bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A05: An in vivo model reveals a role for Argonaute 2 in oncogenic KRAS driven pancreatic cancer initiation
Authors: Shankar Sunita , Tien Jean , Dommeti Vijaya L. , Zelenka-Wang Sylvia , Chinnaiyan Arul M.
Published: May 2017

Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we recently identified an interaction between RAS and Argonaute 2 (AGO2), the core component of the RNA silencing machinery exerting translational control of mRNA transcripts. RAS and AGO2 co-sediment and co-localize in intracellular endomembrane bound organelles. The AGO2 N-terminal domain directly binds the KRAS Switch II region, irrespective of GDP/GTP bound to RAS. Functionally, we observed that AGO2 was required for maximal oncogenic KRAS levels and AGO2 knock-down attenuates cell proliferation in mutant KRAS-dependent cells. Intriguingly, AGO2 mediated microRNA processing (RISC activity) was attenuated in cancer cells expressing mutant KRAS compared to those expressing wild type RAS. Yet, these initial investigations using cell line models do not reveal a clear role for AGO2 in KRAS driven oncogenesis. Therefore, we probed the role of AGO2 in the well-established pancreatic ductal adenocarcinoma (PDAC) mouse model driven by oncogenic KRAS.

Towards this end, we generated LSL-KrasG12D; Pft1a Cre; AGO2flox/flox (KCA) mice. Preliminary analysis (8-10 weeks of age) suggests that compared to LSL-KRASG12D (KC) mice, homozygous loss of AGO2 results in increased KRAS driven Acinar to Ductal Metaplasia (ADM) phenotype considered as precursors of PanIN (pancreatic intraepithelial neoplasia) and PDAC. This mirrors the phenotype of loss of Dicer, another microRNA processing enzyme, in the same model further reinforcing a role for microRNAs in restraining KRAS oncogenic programs. Yet unlike Dicer, loss of AGO2 alone did not cause any gross or histological changes in the development of the mouse pancreata. In an effort to understand the underlying mechanisms that are regulated by AGO2, we also studied the activated levels of a variety of signaling molecules in pancreata obtained from different genotypes. Using both Western blot and Immunohistochemical analyses, we demonstrate a previously unknown and critical role for AGO2 in KRAS-MAPK signaling pathway.

Together our data from the in vivo mouse model suggests that AGO2 is an important regulator of KRAS signaling and oncogenic KRAS alters the translational machinery through its interaction with AGO2.

Citation Format: Sunita Shankar, Jean Tien, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Arul M. Chinnaiyan. An in vivo model reveals a role for Argonaute 2 in oncogenic KRAS driven pancreatic cancer initiation. [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 A05.
Abstract A11: Profiling of miRNAs expression in pediatric brain tumors
Authors: Tantawy Marwa , Elzayat Mariam , Yehia Dina , Taha Hala
Published: May 2017

Introduction: The understanding of pediatric CNS tumors biology is essential in the development of disease stratification and in development of less toxic therapeutic agents as well as finding novel markers for early diagnosis. MicroRNAs are short 18-25 nucleotide small non-coding RNA molecules regulate gene expression. Recent studies showed that miRNAs play a significant role in brain tumor biology; and may up-regulated or down-regulated in malignancies, which referred their oncogenic or tumor suppressor effect. MiRNA expression patterns have been linked to clinical outcomes, tumor regulation; such as tumor progression, cell growth, cell death and metastasis. The identification of tumor- specific miRNA signatures may assist in future in the discovery of new biomarkers with diagnostic and prognostic utility. The main objective of the present study is to detect the expression of different miRNAs in different subtypes of pediatric CNS tumors to distinguish between them in discovering biomarkers for early detection in addition to develop novel therapies.

Methods: The expression level of 82 miRNAs were detected in 120 cases of pediatric CNS tumors from fixed formalin paraffin embedded tissues (FFPE), divided into four subtypes including; Low Grade Glioma, High Grade Glioma, Ependymoma, and Medulloblastoma using quantitative real time PCR (qRTPCR).

Results: Analysis of qRT-PCR data showed significant differences in miRNA expression between tumor subtypes with P value< 0.05. Low expression of (miR-221, miR-9, and miR-181c/d) and over expression in miR-101, miR-222, miR-139, miR-1827 and miR-34c) in Medulloblastoma patients compared to other subtypes. Low expression of miR-10a and overexpression in (miR-10b, and miR-29a) in Ependymoma patients compared to other subtypes. Low expression of miR-26a and over expression in (miR-19a/b, miR-24, miR-27a, miR- 584 and miR-527) in Low Grade Glioma patients compared to other subtypes.

Conclusion: MicroRNAs are differentially expressed between different subtypes of pediatric CNS tumors suggesting that they may play a significant role in diagnosis to distinguish between different subtypes. A greater understanding of aberrant miRNA expression in pediatric brain tumors may support in the development of novel therapies. In addition, the characterization of tumor-specific miRNA signatures may play an important role in the discovery of biomarkers with diagnostic or prognostic utility.

Note: This abstract was not presented at the conference.

