bluuebunny/crossref_metadata_2025 huggingface dataset:
Interrogating the provenance of large river systems: multi-proxy
in situ
analyses in the Millstone Grit, Yorkshire
Authors: Lancaster Penelope J. , Daly J. Stephen , Storey Craig D. , Morton Andrew C.
Published: October 2016

Establishing the source(s) of sedimentary material is critical to many geological applications, but is complicated by the ability of some minerals to be recycled. To test the relative utility of current proxies for determining a unique provenance, new samples have been collected from the Namurian Millstone Grit Group of Yorkshire, England. Two K-feldspar
206
Pb/
204
Pb isotope populations between 12.5 and 15.5 and
c.
18.4 are consistent with Archaean–Proterozoic basement and Caledonian granites, respectively. Zircon U–Pb age populations at
c.
2700, 2000 – 1000 and 430 Ma reflect a mixture of Archaean basement, overlying Proterozoic sediments and intrusive Caledonian granites, and εHf values in zircons of all ages indicate crystallization from reworked crust. Garnet major element compositions are relatively rich in Fe and low in Ca, indicative of derivation from a granulitic or charnockitic source. Rutile Cr/Nb ratios indicate that source rocks were dominantly metapelitic, and Zr-in-rutile thermometry records two populations representing lower (
c.
650°C) and higher (
c.
800°C) metamorphic grade material. Combining these results with published monazite and muscovite data suggests overall derivation from the Greenland Caledonides, with additional contributions from NE Scotland and western Norway, highlighting the power of multi-proxy provenance work, especially in tectonically and geologically complicated regions.

Supplementary material
: Sample details, full analytical methods, data tables and references for compilation figures in the text are available at
https://doi.org/10.6084/m9.figshare.c.3515457
.
Synthesis of Hollow ZnSnO3 Nanospheres with High Ethanol Sensing Properties
Authors: Wang Qiong , Yao Na , Liu Chen , An Dongmin , Li Yan , Zou Yunling , Tong Xiaoqiang
Published: October 2016

Hollow ZnSnO3 nanospheres were synthesized by a hydrothermal method using ZnO nanospheres as the hard template and raw material simultaneously. The combined characterizations of X-ray diffraction (XRD), scanning electron microscope (SEM) and high-resolution transmission electron microscopy (HRTEM) confirmed the successful preparation of hollow ZnSnO3 nanospheres. The gas-sensing results indicated that the sensor made from hollow ZnSnO3 nanospheres exhibited high sensitivity, good selectivity, and stability to ethanol at a low operating temperature of 200°C. The sensitivity was about 32 and the response and recovery time were about 4 s and 30 s for 100 ppm ethanol, respectively. The enhancement in gas-sensing properties was attributed to the hollow nanostructures and high specific surface areas of ZnSnO3.
Vibration-Based Adaptive Novelty Detection Method for Monitoring Faults in a Kinematic Chain
Authors: Cariño-Corrales Jesus Adolfo , Saucedo-Dorantes Juan Jose , Zurita-Millán Daniel , Delgado-Prieto Miguel , Ortega-Redondo Juan Antonio , Alfredo Osornio-Rios Roque , de Jesus Romero-Troncoso Rene
Published: October 2016

This paper presents an adaptive novelty detection methodology applied to a kinematic chain for the monitoring of faults. The proposed approach has the premise that only information of the healthy operation of the machine is initially available and fault scenarios will eventually develop. This approach aims to cover some of the challenges presented when condition monitoring is applied under a continuous learning framework. The structure of the method is divided into two recursive stages: first, an offline stage for initialization and retraining of the feature reduction and novelty detection modules and, second, an online monitoring stage to continuously assess the condition of the machine. Contrary to classical static feature reduction approaches, the proposed method reformulates the features by employing first a Laplacian Score ranking and then the Fisher Score ranking for retraining. The proposed methodology is validated experimentally by monitoring the vibration measurements of a kinematic chain driven by an induction motor. Two faults are induced in the motor to validate the method performance to detect anomalies and adapt the feature reduction and novelty detection modules to the new information. The obtained results show the advantages of employing an adaptive approach for novelty detection and feature reduction making the proposed method suitable for industrial machinery diagnosis applications.
Prognostic Role of the Circulating Tumor Cells Detected by Cytological Methods in Gastric Cancer: A Meta-Analysis
Authors: Zou Kun , Yang Shuailong , Zheng Liang , Wang Shuyi , Xiong Bin
Published: October 2016

