bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5873: BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors
Authors: Lemos Clara , Schulze Volker K. , Bader Benjamin , Christ Clara D. , Briem Hans , Politz Oliver , Prinz Florian , Holton Simon , Heinrich Tobias , Lefranc Julien , Lienau Philip , Scholz Arne , Nussbaum Franz von , Nising Carl Friedrich , Mumberg Dominik , Bauser Marcus , Hägebarth Andrea
Published: August 2018

The AMP-activated protein kinase (AMPK) is a sensor of the energy status in the cells, playing a key role in controlling their metabolism. For many years, AMPK was mainly perceived as a tumor suppressor in agreement with being a component of the LKB1 tumor suppressor cascade, which inhibits mTORC1. However, in the last few years, some studies suggested that AMPK might actually exert a pro-tumorigenic role in certain contexts. For instance, Liu and colleagues demonstrated that dysregulated MYC expression renders tumor cells sensitive to AMPK depletion (Liu et al, 2012. Nature). The authors showed that, due to their increased anabolism, MYC-dependent cells rely on AMPK to restore ATP levels and to prevent an energy crisis that results in apoptosis and cell death. Here we report the discovery of a new lead structure for the inhibition of AMPK by biochemical high throughput screening. The optimization of this lead structure towards potency and selectivity led to the probe compound BAY-3827 and the use of this tool compound to evaluate the therapeutic potential of AMPK inhibition in MYC-dependent tumors. To demonstrate a cellular effect of BAY-3827 an HRTF® assay (Homogeneous Time Resolved Fluorescence, cisbio) for phospho-Acetyl-CoA carboxylase (p-ACC, Ser79), a direct substrate of AMPK, was used. ACC phosphorylation was strongly inhibited by BAY-3827 in COLO 320DM and IMR-32 cells. However, despite its high potency, BAY-3827 failed to inhibit the proliferation of cells with dysregulated c-MYC or N-MYC. In conclusion, we have identified a potent and selective AMPK inhibitor. Despite demonstrated inhibition of AMPK kinase activity, BAY-3827 treatment did not translate into antiproliferative activity in MYC-dependent cells. While we could not confirm our initial hypothesis, one might speculate that inhibition of AMPK might be of therapeutic utility in other biological contexts. Therefore, the availability of potent and selective inhibitors, as described here, will contribute to further insight into the potential of AMPK inhibition as a therapeutic target in cancer.

Citation Format: Clara Lemos, Volker K. Schulze, Benjamin Bader, Clara D. Christ, Hans Briem, Oliver Politz, Florian Prinz, Simon Holton, Tobias Heinrich, Julien Lefranc, Philip Lienau, Arne Scholz, Franz von Nussbaum, Carl Friedrich Nising, Dominik Mumberg, Marcus Bauser, Andrea Hägebarth. BAY-3827, a selective inhibitor of AMPK for the evaluation of the role of AMPK in Myc-dependent tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5873.
Abstract 892: Doxorubicin-induced cardiotoxicity in iPSC-cardiomyocytes: Altered mitochondrial gene expression and function
Authors: Reyes Monica E. , Callender Rashida , Ma Jianzhong , Grove Megan L. , Morrison Alanna C. , Hildebrandt Michelle A.
Published: August 2018

Introduction: Cardiomyocytes are highly vulnerable to anthracycline-induced toxicity, which may lead to heart failure. This includes doxorubicin, which is a commonly used chemotherapeutic agent. Although mitochondrial function has been implicated as a mechanism of anthracycline-induced toxicity in rodent heart cells, the precise genes that regulate this response in humans remain to be elucidated. We hypothesized that doxorubicin significantly alters expression of mitochondrial genes in human cardiomyocytes, which impairs mitochondrial function.

Methods: Human inducible pluripotent stem cell (iPSC)-derived cardiomyocytes were treated with doxorubicin or left untreated for control to assess changes in gene expression using RNAseq. A total of 169 genes involved in mitochondrial function, as defined by Ingenuity Pathway Analysis and KEGG, were analyzed for significant differences between untreated and treated conditions using DESeq2 and GenePattern 2.0. Mitochondrial respiration was measured in control and doxorubicin-treated cells using the Seahorse Bioscience XFe96 Cell Mito Stress Test kit. We used a Spearman's partial correlation coefficient analysis to correlate gene expression levels with mitochondrial basal respiration, ATP production, maximal respiration, and spare respiratory capacity for untreated and doxorubicin-treated iPSC-cardiomyocytes.

Results: Of the 169 mitochondrial genes analyzed, we identified 25 genes that were significant in our global differential expression analysis across all conditions (P<0.05). Seven of these genes (ATP5D, COX5A, CYC1, HSD17B10, NDUFB10, NDUFS8, UQCRC1) remained significant in pairwise analyses between control and doxorubicin treated cells. We observed a decrease in mitochondrial respiration following treatment with doxorubicin. Maximal respiration (r=-0.929; P=0.022) and spare respiratory capacity (r=-0.98;P=0.0025) negatively correlated with NDUFS8 expression in doxorubicin-treated iPSC-cardiomyocytes.

Conclusion: Our findings underscore a role for mitochondrial function in the development of doxorubicin-induced cardiotoxicity and implicate specific genes in this process. Doxorubicin-altered gene expression in cardiomyocytes may provide insight into how impaired mitochondrial function leads to heart failure in cancer survivors.

