bluuebunny/crossref_metadata_2025 huggingface dataset:
Shadowing property and topological ergodicity for iterated function systems
Authors: Zhao Yingcui , Wang Lidong , Lei Fengchun
Published: August 2019

Let [Formula: see text] be a compact metric space and [Formula: see text] be two continuous maps on [Formula: see text]. The iterated function system [Formula: see text] is the action of the semi-group generated by [Formula: see text] on [Formula: see text]. In this paper, we introduce the definitions of shadowing property, average shadowing property and topological ergodicity for [Formula: see text] and give some examples. Then we show that (1) if [Formula: see text] has the shadowing property then so do [Formula: see text] and [Formula: see text]; (2) [Formula: see text] has the shadowing property if and only if the step skew product corresponding to [Formula: see text] has the shadowing property. At last, we prove a Lyapunov stable iterated function system having the average shadowing property is topologically ergodic.
TUNING THE ELECTRICAL PROPERTIES WITH HIGHER GAMMA-RAY IRRADIATION: POLY (METHYL METHACRYLATE)/LEAD OXIDE (PbO) COMPOSITE NANOSTRUCTURES
Authors: AKAY D. , OCAK S. B.
Published: August 2019

In this study the effects of [Formula: see text]Co gamma-ray irradiation on the electrical properties of the poly (methyl methacrylate)/lead oxide nanoparticle (PMMA/PbO) have been investigated. To show the influence of [Formula: see text]Co gamma-ray irradiation on the current–voltage ([Formula: see text]–[Formula: see text]) characteristics of the composite structure, which are based on the PMMA/PbO, have been measured before and after gamma-ray irradiation at room temperature and in dark. The analyze of the electrical parameters which are found out as strong function of voltage. Thus, structures has been investigated in the wide range of voltage (– 2 V to + 4 V) using Standard and Cheung methods.
The Development of Accounting and Financial Reporting Practices in Sri Lanka: An Exploratory Investigation
Authors: Hewa Dulige Jayasinghe , Abayadeera Nadana , Jahangir Ali Muhammad , Mather Paul
Published: August 2019

In this paper, we examine the factors that influence the development of accounting and reporting practices in Sri Lanka in the backdrop of its political and economic environment. We find that the early days of accounting in Sri Lanka were heavily influenced by the British colonial system. Subsequently, its greatest influence was derived from the regulatory and institutional framework backed by local and British professional accounting bodies. We also interview key stakeholders to draw insights on how the institutional factors contribute to the development of financial reporting in Sri Lanka. We discover that the Institute of Chartered Accountants of Sri Lanka (ICASL) is a key player in developing and implementing accounting standards and the best financial reporting practices. We observe that although the Sri Lankan Government has undertaken many initiatives to improve the quality of financial reporting, monitoring and enforcing regulations remain weak partly due to political interference. Therefore, we suggest that strengthening the existing regulatory mechanisms will help to improve the reporting quality and build investor confidence.
INTERORGANISATIONAL COLLABORATION FOR INNOVATION IMPROVEMENT IN MANUFACTURING FIRMS’S: THE MEDIATING ROLE OF SOCIAL PERFORMANCE
Authors: AWAN USAMA , SROUFE ROBERT
Published: August 2019

The impact of collaboration on innovation performance has been investigated in many studies. This study provides a unique view on innovation performance by exploring the mediating role of social performance between collaboration and innovation performance. For this, a structural model was tested through an empirical investigation with partial least squares structural equation modelling (PLS-SEM) using a sample made up of 239 export manufacturing firms. The results of the empirical study show that social performance appears to be a necessary condition for innovation performance. Our findings confirm the great potential of addressing social concern increasingly drive innovation performance. The next decade is likely to be a period of rapidly expanding social performance practices in the manufacturing firms. The managers could foster sustainable innovation by collaborating customers and enhance their firm social performance.
Geometry of semi-transversal lightlike warped product submanifolds of indefinite Kaehler manifolds
Authors: Kumar Sangeet
Published: August 2019

In this paper, we investigate warped product semi-transversal lightlike submanifolds of indefinite Kaehler manifolds. It is shown that there does not exist any warped product semi-transversal lightlike submanifold of the type [Formula: see text] in an indefinite Kaehler manifold. Moreover, a necessary and sufficient condition for an isometrically immersed semi-transversal lightlike submanifold of an indefinite Kaehler manifold to be a semi-transversal lightlike warped product of the type [Formula: see text] is obtained, in terms of the shape operator.
Congruence relations on almost distributive lattices-II
Authors: Addis Gezahagne Mulat
Published: August 2019

