciferase/renilla luciferase as a surrogate for changes in ORF stability. In this way we discovered that cereblon, once bound to lenalidomide, destabilizes IKZF1 and IKZF3. We went on to show that downregulation of IKZF1 and IKZF3 is intimately linked to the antimyeloma activity of the IMiDs. Ben Ebert and his group working in parallel and using complimentary approaches reached the same conclusion. Published and unpublished work from investigators such as Jay Bradner and Craig Crews suggests IMiDs can be reengineered to serve as molecular matchmakers between cereblon and novel targets. We are currently developing new screening methodologies to identify chemicals and genetic perturbants that directly or indirectly destabilize proteins of interest.

Citation Format: William G. Kaelin, Jr. Targeting undruggable proteins for degradation with small molecules. [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 IA29.
Abstract IA31: Phthalimide conjugation as a strategy for targeted protein degradation
Authors: Winter Georg E. , Buckley Dennis L. , Bradner James E.
Published: May 2017

Ligand-induced target protein destabilization is an efficacious therapeutic strategy in cancer, but discovery in this field has historically been serendipitous given the lack of rational design principles. Building on the molecular logic of immunomodulatory drugs (“IMiDs”), we innovated a facile chemical solution for targeted protein degradation using bifunctional small molecules capable of recruiting the E3 ligase cereblon (CRBN). These bifunctional molecules induce immediate, and complete proteasomal degradation of their target proteins and thus represent a novel class of small molecule therapeutics with an entirely uncharted and unique molecular pharmacology.

Focusing our initial efforts on degraders of the BET family of proteins, we observed that they exhibit superior efficacy than BET inhibitors through unknown mechanisms. In order to dissect and mechanistically explain that differential molecular pharmacology, we used optimized small-molecule degraders and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in global control of transcriptional pause-release. Targeted BET degradation nucleates a collapse in the transcriptional core regulatory circuitry and thus enabled us to exploit transcriptional addictions in T-Cell acute lymphoblastic leukemia (T-ALL) that were intractable using competitive BET bromodomain inhibitors.

Citation Format: Georg E. Winter, Dennis L. Buckley, James E. Bradner. Phthalimide conjugation as a strategy for targeted protein degradation. [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 IA31.
Abstract PR03: Molecular characterization of in vitro exhausted T cells
Authors: Hastings William , MacIsaac Kenzie , Guan Wei , Shaw Pamela , Dranoff Glenn , Cao Z Alexander
Published: May 2017

In previous work we observed that restimulating human PBMCs with anti-CD3/28 beads 4 days after a primary stimulation resulted in an exhausted phenotype, as characterized by loss of T cells' ability to secrete IL-2, TNFa, and IFNg. To further characterize the molecular phenotype of these cells, we isolated CD4+ and CD8+ T cells from our exhausted and non-exhausted samples and performed Nanostring gene expression analysis. Both exhausted CD4+ and CD8+ T cells exhibited upregulation of a 25-gene exhaustion gene signature, as compared to non-exhausted control cells. In addition, a number of immunologically important molecules are modulated in the exhausted cells. For example, MIF (macrophage migration inhibitory factor) mRNA is induced in the exhausted T cells. Closer examination of MIF expression in TCGA suggests that MIF level is inversely correlated to survival in indications such as HCC and H/N cancer. Furthermore, pathway analysis of differential gene expression revealed the JAK/STAT signaling pathway as significantly upregulated in the exhausted cells. Treatment of exhausted cells with a JAK inhibitor resulted in a partial reversal of the exhausted phenotype, as shown by restored cytokine secretion. Thus we show for the first time the involvement of JAK signaling in human T cell exhaustion, which may provide rationale for combining JAK inhibitors with other immune therapies for cancer. In summary, the in vitro T cell exhaustion model system has yielded intriguing activity nodes during T cell function. Future exploration in such immunological states may identify novel therapeutic targets and combination opportunities for immuno-oncology.

This abstract is also being presented as Poster B17.