Citation Format: Monica E. Reyes, Rashida Callender, Jianzhong Ma, Megan L. Grove, Alanna C. Morrison, Michelle A. Hildebrandt. Doxorubicin-induced cardiotoxicity in iPSC-cardiomyocytes: Altered mitochondrial gene expression and function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 892.
Abstract 982: Pharmacological DNA-PK inhibition induces ATM/p53 dependent premature senescence with immunomodulatory phenotype in irradiated cancer cells
Authors: Guo Yige , Sun Qing , Liu Xiaohong , Puc Janusz , Czauderna Frank , Zenke Frank , Blaukat Andree , Vassilev Lyubomir T.
Published: August 2018

A new generation, clinical-stage DNA-PK inhibitor, M3814, potently and selectively blocks one of the two major pathways for repair of DNA double strand breaks (DSB) and synergizes with ionizing radiation (IR) and DSB-inducing chemotherapy. We show that by inhibiting DNA-PK catalytic activity in the presence of DNA DSBs, M3814 simultaneously suppresses DNA repair and a negative regulatory signal to ATM, leading to enhanced activation of the ATM dependent signaling, including CHK2 and p53-dependent cell cycle arrest. Combination treatment of proliferating p53 wild-type cancer cells (A549, A375, H460) with a single dose of ionizing radiation (2-5Gy) and sustained exposure to M3814 induced a complete G1/S and G2/M cell cycle block. Within 4-7 days of treatment cells acquired a typical senescence phenotype with large/flat morphology and β-Gal staining. Live cell imaging and BrdU labeling in A549 cells demonstrated that this phenotype is not reversible following M3814 removal, in contrast to a fully reversible senescence-like phenotype caused by selective p53 activation by MDM2 inhibitor Nutlin-3a. Isogenic p53-null A549 cells lost the ability to fully arrest their cell cycle, confirming the role of p53 in senescence induction. Analysis of mRNA from IR/M3814 induced senescent A549 and A375 cells by the Nanostring PanCancer Immune profiling panel revealed activation of a large group of genes from several immune response pathways, including interferon, cytokine/chemokine, and complement. Eighteen genes were commonly upregulated >3-150 fold compared to controls. These substantial changes in gene expression were built gradually and correlated with the development of senescence phenotype. Several proteins from the induced subset were measured in the cell media (MesoScale Discovery) and confirmed that they are secreted by senescent cells in the absence of M3814. Culture media from M3814-induced senescent cells showed increased immunomodulatory effect on human PBMC-derived immune cells, suggesting increased probability for clearance of IR+M3814 induced senescent cancer cells by the immune system.

Citation Format: Yige Guo, Qing Sun, Xiaohong Liu, Janusz Puc, Frank Czauderna, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev. Pharmacological DNA-PK inhibition induces ATM/p53 dependent premature senescence with immunomodulatory phenotype in irradiated cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 982.
Abstract LB-080: Discovery of an unconventional form of cell-death in colorectal cancer
Authors: Tiwari Amit K. , Amawi Haneen , Chandrabose Karthikeyan , Erhardt Paul , Trivedi Piyush
Published: August 2018

We recently discovered unique, structurally constrained 4-pyridinyl - containing compounds that induce a form of caspase-independent cell death in colorectal cancer (CRC) cells. This was characterized by the simultaneous induction of dysregulated macropinocytosis and macroautophagy, a type of cell death we have termed ‘methuophagy' (this neologism arises from the Greek ‘methuo', to drink to intoxication and ‘phagy', self-eating). Our new class of small molecular probes (BAPT analogues) do not induce cell death via activation of the well characterized classical apoptotic pathways. In contrast, our BAPT compounds cause methuophagy by inducing the formation and accumulation of fluid-filled, heterogeneous vacuoles and autophagosomes, resulting in metabolic failure, loss of membrane integrity, and detachment of cells from the substratum. Methuophagy produces extensive autophagy without cell shrinkage, chromatin condensation, alteration of mitochondrial membrane potential or nuclear membrane damage. The optimization of the BAPT structure led to the discovery of BAPT-27, which has nanomolar potency in inducing methuophagy in broad spectrum of CRC cell lines and may serve as a prototype for a new class of drugs. BAPT-27 produces methuophagy and surmounts MDR in CRC cells independent of Ras, p53 or other apoptotic protein (i.e. Bax, Bak) or expression of ATP-binding cassette (ABC) transporters. Furthermore, BAPT-27 is non-toxic in normal cells and zebrafish. Based on our findings, we postulate that the induction of methuophagy by BAPT-27 produces endolysosomal trafficking defects that prevent recycling of lysosomes and cause lysosome-to-nucleus signaling defect, a mechanism that disturb cellular clearance and energy metabolism. The selected compounds will allow us to understand the biology of methuophagy-induced cell death and will be particularly beneficial for treatment of patients with apoptotic-resistant and aggressive CRCs.