For a given ideal [Formula: see text] of an almost distributive lattice [Formula: see text], we study the smallest and the largest congruence relation on [Formula: see text] having [Formula: see text] as a congruence class.
Subsurface observations of deformation bands and their impact on hydrocarbon production within the Holstein Field, Gulf of Mexico, USA
Authors: Wilkins Scott J. , Davies Russell K. , Naruk Steve J.
Published: August 2019

The Holstein Field consists of poorly lithified turbidite sands deposited during the Pliocene Epoch. Dense arrays of cataclastic deformation bands have been observed in all cores from wells that penetrate the K2 reservoir sand, the highest density of which are located near the hinge of a monocline. The predominant set of deformation bands strikes parallel to the fold axis, and dips at both high and low angles with respect to bedding. Deformation band orientation and offset of marker beds indicate reverse shear and are consistent with a flexural slip origin during folding. Restorations suggest that the monocline and associated deformation bands formed early during the burial process with high pore pressure.

Reservoir permeability estimates from well tests indicate a bulk permeability approximately one-third of the reservoir core permeability in regions with deformation bands, whereas other areas are unaffected. Bulk permeability estimated from the permeability of the reservoir and deformation band network is lower than the reservoir permeability alone, but exceeds the permeability observed in the well tests by a factor of 2. A reduction in permeability of oil relative to water for both the fault and host sand is required to match the well-test permeability with that measured from core.
A knowledge database of hanging-wall traps that are dependent on fault-rock seal
Authors: Bretan Peter G. , Yielding Graham , Sverdrup Einar
Published: August 2019

Hanging-wall traps are successful trapping styles with discoveries made in many sedimentary basins worldwide. Examples of hanging-wall traps are documented in the literature but very few describe the role played by fault-rock seal on trap integrity. This contribution focuses on hanging-wall traps that are dependent on fault-rock seal. Analysis of 18 examples of hanging-wall traps has revealed that the hydrocarbon column height trapped by fault-rock seal is typically less than 190 m. Cross-plots of shale gouge ratio (SGR) and buoyancy pressure from hanging-wall traps have a similar data distribution to published SGR–buoyancy pressure calibration plots. The similarity in data distribution indicates a similarity in the overall fault-sealing mechanism: namely, the capillary fault sealing through the incorporation of clay/shale material into the fault zone. Published ‘global’ calibration plots of SGR v. buoyancy pressure can be used to evaluate the sealing or non-sealing risk of hanging-wall traps in the same manner as for footwall traps.
Validation and analysis procedures for juxtaposition and membrane fault seals in oil and gas exploration
Authors: Murray Titus A. , Power William L. , Johnson Anthony J. , Christie Greg J. , Richards David R.
Published: August 2019

We propose and validate methods for risk analysis of fault-bounded hydrocarbon traps in exploration. We concentrate on cross-fault leakage and consider lateral seals due to (1) juxtaposition and (2) high capillary-entry-pressure fault rock (membrane seal). We conclude that stochastic methods for fault seal analysis are essential, due to the large number of structural and stratigraphic parameters and the uncertainties. Central to the methods proposed is a Monte Carlo simulation which models geometrical and stratigraphic uncertainty. Multiple Allan maps (fault-parallel cross-sections) are produced and analysed for juxtaposition and shale gouge ratio (SGR). For validation, known discoveries with independently observed hydrocarbon–water contacts (IHWC) have been back-analysed. We present two case studies in this paper, and an additional 40 case studies are summarized (four public domain and 36 confidential case studies). The model outputs were compared with the IHWC. Juxtaposition analysis with no SGR contribution gives the smallest error. The inclusion of any fault rock seal mechanisms (such as SGR) matches or increases predicted hydrocarbon column heights compared to juxtaposition and gives larger errors. We conclude there is no reason to include fault rock membrane seals in exploration prospect risking.
Effect of varying chemoreflex stress on sympathetic neural recruitment strategies during apnea
Authors: Ott Elizabeth P. , Baker Sarah E. , Holbein Walter W. , Shoemaker J. Kevin , Limberg Jacqueline K.
Published: August 2019