Citation Format: William Hastings, Kenzie MacIsaac, Wei Guan, Pamela Shaw, Glenn Dranoff, Z Alexander Cao. Molecular characterization of in vitro exhausted T cells. [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 PR03.
Fetal and Postnatal Head Circumference Growth: Synergetic Factors for Neurodevelopmental Outcome at 2 Years of Age for Preterm Infants
Authors: Sicard Mélanie , Nusinovici Simon , Hanf Matthieu , Muller Jean-Baptiste , Guellec Isabelle , Ancel Pierre-Yves , Gascoin Géraldine , Rozé Jean-Christophe , Flamant Cyril
Published: May 2017

Abstract: Preterm infants present higher risk of non-optimal neurodevelopmental outcome. Fetal and postnatal growth, in particular head circumference (HC), is associated with neurodevelopmental outcome. Objectives: We aimed to calculate the relationship between HC at birth, HC delta Z-score (between birth and hospital discharge), and non-optimal neurodevelopmental outcome at 2 years of corrected age in preterm infants. Methods: Surviving infants born ≤34 weeks of gestation were included in the analysis. The relationship between the risk of being non-optimal at 2 years and both HC at birth and HC growth was assessed. The 2 Z-scores were considered first independently and then simultaneously to investigate their effect on the risk of non-optimality using a generalized additive model. Results: A total of 4,046 infants with both HC measures at birth and hospital discharge were included. Infants with small HC at birth (Z-score <-2 SD), or presenting suboptimal HC growth (dZ-score <-2 SD), are at higher risk of non-optimal neurodevelopmental outcome at 2 years (respectively OR 1.7 [95% CI 1.4-2] and OR 1.4 [95% CI 1.2-1.8]). Interestingly, patients cumulating small HC Z-score at birth (-2 SD) and presenting catch-down growth (HC dZ-score [-2 SD]) have a significantly increased risk for neurocognitive impairment (OR >2) while adjusting for gestational age, twin status, sex, and socioeconomic information. Conclusions: HC at birth and HC dZ-score between birth and hospital discharge are synergistically associated to neurodevelopmental outcome at 2 years of corrected age, in a population-based prospective cohort of preterm infants born ≤34 weeks of gestation.
NORAD Expression Is Associated with Adverse Prognosis in Esophageal Squamous Cell Carcinoma
Authors: Wu Xiaoliang , Lim Zuan-Fu , Li Zhongwen , Gu Ling , Ma Wenjuan , Zhou Qianghua , Su Huifang , Wang Xing , Yang Xianzi , Zhang Zhenfeng
Published: May 2017

Background: NORAD (non-coding RNA-activated by DNA damage) is a conserved, abundant, and broadly expressed long non-coding RNA, which functions to preserve genome stability. However, its prognostic significance in esophageal squamous cell carcinoma (ESCC) remains unclear. Material and Methods: The expression of NORAD was detected by quantitative real-time polymerase chain reaction in pairs of tumorous and adjacent normal tissues derived from 106 ESCC patients. We analyzed the potential relationship between NORAD expression levels in tumor tissues and clinicopathological features of ESCC patients and clinical outcome. Results: The relative expression levels of NORAD were significantly upregulated in tumor tissues (p < 0.001) compared to adjacent normal tissues. In addition, high expression of NORAD was correlated with larger tumor size (p = 0.021) and T stage (p = 0.045). Kaplan-Meier analysis indicated that patients with high NORAD expression had poor overall and disease-free survival (p < 0.001). Moreover, multivariate analysis showed that increased expression of NORAD was an independent predictor of overall survival (p = 0.001). Conclusion: Our data indicate that increased NORAD expression might serve as a novel molecular predictor of poor prognosis in ESCC patients and maybe a potential target for diagnosis and gene therapy.
Sex Differences in Forebrain Monoaminergic Response to Song Performance
Authors: Lyons Susan M. , Sockman Keith W.
Published: May 2017