Citation Format: Amit K. Tiwari, Haneen Amawi, Karthikeyan Chandrabose, Paul Erhardt, Piyush Trivedi. Discovery of an unconventional form of cell-death in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-080.
Abstract LB-296: Discovery and development of MEDI7247, a novel Pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2, for treating hematological and solid cancers
Authors: Pore Nabendu , Borrok M Jack , Rebellato Marlon , Hinrichs MaryJane , Schifferli Kevin P. , Monks Noel R. , Tammali Ravinder , Herbst Ronald , Coats Steven R. , Tice David A.
Published: August 2018

The sodium dependent neutral amino acid transporter, ASCT2/SLC1A5 is frequently overexpressed in cancer to sustain “glutamine addiction” of cancer cells and to meet their increased demand for energy and nutrients. High expression of ASCT2 is often associated with poor disease prognosis. Immuno-histochemistry (IHC) data from 600+ tumor samples suggest ASCT2 expression in hematologic and solid cancers, including MM, AML, and DLBCL (≥ 95% positive in respective tumor samples), as well as squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), prostate, pancreatic, and colorectal cancer (66% to 95% positivity in respective tumors). Broad expression across various cancers and restricted expression in normal tissues warrant ASCT2 as an attractive candidate for an antibody drug conjugate. MEDI7247 is a novel investigational antibody-drug conjugate (ADC) comprising an anti-ASCT2 human monoclonal antibody site-specifically conjugated to pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker, with a drug to antibody ratio (DAR) of 2. MEDI7247 specifically binds to cell surface ASCT2 while exhibiting no affinity to the other members of the family, including ASCT1. Following binding, MEDI7247 is internalized and trafficked to the lysosomes to subsequently release the PBD warhead. PBD enters the nucleus where it induces DNA damage and results in tumor cell death. MEDI7247 shows potent in vitro cytotoxicity in several human cancer cell lines expressing variable levels of ASCT2. Dose dependent in vivo efficacy of MEDI7247 was determined in solid tumor xenografts and disseminated hematological malignancy models. MEDI7247 is cross-reactive with cynomolgous monkey ASCT2 and shows similar binding and killing with cyno ASCT2 expressing cells. MEDI7247 demonstrated acceptable safety profile in toxicity studies with non-human primates to support first in human trials. Based on its combined efficacy and safety, MEDI7247 is in clinical development for the treatment of ASCT2 positive cancers.

Citation Format: Nabendu Pore, M Jack Borrok, Marlon Rebellato, MaryJane Hinrichs, Kevin P. Schifferli, Noel R. Monks, Ravinder Tammali, Ronald Herbst, Steven R. Coats, David A. Tice. Discovery and development of MEDI7247, a novel Pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2, for treating hematological and solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-296.
Abstract LB-298: MEDI7247: A first in class antibody drug conjugate targeting ASCT2 in a range of solid tumors
Authors: Schifferli Kevin P. , Monks Noel R. , Tammali Ravinder , Borrok M Jack , Flynn Matthew G. , Hurt Elaine M. , Coats Steven R. , Herbst Ronald , Tice David A. , Pore Nabendu
Published: August 2018

MEDI7247 is a first in class ADC consisting of a human anti-ASCT2 monoclonal antibody, site specifically conjugated to highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimers (DAR of 2) via a protease-cleavable linker. ASCT2 (SLC1A5) is a multi-pass, Na+-dependent, neutral amino acid transporter that mediates the uptake of amino acids required for tumor growth and progression. ASCT2 over-expression has been identified on numerous solid tumor indications including pancreatic (94% Positive), small cell (SCLC) and non-small cell (NSCLC) lung cancer (65% positive), colorectal (73% positive), squamous cell carcinoma of the head and neck (SCCHN - 94% positive) and prostate (65% positive). MEDI7247 binds to ASCT2 facilitating internalization and ultimately cell death. We have evaluated the in vivo anti-tumor activity of MEDI7247 in both cell line-derived xenografts (CDX) and patient-derived xenografts (PDX). Cell line-derived xenografts were utilized to examine the anti-tumor activity in colorectal (WiDR), small cell lung cancer (H69) and squamous head and neck (FADU) tumors. Expression of ASCT2 was determined to be high in WiDR and low in both H69 and FADU. Regardless of ASCT2 expression level MEDI7247 controlled tumor growth in each of these models. MEDI7247 was further examined in numerous PDX models of pancreatic, NSCLC and colorectal tumors. Activity was observed across all the PDX models tested. Two pancreatic cancer PDX with both low and high ASCT2 expression levels showed anti-tumor responses to MEDI7247 at all dose levels tested (0.1, 0.2, 0.3 and 0.4 mg/kg). In both models, tumor regressions were observed with durable responses observed beyond 100 days. Flow cytometry analyses reveal high ASCT2 expression of cancer stem cells (CSCs) in Patient Derived Xenografts(PDX). Additionally, MEDI7247 ablates CSCs in vivo in PDX tumors, which may yield opportunity for more durable clinical responses. In summary, preclinical in vivo evaluation of MEDI7247 demonstrates target dependent anti-tumor activity across all the solid tumor indications evaluated and may be important in tumor initiating cell populations. MEDI7247 is currently in Phase I clinical trials.

Citation Format: Kevin P. Schifferli, Noel R. Monks, Ravinder Tammali, M Jack Borrok, Matthew G. Flynn, Elaine M. Hurt, Steven R. Coats, Ronald Herbst, David A. Tice, Nabendu Pore. MEDI7247: A first in class antibody drug conjugate targeting ASCT2 in a range of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-298.
Abstract A45: Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer
Authors: Donnella Hayley , Webber James , Shokat Kevan , Goga Andrei , Gordan John , Bandyopadhyay Sourav
Published: August 2018

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest. We hypothesized that dynamic changes in signaling, including adaptation and feedback, limit drug efficacy. Using a quantitative proteomics approach, we mapped dynamic changes in the kinome in response to various agents and identified signaling changes that correlate with drug sensitivity. Measurement of dynamics across a panel of breast cancer cell lines identified that maintenance of CDK4 and AURKA activity was associated with drug resistance. We tested whether incomplete inhibition of CDK4 or AURKA was a source of therapy failure and found that inhibition of either was sufficient to sensitize most breast cancer cells to PI3K, AKT, and mTOR inhibitors. In particular, drug combinations including the AURKA inhibitor MLN8237 were highly synergistic and induced apoptosis through enhanced suppression of mTOR signaling to S6 and 4E-BP1 leading to tumor regression in vivo. This approach identifies survival factors whose presence limits the efficacy of target therapy and suggests that Aurora kinase coinhibition could unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.

