bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-278: Whole exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component
Authors: Avigdor Bracha E. , Beierl Katie , Gocke Christopher D. , Zabransky Daniel J. , Cravero Karen , Kyker-Snowmana Kelly , Button Berry , Chu David , Croessmann Sarah , Cochran Rory L. , Connolly Roisin M. , Park Ben H. , Cimino-Mathews Ashley , Wheelan Sarah J.
Published: July 2017

Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma. Metaplastic breast carcinoma is a rare but aggressive cancer with a heterogenous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer, or one histology as a clonal outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions. We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in eight patients and created a pipeline to identify somatic variants and predict their functional impact in these samples, without having matched normal tissue. We then determined the genetic relationships between the histologically distinct compartments. In each case, the tumor components have nearly identical landscapes of somatic variation, implying that the differing histologies do not derive from genetic clonal divergence, suggesting that epigenetic or noncoding changes mediate the metaplastic phenotype. This indicates that alternative therapeutic approaches, including epigenetic therapies, may render metaplastic breast cancers susceptible to current and future therapies.

Citation Format: Bracha E. Avigdor, Katie Beierl, Christopher D. Gocke, Daniel J. Zabransky, Karen Cravero, Kelly Kyker-Snowmana, Berry Button, David Chu, Sarah Croessmann, Rory L. Cochran, Roisin M. Connolly, Ben H. Park, Ashley Cimino-Mathews, Sarah J. Wheelan. Whole exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-278. doi:10.1158/1538-7445.AM2017-LB-278
Abstract LB-300: In vivo evaluation of the intravenous MDM2-p53 antagonist RO6839921 alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma
Authors: Chen Lindi , Pastorino Fabio , Berry Philip , Bonner Jennifer , Wood Katrina , Veal Gareth , Ponzoni Mirco , Lunec John , Newell David R. , Tweddle Deborah A.
Published: July 2017

Background. Neuroblastoma is a predominantly TP53 wt tumor which supports the use of MDM2-p53 antagonists as a novel therapy for neuroblastoma patients. This is the first study to evaluate the efficacy of RO6839921, an IV prodrug of RG7388, alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma.

Methods. Studies were conducted using a well-established orthotopic model of neuroblastoma, implanted with SHSY5Y-Luc (TP53 wt; non-MYCN amplified) and NB1691-Luc (TP53 wt; MYCN and MDM2 amplified) cells, and randomized into control, intravenous RO6839921, oral temozolomide or RO6839921 and temozolomide in combination. Tumor growth was monitored using bioluminescence imaging. Active RG7388 in plasma and tumor samples were detected using liquid chromatography-mass spectrometry, and p53 pathway activation assessed by MIC-1 ELISA assays, Western analysis and/or immunohistochemistry for p53, p21 and cleaved caspase 3.

Results. Pharmacokinetic and pharmacodynamic analysis of RO6839921 observed peak plasma levels of active RG7388 at 1h posttreatment with maximal activation of the p53 pathway observed 3-6h posttreatment. RO6839921 had a favorable pharmacodynamic profile consistent with intermittent dosing. Assessment of anti-tumor efficacy demonstrated that RO6839921 was as effective as temozolomide and that RO6839921 in combination with temozolomide led to significantly greater tumor growth inhibition and survival than either agent given alone. RO6839921 alone and in combination with temozolomide was well tolerated.

Conclusions. These preclinical studies support the evaluation of combining RO6839921 with temozolomide in early phase clinical trials of neuroblastoma patients with wt TP53.

Citation Format: Lindi Chen, Fabio Pastorino, Philip Berry, Jennifer Bonner, Katrina Wood, Gareth Veal, Mirco Ponzoni, John Lunec, David R. Newell, Deborah A. Tweddle. In vivo evaluation of the intravenous MDM2-p53 antagonist RO6839921 alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-300. doi:10.1158/1538-7445.AM2017-LB-300
Abstract LB-307: Dissecting mutual exclusiveness of oncogenic mutations in melanoma
Authors: Kumar Raj , Njauw Ching-Ni-Jenny , Ji Zhenyu , Rajadurai Anpuchchelvi , Tsao Hensin
Published: July 2017