Citation Format: Marwa Tantawy, Mariam Elzayat, Dina Yehia, Hala Taha. Profiling of miRNAs expression in pediatric brain tumors. [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 A11.
Abstract A32: The role of the ribosome in GCN2's ability to sense amino acid deprivation and initiate the integrated stress response
Authors: Inglis Alison J. , Shao Sichen , Masson Glenn R. , Perisic Olga , Hegde Ramanujan S. , Williams Roger L.
Published: May 2017

The ability to replicate without limit is one of the traditional hallmarks of cancer. It is therefore evident that the majority of tumor cells are operating in environments with limited nutrients. This means that tumor cells are disproportionately reliant on their stress response pathways in comparison to healthy cells. One such stress response pathway is a component of the integrated stress response pathway that responds to deprivation of amino acids. GCN2 is a serine/threonine protein kinase that is activated in response to a drop in the intracellular concentration of amino acids. Upon activation, GCN2 phosphorylates the translational initiation factor eIF2, inhibiting its activity in the translational cycle. This leads to a global inhibition of translation, whilst paradoxically upregulating the expression of certain genes involved in stress responses. It has been shown that knocking out GCN2 leads to a significant reduction in the growth of tumors in mice, suggesting that GCN2 could be a useful therapeutic target.

We have expressed and purified human GCN2 and found it to be a dimer, as has been observed for yeast GCN2. We have shown in vitro that GCN2 becomes autophosphorylated, and it catalyses phosphorylation of a putative binding partner GCN1 as well as eIF2. We have found that human GCN2 forms a stable complex with 80S ribosomes, and mammalian 80S ribosomes significantly increase GCN2 kinase activity in vitro, consistent with a previous report that an increase in ribosomal stalling leads to a rise in eIF2 phosphorylation in vivo. We are attempting to determine the structure of GCN2 bound to ribosomes in order to understand the detailed interactions and the molecular mechanisms that lead to GCN2 activation.

Citation Format: Alison J. Inglis, Sichen Shao, Glenn R. Masson, Olga Perisic, Ramanujan S. Hegde, Roger L. Williams. The role of the ribosome in GCN2's ability to sense amino acid deprivation and initiate the integrated stress response. [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 A32.
Abstract A33: Understanding the functional role of enhanced FASN activity in regulating protein translation in DLCBL
Authors: Kapadia Bandish , Gartenhaus Ronald
Published: May 2017

Fatty acid synthase (FASN) and protein translational machinery are two emerging cancer therapeutic targets, but their mutual dependency on each other for tumor growth especially in diffuse B-cell large lymphoma (DLBCL) is currently unknown. Therefore, we investigated the functional consequences of enhanced FASN activity on protein translational machinery in both DLCBL cell lines as well as primary samples. Inhibition of FASN activity by a specific inhibitor, C75 or shRNA mediated knockdown, suppressed de novo protein synthesis in SUDHL2, Pfeiffer, and HLY-1 cells, whereas SUDHL4 and SUDHL6 cells displayed minimal impact. Assessing the core translational machinery, the eif4b (eukaryotic initiation factor 4b) levels were depleted in a dose dependent manner of C75 treatment or shRNA mediated knock down of FASN. Mechanistically, eif4b undergoes ubiquitin mediated protein degradation upon FASN depletion. Importantly there seems to be a direct correlation between FASN levels and eif4b expression in DLBCL samples. Depleting the expression of eif4b significantly reduced the cell proliferative capacity of both FASN sensitive as well as resistant DLBCL cells. Screening the interacting protein partners from the available databases, we observed that USP11 interacts and deubiquitinates eif4b which increases its overall stability. Furthermore altering the expression of USP11 or its activity by either chemical inhibition or mutations significantly alters nascent peptide synthesis. Significantly, either down regulating USP11 or inhibiting via small molecules significantly reduced the cell proliferation with increased apoptosis of either FASN activity sensitive or resistant DLBCL cells. USP11 expression was also elevated in DLBCL tissues. Importantly, there is a strong correlation between USP11 and FASN as well as eif4b expression in DLBCL with higher level of this proteins associated with poorer survival. Enhanced FASN activity increased the Akt kinase activity, which phosphorylates USP11 at an evolutionary conserved site. FASN stimulated Akt-meditated phosphorylation events is critical for USP11 recruitment on translational initiation machinery as well as interaction with eif4b to alter protein biosynthesis. These results demonstrate that FASN mediated eif4b/USP11 axis is required for cell proliferation and survival by regulating the translation of proliferative and prosurvival mRNAs. Targeting the eif4b/USP11 axis for therapeutic intervention may add additional treatment options for resistant/relapsed DLBCL patients.

Citation Format: Bandish Kapadia, Ronald Gartenhaus. Understanding the functional role of enhanced FASN activity in regulating protein translation in DLCBL. [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 A33.
Abstract A40: Expression of cancer-associated fibroblast-related proteins differs between invasive lobular carcinoma and invasive ductal carcinoma
Authors: Eun-Sol Kim , Seung Koo Ja
Published: May 2017

Purpose: Cancer-associated fibroblasts (CAFs) are classified into various functional subtypes such as fibroblast activation protein-α (FAP-α), fibroblast specific protein-1 (FSP-1), platelet-derived growth factor receptor-α (PDGFR-α), and PDGFR-β. In this study, we compared the expression of CAF-related proteins in invasive lobular carcinoma (ILC) with those in invasive carcinoma of no special type (NST), and assessed the implications of the differences observed.