Objective. We performed a meta-analysis of available studies to assess the prognostic value of circulating tumor cells detected by cytological methods for patients with gastric cancer. Methods. Two authors systematically searched the studies independently with key words in PubMed, MEDLINE, EMBASE, Science Citation Index Expanded, and Cochrane Library (from inception to April 2016). The estimated hazard ratio, risk ratio, odds ratio, and their 95% confidence intervals were set as effect measures. All analyses were performed by STATA 12.0. Results. Sixteen studies were included in this meta-analysis. CTCs-high status was significantly associated with poor overall survival (HR=2.23, 95% CI: 1.86–2.66) and progression-free survival (HR=2.02, 95% CI: 1.36–2.99). CTCs-high status was also associated with depth of infiltration (OR = 2.07, 95% CI: 1.16–3.70), regional lymph nodes metastasis (OR = 1.85, 95% CI: 1.26–2.71), and distant metastasis (OR = 2.83, 95% CI: 1.77–4.52). For unresectable gastric cancer patients, CTCs-high status was significantly associated with poor overall survival, progression-free survival, and disease control rate before and during chemotherapy group. Conclusions. Our meta-analysis has evidenced the significant prognostic value of CTCs detected for both PFS and OS in gastric cancer patients. For patients treated with chemotherapy alone, we proved that CTCs detected by cytological method showed a significant prognostic value and poor response to chemotherapy.
Bearing Performance Degradation Assessment Using Lifting Wavelet Packet Symbolic Entropy and SVDD
Authors: Zhou Jianmin , Guo Huijuan , Zhang Long , Xu Qingyao , Li Hui
Published: October 2016

Bearing performance degradation assessment is of great significance for proactive maintenance and near-zero downtime. For this purpose, a novel assessment method is proposed based on lifting wavelet packet symbolic entropy (LWPSE) and support vector data description (SVDD). LWPSE is presented for feature extraction by jointing use of lifting wavelet packet transform and symbolic entropy. Firstly, the LWPSEs of bearing signals from normal bearing condition are extracted to train an SVDD model by fitting a tight hypersphere around normal samples. Then, the relative distance from the LWPSEs of testing signals to the hypersphere boundary is calculated as a quantitative index for bearing performance degradation assessment. The feasibility and efficiency of the proposed method were validated by the life-cycle data obtained from NASA’s prognostics data repository and the comparison with Hidden Markov Model (HMM). Finally, the assessment results were verified by the envelope spectrum analysis method based on empirical mode decomposition and Hilbert envelope demodulation.
A Note on First Passage Functionals for Lévy Processes with Jumps of Rational Laplace Transforms
Authors: Ait-Aoudia Djilali
Published: October 2016

This paper investigates the two-sided first exit problem for a jump process having jumps with rational Laplace transform. The corresponding boundary value problem is solved to obtain an explicit formula for the first passage functional. Also, we derive the distribution of the first passage time to two-sided barriers and the value at the first passage time.
Relationship between Interdialytic Weight Gain and Blood Pressure in Pediatric Patients on Chronic Hemodialysis
Authors: Marsenic Olivera , Anderson Michael , Couloures Kevin G.
Published: October 2016

Overhydration is reported to be the main cause of hypertension (HTN) as well as to have no association with HTN in hemodialysis (HD) population. This is the first report of the relationship between interdialytic weight gain (IDWG) and pre-HD blood pressure (BP) in pediatric patients in relation to residual urine output (RUO). We studied 170 HD sessions and interdialytic periods performed during a 12-week period in 5 patients [age 4–17 years, weight 20.8–66 kg, 3 anuric (102 HD sessions), and 2 nonanuric (68 HD sessions)]. BP is presented as systolic BP index (SBPI) and diastolic BP index (DBPI), calculated as systolic or diastolic BP/95th percentile for age, height, and gender. IDWG did not differ (P>0.05) between anuric and nonanuric pts. There was a positive but not significant correlation between IDWG and both pre-HD SBPI (r=0.833,P=0.080) and pre-HD DBPI (r=0.841,P=0.074). Pre-HD SBPI (1.01±0.12versus1.13±0.18) and DBPI (0.92±0.16versus1.01±0.24) were higher in nonanuric patents (P<0.001andP<0.01, resp.). Pre-HD HTN may not be solely related to IDWG and therapies beyond fluid removal may be needed. Individualized approach to HTN management is necessary in pediatric dialysis population.
Virtual Correlations in Single Qutrit
Authors: Strakhov Alexey A. , Man’ko Vladimir I.
Published: October 2016

We construct the positive invertible map of the mixed states of a single qutrit onto the antisymmetrized bipartite qutrit states (quasifermions). It is shown that using this one-to-one correspondence between qutrit states and states of two three-dimensional quasifermions one may attribute hidden entanglement to a single mixed state of qutrit.
Antibacterial Nanocomposites Based on Fe3O4–Ag Hybrid Nanoparticles and Natural Rubber-Polyethylene Blends
Authors: Ngo Thanh Dung , Le Thi My Hanh , Nguyen The Huu , Nguyen Thien Vuong , Nguyen Tuan Anh , Le Trong Lu , Nguyen Thi Thai , Tran Thi Thanh Van , Le Thi Bich Thao , Doan Ngoc Hai
Published: October 2016