Mutual exclusiveness of oncogenes is a general phenomenon in cancer. Specifically in melanoma BRAF and NRAS mutations do not co-exist except a few (0.7%) cases. Here, we are looking for critical exclusive common target(s) of BRAF and NRAS mutations meant for synthetic lethality in melanoma therapy. To specifically evaluate BRAF and NRAS mutation dependent gene regulation in melanoma, mRNA microarray gene expression analysis was performed in melanoma cell lines where growth suppressive and non-suppressive properties depend on mutual targets of BRAFV600E and NRASQ61R/K mutation. We identified the tumor suppressor gene SPRY4 as a novel transcriptional target of second oncogenes BRAFV600E or NRASQ61R/K responsible for suppressive growth phenotype in various melanoma cell lines. Sprouty4 (SPRY4) acts as a feedback suppressor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. It has a role in the regulation of cell growth, motility and progression of various cancer types’ breast cancer, osteosarcoma, endometrial adenocarcinoma, myeloid leukemia including melanoma. Remote inducible expression of either BRAFV600E or NRASQ61R/K enhances the expression of SPRY4 at mRNA and protein level only in poor growth cell lines such as NRASQ61R (Tet-On BRAFV600E: SKmel119, WM1361 and BRAFV600E (Tet-On NRASQ61R: Gmel and MGH-CH-1) but not in NRASQ61R (Tet-On BRAFV600E: SKmel-63), BRAFV600E (Tet-On NRASVQ61R: A375) mutation. In addition, we observed that BRAFV600E expression exhibit constitutive activation of stress pathway signaling that is presumed to induce secondary senescence, as it does in nevi or normal cells. SPRY4 modify second oncogene induced changes such as inhibition of SPRY4 rescues cell growth impaired by BRAF or NRAS mutation expression. Hence, second oncogene enhances SPRY4 expression in part through stress pathway as confirmed by phospho kinase array. These findings suggest that in SPRY4/MAPK/Stress pathway, SPRY4 as a common target of BRAF and NRAS mutations affecting melanoma growth.

Citation Format: Raj Kumar, Ching-Ni-Jenny Njauw, Zhenyu Ji, Anpuchchelvi Rajadurai, Hensin Tsao. Dissecting mutual exclusiveness of oncogenic mutations in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-307. doi:10.1158/1538-7445.AM2017-LB-307
Abstract LB-311: Characterization of the antizyme/antizyme inhibitor protein-protein interaction using a novel FRET sensor
Authors: Rice James M. , Rogers Michael S. , Zetter Bruce R.
Published: July 2017

The protein-protein interaction (PPI) between the tumor suppressor antizyme (AZ) and its endogenous regulator antizyme inhibitor (AZIN) has recently been demonstrated to be important in several human cancers. AZIN siRNA treatment reduces AZIN expression and slows prostate cancer cell growth in vitro and in vivo but is not currently a viable therapeutic strategy. To further probe the AZ/AZIN PPI and to screen for potential small molecule inhibitors, we have developed a FRET assay (Z score >0.7) utilizing the Clover (donor) and mRuby2 (acceptor) fluorescent proteins linked to AZIN and AZ, respectively. An alanine mutant screen of 43 amino acid positions in the AZIN protein revealed 2 hotspots that dramatically affect the affinity for the AZ protein, thereby identifying key regions for disruption by potential therapeutics. Furthermore, mutating the N327 and Y331 positions in ornithine decarboxylase (ODC) to equivalent residues in the homologous AZIN protein, increased the affinity of ODC for AZ, providing evidence for key residues that contribute to AZ/AZIN PPI. In addition, the S367G AZIN mutation, which is associated with an mRNA editing event in hepatocellular carcinoma, further increases the affinity of AZIN for AZ and supports a mechanism of AZ sequestration as an important driver in cancer cell growth. Taken together, this data expands our current understanding of the contribution of different amino acid residues to the AZ/AZIN binding interaction. The development of small molecule inhibitors to target these regions of the AZIN protein would rescue the tumor suppressive activity of AZ and present a novel therapeutic opportunity for the treatment of prostate cancer and hepatocellular carcinoma.

Note: This abstract was not presented at the meeting.

Citation Format: James M. Rice, Michael S. Rogers, Bruce R. Zetter. Characterization of the antizyme/antizyme inhibitor protein-protein interaction using a novel FRET sensor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-311. doi:10.1158/1538-7445.AM2017-LB-311
Abstract LB-312: Breast cancer targeting by theranostic gold nanorods
Authors: Jenkins Samir V. , Nima Zeid A. , Vang Kieng B. , Nedosekin Dmitry , Zharov Vladimir P. , Griffin Robert J. , Biris Alexandru S. , Dings Ruud P.
Published: July 2017

An ongoing need for new cancer therapeutics exists, especially ones that specifically home and target triple negative breast cancer (TNBC) tumors. Because TNBC does not express estrogen, progesterone, or Her2/Neu receptors, another target must be used for advanced drug delivery strategies. Here, we engineered a nanodrug delivery system consisting of silver-coated gold nanorods targeting EpCAM and loaded with doxorubicin. This novel nanodrug system, EpCAM-AuNR/Ag/Dox, was found to specifically target EpCAM-expressing tumor cells compared to low EpCAM-expressing tumors. Namely, the system had an inhibiting cell viability effective dose (ED50) of 3μM on 4T1 cells and an ED50 of 110μM for MDA-MD-231 cells. Flow cytometry indicated that 4T1 cells, on average, express two orders of magnitude more EpCAM than MDA-MD-231 cells, which correlates with our ED50 findings. Moreover, due to its thin silver coating, the AuNR/Ag allowed for detection by surface-enhanced Raman spectroscopy (SERS) and photoacoustics (PA). Analysis by both imaging detection techniques showed that the targeted nanodrug system was taken up by EpCAM-expressing cells and tumors at significantly higher rates than untargeted nanoparticles (p<0.05). In conclusion, our novel approach establishes a plasmonically-active nanodrug therapeutic system for TNBC and, potentially, a delivery system with improved multimodal imaging capability for other clinically approved chemotherapeutics with dose-limiting toxicities, such as platinum-based or taxane-based therapies.