In many species, successful reproduction is dependent on the ability to adjust social behavior in response to an ever-changing social environment. Because a sexual signal's value and meaning can differ between females and males, responses to those signals should also differ. One way individuals can modulate social behavior is through experience-dependent modulation of the sensory systems that process social signals. Central monoamines (norepinephrine, dopamine, serotonin) modulate neural sensitivity to social stimuli and are key regulators of experience-dependent neuroplasticity in vertebrate sensory systems. However, few studies have examined how exposure to different sexual signals influences monoaminergic activity in female compared to male sensory systems. We used Lincoln's sparrows (Melospiza lincolnii) to examine sex differences in how variation in the trill performance of song influences central monoaminergic activity in the auditory telencephalon. Trill performance measures the rate at which a song syllable is produced relative to the syllable's frequency bandwidth and is thought to reflect the difficulty with which songs are produced. High-performance trills are more threatening to males but more attractive to females. We found that the effects of trill performance on monoaminergic activity were sex-dependent. Relative to the response to low-performance songs, exposure to high-performance songs decreased noradrenergic activity in the caudomedial nidopallium, and tended to decrease serotoninergic activity in the caudomedial mesopallium and caudomedial nidopallium of the auditory telencephalon in females, but in males, the monoamine measurements were indistinguishable between song treatments. These results suggest that the mechanisms underlying sensory processing of male sexual signals differ between the sexes.
Cisplatin Therapy Does Not Worsen Renal Function in Severe Antenatal Bartter Syndrome
Authors: Welch Thomas R. , Shaffer David R. , Feldman Darren R.
Published: May 2017

A 30-year-old man with severe antenatal Bartter syndrome, diagnosed and treated in infancy, developed testicular carcinoma. Despite the known renal complications of cisplatin, this drug was used for his chemotherapy because of its superior antineoplastic effect. Nonsteroidal anti-inflammatory drug administration was continued during cisplatin therapy. Despite an increase in his oral potassium requirement, renal function was maintained following completion of chemotherapy. In spite of its significant associated nephrotoxicity, cisplatin can be used in patients with severe antenatal Bartter syndrome if required for therapy of malignancy.
Contribution to the knowledge of Bonamia (Convolvulaceae) in Brazil: a new species and a new occurrence
Authors: MOREIRA ANDRÉ LUIZ DA COSTA , ANTAR GUILHERME MEDEIROS , SIMÃO-BIANCHINI ROSÂNGELA , CAVALCANTI TACIANA BARBOSA
Published: May 2017

A new species, Bonamia campestris A.Moreira & Sim.-Bianch., from the Jalapão region in the state of Tocantins, Brazil, is described and illustrated. It is compared with morphologically similar species. Additional collections of the recently described Bonamia rosiewiseae J.R.I.Wood extend its range from two locations in eastern Bolivia to Mato Grosso do Sul in southwest Brazil.
A new species of Hippopsis Lepeletier & Audinet-Serville, 1825 from Panama and key to species (Coleoptera, Cerambycidae, Lamiinae)
Authors: GALILEO MARIA HELENA M. , SANTOS-SILVA ANTONIO , HEFFERN DANIEL
Published: May 2017

Hippopsis raberi sp. nov. is described from Darién National Park, Panama. A key to 40 species of the genus is provided.
Chronological Development of Terrestrial Mean Precipitation
Authors: Park Kylie J. , Yoshimura Kei , Kim Hyungjun , Oki Taikan
Published: May 2017

Over 150 years of investigations into global terrestrial precipitation are revisited to reveal how researchers estimated annual means from in situ observations before the age of digitization. After introducing early regional efforts to measure precipitation, the pioneering estimates of terrestrial mean precipitation from the late nineteenth and early twentieth centuries are compared to successive estimates, including those using the latest gridded precipitation datasets available. The investigation reveals that the range of the early estimates is comparable to the interannual variation in terrestrial mean precipitation derived from the latest Climatic Research Unit (CRU) dataset. In-depth revisions of the estimates were infrequent up to the 1970s, due in part to difficulty obtaining and maintaining up-to-date datasets with global coverage. This point is illustrated in a “family tree” that identifies the key publications that subsequent authors referenced, sometimes decades after the original publication. Significant efforts to collate global observations facilitated new investigations and improved data exchange, for example, in the International Hydrological Decade (1965–74) and following the establishment of the Global Telecommunication System under the World Weather Watch Programme of the World Meteorological Organization. Also in the 1970s were the first attempts to adjust in situ observations on a global scale to account for gauge undercatch, and this had a noticeable impact on mean annual estimates. There remains no single satisfactory approach to gauge bias adjustment. Echoing the repeated message of past researchers, today’s authors cite poor spatial coverage, temporal inhomogeneity, and inadequate sharing of in situ observations as the key obstacles to obtaining more accurate estimates of terrestrial mean precipitation.
Youth Bulges and Civil Conflict
Authors: Flückiger Matthias , Ludwig Markus
Published: May 2017