Citation Format: Hayley Donnella, James Webber, Kevan Shokat, Andrei Goga, John Gordan, Sourav Bandyopadhyay. Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A45.
Abstract B12: Therapeutic potential of NTRK3 in desmoplastic small round cell tumor
Authors: Spraggon Lee , Hmeljak Julija , Magnan Heather , Somwar Romel , Asher Marina , Hartono Alifiani B. , Lee Sean Bong , Ladanyi Marc
Published: August 2018

Desmoplastic small round cell tumor (DSRCT) is a soft-tissue sarcoma that predominantly affects adolescent and young adult males and has a dismal prognosis, despite aggressive treatment. It is characterized by the t(11;22)(p13:q12) translocation that generates the EWSR1-WT1 chimeric transcription factor, a powerful oncogene and the main molecular driver of DSRCT.

EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that contribute to an oncogenic expression program. It has been previously described that EWSR1-WT1 can activate neural gene expression (1), supporting the hypothesis that targeting neural differentiation markers might offer a novel therapeutic approach to treat DSRCT.

Among those markers, our analysis of DSRCT tumors demonstrated prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3; TrkC), a druggable receptor tyrosine kinase, specifically expressed in DSRCT compared to other translocation-driven sarcomas. We show that EWSR1-WT1 directly activates its expression, and that abrogation of NTRK3 reduces growth of DSRCT cells. Conversely, we show that pharmacologic targeting of NTRK3 is effective both in in vitro and in vivo models of DSRCT, suggesting that NTRK3 is a viable therapeutic target, especially in light of the recent clinical development of highly specific and effective NTRK inhibitors.

Reference

1. Kang et al., Cancer Res 2014;15;74(16):4526-35.

Citation Format: Lee Spraggon, Julija Hmeljak, Heather Magnan, Romel Somwar, Marina Asher, Alifiani B. Hartono, Sean Bong Lee, Marc Ladanyi. Therapeutic potential of NTRK3 in desmoplastic small round cell tumor [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B12.
Baseline Cytokine Profiles of Tuberculin-Specific CD4+ T Cells in Non–Muscle-Invasive Bladder Cancer May Predict Outcomes of BCG Immunotherapy
Authors: Jallad Samer , Thomas Philip , Newport Melanie J. , Kern Florian
Published: August 2018

Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy preserves the bladder after resection of high-risk non–muscle-invasive bladder cancer (NMIBC). About 30% of patients experience treatment failure, which cannot be predicted a priori and carries a high risk of disease progression. We examined the in vitro tuberculin responsiveness of CD4+ T cells before BCG immunotherapy in 42 patients with high-risk NMIBC. The frequencies and functionalities of cytokine-expressing CD4+ T cells immediately before and after BCG immunotherapy induction were assessed by flow cytometry after overnight tuberculin stimulation. Tuberculin-induced secreted mediators were measured by electrochemiluminescence. We correlated the results with recurrence-free patient survival 6 months after induction. A tuberculin-induced, secreted, IL2 concentration > 250 pg/mL was the best predictor of recurrence-free survival, providing 79% sensitivity, 86% specificity (AUC = 0.852, P = 0.000), and overall correct classification in 78.6% of cases. In 50% of patients later experiencing recurrence, but not in any of the recurrence-free survivors, IL2 secretion was < 120 pg/mL. Other parameters predicting recurrence-free survival included secreted IFNγ (AUC = 0.796, P = 0.002) and the frequencies of TNF-producing (TNF+) CD4+ T cells (AUC = 0.745, P = 0.010). “Polyfunctional” CD4+ T cells (IFNγ+/IL2+/TNF+) were significantly associated with recurrence-free survival (AUC = 0.801, P = 0.002). Thus, the amount of IL2 secretion from CD4+ T cells after overnight in vitro incubation with tuberculin predicted the outcome of BCG immunotherapy. As many as half of potential BCG failures could be identified before induction therapy is begun, enabling better choices regarding treatment. Cancer Immunol Res; 6(10); 1212–9. ©2018 AACR.
Pulmonary Vein Flow Impedance: An Early Predictor of Cardiac Dysfunction in Intrauterine Growth Restriction
Authors: Bravo-Valenzuela Nathalie J.M. , Zielinsky Paulo , Zurita-Peralta Jesús , Nicoloso Luiz Henrique , Piccoli Jr. Antonio , Ferreira Van der Sand Luiza , Miranda Sulis Natássia , Carvalho Ritter Camila
Published: August 2018