Citation Format: Samir V. Jenkins, Zeid A. Nima, Kieng B. Vang, Dmitry Nedosekin, Vladimir P. Zharov, Robert J. Griffin, Alexandru S. Biris, Ruud P. Dings. Breast cancer targeting by theranostic gold nanorods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-312. doi:10.1158/1538-7445.AM2017-LB-312
Abstract LB-324: Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness via targeting GRB7
Authors: Chen Kangmei , Ngan Hextan YS , Chan David W.
Published: July 2017

The human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. We and others have reported that GRB7 is frequently upregulated and associated with the progression of human cancers. Clinicopathological analysis has shown that the overexpressed GRB7 is correlated with high grade and metastatic ovarian cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. In this study, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in ovarian cancers. We found that the protein level of GRB7 was much higher than its mRNA levels in a subset of ovarian cancer cell lines, indicating aberrant post-transcriptional alterations in GRB7. Using an in silico study, we identified miR-193a-3p and its isoform, miR-193b-3p, by specifically targeting the conserved site (GGCCAGT) at position 332-338 in the 3’ UTR (length: 387) of the human GRB7 gene. QPCR and western blot analyses revealed that only the expression levels of miR-193a-3p but not miR-193b-3p were inversely correlated in ovarian cancer cell lines accompanied with high levels of GRB7 protein levels. Further biochemical analyses using luciferase reporter assays in combination with mutational analyses identified miR-193a-3p specifically targeting GRB7 3’UTR, confirming miR-193a-3p, instead of its isoform miR-193b-3p, has a more important role in GRB7 post-transcriptional regulation in ovarian cancer cells. Constitutive expression or knockdown of miR-193a-3p could significantly alter GRB7 expression, as well as oncogenic capacities of ovarian cancer cells such as cell growth, cell migration and cell invasion. Importantly, we observed that there was a significant stepwise decrease of miR-193a-3p expression from low to high grade ovarian cancers, and was inversely correlated with GRB7 expressions. Intriguingly, treatment with the DNA methyl transferase inhibitor (5’-Aza-dc) could restore the expression of miR-193a-3p, suggesting the epigenetic inhibition of miR-193a-3p is clinically relevant. Importantly, such epigenetic alteration may be the clue leading to overexpression of GRB7 in ovarian cancer cells. Taken together, our findings suggest that epigenetically silencing of miR-193a-3p upregulates GRB7 and contribute to ovarian cancer aggressiveness in tumor progression.

Citation Format: Kangmei Chen, Hextan YS Ngan, David W. Chan. Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness via targeting GRB7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-324. doi:10.1158/1538-7445.AM2017-LB-324
Abstract LB-333: Lymphatic endothelium increases antioxidant capacity of triple-negative breast cancer cells and protects from cell death
Authors: Berisa Mirela , Podgrabinska Simona , Chipuk Jerry , Skobe Mihaela
Published: July 2017

Involvement of lymphatic system with cancer and the extent of lymph node metastases are directly correlated with the poor patient outcome. However, it is not understood whether the presence of lymphatic metastases is only indicative of an aggressive cancer or if the lymphatic vessel microenvironment directly contributes to the metastatic progression. We demonstrate that soluble factors produced by lymphatic endothelial cells (LECs) protect triple negative breast cancer cells from cell death in vitro. Co-culture with LECs or LEC-conditioned medium (LEC-CM) protected cancer cells from death induced by the loss of homotypic cell adhesion, nutrient deprivation, or loss of matrix attachment. High levels of reactive oxygen species (ROS) preceded cell death, and were significantly decreased in tumor cells upon treatment with LEC-CM. Furthermore, LEC-CM protected tumor cells from death induced by exogenous oxidative stress (H2O2), while treatment with the anti-oxidant N-acetyl-cysteine (NAC) recapitulated the cytoprotective effect of LEC-CM. RNA-Seq analysis revealed Nrf2 pathway as the most upregulated stress-pathway induced in tumor cells upon loss of adhesion. Nrf2 and other stress signaling pathways were significantly diminished in the presence of LEC-CM. Pharmacological inhibition of the pentose phosphate pathway (PPP) and the components of thioredoxin and glutathione scavanging systems increased ROS and cell death in LEC-CM indicating that the maintenance of redox homeostasis and cell viability by LEC-CM is dependent on the PPP pathway and in particular thioredoxin system. Furthermore, LEC-CM preserved integrity and function of mitochondria. These results demonstrate that soluble factors produced by lymphatic endothelium promote survival of triple-negative breast cancer cells under stress by regulating tumor cell redox homeostasis and promoting mitochondrial function.