The presence of an exceptionally large youth population, that is, a youth bulge, is often associated with an elevated risk of civil conflict. In this article, we develop an instrumental variable approach in which the size of the youth cohorts in Sub-Saharan Africa is identified using variation in birth-year drought incidence. Our results show that an increase in the size of the population group aged fifteen to nineteen raises the risk of low-intensity conflict. A 1 percent increase in the size of this age-group augments the likelihood of civil conflict incidence (onset) by 2.3 (1.2) percentage points. On the other hand, we do not find any association between the size of the two adjacent youth cohorts, that is, the population groups aged ten to fourteen and twenty to twenty-four.
Decomposition patterns of buried remains at different intervals in the Central Highveld region of South Africa
Authors: Marais-Werner A , Myburgh J , Meyer A , Nienaber WC , Steyn M
Published: May 2017

Burial of remains is an important factor when one attempts to establish the post-mortem interval as it reduces, and in extreme cases, excludes oviposition by Diptera species. This in turn leads to modification of the decomposition process. The aim of this study was to record decomposition patterns of buried remains using a pig model. The pattern of decomposition was evaluated at different intervals and recorded according to existing guidelines. In order to contribute to our knowledge on decomposition in different settings, a quantifiable approach was followed. Results indicated that early stages of decomposition occurred rapidly for buried remains within 7–33 days. Between 14 and 33 days, buried pigs displayed common features associated with the early to middle stages of decomposition, such as discoloration and bloating. From 33 to 90 days advanced decomposition manifested on the remains, and pigs then reached a stage of advanced decomposition where little change was observed in the next ±90–183 days after interment. Throughout this study, total body scores remained higher for surface remains. Overall, buried pigs followed a similar pattern of decomposition to those of surface remains, although at a much slower rate when compared with similar post-mortem intervals in surface remains. In this study, the decomposition patterns and rates of buried remains were mostly influenced by limited insect activity and adipocere formation which reduces the rate of decay in a conducive environment (i.e. burial in soil).
Socializing Agents for Sport and Physical Activities in Teenage Students: Comparative Studies in Samples From Costa Rica, Mexico, and Spain
Authors: Ruiz-Juan Francisco , Baena-Extremera Antonio , Granero-Gallegos Antonio
Published: May 2017

The aim of this study is to analyze a set of socializing agents for sport and physical activities and to establish their relationship with leisure time sport and physical activities behaviors and practice patterns in samples of teenage students with different sociocultural backgrounds. The sample included 2168 students in their first year of secondary education, 423 of them being from Costa Rica, 408 from Mexico, and 1337 from Spain (1052 male students, 1037 female students, and 79 students who did not specify gender) aged 11–16 years old ( M = 12.49; SD = .81). A validated questionnaire with questions about leisure time sport and physical activities and socializing agents was used. Descriptive, inferential, and multinomial logistic regression analyses were carried out with SPSS 17.0 to compare all three countries. Costa Rica had the most active students, best friends’ inactivity, and unsupportive parents being the agents predicting inactivity and a low level of sport and physical activities. Mexico has a high dropout rate and inactive students exceed active ones; no agent predicts inactivity or sport and physical activities pattern. Spain has the highest level of sport and physical activities practice, and parents, siblings, and friends are predicting agents of inactivity together with unsupportive parents and friends.
Web-based Simulations of Multi-agent Systems
Authors: De Benedetti Massimiliano , Messina Fabrizio , Pappalardo Giuseppe , Santoro Corrado
Published: May 2017

This paper describes the architecture of AgentSimJs, a Javascript-based multi-agent simulator intended to execute and visualize simulations through a Web browser. It includes the needed capabilities to render a 3D scene with objects and agents. AgentSimJs has a modular architecture, the several different components provide a set of flexible primitives to program the agent behaviour. With AgentSimJs, a user can perform a fine tuning of all the aspects related to communication, motion, and group formation. Users can also define a custom network topology and communication model.
Sport summer camp for children and youth with visual impairment: Descriptive case study of Camp Abilities
Authors: Furtado Otávio LPC , Lieberman Lauren J , Gutierrez Gustavo L
Published: May 2017