Methods: Using tissue microarrays of 104 ILC and 524 invasive carcinoma (NST) cases, immunohistochemistry for CAF-related proteins [podoplanin, prolyl 4-hydroxylase, FAP-α, FSP-1/S100A4, PDGFR-α, PDGFR-β, and chondroitin sulfate proteoglycan (NG2)] was conducted.

Results: In invasive carcinoma (NST), tumor cells expressed a high level of PDGFR-α, whereas ILC tumor cells expressed high levels of podoplanin, prolyl 4-hydroxylase, FAP-α, and FSP-1/S100A4. In stromal cells of invasive carcinoma (NST), high expression levels of prolyl 4-hydroxylase, PDGFR-α, and NG2 were observed, whereas ILC stromal cells expressed high levels of FAP-α, FSP-1/S100A4, and PDGFR-β. In ILC, tumoral FSP-1/S100A4 positivity was associated with higher Ki-67 labeling index (p = 0.010) and non-luminal A type cancer (p = 0.014). Stromal PDGFR-α positivity was associated with lymph node metastasis (p = 0.011). On survival analysis of entire cases, tumoral FSP-1/S100A4 positivity (p = 0.001) and stromal podoplanin positivity (p = 0.035) were associated with shorter disease-free survival; only tumoral FSP-1/S100A4 positivity (p = 0.001) was associated with shorter overall survival.

Conclusion: In ILC, the expression of FAP-α and FSP-1/S100A4 was higher in both tumor and stromal cells than that observed in invasive carcinoma (NST). These results indicate that CAFs are a potential target in ILC treatment.

Citation Format: Lee YuKyung, Kim Eun-Sol, Koo Ja Seung. Expression of cancer-associated fibroblast-related proteins differs between invasive lobular carcinoma and invasive ductal carcinoma. [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 A40.
Abstract B05: Characterization of the pre-ribosomal complex, which mediates the p53 Impaired Ribosome Biogenesis Checkpoint (IRBC)
Authors: Menoyo Sandra , Gentilella Antonio , Thomas George
Published: May 2017

Ribosome biogenesis is one of the most energy consuming anabolic processes in a growing tumor cell. For more than a century it has been recognized that the increased size and abnormal morphology of nucleoli, the sites of ribosome biogenesis, are markers of aggressive cancers, particularly sporadic colorectal cancers (sCRC). The TCGA has recently published that over 90% of sCRCs have a mutation in the WNT/APC signaling pathway, leading to persistent c-Myc activation in almost all cases. As c-Myc tumors are addicted to high rates of ribosome biogenesis, recent studies have suggested that impaired ribosome biogenesis, leading to the activation of p53 may serve as an Achilles' heel in the treatment of such tumors. Although a number of ribosomal proteins (RPs) have been implicated in inducing p53 stabilization following impaired ribosome biogenesis, our laboratory has shown that this response is mediated by a ribosomal precursor complex made-up of RPL5, RPL11 and non-coding 5S rRNA, which upon a lesion in ribosome biogenesis is redirected from assembly into nascent 60S ribosomal subunits to the binding and inhibition of Hdm2, leading to p53 stabilization, cell cycle arrest and apoptosis. We have termed this response the Impaired Ribosome Biogenesis Checkpoint (IRBC). However the sequence of molecular events that determine the transition of the RPL5/RPL11/5S rRNA-precursor complex upon impaired ribosome biogenesis into a tumor suppressor, the IRBC complex, are unknown. Here we present the use of a colon cancer cell line endogenously tagged by means of CRISPR/Cas9 with a GFP-fusion moiety placed at the eukaryotic-specific N-terminal extension of one copy of the gene coding for RPL11, which behaves as the wild type allele in terms of ribosome assembly and protein synthesis. We are using cells expressing this allele i) to follow by live imaging the endogenous IRBC complex localization over time under normal growing conditions or upon inducing lesions in ribosome biogenesis known to trigger the IRBC and p53 stabilization and (ii) to determine underlying molecular and biochemical alterations leading to the transition of the RPL5/RPL11/5S rRNA-precursor complex into of the IRBC complex.