For the vulcanized natural rubber (NR), incorporation of silver nanoparticles (AgNPs) into the NR matrix did not exhibit the bactericidal property against Escherichia coli (E. coli). However, incorporation of AgNPs into polyethylene (PE) matrix showed good antibacterial activities to both Gram-negative and Gram-positive bacteria. In the present work, NR/PE (85/15) blends have been prepared by melt blending with presence of compatibilizer in an internal mixer. To possess antibacterial property, AgNPs (5–10 nm) or Fe3O4–Ag hybrid nanoparticles (FAgNPs, 8 nm/16 nm) were added into PE matrix before its blending with NR component. The tensile test indicated that the presence of compatibilizer in NR/PE blend significantly enhanced the tensile strength and elongation at break (up to 35% and 38% increases, resp.). The antibacterial activity test was performed by monitoring of the bacterial lag-log growth phases with the presence of nanocomposites in the E. coli cell culture reactor. The antibacterial test showed that the presence of FAgNPs in NR/PE blend had a better antibacterial activity than that obtained with the lone AgNPs. Two similar reasons were proposed: (i) the faster Ag+ release rate from the Fe3O4–Ag hybrid nanoparticles due to the electron transfer from AgNP to Fe3O4 nanoparticle and (ii) the fact that the ionization of AgNPs in hybrid nanostructure might be accelerated by Fe3+ ions.
miR-155 Regulated Inflammation Response by the SOCS1-STAT3-PDCD4 Axis in Atherogenesis
Authors: Ye Jinshan , Guo Ruiwei , Shi Yankun , Qi Feng , Guo Chuanming , Yang Lixia
Published: October 2016

Inflammation response plays a critical role in all phases of atherosclerosis (AS). Increased evidence has demonstrated that miR-155 mediates inflammatory mediators in macrophages to promote plaque formation and rupture. However, the precise mechanism of miR-155 remains unclear in AS. Here, we also found that miR-155 and PDCD4 were elevated in the aortic tissue of atherosclerotic mice and ox-LDL treated RAW264.7 cells. Further studies showed that miR-155 not only directly inhibited SOCS1 expression, but also increased the expression of p-STAT and PDCD4, as well as the production of proinflammation mediators IL-6 and TNF-α. Downregulation of miR-155 and PDCD4 and upregulation of SOCS1 obviously decreased the IL-6 and TNF-αexpression. In addition, inhibition of miR-155 levels in atherosclerotic mice could notably reduce the IL-6 and TNF-αlevel in plasma and aortic tissue, accompanied with increased p-STAT3 and PDCD4 and decreased SOCS1. Thus, miR-155 might mediate the inflammation in AS via the SOCS1-STAT3-PDCD4 axis. These results provide a rationale for intervention of intracellular miR-155 as possible antiatherosclerotic targets.
Short-Term Efficacy of Laparoscopic Treatment for Colorectal Cancer in Patients with Schistosomiasis Japonica
Authors: Yi Zhu , Hong-Gang Jiang , Zhi-Heng Chen , Bo-Hao Lu
Published: October 2016

Introduction. Schistosomiasis is associated with numerous complications such as thrombocytopenia, liver cirrhosis, portal hypertension, and colitis. To the best of our knowledge, the feasibility and outcomes of laparoscopic colorectal surgery in patients with schistosomiasis have not yet been studied.Methods. In this study, the data of 280 patients with colorectal carcinoma along with schistosomiasis japonica infection who underwent laparoscopic or open colorectal surgery were retrospectively analyzed. Preoperative data, operative data, pathological outcomes, postoperative complications, and recovery were compared between patients in the laparoscopic (LAC) and open (OC) groups.Results. There were no significant differences in the preoperative data between the groups. However, fewer postoperative complications, especially severe hypoproteinemia, early postoperative feeding, and shorter postoperative hospital stay, were observed in patients in the LAC group (P<0.001). The mean operative time was higher in the LAC group (180 min versus 158 min;P<0.001), while the mean blood loss was similar (95 mL versus 108 mL;P=0.196) between groups. The mean number of lymph nodes harvested was also similar in both groups (15 versus 16;P=0.133).Conclusion. Laparoscopic surgery for colorectal cancer is safe in patients with schistosomiasis japonica and has better short-term outcomes than open surgery.
Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer
Authors: Metelli Alessandra , Wu Bill X. , Fugle Caroline W. , Rachidi Saleh , Sun Shaoli , Zhang Yongliang , Wu Jennifer , Tomlinson Stephen , Howe Philip H. , Yang Yi , Garrett-Mayer Elizabeth , Liu Bei , Li Zihai
Published: October 2016

GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ, which is expressed naturally by platelets and regulatory T cells (Treg). Although Lrrc32 is amplified frequently in breast cancer, the expression and relevant functions of GARP in cancer have not been explored. Here, we report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGFβ in the tumor microenvironment. We found that human breast, lung, and colon cancers expressed GARP aberrantly. In genetic studies in normal mammary gland epithelial and carcinoma cells, GARP expression increased TGFβ bioactivity and promoted malignant transformation in immunodeficient mice. In breast carcinoma–bearing mice that were immunocompetent, GARP overexpression promoted Foxp3+ Treg activity, which in turn contributed to enhancing cancer progression and metastasis. Notably, administration of a GARP-specific mAb limited metastasis in an orthotopic model of human breast cancer. Overall, these results define the oncogenic effects of the GARP–TGFβ axis in the tumor microenvironment and suggest mechanisms that might be exploited for diagnostic and therapeutic purposes. Cancer Res; 76(24); 7106–17. ©2016 AACR.
Abstract A16: Expression of PD-L1 and BCG immunotherapy in non-muscle invasive bladder cancer
Authors: Heo Jun Hyeok , Jin Hyun A. , Kang You Hyun , Kim Ki Hong , Hong Sung Joon , Han Kyung Seok
Published: October 2016

Background: Immunotherapy based on BCG has been a standard therapy to prevent recurrence and progression in bladder cancer. Activation of immune checkpoints by binding PD-1 to its ligands, PD-L1, is vital for physiologic regulation of immune system.