Citation Format: Mirela Berisa, Simona Podgrabinska, Jerry Chipuk, Mihaela Skobe. Lymphatic endothelium increases antioxidant capacity of triple-negative breast cancer cells and protects from cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-333. doi:10.1158/1538-7445.AM2017-LB-333
Abstract SY03-02: Preclinical assessment of JTX-2011, an agonist antibody targeting ICOS, supports evaluation in ICONIC clinical trial
Authors: Michaelson Jennifer S. , Harvey Christopher , Elpek Kutlu , Duong Ellen , Shallberg Lindsey , Wallace Matthew , Mabry Robert , Shu Jenny , Deshpande Amit , Zi Tong , Sazinsky Stephen , Apgar Joshua , Mounho-Zamora Barbara , Briskin Michael , Trehu Elizabeth , Reeves Jason , Hirsch Heather , Sathyanarayanan Sriram , Law Deborah
Published: July 2017

ICOS (the inducible T-cell co-stimulator) is a co-stimulatory molecule expressed on the surface of T cells and a member of the CD28 family, which includes clinically validated targets of cancer immunotherapies, such as PD-1 and CTLA-4. Clinical data identified ICOS as a potentially key molecule in providing optimal antitumor benefit following anti-CTLA-4 therapy. We have developed a species cross-reactive humanized IgG1 agonist antibody, JTX-2011, that binds ICOS and is designed to induce an antitumor immune response. Our preclinical data suggest that JTX-2011 functions through a dual mechanism of action, by stimulating T effector cells (Teff) and depleting intratumoral T regulatory cells (Tregs). The ICOS antibody is efficacious as a single agent in mouse syngeneic tumor models and demonstrates enhanced activity when administered in combination with anti-PD-1. Single-agent activity in the preclinical models appears to correlate with ICOS expression, with greater efficacy observed in tumor models that exhibit a higher percentage of ICOS-expressing immune cell infiltrate. An integrated expression analysis of human tumors identified non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) as indications with higher percentages of ICOS-expressing cell infiltrate. Preclinical studies performed in rodent and monkeys evaluated safety, pharmacokinetics, and pharmacodynamics of JTX-2011 to inform the first in-human study. The ICONIC phase I/II clinical trial is currently ongoing for evaluation of JTX-2011 alone or in combination with the anti-PD-1 antibody Nivolumab in patients with advanced solid tumors and incorporates a patient enrichment strategy design based on the preclinical and translational findings.

Citation Format: Jennifer S. Michaelson, Christopher Harvey, Kutlu Elpek, Ellen Duong, Lindsey Shallberg, Matthew Wallace, Robert Mabry, Jenny Shu, Amit Deshpande, Tong Zi, Stephen Sazinsky, Joshua Apgar, Barbara Mounho-Zamora, Michael Briskin, Elizabeth Trehu, Jason Reeves, Heather Hirsch, Sriram Sathyanarayanan, Deborah Law. Preclinical assessment of JTX-2011, an agonist antibody targeting ICOS, supports evaluation in ICONIC clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY03-02. doi:10.1158/1538-7445.AM2017-SY03-02
Abstract SY23-03: How does HTLV-1 cause leukemia
Authors: Bangham Charles
Published: July 2017

The retrovirus human T-lymphotropic virus type 1 (HTLV-1) causes an aggressive, rapidly fatal malignancy of CD4+ T cells, called adult T-cell leukemia/lymphoma (ATL), in 5% of infected individuals. Recent evidence on the clonal diversity and molecular virology of HTLV-1 and on the host genetic and immune response is changing the understanding of oncogenesis in HTLV-1 infection. It was previously believed that HTLV-1 was latent in vivo and persisted by continuous oligoclonal proliferation of about 100 clones of HTLV-1-infected CD4+ T cells, and that this oligoclonal proliferation predisposed to the malignancy ATL. However, we have shown that a typical individual carries between 104 and 105 clones and that the proviral load–the chief correlate of disease–is determined by the number of clones, not by oligoclonal proliferation. The central challenge remains to explain the regulation of HTLV-1 latency in vivo and the role of the host immune response in determining the set-point proviral load and the risk of ATL. I propose here three hypotheses. First, that ATL results from the accumulation of replicative mutations in HTLV-1-infected T-cell clones that persist for decades, typically over 40 years. Second, that the quality of the host immune response, chiefly the CTL response, determines the size and clonal diversity of the HTLV-1 reservoir, the net proliferation rate of HTLV-1-infected T cells, and therefore the risk of ATL. Third, that abnormal chromatin looping in the host genome caused by HTLV-1 can deregulate host gene expression and so contribute to the risk of ATL.