The purpose of this study was to describe the operational characteristics of Camp Abilities, an educational sports summer camp for children and youth with visual impairment. In this descriptive multiple case study, the data collected comprises interviews with seven adapted physical education faculty members, questionnaire, and document analysis. Camps were often run at university campuses, where undergraduate and graduate physical education students perform the role of instructing campers and eventually helping in the camp organizing process. These camps include a minimum of 30 to more than 120 participants (i.e. directors, campers, coaches, and specialist) each session, lasting from 4 to 7 days. In this scenario, although each camp has particular features, camps’ purposes, participants, activities, and schedules are very similar, showing that this is a feasible and reproducible approach, which can provide enriching opportunities for diverse groups.
Physical activity patterns of adults with visual impairments
Authors: Starkoff Brooke E , Lenz Elizabeth K , Lieberman Lauren J , Foley John , Too Danny
Published: May 2017

This study examined physical activity (PA) patterns in adults with visual impairments (VI) using the International Physical Activity Questionnaire–Short Form, assessing moderate physical activity (MPA), vigorous physical activity (VPA), and moderate-to-vigorous physical activity (MVPA). A total of 115 individuals (age: 36.1 ± 13.9 years, body mass index [BMI]: 28 ± 6.9 kg/m2) with VI completed the study. One-way analyses of variance (ANOVAs) were performed on VI (B1, B2, B3, and B4), collapsed VI (blind [B1] vs VI [B2–B4]), gender, and BMI across PA. A 2 × 4 factor ANOVA examined the impact of gender and BMI on PA. B2 walked more than B1 ( p = .021) and walk time was less in B1 ( p = .021) than VI. Males accumulated more MPA ( p = .002) and MVPA ( p = .008), and a greater percentage of males acquired recommended PA ( p = .008). Overweight participants acquired more VPA than normal-weight participants ( p = .020). A main effect for gender ( p = .000) and interaction between gender and BMI ( p = .049) were identified with MPA. Differences in PA based on VI may be a result of barriers specific to B1, suggesting the need for education in this population.
Assistive grasping with an augmented reality user interface
Authors: Weisz Jonathan , Allen Peter K , Barszap Alexander G , Joshi Sanjay S
Published: May 2017

Assisting impaired individuals with robotic devices is an emerging and potentially transformative technology. This paper describes the design of an assistive robotic grasping system that allows impaired individuals to interact with the system in a human-in-the-loop manner, including the use of a novel cranio-facial electromyography input device. The system uses an augmented reality interface that allows users to plan grasps online that match their task-oriented intents. The system uses grasp quality measurements that generate more robust grasps by considering the local geometry of the object and the effect of uncertainty during grasp acquisition. This interface is validated by testing with real users, both healthy and impaired. This work forms the foundation for a flexible, fully featured human-in-the-loop system that allows users to grasp known and unknown objects in cluttered spaces using novel, practical human–robot interaction paradigms that have the potential to bring human-in-the-loop assistive devices out of the research environment and into the lives of those that need them.
Environmental effects on the bond at the interface of fiber-reinforced polymer and masonry brick
Authors: Toufigh Vahab , Yarigarravesh Mahdireza , Mofid Masood
Published: May 2017

This study examined the bond at the interface of masonry bricks and fiber-reinforced polymer when exposed to five environments. Three fabrics (aramid, carbon, and glass) and one type of epoxy resin were used. A total of 375 brick-fiber-reinforced polymer specimens were made using wet lay-up technic and exposed to chemical solutions at four pH values (2.5, 7, 10, and 12.5) and substitute seawater. The effect of dry heat on the bond at the interface was also investigated. Single-lap shear tests were then carried out on the samples after 2, 4, 6, 8, 10, and 13 weeks of exposure. The experimental results indicated that freshwater and seawater had a considerable effect on the bond strength of brick-aramid fiber reinforced polymer (AFRP) and brick-carbon fiber reinforced polymer (CFRP) samples; however, they did not significantly affect the bond strength of brick-glass fiber reinforced polymer (GFRP). Exposure to the severe environments was detrimental to bond strength. The results showed a significant loss of approximately 60% after 13 weeks of exposure to alkaline and acidic solutions. Dry heat did not significantly affect the bond strength of the tested samples.
A Novel Treatment for Opioid-Induced Constipation After Abdominoplasty
Authors: Deal R. Chad , Maningas Talon , Bonnor Ricardo , Fogleman Trent
Published: May 2017