Tumor cells can co-opt the PD-1 pathway to escape from immunosurveillance mechanism. We investigated expression of immune checkpoints and their effects on T cells in bladder cancer.

Methods: A panel of transitional cell carcinoma cell lines (UC-3,T24,KU1919 and 253J) and normal human bladder urothelial cells (SVHUC1) were used to evaluate expression of immune checkpoints. Western blot analysis was used for protein expressions from cell lines and qPCR for RNA expression from human bladder tissues. Human bladder cancer/normal paired tissues were obtained at two time points; surgical resection and then after BCG immunotherapy. Immunohistochemical staining was performed to assess infiltration and distribution of CD4+ and CD8+ T cells in bladder tumor tissues and normal bladder tissues. Immune cells were isolated and T cells were isolated by FACS sorting after immune cell isolation from tumor/normal tissues.

Results: PD-L1 proteins were highly expressed in bladder cancer cell lines compared to normal bladder epithelial cell line (SVHUC1). In paired human samples (cancer and normal tissues), PD-L1 were also highly expressed in bladder cancer tissues compared with paired normal tissues. Real time RT-PCR confirmed the high expression of PD-L1 in bladder cancer tissues. Interestingly, normal epithelial tissues regenerated after surgical resection of the tumor and BCG immunotherapy had low PD- after surgical resection and BCG immunotherapy while recurred tumor showed high expression of PD-L1. Isolation of TIL and immunohistochemical staining with CD4/CD8 showed that T cells were more infiltrated in bladder cancer tissues compared to paired normal tissues. Mouse bladder tumor model expressing PD-L1 showed increased CD3+CD4+ T cells and Treg cells.

Conclusion: PD-L1 are highly expressed in bladder cancer. CD3+CD4+ T cells and Treg cells are highly infiltrated in human and mouse bladder cancer tissues. Our data suggest that PD-L1 might be involved in tumor recurrence after BCG immunotherapy and might be a novel targets in bladder cancer.

Citation Format: Jun Hyeok Heo, Hyun A. Jin, You Hyun Kang, Ki Hong Kim, Sung Joon Hong, Kyung Seok Han. Expression of PD-L1 and BCG immunotherapy in non-muscle invasive bladder cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A16.
Abstract A17: An integrin agonist suppresses breast cancer by reducing CD11b+ leukocytes, promoting anti-tumor immunity
Authors: Khan Samia Q. , Faridi Mohd H. , Ruffell Brian , Lopez Ana M. S. , Jehangir Shehryar , Barbosa Antonio J. , Torroella-Kouri Marta , Coussens Lisa M. , Varner Judith , Gupta Vineet
Published: October 2016

Breast cancer remains the second highest cancer-related cause of death in women today. Neoadjuvant therapies reduce tumor size in patients but long-term survival remains poor. Tumor microenvironment shows a significant infiltration of CD11b+ tumor associated macrophages (TAMs) that promote tumor growth and metastases, while suppressing T-cell mediated anti-tumor immunity, suggesting that reducing infiltration of CD11b+ TAMs could have a therapeutic benefit. We recently developed a novel small molecule that targets CD11b+ cells and reduces their migration and tissue recruitment. Unlike previously described strategies, our methodology involves allosteric activation of CD11b, which induces transient increase in adhesion of CD11b+ cells to the vascular endothelium, thereby reducing the ability of the myeloid cells to transmigrate out of circulation and suppressing their recruitment into tumor and inflamed tissues. However, it is currently not known as to whether small molecule mediated CD11b activation can reduce TAM infiltration in tumors and whether that will have a therapeutic benefit. Here, we present results from studies with our lead compound leukadherin1 (LA1) in murine models of breast cancer. Our studies show that treatment of established syngeneic Cl66 orthotopic breast tumors in Balb/c mice with LA1 significantly reduces tumor growth and increases survival. LA1 treatment significantly reduced infiltration of CD11b+ cells into the tumor stroma, without affecting the levels of cells in circulation. LA1 treatment also significantly reduced expression of molecules that promote angiogenesis and tumor growth including MMP9, S100A8 and ARG1 that coincided with decreased CD31 and α-SMA, suggesting tumor vasculature disruption. Immune cell profiling revealed that LA1 treatment further promotes anti-tumor immunity by increasing the influx of cytotoxic CD8+ T cells into tumors. These data provide a rationale for using allosteric CD11b agonists to target TAM recruitment as a novel therapeutic approach for breast cancer.