We sought to examine the effect of varying chemoreflex stress on sympathetic neural recruitment strategies during end-expiratory apnea. We hypothesized that increases in the firing frequency and probability of low-threshold axons at the asphyxic “break point” would be exaggerated during hypoxia and attenuated during hyperoxia. Multiunit muscle sympathetic nervous system activity (MSNA) (peroneal nerve microneurography) was measured in 10 healthy male subjects (31 ± 2 yr, 25 ± 1 kg/m2). Individuals completed maximal voluntary end-expiratory apnea under normoxic, hypoxic (inspired O2 fraction: 0.17 ± 0.01), and hyperoxic (inspired O2 fraction: 0.92 ± 0.03) conditions. Action potential (AP) patterns were examined from the filtered raw signal with wavelet-based methodology. Multiunit MSNA was increased ( P ≤ 0.05) during normoxic apnea, because of an increase in the frequency and incidence of AP spikes (243 ± 75 to 519 ± 134 APs/min, P = 0.048; 412 ± 133 to 733 ± 185 APs/100 heartbeats, P = 0.02). Multiunit MSNA increased from baseline ( P < 0.01) during hypoxic apnea, which was due to an increase in the frequency and incidence of APs (192 ± 59 to 952 ± 266 APs/min, P < 0.01; 326 ± 89 to 1,212 ± 327 APs/100 heartbeats, P < 0.01). Hypoxic apnea also resulted in an increase in the probability of a particular AP cluster firing more than once per burst ( P < 0.01). Hyperoxia attenuated any increase in MSNA with apnea, such that no changes in multiunit MSNA or frequency or incidence of AP spikes were observed ( P > 0.05). We conclude that increases in frequency and incidence of APs during apnea are potentiated during hypoxia and suppressed when individuals are hyperoxic, highlighting the important impact of chemoreflex stress in AP discharge patterns. The results may have implications for neural control of the circulation in recreational activities and/or clinical conditions prone to apnea.

NEW & NOTEWORTHY Our results demonstrate that, compared with normoxic end-expiratory apnea, hypoxic apnea increases the frequency and incidence of action potential spikes as well as the probability of multiple firing. We further show that this response is suppressed when individuals are hyperoxic. These data highlight the potentially important role of chemoreflex stress in neural firing and recruitment and may have implications for neural control of the circulation in recreational and/or clinical conditions prone to apnea.
Brain Organoids as Tools for Modeling Human Neurodevelopmental Disorders
Authors: Adams Jason W. , Cugola Fernanda R. , Muotri Alysson R.
Published: August 2019

Brain organoids recapitulate in vitro the specific stages of in vivo human brain development, thus offering an innovative tool by which to model human neurodevelopmental disease. We review here how brain organoids have been used to study neurodevelopmental disease and consider their potential for both technological advancement and therapeutic development.
Neurodegeneration in Patients with Type 2 Diabetes Mellitus without Diabetic Retinopathy
Authors: Garcia-Martin Elena , Cipres Marta , Melchor Isabel , Gil-Arribas Laura , Vilades Elisa , Polo Vicente , Rodrigo Maria Jesus , Satue Maria
Published: August 2019

Purpose. To evaluate neurodegeneration in patients with type 2 diabetes mellitus (DM2) without diabetic retinopathy and to assess the possible role of systemic vascular complications in retinal changes. Methods. Sixty eyes of 60 patients with DM2 and without any signs of diabetic retinopathy and 60 eyes of 60 healthy controls underwent retinal evaluation using Spectralis optical coherence tomography. Macular ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) were evaluated. Peripapillary RNFL thickness was assessed using Glaucoma and Axonal Analytics applications. Comparison between patients with the presence/absence of systemic vascular complications and different disease duration was made. Results. Macular GCL was reduced in patients compared to controls (p<0.001). Differences in the macular RNFL thickness were only observed in the outer inferior sector (p=0.033). A reduction in the peripapillary RNFL (average, inferior, and inferotemporal thickness, p<0.05 for all three) was observed in patients using both applications. Patients with chronic systemic vascular complications presented a reduction in the temporal RNFL (p=0.019) compared to patients without complications. The superotemporal RNFL thickness was thinner in patients with longer disease duration. Conclusions. Patients with type 2 DM without diabetic retinopathy and good metabolic control present neurodegeneration affecting neurons in the macular area and axons in different sectors of the optic disc. Systemic vascular complications contributed to further axonal damage in these patients, suggesting a possible role of subclinical ischaemia to retinal neurodegeneration in type 2 DM.
On the Stability and Multistability in a Duopoly Game with R&D Spillover and Price Competition
Authors: Zhou Wei , Wang Xiao-Xue
Published: August 2019