Citation Format: Charles Bangham. How does HTLV-1 cause leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY23-03. doi:10.1158/1538-7445.AM2017-SY23-03
Abstract SY25-02: Antigenic strength vs. tumor microenvironment in determining cancer immunosurveillance
Authors: Vonderheide Robert H.
Published: July 2017

We evaluated immune surveillance in pancreatic ductal adenocarcinoma (PDA), which exhibits far fewer missense mutations and potential neoepitopes than classically described carcinogen-induced, highly mutated tumors. In contrast to these immunogenic tumor models from which the theory of elimination-equilibrium-escape was determined, we found no evidence for immunoediting in a mutant Kras-driven murine model of PDA. These tumors progress the same with or without a functional adaptive immune system, similar to other mouse tumors that have also been shown to grow independently of T cells. Tumors arising in T cell–depleted mice grew unchecked in immune-competent hosts. We further show that KPC pancreatic tumors have few if any predicted neoepitopes derived from somatic tumor missense mutations and that an immunoediting phenotype can be rescued by ectopic expression of a neoantigen (OVA) in the same tumor model. Thus, the manifestations of cancer immune surveillance in the KPC model depend on tumor antigenic strength; the lack of neoepitopes is not a consequence of immunoediting in this model. These findings suggest an alternative biologic mechanism in which tumor outgrowth reflects immune quiescence, which is linked to, and regulated by, poor tumor antigenicity—a conclusion with potential relevance to human cancers with a low burden of mutations and minimal neoepitopes.

Citation Format: Robert H. Vonderheide. Antigenic strength vs. tumor microenvironment in determining cancer immunosurveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY25-02. doi:10.1158/1538-7445.AM2017-SY25-02
Abstract SY33-01: Targeting metabolism to enhance immunotherapy
Authors: Powell Jonathan D. , Leone Robert , Englert Judd , Rais Rana , Slusher Barbara
Published: July 2017

The extraordinary proliferative capacity of cancer necessitates specialized metabolic programming on the part of cancer cells. Indeed, this specialized metabolism not only facilitates growth but also creates a hypoxic, acidic, nutrient-deprived tumor microenvironment able to thwart immune destruction. We hypothesized that by targeting tumor metabolism we could not only slow down tumor growth but also “condition” tumors to be more susceptible to immunotherapy. Inherent to the specialized metabolism of tumors is a markedly increased requirement for glutamine. To this end we have devised a novel glutamine antagonist that is delivered as an inert prodrug that is converted to the active drug by enzymatic activity, which is enriched in tumors. In syngeneic mouse models of cancer our prodrug (JHU-083) markedly inhibited tumor growth, leading to cure of mice after only 14 days of monotherapy. Importantly, targeting glutamine metabolism led to a decreased extracellular acidification rate (ECAR), decreased hypoxia, and increased nutrient availability. Furthermore, we observed decreases in MDSC and fibrocytes with a concomitant increase in inflammatory (TNF-producing) tumor-associated macrophages (TAMs). Likewise, there was an increase in the CD8:Treg ratio and in some tumors a decrease in PDL1 expression on both tumors and infiltrating immune cells. Most importantly, JHU-083 markedly enhanced the efficacy of immunotherapy in the form of checkpoint blockade, adoptive cellular therapy (ACT), and A2aR blockade. Overall our studies define a novel compound for targeting metabolism as a means of enhancing immunotherapy for cancer.

Citation Format: Jonathan D. Powell, Robert Leone, Judd Englert, Rana Rais, Barbara Slusher. Targeting metabolism to enhance immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY33-01. doi:10.1158/1538-7445.AM2017-SY33-01
Association of Blood Pressure Control Level With Left Ventricular Morphology and Function and With Subclinical Cerebrovascular Disease
Authors: Nakanishi Koki , Jin Zhezhen , Homma Shunichi , Elkind Mitchell S. V. , Rundek Tatjana , Tugcu Aylin , Sacco Ralph L. , Di Tullio Marco R.
Published: July 2017

Background

Left ventricular (
LV
) hypertrophy and subclinical cerebrovascular disease are early manifestations of cardiac and brain target organ damage caused by hypertension. This study aimed to investigate whether intensive office systolic blood pressure (
SBP
) control has beneficial effects on
LV
morphology and function and subclinical cerebrovascular disease in elderly patients with hypertension.

Methods and Results

We examined 420 patients treated for hypertension without history of heart failure and stroke from the
CABL
(Cardiovascular Abnormalities and Brain Lesions) study. All patients underwent 2‐dimensional echocardiographic examination and brain magnetic resonance imaging. Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume. Patients were divided into 3 groups: SBP <120 mm Hg (intensive control);
SBP
120 to 139 mm Hg (less intensive control); and
SBP
≥140 mm Hg (uncontrolled). Prevalence of
LV
hypertrophy and diastolic dysfunction were lowest in the intensive control, intermediate in the less intensive control, and highest in the uncontrolled groups (12.8%, 31.8%, and 44.7%, respectively [
P
<0.001], for
LV
hypertrophy; 46.8%, 61.7%, and 72.6%, respectively [
P
=0.003], for diastolic dysfunction). Patients with less intensive
SBP
control had greater risk of
LV
hypertrophy than those with intensive control (adjusted odds ratio, 3.26;
P
=0.013). A similar trend was observed for
LV
diastolic dysfunction but did not reach statistical significance (adjusted odds ratio, 1.65;
P
=0.144). Conversely, intensive
SBP
control was not significantly associated with reduced risk of silent brain infarcts and white matter hyperintensity volume compared with less intensive control.