Citation Format: Sandra Menoyo, Antonio Gentilella, George Thomas. Characterization of the pre-ribosomal complex, which mediates the p53 Impaired Ribosome Biogenesis Checkpoint (IRBC). [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 B05.
Abstract B39: Asparagine drives translational adaptation of cancer cells to glutamine deficit
Authors: Pavlova Natalya N. , Zhang Ji , Thompson Craig B.
Published: May 2017

Most proliferating cells consume exogenous glutamine to fuel biosynthesis and cell growth, which leads to its marked depletion from the microenvironment. Glutamine provides carbon and nitrogen for a wide array of biomolecules, among which are non-essential amino acids, glucosamine and nucleotides; in addition, carbon backbone of glutamine is used as a preferred anaplerotic input into the TCA cycle. However, as recent in vivo metabolomic studies indicate, a number of tumor types are capable of utilizing alternative anaplerotic routes and, in fact, synthesize glutamine de novo. In addition, select cancer cell lines are able to proliferate in the absence of exogenous glutamine in culture medium. However, the metabolic and regulatory underpinnings that enable the cellular adaptation to glutamine deficit and de novo glutamine production need further investigation.

In this work, we identified the non-essential amino acid asparagine as essential for the survival and proliferation of cancer cells in the absence of exogenous glutamine supply. Our data indicate that asparagine, though structurally related to glutamine, is not catabolized in the same manner. Instead, asparagine acts by restoring protein translation, which becomes profoundly compromised in the absence of glutamine. This, in turn, enables the post-transcriptional adaptive upregulation of glutamine synthetase (GLUL), which is required for glutamine-independent growth. Taken together, these findings show that the cellular adaptation to glutamine-limiting conditions relies upon the availability of asparagine, which may represent an important therapeutic vulnerability.

Citation Format: Natalya N. Pavlova, Ji Zhang, Craig B. Thompson. Asparagine drives translational adaptation of cancer cells to glutamine deficit. [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 B39.
Abstract IA14: Rare codons capacitate Kras-driven de novo tumorigenesis
Authors: Pershing Nicole L.K. , Lampson Benjamin L. , Counter Christopher M.
Published: May 2017

The KRAS gene is commonly mutated in human cancers, rendering the encoded small GTPase constitutively active and oncogenic. We discovered that this gene has the unusual feature of having a bias towards rare codons, which are associated with poor translation. Indeed, by changing rare codons to common the amount of KRAS mRNA detected in the heavy fraction by polysome profiling was reduced in lockstep with an increase in protein expression. This poor translation of KRAS has a direct impact on oncogenesis, but curiously, not in the direction one might expect. Specifically, we treated mice in which rare codons in the Kras gene were changed to common with a carcinogen known to induce lung tumors characterized by oncogenic Q61L/R mutations in Kras. Interestingly, these mice exhibited a reduction in tumor burden. Moreover, not only was the altered Kras allele mutated less often, but when it was mutated, completely different mutations were detected, namely G12V/D. We attribute this to a selection against the stronger Q61L/R mutations in favor of weaker G12V mutations in the higher expressed modified Kras allele, as strong oncogenic signaling leads to growth arrest instead of proliferation. As such, the poor translation of KRAS may reduce the chance that an oncogenic mutation induces growth arrest, which perhaps is related to the high frequency this gene is mutated in human cancers or even why specific KRAS mutations map to certain cancers.

Citation Format: Nicole L.K. Pershing, Benjamin L. Lampson, Christopher M. Counter. Rare codons capacitate Kras-driven de novo tumorigenesis. [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 IA14.
Abstract IA12: Targeting DNA repair in cancer therapy
Authors: D'Andrea Alan D.
Published: May 2017

Human cancer cells have genomic instability resulting from germline or acquired defects in DNA repair. One DNA repair pathway—the Fanconi Anemia/BRCA pathway (D'Andrea, A., N Engl J Med 362:1909, 2010)—is defective in many human cancers, including breast, ovarian, and pancreatic neoplasms. Disruption of the FA/BRCA Pathway results in the characteristic chromosome instability and radiation/crosslinker hypersensitivity of these tumors. In general, loss of one DNA repair pathway often leads to hyperdependence on another pathway for tumor cell survival. This hyperdependence offers a unique opportunity for the development of anticancer therapeutics. For instance, FA/BRCA pathway deficient tumors are hyperdependent on Base Excision Repair (BER) and, accordingly, these tumors are hypersensitive to single agent treatment with PARP1 inhibitors, which block BER, or with ATM inhibitors. Our research program is focused on profiling the FA/BRCA pathway and the other five major DNA repair pathways in tumor cells (Kennedy and D'Andrea, JCO 24: 3799, 2006). Each DNA repair pathway has a characteristic biomarker and repairs a specific type of DNA lesion. By profiling these pathways in primary tumor samples with activation-specific antibodies to DNA repair proteins, we have been able (1) to predict the sensitivity of tumors to conventional chemotherapy and radiation (2) to subset tumors for their sensitivity to novel classes of DNA repair inhibitors, (i.e., PARP1, Chk1, ATM, and proteasome inhibitors) and (3) to screen for new small molecule inhibitors of other DNA repair pathways. This combination of novel DNA repair inhibitors, conventional DNA damaging agents, and DNA repair biomarkers offers new opportunities for developing more effective anticancer therapy. In my presentation, I will also discuss novel approaches to sensitizing Triple Negative Breast Cancers (TNBCs) and Ovarian Tumors (OCs) to PARP1 inhibitors. We have previously shown that exposure of these tumors to either a CDK inhibitor or a proteasome inhibitor can block homologous recombination (HR) repair and thereby sensitize the tumor cells to PARP1 inhibitor. The CDK inhibitor/PARP1 inhibitor combination has been examined in orthotopic primary TNBC and OC xenograft models. Finally, we have identified an additional PARP1-dependent DNA repair mechanism in TNBCs and OCs. This pathway is driven by a novel alternative end-joining polymerase, POLθ. These tumors are hypersensitive to inhibitors of this new pathway, suggesting a new target for DNA repair therapies.