In this paper, a dynamical two-stage game with R&D competition and joint profit maximization is built. The stability of all the equilibrium points is discussed through Jury condition, and the stability region of the Nash equilibrium point is then given. The influence of the parameters on the system is discussed, and we find that the firm can even benefit from chaos, when it has higher innovation efficiency and higher adjusting speed. And then the coexistence of multiple attractors is studied using basin of attraction. Our research result shows that the coexisting attractors can be observed in the two-parameter bifurcation diagram. At last, the boundary of feasible region, global bifurcations, and formation mechanism of fractal structure of attracting basin are analyzed through critical curves and noninvertible map theory.
Impact of Primary Care Delay on Progression of Breast Cancer in a Black African Population: A Multicentered Survey
Authors: Agodirin Olayide , Olatoke Samuel , Rahman Ganiyu , Olaogun Julius , Kolawole Oladapo , Agboola John , Olasehinde Olalekan , Katung Aba , Ayandipo Omobolaji , Etonyeaku Amarachukwu , Ajiboye Anthony , Oguntola Soliu , Fatudimu Oluwafemi
Published: August 2019

Background. Reports are scanty on the impact of long primary care interval in breast cancer. Exploratory reports in Nigeria and other low-middle-income countries suggest detrimental impact. The primary aim was to describe the impact of long primary care interval on breast cancer progression, and the secondary aim was to describe the factors perceived by patients as the reason(s) for long intervals. Method. Questionnaire-based survey was used in 9 Nigerian tertiary institutions between May 2017 and July 2018. The study hypothesis was that the majority of patients stayed >30 days, and the majority experienced stage migration in primary care interval. Assessment of the impact of the length of interval on tumor stage was done by survival analysis technique, and clustering analysis was used to find subgroups of the patient journey. Results. A total of 237 patients presented to primary care personnel with tumor ≤5cm (mean 3.4±1.2cm). A total of 151 (69.3%, 95% CI 62.0-75.0) stayed >30 days in primary care interval. Risk of stage migration in primary care interval was 49.3% (95% CI 42.5%-56.3%). The most common reasons for long intervals were symptom misinformation and misdiagnosis. Clustering analysis showed 4 clusters of patients’ experience and journey: long interval due to distance, long interval due to misinformation, long interval due to deliberate delaying, and not short interval—prepared for treatment. Conclusion. The majority of patients stayed longer than 30 days in primary care interval. Long primary care interval was associated with a higher risk of stage migration, and more patients reported misinformation and misdiagnosis as reasons for a long interval.
Impact of Submicroscopic Plasmodium falciparum Parasitaemia on Maternal Anaemia and Low Birth Weight in Blue Nile State, Sudan
Authors: Omer Samia A. , Noureldein Ali N. , Eisa Hadeel , Abdelrahim Mutasim , Idress Hagir E. , Abdelrazig Abdelrahim M. , Adam Ishag
Published: August 2019

The aim of the present study was to investigate the prevalence of submicroscopic infections and to assess its impact on maternal anaemia and low birth weight. A cross-sectional study was carried out with 1149 consented pregnant women who delivered at 3 main hospitals in the Blue Nile State, between January 2012 and December 2015. From a matched maternal peripheral, placental maternal side, and cord blood sample, blood films and dried spots were prepared for microscopic examination and nested polymerase chain reaction (n-PCR), respectively. 107 out of 447 negative blood films were found to have submicroscopic infection detected using n-PCR in any of the three compartments. Placental samples had a significantly higher prevalence (142) of submicroscopic infections compared with the peripheral (6.5%) and cord (8.1%) samples. The mean (SD) of the maternal haemoglobin (Hb) was significantly lower in cases with submicroscopic parasitaemia (10.9 (0.8) vs. 12.1 (0.7) g/dl, P<0.001) compared with those who had no submicroscopic parasitaemia. Submicroscopic malaria infection was associated with anaemia (OR 19.7, (95% CI, 10.3–37.8)). Thirty-eight babies born to women with submicroscopic infections were low birth weight (LBW) and was significantly lower in submicroscopic parasitaemia (2.663 (0.235) vs. 2.926 (0.341) kg, P<0.001). Submicroscopic malaria infection was associated with LBW (OR = 2.7, (95% CI, 1.2–5.6)). There is a high incidence of submicroscopic infections in any of the three compartments regardless of age or parity. Submicroscopic infection is a risk of maternal anaemia and low birth weight in women in this area of high seasonal malaria transmission.
Nonlinear Dynamic Modeling and Model Reduction Strategy for Rotating Thin Cylindrical Shells
Authors: Sun Shupeng , Liu Lun
Published: August 2019