Conclusions

Compared with less intensive control, intensive
SBP
control may have a stronger beneficial effect on cardiac than cerebral subclinical disease.
Influence of Pycnocline Smoothing and Subgrid-Scale Variability of Density Profiles on the Determination of Mixed Layer Depth
Authors: Ok Hyejin , Noh Yign , Choi Yeonju
Published: July 2017

This study investigates how pycnocline smoothing and subgrid-scale variability of density profiles influence the determination of the mixed layer depth (MLD) in the global ocean, and applies the results of analysis to assess the ability of ocean general circulation models (OGCM) to simulate the MLD. For this purpose, individual, monthly mean, and climatological profiles are analyzed over a horizontal resolution of 1° × 1° for both observation data (Argo) and eddy-resolving OGCM (OFES) results. It is found that the MLDs from averaged profiles are generally smaller than those from individual profiles because of pycnocline smoothing induced by the averaging process. A correlation is found between the decrease in MLD Δh and the increase in pycnocline thickness Δδ of averaged profiles, except during winter in the high-latitude ocean. The relation is estimated as Δh = −αΔδ − β, where α ≃ 0.7 in all cases, but β increases with the subgrid-scale variability of density profiles. A correlation is also found between Δh and the standard deviation of the MLD within a grid. The results are applied to estimate how much of the MLD bias of OFES is due to prediction error and how much is due to profile error, induced by different pycnocline smoothing and the subgrid-scale variability of density profiles. The study also shows how profile error varies with the threshold density difference criterion.
Characterizing the Structure and Phase Transformation of Poly(ethylene Oxide)–Urea Complexes Using Terahertz Time-Domain Spectroscopy
Authors: Ye Hai-Mu , Li Han , Yao Shu-Fang
Published: July 2017

Terahertz time-domain spectroscopy (THz-TDS) was employed to characterize the structure and α→β phase transformation of poly(ethylene oxide) (PEO)–urea complexes. While the THz responses of α- and β-form complexes are both originated from hydrogen bonding interactions, they possess different THz absorption bands. The α-form PEO–urea complex shows two bands at 1.12 and 1.24 THz, which are vibration modes due to the hydrogen bonding among urea and between PEO and urea, respectively; the β-form PEO–urea complex shows a band at 1.48 THz, which is a vibration mode due to the hydrogen bonding among urea. A polarized THz-TDS study demonstrates that the urea–urea hydrogen bonding direction rotates 90° during the β→α transformation process. This study reveals the great potential of THz-TDS for investigating polymer–small molecule complexes.
Global risk governance: what role for public administrations: the paradigm of the EU food safety control and alert systems
Authors: Iurato Andrea
Published: July 2017

This study explores crucial issues arising from the increasing establishment of supranational risk-governance systems that pursue a compromise between the need for effective governance and the necessity to avoid obstacles regarding trade. In these contexts, national public administrations become a peripheral module in a multilevel system where they see their organization altered and the legitimacy of their actions questioned. The analysis uses as a paradigm the systems on food safety controls and rapid alert in the EU and tries to answer the following questions: How do we give public administrations an effective role in the global scene? Are national administrations destined to become mere executors of supranational-set rules? Outcomes show that legal systems whose multilevel integration reached a high level suggest positive implications deriving from a new model of global governance not involving a reduction in state sovereignty, but leading it to a new role, guaranteeing the accomplishment of supranational-set goals and safeguarding the autonomy of national public administrations.

Points for practitioners

Practitioners, especially those who hold managerial positions, may often find themselves disoriented when acting in a multilevel context because of the shrinking of their autonomy as well as their submission to external rules and controls. Starting from the analysis of the elected paradigm, practitioners could find that in a well-functioning multilevel regulatory system, national public administrations are able to use their remaining range of discretion, even if minimal, in order to realize innovative organizational models, through which they may avoid direct intervention from upper levels and propose themselves as a model to be borrowed and applied in the whole system.
Carbon/epoxy filament wound composite drive shafts under torsion and compression
Authors: Stedile Filho Paulo , Almeida José Humberto S , Amico Sandro C
Published: July 2017

Composite cylinders to be used as half shafts must satisfy several requirements, such as critical speed, critical buckling torque, and load carrying ability. This study focused on the investigation of carbon fiber reinforced epoxy composite cylinders produced by filament winding to be used as half shafts. A preliminary torsional test in a [±45]5 cylinder was performed and three other laminates were chosen for the study: [±22/±45], [±89/±45], and [±45/±45]. Radial and longitudinal compression tests were performed. Mechanical analysis has been carried out using analytical and numerical approaches, and good correlation was found between them and the experimental values. The [±45/±45] cylinder showed the best performance under torsional loading, as expected, as well as radial and longitudinal compression, but not critical buckling torque.
Glass fibers/SiCp reinforced epoxy composites: Effect of environmental conditions
Authors: Antil Parvesh , Singh Sarbjit , Manna Alakesh
Published: July 2017