Citation Format: Alan D. D'Andrea. Targeting DNA repair in cancer therapy. [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 IA12.
Abstract IA19: Novel insights into T cell recognition and regulation at the tumor site
Authors: Furness Andrew J. S.
Published: May 2017

Regulation of T cell function represents a key obstacle to the successful clinical application of tumor immunotherapy. Antibody-mediated blockade of co-inhibitory immune checkpoint molecules seeks to address such regulation. Durable remissions and even cure has been observed in patients with advanced cancer, however such responses are limited to a small fraction of treated patients. The identification of biomarkers predictive of response and resistance to therapy therefore remains an area of high scientific priority. Recent studies highlight the impact of the genomic landscape on anti-tumor immunity. Tumor-specific mutations may serve as neoantigens, eliciting T cell responses, and appear to be enriched in patients with advanced melanoma and non-small cell lung cancer (NSCLC) deriving benefit from CTLA-4 and PD-1 blockade respectively.

Genetic heterogeneity within single tumors is well described, however the impact of intra-tumor heterogeneity (ITH) upon the neoantigen landscape and anti-tumor immunity has remained unclear. Through integrated analysis of ITH and neoantigen burden, we demonstrate the impact of clonal neoantigens, present in every cancer cell, on survival in primary lung adenocarcinoma. We identify neoantigen-reactive CD8+ T cells recognizing clonal neoantigens in patients with early stage NSCLC and demonstrate expression of high levels of co-inhibitory immune checkpoint molecules including PD-1. In keeping with these observations, sensitivity to CTLA-4 and PD-1 blockade in patients with advanced melanoma and NSCLC was enhanced in tumors enriched for clonal neoantigens.

Heterogeneity in the neoantigen landscape may therefore influence immune surveillance. Clonal neoantigens, shared by all tumor cells, represent a key substrate for T cell recognition and an attractive target for adoptive cell-based and vaccination strategies which may hold promise to address the challenges of ITH.

Citation Format: Andrew J. S. Furness. Novel insights into T cell recognition and regulation at the tumor site. [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 IA19.
INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction)
Authors: Reddy Yogesh N.V. , Lewis Gregory D. , Shah Sanjiv J. , LeWinter Martin , Semigran Marc , Davila-Roman Victor G. , Anstrom Kevin , Hernandez Adrian , Braunwald Eugene , Redfield Margaret M. , Borlaug Barry A.
Published: May 2017

Approximately half of patients with heart failure have preserved ejection fraction. There is no proven treatment that improves outcome. The pathophysiology of heart failure with preserved ejection fraction is complex and includes left ventricular systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide (NO)-cGMP bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidosis conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when left ventricular filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the National Heart, Lung, and Blood Institute–sponsored Heart Failure Clinical Research Network.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02742129.
Traditional Cardiovascular Risk Factors and Their Relation to Future Surgery for Valvular Heart Disease or Ascending Aortic Disease: A Case–Referent Study
Authors: Ljungberg Johan , Johansson Bengt , Engström Karl Gunnar , Albertsson Elin , Holmer Paul , Norberg Margareta , Bergdahl Ingvar A. , Söderberg Stefan
Published: May 2017

Background

Risk factors for developing heart valve and ascending aortic disease are based mainly on retrospective data. To elucidate these factors in a prospective manner, we have performed a nested case–referent study using data from large, population‐based surveys.

Methods and Results

A total of 777 patients operated for heart valve disease or disease of the ascending aorta had previously participated in population‐based health surveys in Northern Sweden. Median time (interquartile range) from survey to surgery was 10.5 (9.0) years. Primary indications for surgery were aortic stenosis (41%), aortic regurgitation (12%), mitral regurgitation (23%), and dilatation/dissection of the ascending aorta (17%). For each case, referents were allocated, matched for age, sex, and geographical area. In multivariable models, surgery for aortic stenosis was predicted by hypertension, high cholesterol levels, diabetes mellitus, and active smoking. Surgery for aortic regurgitation was associated with a low cholesterol level, whereas a high cholesterol level predicted surgery for mitral regurgitation. Hypertension, blood pressure, and previous smoking predicted surgery for disease of the ascending aorta whereas diabetes mellitus was associated with reduced risk. After exclusion of cases with coronary atherosclerosis, only the inverse associations between cholesterol and aortic regurgitation and between diabetes mellitus and disease of the ascending aorta remained.