Nonlinear dynamic modeling and model reduction strategy are studied in this paper for a rotating thin cylindrical shell. The nonlinear dynamic model is first established in terms of ordinary differential equations, in which the effects of Coriolis and centrifugal forces are considered, as well as the initial hoop tension due to rotation. This model describes both the in‐plane vibrations and the flexural vibration and reflects the coupling effects of those deformations. Based on this original model, a novel model reduction strategy is proposed to reduce the degrees of freedom by neglecting vibration modes predominated by in‐plane vibrations. Meanwhile, for the reduced‐order model, the in‐plane vibrations’ contributions to the rotating shell’s response are still preserved. To validate the dynamic model and the model reduction strategy, comparisons and simulations are carried out. Subsequently, nonlinear dynamic behaviors are investigated preliminarily by analyzing the rotating cylindrical shell’s amplitude‐frequency responses under different excitation levels.
Annexin A2 Expression in Aerogenous Metastasis of Pulmonary Invasive Mucinous Adenocarcinoma: A Case Report including Immunohistochemical Analysis
Authors: Arai Kazumori , Hirose Masahide
Published: August 2019

Aerogenous metastasis (AM) is a form of lung cancer that spreads in a unique fashion, but its mechanisms are still unclear. Annexin A2 (ANX A2), a membrane-binding protein, promotes cancer invasion and is involved in cell adhesion and polarity. The relationship between ANX A2 and cancers with poor stromal invasion capacity has not been studied. We immunohistochemically analyzed ANX A2 expression in AM observed in a patient with pulmonary invasive mucinous adenocarcinoma. In the primary site, ANX A2 immunopositivity on the cell-cell borders weakened as tumor cells projected and separated into alveolar spaces. In AM, tumor cell aggregates with ANX A2 immunopositivity near the surface and within the cytoplasm attached to alveolar epithelial cells, then engulfed them and formed a protrusion. As tumor cell aggregates adhered to the alveolar wall and formed a single layer, cytoplasmic ANX A2-positive products accumulated in the lateral sides of the tumor cells and exhibited distinct membranous positivity. These results indicated that ANX A2 near the tumor cell surface was related to alveolar wall attachment. Furthermore, the translocation of cytoplasmic ANX A2 to cell-cell borders changed cell morphology, adhesion, and polarity restoration.
Signal Detection from Permutated Observations Using Distributed Sensors
Authors: Jiang Naiti , Zhang Ning , Zhang Jindong
Published: August 2019

In this paper, distributed constant level detection in wireless sensor networks (WSNs) is investigated. The permuted linear model with a scalar parameter and additive heteroscedastic Gaussian noise is introduced, where the associations between the observations and the sensors are assumed to be unknown. Several detectors such as the approximations of the generalized likelihood ratio test (GLRT) detector, mean detector, and energy detector are proposed, and their receiver operating characteristics (ROCs) are evaluated. Numerical simulations are performed, and it is shown that the performance degradation of the GLRT detector is small, compared to the permutation known as Neyman-Pearson (NP) detector.
Experimental Verification of the Weibull Distribution in a Reverberation Chamber
Authors: Xu Jianhua , Zhao Yongjiu , Xu Qian
Published: August 2019

A Weibull distribution has been proposed for the probability density function (PDF) of the magnitude of the E-field in a reverberation chamber (RC). However, the Weibull distribution has two parameters, and if the parameters are position sensitive, the use of the Weibull distribution could be very limited. We investigate the sensitivity of the estimated parameters of the Weibull distribution in this study; the measurement results show that the parameters of the Weibull distribution depend on the positions of the antenna (or device under test), but not sensitive, and the statistical behavior of the parameters can be quantified. This means that the model of the Weibull distribution has a wider usable frequency range than that of the Rayleigh distribution and the statistical variation of the parameters needs to be considered.
Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment
Authors: Bernasconi Paolo , Borsani Oscar
Published: August 2019