Introduction: In intrauterine growth restriction (IUGR), increased uteroplacental vascular impedance contributes to preferential flow to left ventricle (LV), with consequent alteration of its compliance and increased left atrial (LA) pressure. Pulmonary vein pulsatility index (PVPI) reflects the increased impedance to LA filling and could be used as a cardiac monitoring parameter in IUGR. Material and Methods: A total of 27 IUGR fetuses (group 1), 28 fetuses with appropriate growth for gestational age from hypertensive mothers (group 2), and 28 controls (group 3) were studied. Pulsatility indices (PIs) of pulmonary veins and ductus venosus were calculated by Doppler echocardiography. Obstetric ultrasound was used to assess the PIs of uterine, umbilical, and middle cerebral arteries. Statistical analysis used analysis of variance, post-hoc Tukey, and Pearson’s tests. Results: Mean PVPI was higher in IUGR group (1.27 ± 0.39) when compared to groups 2 (1.02 ± 0.37; p = 0.01) and 3 (0.75 ± 0.12; p < 0.001). In group 2, moderate correlation between PVPI and ductus venosus pulsatility index (DVPI) was found but not between PVPI and cerebroplacental ratio (CPR). Discussion: Higher PVPI in IUGR reflects decreased LV compliance and altered LA dynamics. As LV dysfunction precedes right ventricle, our results suggest that PVPI could be an early echocardiographic parameter of fetal diastolic function in IUGR.
Cerebral Diffusivity Changes in Fetuses with Chiari II Malformation
Authors: Shrot Shai , Soares Bruno P. , Whitehead Matthew T.
Published: August 2018

Objectives: Chiari II malformation is a congenital abnormality characterized by a small posterior fossa with downward displacement of the hindbrain into the foramen magnum. Diffusion-weighted imaging (DWI) can be used to quantitatively characterize brain injury and physiological maturation. We aim to evaluate DWI parameters of the infra- and supratentorial brain in fetuses with Chiari II malformation. Methods: MRI and US studies of 26 fetuses with Chiari II malformation and 15 controls were evaluated for the presence/severity of hydrocephalus, myelomeningocele level, and brain apparent diffusion coefficient (ADC) values. Cerebral flow impedance parameters (resistance and pulsatile indexes, resistance index [RI], and pulsatility index [PI] respectively) from concurrently preformed fetal US were also evaluated. Results: Of the Chiari II group, 16 fetuses had hydrocephalus. There was increasing severity of lateral ventriculomegaly in the high compared to low spinal dysraphism subgroups. There were significant lower ADC values in the frontal (p = 0.01) and temporal lobes (p = 0.05) in Chiari II group compared with normal, regardless of the presence or severity of hydrocephalus. Fetuses with Chiari II showed significantly lower RI and PI values. Conclusions: Abnormal ADC values indicate supratentorial microstructural changes in fetuses with Chiari II malformation. Further investigation of the role of diffusion imaging metrics in evaluating abnormal brain development, parenchymal damage and efficacy of fetal surgery is needed.
Role of Urotensin-2 in 5-Fluorouracil-Related Arterial Vasoconstriction in Cancer Patients
Authors: Seker Mesut , Isen Hayati C. , Çevirme Nidal , Aydın Sinem , Bilici Ahmet , Bulut Huri , Yasin Ayse I. , Coban Ezgi , Demir Tarık , Aliyev Altay , Kocyigit Abdurrahim , Turk Hacı M.
Published: August 2018

Background: The aim of this study was to identify the possible relationship of 5-fluorouracil (5-FU)-related arterial vasoconstriction with urotensin-2 (UT-2), which has a high potential as an endogenic vasoconstrictor. Methods: We assigned the patients to 1 of 3 groups. Patients in group 1 received a bolus of 5-FU, those in group 2 a continuous infusion (CI) of 5-FU, and those in group 3 no 5-FU, which was also a control group. Pre- and post-treatment UT-2 levels and brachial arterial diameters were measured and recorded in all patients. Results: 132 patients were included in the study. Pre- and post-treatment brachial artery diameters were similar in all groups: in group 1 (3.28 ± 0.52 vs. 3.25 ± 0.44 mm, p = 0.740), in group 2 (3.57 ± 0.47 vs. 3.46 ± 0.45 mm, p = 0.441) and in the control group (3.51 ± 0.52 vs. 3.25 ± 0.44 mm, p = 0.818). Pre- and post-treatment UT-2 levels were significantly different in each group: in group 1 (39.5 ± 30.9 vs. 56.7 ± 27.1 ng/ml, p = 0.0001), in group 2 (37.7 ± 33.7 vs. 62.5 ± 37.7 ng/ml, p = 0.0001) and in the control group (52.9 ± 40.2 vs. 60.8 ± 40.7 ng/ml, p = 0.006). Conclusion: Our findings suggest that UT-2 has a high potential as a vasoconstrictor agent in our bodies and its level increases through a bolus or CI 5-FU. Increased UT-2 levels are likely to play a role in 5-FU-related cardiac toxicity pathogenesis.
Comparable Electrode Impedance and Speech Perception at 12 Months after Cochlear Implantation Using Round Window versus Cochleostomy: An Analysis of 40 Patients
Authors: Cheng Xiaoting , Wang Bing , Liu Yangwenyi , Yuan Yasheng , Shu Yilai , Chen Bing
Published: August 2018

Objective: The objective of this study was to examine whether cochlear implantation using the round window (RW) route versus cochleostomy achieves comparable electrode impedance and hearing results. Methods: This retrospective analysis included 40 patients receiving a cochlear implant (REZ-1): 20 using the RW approach and the remaining 20 using cochleostomy. Electrode impedance and tone, vowel, consonant, disyllable and sentence perception were measured during and after the implantation. Results: Electrode impedance did not differ significantly between the 2 groups at any time points [F(1, 38) = 1.84; p = 0.184]: 1.87, 5.16, 6.47 and 6.70 kΩ in the RW group versus 2.86, 5.33, 6.92 and 8.16 kΩ in the cochleostomy group at 0, 1, 3 and 12 months, respectively. There was no significant difference between the RW and cochleostomy groups for tone (77.50 vs. 80.50%; p = 0.472), vowel (77.70 vs. 78.65%; p = 0.760), consonant (75.50 vs. 78.25%; p = 0.443), disyllable (78.60 vs. 81.50%; p = 0.317) and sentence (50.90 vs. 52.50%; p = 0.684) perception at 12 months. Conclusion: The RW approach is comparable to cochleostomy in electrode placement as reflected by impedance and function as reflected by tone, vowel, consonant, disyllable and sentence perception.
Adoption Patterns of Bronchoscopic Lung Volume Reduction Procedures in Germany and Predicted Procedure Volumes for Other European Countries
Authors: Pietzsch Jan B. , Busca Rachele , Rott Christina , Geisler Benjamin P. , Weber Simon A. , Slebos Dirk-Jan , Deslee Gaëtan , Herth Felix J.F.
Published: August 2018