Conclusions

This is the first truly prospective study of traditional cardiovascular risk factors and their association with valvular heart disease and disease of the ascending aorta. We confirm the strong association between traditional risk factors and aortic stenosis, but only in patients with concomitant coronary artery disease. In isolated valvular heart disease, the impact of traditional risk factors is varying.
Piptocarpha longipedunculata (Asteraceae, Vernonieae) a new species of Serra do Mar, São Paulo, Brazil
Authors: VOLET DANILO POSO , NAKAJIMA JIMI NAOKI , MONGE MARCELO , SEMIR JOÃO
Published: May 2017

Piptocarpha longipedunculata is a new species that is endemic to the São Paulo state in Brazil and occurs in the northern region of Serra do Mar. It is classified as endangered (EN) due to its limited geographic distribution. The species grows in areas of Ombrophilous Dense Forest, riparian forests and forest edges of Atlantic Forest Domain. It resembles Piptocarpha axillaris and Piptocarpha macropoda in its overall appearance, but differs mainly by its long pedunculated capitula with few flowers. Its characteristics and relationships within the genus are discussed here. Illustrations and a distribution map are also provided.
Aspidistra leucographa sp. nov. (Asparagaceae) from Guizhou, China
Authors: ZOU CHUN-YU , PAN BO , HAN MENG-QI , LIN CHUN-RUI
Published: May 2017

Aspidistra Ker Gawler (1822: 628) comprises more than 160 species in subtropical SE-Asia, mainly distributed in southern China and adjacent northern Vietnam (Li 2004, Tillich 2005, 2014). In recent years, many new species have been discovered and described from Guizhou Province, southwestern China (He et al. 2011a, 2011b, 2013, Liu et al. 2015, Sun et al. 2014, Xu et al. 2010, 2015a, 2015b). In May 2013, when investigating limestone plants in Guizhou province, we discovered an unusual Aspidistra Ker Gawl. at Dadaihe Karst Tiankeng (Tangbian, Pingtang county), showing dark purplish red flowers, but the pistil was wilted because the plant was at late stage of anthesis. Therefore plants were collected and transferred to the Guilin Botanical Garden, where they flowered next spring. In November 2015, the second author (Meng-Qi Han) collected again the same Aspidistra pecies at Anjiadong Karst Tiankeng (Tangbian). After consulting herbarium specimens and relevant literature on Aspidistra (Huang et al. 2015, Lin et al. 2015, Liang et al. 2016, Ly & Tillich 2016, Pan et al. 2016, Vislobokov et al. 2016), it turned out that the plant represents a new species, which we describe below.
Bythaelurus vivaldii, a new deep-water catshark (Carcharhiniformes, Scyliorhinidae) from the northwestern Indian Ocean off Somalia
Authors: WEIGMANN SIMON , KASCHNER CARINA JULIA
Published: May 2017

A new very small deep-water catshark, Bythaelurus vivaldii, is described based on two female specimens caught off Somalia in the northwestern Indian Ocean during the German ‘Valdivia’ expedition in 1899. It is morphologically closest to the recently described B. bachi, which is the only other Bythaelurus species in the western Indian Ocean that shares a stout body of large specimens and the presence of oral papillae. It further resembles B. vivaldii in the broad mouth and broad posterior head, but differs in the presence of composite oral papillae and a higher diversity in dermal denticle morphology. Additionally, the new species differs from all congeners in the western Indian Ocean in a larger pre-second dorsal fin length, a longer head, a larger interdorsal space, a larger intergill length, a longer pectoral-fin posterior margin, a shorter caudal fin, an intermediate caudal fin preventral margin, and a larger internarial width. Furthermore, the second dorsal fin of the new species is smaller than in its congeners in the western Indian Ocean except for B. lutarius, which is easily distinguished by the slender body and virtual absence of oral papillae, as well as the aforementioned further characters. An updated key to all valid species of Bythaelurus is provided.
New species of Narberdia Burke from México and Central America (Coleoptera: Curculionidae)
Authors: SOTO-HERNÁNDEZ MACOTULIO
Published: May 2017

Four new species of the previously monotypic genus Narberdia Burke are described. All of them are intimately associated with plants of the genus Bernardia (Euphorbiaceae). Narberdia cervantae Soto-Hernández, new species (México, Jalisco on Bernardia spongiosa McVaugh), N. sarukhani Soto-Hernández, new species (México, Veracruz and Costa Rica on B. mexicana (Hook. & Arn.) Müll. Arg. and B. nicaraguensis Standl. & L.O. Williams), N. dugesi Soto-Hernández (México, Querétaro and Michoacán on B. mexicana and B. albida Lundell), and N. ramuvei Soto-Hernández, new species (México, Durango, Jalisco and Puebla on B. changii A. Cerv. & Flores Olv., B. rzedowskii A. Cerv. & Flores Olv. and B. valdesii A. Cerv. & Flores Olv.). Use of more than one species of plant as a host by one species of weevil is a common occurrence in Anthonomini. Sexual dimorphism is evident in the species with the female rostrum more slender and relatively longer than in male, the antennal scape attached near the midpoint of the rostrum in the female and beyond the midpoint in the male, and female with pro- and mesotibia bearing a tooth adjacent to the mucro, this tooth absent in the male. Specimens were collected at elevations from 62 m to 2288 m. The genus, previously only known from the United States of America and extreme northern México is now also known from Costa Rica as well as other areas of México. Narberdia apparently is most closely related to several Anthonomus squamosus species group members, both with similar characters of the body and form of the male median lobe (broad at the apex and strongly narrowed near the apex).
The People’s Voice During the 2016 Presidential Campaign
Authors: Hart Roderick P.
Published: May 2017