Citation Format: Samia Q. Khan, Mohd H. Faridi, Brian Ruffell, Ana M. S. Lopez, Shehryar Jehangir, Antonio J. Barbosa, Marta Torroella-Kouri, Lisa M. Coussens, Judith Varner, Vineet Gupta. An integrin agonist suppresses breast cancer by reducing CD11b+ leukocytes, promoting anti-tumor immunity. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A17.
Abstract A26: The RON tyrosine kinase accelerates pancreatic duct neoplasia and activates a positive autocrine/paracrine signaling loop that promotes alternative macrophage activation
Authors: Babicky Michele L. , Harper Megan M. , Mose Evangeline S. , Jaquish Dawn J. , French Randall P. , Waltz Susan E.
Published: October 2016

Introduction: The RON (receptor d'origine nantais) tyrosine kinase is overexpressed in >80% of human pancreatic cancers, but its effect on pancreatic carcinogenesis is largely unknown.

Methods: We developed a transgenic mouse that overexpresses RON specifically in the pancreas (Pdx-1-RON). Additionally, we utilized an existing transgenic mouse with a functionally inactive RON tyrosine kinase domain (Pdx-1-RTK-/-). These strains were crossed with the established CK murine model of pancreatic cancer yielding compound strains, RCK and CK/TK-/-. We performed immunofluorescent staining, flow cytometry, and western blot analysis on the tissues from these animals to study the effects of RON overexpression and the loss of RON signaling in the setting of oncogenic Kras.

Results: RON overexpression results in increased acinar-ductal metaplasia, accelerates PanIN progression to invasive cancer, and results in an accumulation of alternatively-activated (MRC1+) macrophages in the tumor microenvironment. We found that RON overexpression results in upregulation of its own ligand, macrophage-stimulating protein (MSP), activating a positive autocrine/paracrine signaling loop that effects tumor growth and the differentiation of tumor-associated macrophages. Knockdown of RON expression and/or MSP expression results in decreased tumor growth in vivo. Additionally, loss of RON signaling in CK/TK-/- mice leads to a profound decrease in alternatively-activated (MRC1+) macrophages in the tumor microenvironment. In contrast, these animals demonstrate an accumulation of classically activated (CD11c+) macrophages. RON signaling is also associated with downregulation of the chemokine, monocyte chemoattractant protein-1 (MCP-1), a known driver of CD11c+ macrophage activation. The correlation of RON and MSP and the inverse correlation with MCP-1 expression were validated in a database analysis of human pancreatic tumor specimens.

Conclusion: Our studies demonstrate that murine RON overexpression accelerates the development of invasive pancreatic cancer in the setting of oncogenic Kras. Active RON signaling results in upregulation of its own ligand, MSP, initiating a positive autocrine/paracrine feedback loop that promotes tumor growth and alters the differentiation of macrophages in the tumor microenvironment.

Citation Format: Michele L. Babicky, Megan M. Harper, Evangeline S. Mose, Dawn J. Jaquish, Randall P. French, Susan E. Waltz. The RON tyrosine kinase accelerates pancreatic duct neoplasia and activates a positive autocrine/paracrine signaling loop that promotes alternative macrophage activation. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A26.
Abstract A29: Effects of obesity on regulation of macrophage population in the prostate tumor microenvironment
Authors: Galvan Gloria C. , Apte Shruti , deGraffenried Linda A.
Published: October 2016

Background: Obesity is associated with a greater risk of prostate cancer mortality, but the mechanisms driving this progression are still unclear. A high concentration of macrophages within the tumor microenvironment, especially tumor-associated macrophages (TAMs), has been linked to progression and metastasis in numerous cancer types, including prostate. Obesity increases circulating levels of monocyte chemotactic protein-1 (MCP-1), a chemokine involved in monocyte migration. In addition, prostaglandin E2 (PGE2), a molecule closely associated with obesity, appears to be involved in macrophage polarization. Our preliminary in vitro data suggest that obese conditions promote both macrophage recruitment and TAM polarization.

Hypothesis: Based upon these preliminary results, we hypothesize that obesity-induced prostate cancer progression is due, in part, to increased TAM concentrations in the prostate tumor micro-environment, promoting pro-metastatic signaling.

Methods: In order to mimic the prostate tumor microenvironment, an in vitro model composed of adipose stromal cells, macrophages, prostate cancer epithelial cells and sera from obese and non-obese men was used to assess the impact of obesity on the paracrine signaling network. Matrigel invasion chambers were used to assess macrophage recruitment. qPCR was used to measure mRNA levels of proteins associated with a TAM phenotype as well as mRNA levels of MCP-1 and cyclooxygenase-2 (COX-2), an enzyme involved in PGE2 production.

Results: Obese conditions resulted in increased macrophage recruitment and increased mRNA levels of TAM markers in macrophages. Furthermore, MCP-1 mRNA levels in adipose stromal cells and prostate cancer cells were higher under obese conditions compared to non-obese conditions. Similarly, obese conditions increased COX-2 mRNA levels in prostate cancer cells.

Conclusions: Data from our in vitro study suggest that obesity may promote macrophage infiltration into the prostate tumor microenvironment and play a role in macrophage polarization towards a tumor-associated phenotype. This study will potentially serve to determine the value of macrophage and TAM concentration as biomarkers in this patient population, and lay the foundation for future studies investigating whether this phenomenon might be an effective therapeutic target.