Background: Bronchoscopic lung volume reduction (BLVR) using valves and coils has been approved for use since 2003 and 2010, respectively. Objective(s): To study adoption patterns of BLVR in an early-adopting country, and to estimate potential treatment volumes in other European countries. Methods: Therapy- and age-specific volumes for endobronchial valve and coil procedures were obtained from German federal statistics for 2007–2016. Therapy-specific and total BLVR procedure volumes and growth were computed, and patterns in treatment age and device utilization analyzed. Patient volumes for other European countries were predicted using mean German patient volumes of the last 3 data years and age-specific population and emphysema incidences. Results: Over the study period, annual BLVR procedure volumes grew from 91 to 2,053 (+2,256%), reaching a peak of 2,556 procedures in 2013. Coil procedures constituted 36% of the total volume in 2016. Treatment age was stable over time, with highest procedure counts in age group 60–64 years for valves and 65–69 years for coils. A limited increase in device use per procedure was observed. For ­Germany, 1,655 newly treated BLVR patients were estimated per year, approximating about 5% of the annual newly diagnosed severe emphysema cases. Predicted volume estimates for other European countries ranged from 1 for Liechtenstein to 1,226 for France. Conclusions: Analysis of ­German procedure data show pronounced BLVR therapy uptake in the early years of adoption, with the more recently introduced coil therapy used in about one-third of patients. Estimated patient volumes to date constitute only a small fraction of the severe emphysema population.
High Platelet Levels Attenuate the Efficacy of Platinum-Based Treatment in Non-Small Cell Lung Cancer
Authors: Wang Zhangfei , Fang Man , Li Juan , Yang Ruining , Du Jianping , Luo Yiqin
Published: August 2018

Background/Aims: The correlation between platelet levels and clinical outcomes has received increasing attention, but it is not yet clear whether and how platelet levels affect the therapeutic response in non-small cell lung cancer (NSCLC). In the current study, we aimed to explore the role of platelet levels in responsive to platinum-based chemotherapy and investigated the underlying mechanism. Methods: We evaluated the possibility of platelet level as a biomarker for response to platinum-based therapy in NSCLC by retrospective analysis of NSCLC patients. Cell proliferation was evaluated using cell counter and flow cytometry. Cell capillary-like structures of HPMEC were estimated with ECMatrix. The effect of platelets on A549, H1299, and HPMEC apoptosis was measured by flow cytometry. A A549-bearing NOD/ SCID mice model was employed to determine whether platelets could counteract cisplatin-induced apoptosis in vivo. In vivo cell proliferation and apoptosis were evaluated with Ki-67 antibody and TUNEL staining respectively. The angiogenesis of tumor was estimated by CD31 microvessel density. The protein levels of Akt, Bad and Bcl-2 were assessed by western blot. To further examine platelet-driven effects of the chemotherapeutic response, we used platelet depletion and platelet transfusion in A549-bearing NOD/SCID mice. Results: Thrombocytosis at NSCLC diagnosis was associated with lower progression-free survival and median overall survival. Platelet levels before chemotherapy in the no response group were markedly higher than in the responsive group. Platelets rescued the inhibition of cell proliferation and angiogenesis and protected against cell apoptosis induced by cisplatin, platelets rescued cisplatin-induced apoptosis via the Akt/Bad/Bcl-2 signaling pathway under endoplasmic reticulum stress. Platelet transfusion decreased the therapeutic effect of cisplatin, while it was increased by platelet depletion. Conclusion: We confirmed an important anti-apoptosis mechanism mediated by platelets and found that platelets could counteract cisplatin-induced apoptosis. Reducing platelet levels or blocking platelet-based cytoprotection may represent new methods for improving the chemotherapeutic effect.
Subclinical intramammary infection does not affect bovine milk ethanol stability
Authors: Martins Cristian Marlon de Magalhães Rodrigues , Gonçalves Juliano Leonel , Alves Bruna Gomes , Arcari Marcos André , Santos Marcos Veiga dos
Published: August 2018

The present study hypothesized that intramammary infection (IMI) might reduce milk ethanol stability (MES), mainly when IMI is caused by major pathogens. Thus, this study evaluated the effect of IMI on bovine MES using a natural exposure experimental design. Ninety-four lactating cows from five dairy herds were selected once they were determined to have an IMI, based on milk bacteriological culturing with positive isolation and somatic cell count (SCC) > 200×103 cells/mL in two out of three composite milk samples collected during three consecutive weeks. After selection, cows were sampled a second time (within two weeks) for evaluation at mammary quarter level (n = 326): milk yield (kg/quarter/day), MES, composition (fat, protein, lactose, casein, total solids and solids-non-fat), and bacteriologic culture. The effect of subclinical mastitis on MES was tested by two models: 1) comparison of healthy vs. infected quarters; and 2) comparison of contralateral mammary quarter within cow. The only milk composition variable associated with MES was lactose (r = 0.18; P < 0.01). Subclinical IMI did not affect MES when the comparison was performed using both models (1 and 2). Likewise, MES did not change when infected quarters were sorted into two groups of pathogens (major, minor and infrequent; and contagious, environmental, minor and infrequent) and compared with healthy mammary quarters. Considering the results of both models, subclinical IMI did not affect MES of dairy cows.
Review of the family Coccidae (Hemiptera: Coccomorpha) in Laos
Authors: CHOI JINYEONG , SOYSOUVANH PHEOPHANH , LEE SEUNGHWAN , HONG KI-JEONG
Published: August 2018