The acceptability of polymer-based composite materials is increasing with time due to superior mechanical and chemical properties. Still, scope of advancement in mechanical behavior of these materials motivated research fraternity to develop new materials. The present article aims to analyze the effect of environment conditions on newly fabricated glass fiber epoxy composites reinforced with variable SiC particles as secondary reinforcement. The evaluation of mechanical strength and effect of environmental conditions on composite performance was analyzed using tensile, compression, flexural, and impact strength testing on universal testing machine. The mechanical strength characterization demonstrated the effect of size and weight fraction of reinforced SiC particles on mechanical strength of composites. The surface morphology of samples was examined by field emission scanning electron microscopy with energy dispersive spectroscopy. Based on mechanical strength evaluation results, an exponential equation was developed to predict the composite life.
“Sound Finances”: Strategy or Soundbite
Authors: McMahon Michael
Published: July 2017

A defining feature of (at least) the last three general elections has been the emphasis placed on each political party's fiscal credibility and their ability to deliver “sound public finances”. Applying the logic of household book-keeping, balancing the fiscal budget is said to capture such soundness. There is, however, little evidence that a balanced budget is necessarily sound. Instead, the evolution of public finances depends on (1) both the fiscal choices made on the level of spending and taxation, (2) the underlying growth of the economy which depends on far more than the fiscal decisions, and (3) interest rates on government debt and the financing needs of the government. As the economic situation changes, so too does the likely path of debt to GDP and hence the possible fiscal options open to a country. Sticking to the soundbite of “sound finances” has often distracted from the underlying menu of political choices and as such is a disruptive narrative in UK economics today.
Building on Incomplete Foundations: Financial Stability Policy since the Crash
Authors: Barwell Richard
Published: July 2017

Economists understand that a fit for purpose policy regime requires a reliable general equilibrium model of the system in question and a well specified description of the objectives that the policymaker is trying to pursue. The current financial stability regime has neither and without these critical foundations the regime is fundamentally fragile and incomplete. There is no anchor on the conduct of policy, an absence in genuine accountability and, as a result, reputational risks for policy institutions.
Unwinding: A Tale of Corridors and Floors
Authors: Farmer Roger E.A.
Published: July 2017

I discuss six tools available to monetary policy makers. Three of these have been used since the inception of central banking. Three are new and were introduced in the aftermath of the 2008 financial crisis. I argue that, when the UK Monetary Policy Committee raises the interest rate, it should maintain a large balance sheet that consists of both risky and safe assets. Further, the Bank should trade the risk composition of its balance sheet to promote the stability of asset prices.
Market-friendly agricultural development: Implications for seeds and smallholders in Sub-Saharan Africa
Authors: Sutcliffe Chloe
Published: July 2017

Across Sub-Saharan Africa, efforts to produce and supply the agricultural technologies that are expected to intensify smallholder agricultural production are strongly market-oriented. Here, the case of maize seeds in Malawi provides new insights into some of the implications of this orientation. Malawi presents a context where market liberalization coupled with a national input subsidy programme has led to the growth of corporate power within the formal maize seed system and a strong reliance upon commercial providers to breed, multiply and diffuse new cultivars. At both the local and national levels, facets of this market-orientation mean that poverty reduction and climate change adaptation goals may not be met. In order to address these potential shortcomings, multiple measures are required. Institutions are needed to oversee the coordination of appropriate breeding and marketing efforts by corporate actors within the formal seed system; research programmes are required which can enhance understandings of genetic evolution within farmer-saved varieties and its implications for climate resilience; and policies must be carefully implemented which can support market participation by the poorest.
Relative Age Effect in Physical Fitness Among Elementary and Junior High School Students
Authors: Nakata Hiroki , Akido Miki , Naruse Kumi , Fujiwara Motoko
Published: July 2017

The present study investigated characteristics of the relative age effect (RAE) among a general sample of Japanese elementary and junior high school students. Japan applies a unique annual age-grouping by birthdates between April 1 and March 31 of the following year for sport and education. Anthropometric and physical fitness data were obtained from 3,610 Japanese students, including height, weight, the 50-m sprint, standing long jump, grip strength, bent-leg sit-ups, sit and reach, side steps, 20-m shuttle run, and ball throw. We examined RAE-related differences in these data using a one-way analysis of variance by comparing students with birthdates in the first (April–September) versus second (October–March of the following year) semesters. We observed a significant RAE for boys aged 7 to 15 years on both anthropometric and fitness data, but a significant RAE for girls was only evident for physical fitness tests among elementary school and not junior high school students. Thus, a significant RAE in anthropometry and physical fitness was evident in a general sample of school children, and there were RAE gender differences among adolescents.
Spirituality in Rehabilitation Counseling of Adults With Physical Disabilities: Views of Practitioners Across Countries
Authors: Pandya Samta P.
Published: July 2017