This study examines the 2016 presidential campaign by comparing the voice of the people with that of the press and the political establishment. By systematically collecting some 5,000 texts (political speeches, ads, and debates alongside print and broadcast coverage) during the campaign and comparing them with 1,200 letters to the editor written in 12 small American cities, an overview of the nation’s quadrennial dialogue was made possible. By also comparing this sample with similar texts gathered for the 1948 through 2012 presidential campaigns, the 2016 campaign could be seen in sharper relief. These comparisons were facilitated by DICTION, a lexically based, content analytic program capable of producing rhetorical profiles of the discourse sampled. Overall, I found (a) that each voice produces distinct verbal patterns, thereby revealing its unique role in the polity; (b) that all three voices—politicians, the press, and the people—were more strident and more philosophical in 2016 than in prior years; (c) that Donald Trump and his letter writing supporters were especially dismayed by the status quo; and (d) that many of the stereotypes about letter writers turn out not to be true, with only a small percentage being blind ideologues. The rest were either issue specialists, analytical problem solvers, champions of a particular worldview, or voters interested in dissecting the psychological makeup of the candidates.
Diagnostic Error in Pediatric Cancer
Authors: Carberry Andrea R. , Hanson Keith , Flannery Ashley , Fischer Megan , Gehlbach Jonathan , Diamond Carol , Wald Ellen R.
Published: May 2017

The purpose of this study was to ( a) determine the frequency of diagnostic errors in pediatric cancer, ( b) categorize errors, and ( c) underscore themes associated with misdiagnosis. This is a retrospective cohort study at a tertiary children’s hospital of 265 patients with new oncologic diagnoses. The diagnostic error rate was 28%. Compared with those with no diagnostic error, those in whom there was an error were more likely to have ( a) more visits before diagnosis ( P < .001), ( b) not been seen in an acute care setting ( P = .03), ( c) inappropriate treatment ( P < .001), and ( d) misinterpreted laboratory studies or imaging ( P < .001). Themes in diagnostic errors were lack of appropriate evaluation for persistent symptoms (47%), failure to recognize signs and symptoms suggestive of malignancy (45%), and misinterpretation of tests (8%). Clinicians should consider diagnostic evaluation for multiple visits for the same complaint or a constellation of signs and symptoms suggestive of malignancy.
Predictors of Mental Health Symptoms, Automatic Thoughts, and Self-Esteem Among University Students
Authors: Hiçdurmaz Duygu , İnci Figen , Karahan Sevilay
Published: May 2017

University youth is a risk group regarding mental health, and many mental health problems are frequent in this group. Sociodemographic factors such as level of income and familial factors such as relationship with father are reported to be associated with mental health symptoms, automatic thoughts, and self-esteem. Also, there are interrelations between mental health problems, automatic thoughts, and self-esteem. The extent of predictive effect of each of these variables on automatic thoughts, self-esteem, and mental health symptoms is not known. We aimed to determine the predictive factors of mental health symptoms, automatic thoughts, and self-esteem in university students. Participants were 530 students enrolled at a university in Turkey, during 2014–2015 academic year. Data were collected using the student information form, the Brief Symptom Inventory, the Automatic Thoughts Questionnaire, and the Rosenberg Self-Esteem Scale. Mental health symptoms, self-esteem, perception of the relationship with the father, and level of income as a student significantly predicted automatic thoughts. Automatic thoughts, mental health symptoms, participation in family decisions, and age had significant predictive effects on self-esteem. Finally, automatic thoughts, self-esteem, age, and perception of the relationship with the father had significant predictive effects on mental health symptoms. The predictive factors revealed in our study provide important information to practitioners and researchers by showing the elements that need to be screened for mental health of university students and issues that need to be included in counseling activities.
A Meeting of the Minds: Exploring the Core–Periphery Structure and Retrieval Paths of Destination Image Using Social Network Analysis
Authors: Wang Yuan , Li Xiang (Robert) , Lai Kun
Published: May 2017

This study looks at how destination image elements are connected in people’s minds and how tourists retrieve these elements from memory. Based on the spreading activation theory of memory, the study examines destination image as a network, applies social network analysis to test the core–periphery structure of destination image, and identifies image retrieval patterns among potential tourists. Image descriptions of the Shanghai Disney Resort (SHDR) were collected from 1,000 respondents via a survey. Results indicated that the image of SHDR has single and multiple core–periphery structures, and respondents were most likely to retrieve image associations outward from the core to the periphery or use image associations at the same or closest levels of centrality. This study consolidates the core–periphery structure of destination image and offers new insights into destination image management.
Psychometrics versus Representational Theory of Measurement
Authors: Vessonen Elina
Published: May 2017