The family Coccidae Fallén, 1814 (Hemiptera: Coccomorpha), known as soft scale insects, is represented in Laos by 26 species. This includes 15 new country records: Ceroplastes cirripediformis (Comstock, 1881), C. floridensis Comstock, 1881, Coccus capparidis (Green, 1904), C. celatus De Lotto, 1960, C. formicarii (Green, 1896), C. gymnospori (Green, 1908), C. latioperculatum (Green, 1922), Drepanococcus cajani (Maskell, 1891), Eucalymnatus tessellatus (Signoret, 1873), Megapulvinaria maxima (Green, 1904), Paralecanium expansum (Green, 1896), Pulvinaria floccifera (Westwood, 1870), P. psidii Maskell, 1893, Saissetia miranda (Cockerell & Parrott in Cockerell, 1899), and S. oleae (Olivier, 1791). An identification key to adult females of all the soft scale species known from Laos is provided, together with diagnoses, photographs and host information. The economic importance of each species is also discussed.
Ancient Egyptian Roots of Trademarks
Authors: VerSteeg Russ
Published: August 2018

This article examines such names and symbols that appear on a variety of ancient objects and attempts to draw conclusions about their nature. More specifically, this article offers suggestions about the purposes of such marks and considers how the nature of commerce in ancient Egypt may have influenced the development—or lack thereof—of trademarks there. And although there is a decided paucity of what we today might consider true trademarks, we can be certain that both the legal principles and the well-developed use of symbolic communication of the ancient Egyptians planted the seeds for the later growth of modern trademarks and trademark law.
‘Brand work’: Constructing assemblages in gendered creative labour
Authors: Kivinen Nina H , Hunter Carolyn
Published: August 2018

Recent work has highlighted how brands play an important role within organizational practice. To extend this discussion, we ask: how do gendered media brands come into being in an organization by connecting ideas, objects and people? This article challenges the assumption that brands simply reflect management norms by positioning the brand as an ‘assemblage’ of multiple connections and linkages, simultaneously shaping and being shaped by those that partake in its production. Employees engage in ‘brand work’; that is, the negotiation of the assemblages of the brand in situated and gendered practices. Brand work is explored here in the gendered creative labour of producing girls’ magazines. Two studies of pre-teen and teenage girls’ magazines in the UK and a Nordic country were analysed in relation to how multiple brand fragments were situated in gendered practices and power relations. Brand work offers an alternative, fragmented perspective to normative forms of control, introducing a simultaneous territorialization and deterritorialization process of stabilization and contestation of the assemblage.
Tuning of nanotube/elastomer ratio for high damping/tough and creep resistant polypropylene/SEBS-g-MA/HNT blend nanocomposites
Authors: Tekay Emre , Nugay Nihan , Nugay Turgut , Şen Sinan
Published: August 2018

Polypropylene (PP)/maleic anhydride grafted polystyrene-b-poly (ethylene/butylene)-b-polystyrene (SEBS-g-MA)/organophilic halloysite nanotube clay ternary nanocomposites were produced by using HNT/SEBS-g-MA masterbatches at different nanotube loadings (1 wt%, 3 wt%, and 5 wt%). The masterbatches with different ratios of HNT/SEBS-g-MA (1/1, 1/2, and 1/3) were prepared via a revolution/rotation type mixing-assisted masterbatch process. All nanocomposites showed higher storage moduli and damping at low temperatures as compared to neat polypropylene. The nanocomposites having HNT/SEBS-g-MA ratio of 1/3 were found to act as effective dampers with their relatively higher damping values. In terms of short-term creep performance, 1 wt% and 3 wt% organophilic halloysite nanotube loaded systems with low amount of SEBS-g-MA (<9 wt%) enhanced dimensional stability of polypropylene with their lower creep strain and permanent deformation values. More specifically, among the nanocomposites, 3 wt% organophilic halloysite nanotube loaded nanocomposite with HNT/SEBS-g-MA ratio of 1/3 and co-continuous like morphology not only exhibited an effective damping over a wide range of temperature (from −70℃ to 50℃) but also showed relatively higher storage moduli at low temperature region together with lower permanent creep deformation as compared to neat polypropylene. As a result, the HNT/SEBS-g-MA masterbatch in 1/3 ratio was found to be the most suitable in polypropylene blend nanocomposites. It may be advantageous for polypropylene nanocomposite based applications where high damping/toughness at low temperature conditions and high dimensional stability under load are desired.
In Memory of Henry Houck
Authors: Corson O. T.
Published: August 2018

An abstract of address delivered before the Pennoylvania State Educational Association, Johnstown, Pennsylvania, December 28, 1917.
A Platoon School in Concord, N. H
Authors: Lewis Della I.
Published: August 2018