The purpose of the study is to understand the views of practitioners across countries, on spirituality for rehabilitation counseling of adults with congenital and acquired disabilities. A survey of 1,269 practitioners in the field of disability across 15 countries was conducted. Results showed that practitioners had a favorable view of spirituality. Logistic regression results highlight several cross-country nuances in practitioners’ views toward spirituality for rehabilitation counseling, and more so, differentials in terms of adults with congenital and acquired physical disabilities. Practitioners who focused on a client-centered approach vis-à-vis those who diversified also into macro-level work of networking and advocacy, and specifically those who had high self-reported spirituality, proposed that for adults with congenital physical disabilities, spirituality enabled living with disabilities, as against a rationalization and justification of the disability. They favored mindfulness techniques as the modes of working with the clients and reported that by cultivating relational consciousness, spirituality enabled meeting the social goal of rehabilitation counseling. Furthermore, practitioners from affluent nations placed a premium on the deconstructing potential of spirituality and its facilitative role in enabling the clients themselves, and significant others, to transcend the ability/disability binary. The study foregrounds the importance of spiritually sensitive approaches in rehabilitation counseling.
An agent-based model of school closing in under-vaccinated communities during measles outbreaks
Authors: Getz Wayne M , Carlson Colin , Dougherty Eric , Porco Travis C , Salter Richard
Published: July 2017

The winter 2014–15 measles outbreak in the United States represents a significant crisis in the emergence of a functionally extirpated pathogen. Conclusively linking this outbreak to decreases in the measles, mumps, and rubella (MMR) vaccination rate (driven by anti-vaccine sentiment) is critical to motivating MMR vaccination. We used the NOVA modeling platform to build a stochastic, spatially-structured, individual-based SEIR model of outbreaks, under the assumption that [Formula: see text] for measles. We show this implies that herd immunity requires vaccination coverage of greater than approximately 85%. We used a network structured version of our NOVA model that involved two communities, one at the relatively low coverage of 85% coverage and one at the higher coverage of 95%, both of which had 400-student schools embedded, as well as students occasionally visiting superspreading sites (e.g., high-density theme parks, and cinemas). These two vaccination coverage levels are within the range of values occurring across Californian counties. Transmission rates at schools and superspreading sites were arbitrarily set to respectively 5 and 15 times the background community rates. Simulations of our model demonstrate that a ‘send unvaccinated students home’ policy in low coverage counties is extremely effective at shutting down outbreaks of measles.
Physicochemical properties of keratin extracted from wool by various methods
Authors: Rajabinejad Hossein , Zoccola Marina , Patrucco Alessia , Montarsolo Alessio , Rovero Giorgio , Tonin Claudio
Published: July 2017

Keratin from wool fibers was extracted with different extraction methods, for example oxidation, reduction, sulfitolysis, and superheated water hydrolysis.

Different samples of extracted keratin were characterized by molecular weight determination, FT-IR and NIR spectroscopy, amino acid analysis, and thermal behavior.

While using oxidation, reduction, and sulfitolysis, only the cleavage of disulfide bonds takes place; keratin hydrolysis leads to the breaking of peptide bonds with the formation of low molecular weight proteins and peptides. In the FT-IR spectra of keratoses, the formation of cysteic acid appears, as well as the formation of Bunte salts (–S–SO3–) after the cleavage of disulfide bonds by sulfitolysis. The amino acid composition confirms the transformation of amino acid cystine, which is totally converted into cysteic acid following oxidative extraction and almost completely destroyed during superheated water hydrolysis. Thermal behavior shows that keratoses, which are characterized by stronger ionic interaction and higher molecular weight, are the most temperature stable keratin, while hydrolyzed wool shows a poor thermal stability.
Organizing Solidarity Initiatives: A Socio-spatial Conceptualization of Resistance
Authors: Daskalaki Maria , Kokkinidis George
Published: July 2017

This paper offers a spatial conceptualization of resistance by focusing on the practices through which solidarity initiatives constitute new resistance socio-spatialities. We discuss two solidarity initiatives in Greece, WCNA and Vio.Me.SI, and explore how they institute distinctive local and translocal organizational practices that make the production of new forms of resistance possible. In particular, we adopt a productive and transformative view of resistance. First, we identify three local practices of organizing solidarity initiatives, namely, the organization of general assembly meetings, the constitution of resistance laboratories and the (re)articulation of socio-spatial relations in local sites. Then, we turn to flows, movements and translocal social formations, and examine the role of solidarity mobilizations, the material and symbolic co-production of resources and members’ mobility in the production of resistance. We conclude that new resistance socio-spatialities become constitutive of a broader reconfiguration of political agencies, a creative process that challenges existing relations and invites alternative ways of working and organizing.
The Aesthetics of Entrepreneurship: How Arts Entrepreneurs and their Customers Co-create Aesthetic Value
Authors: Elias Sara R. S. T. A. , Chiles Todd H. , Duncan Carrie M. , Vultee Denise M.
Published: July 2017

Despite the fundamental role customers play in entrepreneurial creation processes, little is known about how value emerges from interactions and collaborations between entrepreneurs and their customers. We begin to address this question by exploring the relational and embodied processes through which entrepreneurs and their customers interact to co-create aesthetic value. On the basis of an 11-month multi-sited micro-ethnography of arts entrepreneurs, we abductively derive three interrelated processes: imagining, contemplating, and consensus building. Our key insight is that the customer plays a vital role throughout the entrepreneurial creation process: neither the entrepreneur nor the customer has the final say; rather, their embodied experiences combine with an evolving product to co-create aesthetic value.