Citation Format: Gloria C. Galvan, Shruti Apte, Linda A. deGraffenried. Effects of obesity on regulation of macrophage population in the prostate tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A29.
Abstract B02: Oncogene MCT-1 deregulates oxidative metabolism and promotes tumor metastasis via YY1 signaling network
Authors: Tseng Hong-Yu , Chen Yen-An , Chen Yi-Rong , Hsu Hsin-Ling
Published: October 2016

The underlying mechanism of oncogene activation that induces reactive oxygen species (ROS) generation and promotes tumor progression and metastasis is still ambiguous. We now demonstrate that the oncogenic MCT-1 activation protects cells from oxidative damage via increase of YY1 and subsequently enhances EGFR expression and activation. Overexpressing MCT-1 induces cell invasion, intracellular ROS generation and MnSOD expression in mitochondria via YY1 pathway, thus targeting YY1 suppresses cancer cell invasion and blocks EGFR-MnSOD signaling function enhanced by MCT-1. Recapitulating in vitro outcomes, MCT-1 increment promotes tumor angiogenesis, necrosis and metastasis with oxidative metabolism deregulation and malignant microenvironment development in xenograft mice. Clinical data also confirms that MCT-1 enrichment connects to poor survival and prognosis coincident with YY1, EGFR and MnSOD upregulation in patients with lung cancer. Collectively, MCT-1 is a key inducer of YY1-EGFR-MnSOD axis involving the redox mechanism in the process of carcinogenesis.

Citation Format: Hong-Yu Tseng, Yen-An Chen, Yi-Rong Chen, Hsin-Ling Hsu. Oncogene MCT-1 deregulates oxidative metabolism and promotes tumor metastasis via YY1 signaling network. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B02.
Abstract B03: Control of pancreatic cancer metabolism and histone acetylation by the tumor microenvironment
Authors: Sherman Mara H. , Evans Ronald M.
Published: October 2016

Though the significance of reciprocal interactions between genetically altered tumor cells and adjacent stroma is increasingly appreciated, this complex crosstalk remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) has a particularly prominent stromal compartment, shown to exert both tumor-supportive and tumor-suppressive or homeostatic functions in the context of the wound-like tumor microenvironment. To investigate the paracrine effects of PDAC stromal elements on pancreatic cancer cells, we developed a “stromal” culture system, which incorporates structural and diffusible stroma-derived elements into homotypic PDAC cell cultures amenable to functional genomics and metabolomics. These analyses revealed that microenvironmental cues co-regulate cancer metabolism and gene expression. Stromal inputs broadly influenced histone acetylation in the PDAC epigenome, which coincided with induction of genes implicated in anabolic metabolism and inflammation. The gene expression and metabolic changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental pathways characteristic of PDAC. As epigenome modification results in changes in gene expression through the functions of readers, such as the bromodomain-containing BET proteins, we tested JQ1, a small molecule inhibitor of BET family bromodomain-containing proteins, for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by JQ1, suggesting that the BET family serves as a key transducer of stromal inputs to drive alterations in gene expression. Inhibition of acetyl-lysine sensing by the BET family reduced pancreatic tumor growth and associated inflammation in vivo, with significant reduction in expression of genes implicated in macromolecule biosynthesis and tumor-permissive immune regulation. This work suggests paracrine epigenome regulation as a conduit through which stromal signals drive metabolic and immune adaptation to a challenging tumor microenvironment.

Citation Format: Mara H. Sherman, Ronald M. Evans. Control of pancreatic cancer metabolism and histone acetylation by the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B03.
Abstract B17: Disrupting tumor growth through targeting TEM8
Authors: Høye Anette M. , Tolstrup Sofie , Cox Thomas R. , Mauldin Jeremy P. , Frankel Arthur E. , Erler Janine T.
Published: October 2016

Tumor Endothelial Marker 8 (TEM8) is an integrin-like cell-surface receptor originally identified being specific to tumor endothelial cells in colorectal cancer (CRC) blood vessels. Further investigation showed upregulated TEM8 expression in tumor vessels of various tumor types, as well as in certain tumor cells. We observe an increase in TEM8 expression in metastatic cancer cell lines compared to their non-metastatic counterpart in both colon and breast cancer cell lines.

In order to investigate whether TEM8 is required for tumor growth and metastasis we have developed a humanized anti-TEM8-toxin-conjugated antibody. The antibody shows preclinical effectiveness in a CRC model in vivo. We have also utilized the CRISPR-Cas9 technology to create TEM8 knockout cell lines, which show impaired proliferation and invasion in vitro and reduced tumor growth in vivo compared to control cell lines.

Intriguingly, microarray analysis showed a significant increase in TEM8 mRNA levels in breast cancer cells seeded on collagen modified by the crosslinking enzyme lysyl oxidase (LOX). We have previously shown that LOX plays a role in tumor progression, metastasis, and pre-metastatic niche formation through its ability to modulate matrix stiffness. Importantly, both high TEM8 and LOX expression is correlated with decreased survival in ER- breast cancer patients.

Collagen VI, a TEM8 ligand, and their interaction have been implicated in being important for migration and for stimulating Wnt-signaling in breast cancer stem cells. Using global quantitative mass spectrometry we observe an increase in collagen VI in the extracellular matrix of CRC tumors overexpressing catalytically active, but not catalytically inactive, LOX compared to low-LOX expressing tumors. Furthermore, using publicly available databases TEM8 and collagen VI are found to be co-expressed in CRC patient datasets.