Erik Angner has argued that simultaneous endorsement of the representational theory of measurement (RTM) and psychometrics leads to inconsistency. His claim rests on an implicit assumption: RTM and psychometrics are full-fledged approaches to measurement. I argue that RTM and psychometrics are only partial approaches that deal with different aspects of measurement, and that therefore simultaneous endorsement of the two is not inconsistent. The argument has implications for the improvement of measurement practices.
Myoelectric signal classification based on S transform and two-directional two-dimensional principal component analysis
Authors: Ji Yi , Xie Hong-Bo
Published: May 2017

Time-frequency representiation has been intensively employed for the analysis of biomedical signals. In order to extract discriminative information, time-frequency matrix is often transformed into a 1D vector followed by principal component analysis (PCA). This study contributes a two-directional two-dimensional principal component analysis (2D2PCA)-based technique for time-frequency feature extraction. The S transform, integrating the strengths of short time Fourier transform and wavelet transform, is applied to perform the time-frequency decomposition. Then, 2D2PCA is directly conducted on the time-frequency matrix rather than 1D vectors for feature extraction. The proposed method can significantly reduce the computational cost while capture the directions of maximal time-frequency matrix variance. The efficiency and effectiveness of the proposed method is demonstrated by classifying eight hand motions using 4-channel myoelectric signals recorded in health subjects and amputees.
United and Divided by Stress: How Stressors Differentially Influence Social Support in African American Couples Over Time
Authors: Clavél Frederick D. , Cutrona Carolyn E. , Russell Daniel W.
Published: May 2017

The factors that allow people to be good support providers in relationships are not fully understood. We examined how support providers’ stressful experiences (financial strain and racial discrimination) differentially influence their supportiveness, using longitudinal data from two samples of African American couples. Among couples that provided observational data ( N = 163 couples), providers who experienced high chronic financial strain behaved less supportively toward their partners, while those who experienced frequent racial discrimination behaved more supportively over a 2-year period. In a second sample of 213 couples over a 3-year period, support providers who experienced financial strain were perceived by their partners as slightly less supportive, while providers who experienced frequent racial discrimination were perceived by their partners as more supportive. Findings suggest that supportiveness in relationships may be differentially shaped by the specific stresses and strains that partners face.
Singaporean pre-service music teachers’ identities, motivations and career intentions
Authors: Bennett Dawn , Chong Eddy K. M.
Published: May 2017

This article explores pre-service music teachers’ professional identities during pre-service training. Its focus is a student cohort whose studies are funded by the Singaporean Ministry of Education in return for a commitment—a teaching bond or contract—to work as teachers in schools. An overview of pre-service teacher education and the challenges of attraction and retention in Singapore is followed by discussion of the literature relating to identity formation, with a focus on music teacher and musician identities. Next, analysis and discussion of the findings highlight that participants’ teacher identities did not align with their level of performance proficiency. Teacher identity did, however, align with participants’ intentions to remain in teaching; participants who defined themselves first and foremost as music teachers were more likely than their peers to plan long-term teaching careers. The article considers the influence of teaching bonds, or contracts, signed by students in advance of their post-secondary studies. It concludes by considering the implications for recruitment and for developing professional identity among pre-service music teachers.
Risk factors associated with multi-drug-resistant Acinetobacter baumannii nosocomial infections at a tertiary care hospital in Makkah, Saudi Arabia - a matched case–control study
Authors: Al-Gethamy Manal M , Faidah Hani S , Adetunji Hamed Ademola , Haseeb Abdul , Ashgar Sami S , Mohanned Tayeb K , Mohammed Al-Haj , Khurram Muhammad , Hassali Mohamed A
Published: May 2017

Objective

To determine risk factors for multi-drug-resistant Acinetobacter baumannii (MDR-AB) nosocomial infections in intensive care units in a tertiary care hospital, Makkah, Saudi Arabia.

Methods

We performed a hospital-based, matched case–control study in patients who were admitted to Al Noor Specialist Hospital between 1 January 2012 and 31 August 2012. The study included cases of A. baumannii nosocomial infection and controls without infection. Controls were matched to cases by age and ward of admission.

Results

The most frequent site of infection was the respiratory tract (77.3%). Susceptibility to antimicrobial MDR-AB was 92.0% for ceftazidime and ciprofloxacin, while it was 83.3% for imipenem, 83.0% for trimethoprim, 79.0% for amikacin, and 72.7% for gentamicin. Multiple logistic regression of risk factors showed that immunosuppression (OR = 2.9; 95% CI 1.5–5.6; p = 0.002), clinical outcome (OR = 0.4; 95% CI 0.3–0.9; p = 0.01), invasive procedures (OR = 7.9; 95% CI 1.8–34.2; p = 0.002), a central venous catheter (OR = 2.9; 95% CI 1.5–5.6; p = 0.000), and an endotracheal tube (OR = 3.4; 95% CI 1.6–7.3; p = 0.001) were associated with MDR-AB.

Conclusions

Acinetobacter nosocomial infections are associated with admission to the ICU (Intensive care unit) and exposure to invasive procedures.