That the platoon form of organization is adaptable to schools of moderate size is indicated by the experience of Concord, here described. The beaming faces of juvenile learners are said to attest approval of the procedures used in South End School.
Home Room Guidance in Grantwood
Authors: Burns Robert , Van Wagner Miss Edith
Published: August 2018

Pupils in the Junior High School grades are exposed to a thoughtfully organized program of guidance, both educational and vocational, conducted by the home room teachers. The program here outlined is manifesting numerous advantages.
Reading for Appreciation
Authors: Rinehardt Emma
Published: August 2018

“Children learn how to read, but often they miss the better part–they do not learn to want to read.”
Mental Health as Educational Aim
Authors: Fowler Burton P.
Published: August 2018

Look for the author's five-point criterion for checking everything that goes on in school.
Every Teacher a Teacher of Reading
Authors: Penhale Randall R.
Published: August 2018

This article is based on observations made while Mr. Penhale was a teacher at Negaunee, Michigan.
Improvement for Slow Readers
Authors: Henry Gayle K.
Published: August 2018

Why the wide differences in reading rate? How can we train for quicker comprehension?
If I Were King
Authors: Popham Estelle L.
Published: August 2018

… or perchance a School Administrator … what then should I do about Commercial Studies?
Performance of police personal protective equipment challenged with a military grenade
Authors: Williams MGG , Turner GR , Lee M , Smith BD , Carr DJ , Malbon C , Nelson E
Published: August 2018

Police body armour in the United Kingdom (UK) is designed to provide protection from edged weapons and low-velocity pistol ammunition. Recent events have raised concern about whether UK police body armour and associated personal protective equipment (PPE) provides protection from military threats such as improvised explosive devices (IED) and grenades. In this paper PPE worn by specialised police officers was assessed for its protective performance from a specified grenade threat. The major cause of injury suffered by police officers challenged by a modern military grenade would be from the associated fragmentation which perforated coveralls, boots, helmet and soft body armour, but not hard armour plates.
Spoilers Affect the Enjoyment of Television Episodes but Not Short Stories
Authors: Daniel Thomas A. , Katz Jeffrey S.
Published: August 2018

While spoilers are culturally regarded as something that detracts enjoyment from a narrative, research has presented a complicated picture. When Leavitt and Christenfeld presented participants plot-crucial information to individuals before reading a short story, the story was subsequently enjoyed as much as, or more than, unspoiled stories. Other research shows that these findings may be driven by an interaction of individual differences, such as need for cognition, rather than a broad spoiling effect. In Experiment 1, we tested if reported enjoyment of a narrative decreased even when participants were alerted to the presence of a plot spoiler, to extend previous findings for short stories while adding a condition informing participants beforehand that their short stories was being spoiled. Experiment 2 extended this methodology to full-length episodes of television. Our results were different from previously reported positive effects of spoilers and show that spoilers, under certain circumstances, have a negative effect on enjoyment for television but not short stories.
Rules of Disengagement: Negative Relationships and Interactions Between Adults and Youth
Authors: Buehler Kathleen , Sánchez Bernadette , Vaclavik Danielle , Rodriguez Elsa , Gray Tenè
Published: August 2018

This study examined the negative adult characteristics and practices that prohibit connection between youth and nonparental adults. Racially/ethnically diverse youth from five community-based out-of-school-time programs participated in focus groups on youth–adult relationships. Analyses revealed that the following adult characteristics and practices prohibited connection: (a) unengaging communication styles, (b) inappropriate behavior, (c) lack of respect, (d) contradictory expectations, and (e) adult-driven approaches. Participants also reported the negative psychological consequences of these practices: (a) decreased self-esteem, (b) decreased motivation, and (c) disconnect from adults. This study provides a unique contribution to the literature on negative youth–adult interactions and has implications for training programs for adults who work with youth to improve relationships and promote positive youth outcomes.
DCE-MR imaging of orbital lesions: diagnostic performance of the tumor flow residence time τ calculated by a multi-compartmental pharmacokinetic tumor model based on individual factors
Authors: Erb-Eigner Katharina , Asbach Patrick , Ro Sa-Ra , Haas Matthias , Bertelmann Eckart , Pietsch Hubertus , Schwenke Carsten , Taupitz Matthias , Denecke Timm , Hamm Bernd , Lawaczeck Rüdiger
Published: August 2018

Background

Differentiating benign from malignant orbital lesions by imaging and clinical presentation can be challenging.

Purpose

To differentiate benign from malignant orbital masses using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) based on tumor flow residence time τ calculated with the aid of a pharmacokinetic tumor model.

Material and Methods

Sixty patients with orbital masses were investigated by 3-T MRI including dynamic sequences. The signal intensity-time curve after i.v. contrast medium administration within lesions was approximated by Gd-concentration profiles on the basis of model calculations where the tumor is embedded in a whole-body kinetic model. One output of the model was tumor flow residence time τ, defined as the ratio of the tumor volume and the tumor blood flow rate. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic performance of τ. The results were compared with those of Ktrans, kep, ve, iAUC, and ADC.

Results

Thirty-one benign and 29 malignant orbital masses were identified (reference standard: histopathology, clinical characteristics). Mean τ was significantly longer for benign masses (94 ± 48 s) than for malignant masses (21 ± 19 s, P < 0.001). ROC analysis revealed the highest area under the curve (AUC = 0.94) for τ in orbital masses compared to standard methods.

Conclusion

Tumor flow residence times τ of benign and malignant orbital masses are valuable in the diagnostic work-up of orbital tumors. Measures of diagnostic accuracy were superior for τ compared to ADC, Ktrans, ve, and iAUC.