Thus, we speculate that another possible mechanism of LOX mediated tumor and metastasis progression is through TEM8. Further, that combined targeting of TEM8 and LOX may inhibit primary and metastatic tumor growth.

Citation Format: Anette M. Høye, Sofie Tolstrup, Thomas R. Cox, Jeremy P. Mauldin, Arthur E. Frankel, Janine T. Erler. Disrupting tumor growth through targeting TEM8. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B17.
Abstract B18: CXCL10 suppresses tumor angiogenesis and impedes expression of critical angiogenic factors in renal cell carcinoma
Authors: Jin Hyun A , Heo Jun Hyeok , Kang You Hyun , Kim Ki Hong , Han Kyung Suk , Hong Sung Joon
Published: October 2016

Background: Angiogenic progress is complex and several factors are involved as a promoter or inhibitor of angiogenesis. Tumor can use the imbalance of pro- and antiangiogenic factors in progression. The CXC chemokine family are consisted of pro- or antiangiogenic factors. Recent studies revealed CXCL10 as an anti-angiogenic factor in response to angiogenic factors like bFGF or VEGF. However, a role of CXCL10 in cancer and angiogenesis is unclear. Here, we investigated the role of CXCL10 on tumor angiogenesis and its mechanisms in renal cell carcinoma.

Methods: Human vascular endothelial cell (HUVEC) was used to evaluate the effects of CXCL10 on endothelial cells. MTS assay was performed to assess cell proliferation. Cell cycle analysis was performed using flow cytometry with propidium iodide. RT-PCR and western blot were performed to assess the baseline expression of CXCL10 in a panel of renal cell carcinoma cells. Overexpression of CXCL10 was developed by lentiviral transfection. Quantitative RT-PCR for angiogenic factors (VEGF, PDGF, FGF, MMP9) was performed by angiogenesis multigene screening array. Subcutaneous tumor xenografts were developed using Caki-1 cells to evaluate in vivo effects of CXCL10.

Results: CXCL10 inhibited proliferation and tube formation of HUVEC in a dose-dependent manner, while it did not affect in vitro tumor proliferation of renal cell carcinoma cells. Expression of CXCL10 was downregulated in Caki-1, UMRC3 and UMRC6 cells. Overexpression of CXCL10 suppressed expression of angiogenic factors including VEGF-A, PDGF, FGF2 and MMP9 in Caki-1 cells, suggesting that CXCL10 is involved non only as an anti-angiogenic factor but also as a suppressor of critical angiogenic factors in renal cell carcinoma. In vivo Restoration of CXCL10 expression suppresses tumor growth in renal cell carcinoma by suppressing tumor angiogenesis in xenografts.

Conclusions: CXCL10 has a role as an anti-angiogenic factor and also as a suppressor of critical angiogenic factors in renal cell carcinoma. Restoration of CXCL10 expression suppresses tumor growth in renal cell carcinoma by impeding expression of other angiogenic factors including VEGF, PDGF, FGF, MMP9 in renal cell carcinoma as well as inducing anti-angiogenic effect on endothelial cells. Our data suggest that targeting CXCL10 might be a novel therapeutic option for advanced renal cell carcinoma.

Citation Format: Hyun A Jin, Jun Hyeok Heo, You Hyun Kang, Ki Hong Kim, Kyung Suk Han, Sung Joon Hong. CXCL10 suppresses tumor angiogenesis and impedes expression of critical angiogenic factors in renal cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B18.
Abstract B36: Interrogating cellular metabolism to improve therapy for EGFR mutant NSCLC
Authors: Chiang Chun-Te , Chiu Chi-Li , Arnesano Cosimo , Fraser Scott E. , Agus David B. , Ruderman Dan L. , Mumenthaler Shannon M.
Published: October 2016

Tyrosine kinase inhibitors (TKIs) that target the EGFR are the standard of care for patients with EGFR mutant non-small lung cancer (NSCLC). However, TKIs are not curative; most patients with EGFR-mutant NSCLC treated with EGFR TKIs develop resistance within 9 to 14 months. The tumor microenvironment is thought to influence the fitness of cancer cells and drive the evolution of a tumor, but the effect of altered environmental conditions on oncogenic signaling and therapeutic response is not well understood. In the present study, we used the Operetta® High Content Imaging System to track cell dynamics over time and found that microenvironmental stress, specifically nutrient starvation, had a differential effect on growth rates of TKIs sensitive and resistant cells. Furthermore, we discovered that TKIs sensitive and resistant cells have differential metabolic signaling in response to this microenvironmental stress. To further interrogate cellular metabolism in TKIs sensitive and resistant cells, we utilized fluorescence lifetime imaging microscopy (FLIM), a state-of-the-art live-cell imaging technique to measure the autofluorescence lifetime of metabolic coenzyme NADH, the principle electron acceptor in glycolysis and electron donor in oxidative phosphorylation. Taken together, our data suggest that TKIs sensitive and resistant cells have adopted different metabolic strategies to cope with stressful environmental conditions, and interrogating tumor metabolic adaptations would inform the design of new therapeutic strategies to delay or prevent the outgrowth of resistant clones during treatment of EGFR mutant NSCLC.