Opioid-induced constipation (OIC) is a commonly experienced side effect of those utilizing narcotic pain medication. The current treatment for OIC commonly consists of stool softeners and bowel stimulants which often leads to abdominal bloating and discomfort ultimately resulting in uncomfortable bowel movements and loose stools. We present a novel approach to the treatment of acute OIC after abdominoplasty in patients taking narcotic pain medication utilizing a well-known medication currently approved by the Food and Drug Administration for the treatment of OIC in adult patients with chronic noncancer pain.
Individual Orientations and Career Satisfaction
Authors: Ngo Hang-Yue , Hui Li
Published: May 2017

This study examines the relationships between two different types of individual orientation (i.e., protean career orientation and employment commitment) and career satisfaction. Drawing on self-determination theory and social cognitive theory, we propose that work engagement and self-efficacy act as mediators in the above relationships. Several hypotheses are developed and tested with a sample of 222 employees in Hong Kong. The results of path analysis and bootstrapping indicated that both protean career orientation and employment commitment are positively related to career satisfaction, and these relationships are fully mediated by work engagement and self-efficacy.
The influence of the blade thickness on the pressure pulsations in a ceramic centrifugal slurry pump with annular volute
Authors: Tao Yi , Yuan Shouqi , Liu Jianrui , Zhang Fan , Tao Jianping
Published: May 2017

Due to the serious abrasion caused by the existence of solid phase in slurry, the slurry pumps usually adopt thick impeller blades to prolong its service life. In this paper, the influence of the blade thickness on the transient characteristics, the vibration, and the solid–liquid two-phase flow in a ceramic centrifugal pump with annular volute was investigated by the numerical method. And the experimental test was also conducted for computational fluid dynamics validation. The static pressure, the velocity, the force, and the solid fraction within the impeller passage and the volute casing have been discussed in detail. The results show that the influence of the blade thickness variation on the pressure fluctuation intensity is larger at the impeller inlet than that at the impeller exit and is larger at the pressure sides than that at the suction sides. The pressure fluctuation intensity decreases at the regions close to the volute tongue with the increase in the blade thickness. However, it increases at the regions, which are away from the volute tongue as the blade thickness increases. Moreover, the torque on the impeller, the radial force, and the axial force decreases with the increase in the blade thickness. Meanwhile, increasing the blade thickness will disperse the solid fraction at the impeller back shroud and make the regions with high solid fraction on pressure sides offset towards the impeller exit with a larger blade thickness, thus prolonging the service life of the impeller. However, the best efficiency point offsets to a low flow rate condition. The results are expected to pave the way for further optimization of impeller blade profile.
Inter-observer variability of the histological classification of lupus glomerulonephritis in children
Authors: Oni L , Beresford M W , Witte D , Chatzitolios A , Sebire N , Abulaban K , Shukla R , Ying J , Brunner H I
Published: May 2017

The gold standard for the classification of lupus nephritis is renal histology but reporting variation exists. The aim of this study was to assess the inter-observer variability of the 2003 International Society of Nephrology/Royal Pathology Society (ISN/RPS) lupus nephritis histological classification criteria in children. Histopathologists from a reference centre and three tertiary paediatric centres independently reviewed digitalized renal histology slides from 55 children with lupus nephritis. Histological ISN/RPS Class was assigned and features scored; lupus nephritis-activity [scored 0–24], lupus nephritis-chronicity [0–12] and tubulointerstitial activity [0–21]. In the cohort (73% females), the age at the time of biopsy was 15.5 ± 0.39 (mean ± standard error) years. Based on the reference centre, 42% (23/55) had ISN/RPS Class IV with lupus nephritis-activity score 4.23 ± 0.50, lupus nephritis-chronicity 1.81 ± 0.18 and tubulointerstitial activity 4.45 ± 0.35. There were 4–54 (mean 16.7) glomeruli per biopsy. Pathologists had fair agreement for ISN/RPS assignment (kappa; 0.26 ± 0.12), lupus nephritis-chronicity (intra-class correlation 0.36 ± 0.09) and tubulointerstitial activity (0.22 ± 0.09) scores. There was good agreement for lupus nephritis-activity scores (intra-class correlation 0.69 ± 0.06). When categorized into proliferative and non-proliferative disease, poor agreement among sites remained (kappa 0.24 ± 0.11). Despite unified criteria for the interpretation of histological features of lupus nephritis, marked reporting variation remains in clinical practice. As proliferative lupus nephritis is managed more intensively, this may influence renal outcomes.