Citation Format: Chun-Te Chiang, Chi-Li Chiu, Cosimo Arnesano, Scott E. Fraser, David B. Agus, Dan L. Ruderman, Shannon M. Mumenthaler. Interrogating cellular metabolism to improve therapy for EGFR mutant NSCLC. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B36.
Abstract B42: Dysregulation of key microRNAs controlling tumor-host interactions triggers escape from osteosarcoma dormancy
Authors: Tiram Galia , Ofek Paula , Udagawa Taturo , Shomron Noam , Roniger Maayan , Kerem Batsheva , Shaked Yuval , Aviel-Ronen Sarit , Barshack Iris , Calderon Marcelo , Haag Rainer , Satchi-Fainaro Ronit
Published: October 2016

The presence of dormant, microscopic cancerous lesions possesses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized a human osteosarcoma dormancy model of a pair of cells originating from the same parental tissue; one that remains avascular and non-palpable a year following inoculation into mice and another that generates vascularized palpable tumors one month following inoculation. Using this model of cell lines generating dormant or fast-growing osteosarcomas, we identified three novel regulators of osteosarcoma dormancy: miR-34a, miR-93 and miR-200c. This is the first report showing that loss of these three microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. Furthermore, we validated their downregulation in patients' tumor samples compared to normal bone, making them attractive candidates for osteosarcoma therapy. Reconstitution of these microRNAs into Soas-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their target genes, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, critical to cancer angiogenesis and cancer cells' migration. We further demonstrate that these miRNAs attenuate the angiogenic capabilities of fast-growing osteosarcoma in vitro and in vivo. Moreover, treatment with each of these microRNAs using our novel polyglycerol dendritic nanocarrier significantly prolonged their dormancy period. Taken together, these findings suggest that miR-34a, miR-93 and miR-200c have a key role in osteosarcoma progression, and provide the rationale for the development of novel diagnostic and therapeutic tools for osteosarcoma and other malignancies.

Citation Format: Galia Tiram, Paula Ofek, Taturo Udagawa, Noam Shomron, Maayan Roniger, Batsheva Kerem, Yuval Shaked, Sarit Aviel-Ronen, Iris Barshack, Marcelo Calderon, Rainer Haag, Ronit Satchi-Fainaro. Dysregulation of key microRNAs controlling tumor-host interactions triggers escape from osteosarcoma dormancy. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B42.
Abstract C04: In vivo upregulation of bone morphogenic protein 4 (BMP4) in esophageal cancer is through tumor-stroma crosstalk
Authors: Calpe Silvia , Read Matthew , Sancho-Serra Maria del Carmen , Straub Danielle , Clemons Nick , Liu David , Phillips Wayne , Krishnadath Kausilia K.
Published: October 2016

Bone morphogenic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor-beta (TGFβ;) superfamily. Amongst them, BMP4 is becoming increasingly attractive due to its crucial role in the development of many cancers. Whereas in malignancies such as glioblastoma and myeloma high levels of BMP4 are associated with benign features, in gastrointestinal cancers BMP4 possesses tumorigenic capacities. In these cancers, BMP4 acts on tumor epithelial cells enhancing their pro-metastatic behavior and chemo-resistance. However, whether BMP4 is being secreted by the epithelial cells or by the stroma, has not been well established yet, in part due to a lack of specific anti-BMP4 antibodies.

To elucidate the functional implications of the origin of BMP4 production, we made use of a novel esophageal adenocarcinoma (EAC) tumor xenograft model and a newly generated Llama-derived anti-BMP4 antibody. Using in vivo molecular imaging techniques we find that BMP4 expression in the tumor is increased after engraftment of BMP4 negative human EAC tumor cells into immunodeficient mice. Immunohistochemical studies of the engrafted tissue reveal both a mouse and a human origin of BMP4 protein, suggesting that both epithelial as well as stromal cells are involved in BMP4 secretion. This implies that whereas the stroma directly secretes BMP4; it also produces molecules that activate autocrine BMP4 production by the cancer epithelial cells. In vitro analysis such as co-cultures with different stromal cells, revealed the functional effects of stroma-derived BMP4 on tumor cells, and how our anti-BMP4 antibodies can inhibit these. Further, these studies also uncovered the stromal components that induce BMP4 secretion by the human epithelial cells.

In sum, these studies suggest a pivotal role of the microenvironment in regulating both directly and indirectly BMP4 expression in a model of esophageal cancer. As BMP4 has also been shown to be responsible for tumor progression in other gastrointestinal cancers, stromal regulation of BMP4 production might not be restricted to EAC, and might be a common feature in gastrointestinal cancers. Finally, as our anti-BMP4 Llama-derived antibodies can inhibit these effects in vitro, they might represent a novel therapy in targeting stromal function and preventing metastasis.

Citation Format: Silvia Calpe, Matthew Read, Maria del Carmen Sancho-Serra, Danielle Straub, Nick Clemons, David Liu, Wayne Phillips, Kausilia K. Krishnadath. In vivo upregulation of bone morphogenic protein 4 (BMP4) in esophageal cancer is through tumor-stroma crosstalk. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C04.