One of the most urgent needs in AML is to improve the disease cure rate as relapse still occurs in 60–80% of patients. Recent evidence suggests that dismal clinical outcomes may be improved by a better definition of the tight interaction between the AML cell population and the bone marrow (BM) microenvironment (“the niche”); the latter has been progressively highlighted to have an active role in the disease process. It has now been well established that the leukemic population may misinterpret niche-derived signals and remodel the niche, providing a shelter to AML cells and protecting them from the cytotoxic effects of chemoradiotherapy. Novel imaging technological advances and preclinical disease models have revealed that, due to the finite number of BM niches, leukemic stem cells (LSCs) and normal hematopoietic stem cells (HSCs) compete for the same functional areas. Thus, the removal of LSCs from the BM niche and the promotion of normal HSC engraftment should be the primary goals in antileukemic research. In addition, it is now becoming increasingly clear that AML-niche dynamics are disease stage specific. In AML, the niche has been linked to disease pathogenesis in the preleukemic stage, the niche becomes permissive once leukemic cells are established, and the niche is transformed into a self-reinforcing structure at a later disease stage. These concepts have been fostered by the demonstration that, in unrelated AML types, endosteal vessel loss occurs as a primary AML-induced niche alteration, and additional AML-induced alterations of the niche and normal hematopoiesis evolve focally and in parallel. Obviously, this endosteal vessel loss plays a fundamental role in AML pathogenesis by causing excessive vascular permeability, hypoxia, altered perfusion, and reduced drug delivery. Each of these alterations may be effectively targeted by various therapeutic procedures, but preservation of endosteal vessel integrity might be the best option for any future antileukemic treatment.
Abstract 118: GPR68, a proton-sensing GPCR that mediates interaction of pancreatic cancer associated fibroblasts and cancer cells, is a potential therapeutic target for pancreatic cancer
Authors: Wiley Shu Z. , Sriram Krishna , Salmeron-Salvador Cristina , Nishihara Hiroshi , French Randall , Lowy Andrew M. , Insel Paul A.
Published: August 2019

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma (desmoplasia) that is generated by pancreatic cancer associated fibroblasts (PCAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). We discovered that GPR68, a proton-sensing GPCR, has much higher expression in PCAFs compared to either PFs or PSCs. GPR68 activation in PCAFs enhances interleukin-6 (IL-6) expression via a cAMP/PKA/CREB signaling pathway. GPR68 knockdown with siRNA decreased low pH-induced IL-6 production by PCAFs and increased the proliferation of PDAC cells by PCAF conditioned media. Ogerin, a GPR68 positive allosteric modulator, enhanced the pH-dependent increase in cAMP in PCAFs. A pilot screening of 96 GPCR-specific compounds tested with GPR68-overexpressing HEK293 cells identified two compounds (C1 and C2) that decrease intracellular cAMP at pH6.4, but not isoproterenol (β-adrenergic receptor)-induced cAMP, implying their selective antagonism of GPR68. Furthermore, compound C2 decreased low pH-induced IL-6 levels in the conditioned media of GPR68-overexpressing HEK293 cells We conclude that GPR68 in PCAFs detects low pH, contributes to PDAC cell-PCAF interaction and may be a novel therapeutic target for pancreatic cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Shu Z. Wiley, Krishna Sriram, Cristina Salmeron-Salvador, Hiroshi Nishihara, Randall French, Andrew M. Lowy, Paul A. Insel. GPR68, a proton-sensing GPCR that mediates interaction of pancreatic cancer associated fibroblasts and cancer cells, is a potential therapeutic target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 118.
Abstract 1193: S100A proteins play immune regulatory roles in tumor microenvironment
Authors: Tanaka Nobuyuki , Kodake Natsumi , Ogama Naoko
Published: August 2019

S100A proteins are Ca2+ binding multifunctional molecule in different cellular compartments. Dysregulated expression of S100A is often observed in many types of human cancers, and is assoiciated with cancer pathogenesis. Inside a cell, S100A proteins respond to various stimuli, and some typical intracellular functions such as cytoskeleton control and motility have been extensively studied. Extracellular functions of S100A proteins have recently emerged, and they bind innate immune receptors such as TLR4 and RAGE. Nevertheless, the mode of S100A secretion has been obscure. We designed a secretion system to induce spontaneous S100A release from the cell, and examined their roles towards tumor microenvironment. We found S100A proteins are included in exosomes, and the stability of S100A contributes to their extracellular functions. Using a syngeneic tumor model, we investigated some S100A proteins show immune regulatory functions on tumor-associated macrophages. These results suggest that S100A secretion affects tumor immune environment.

Note: This abstract was not presented at the meeting.

Citation Format: Nobuyuki Tanaka, Natsumi Kodake, Naoko Ogama. S100A proteins play immune regulatory roles in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1193.
Abstract 1240: Identification of molecular targets of Tris DBA [Tris(dibenzylideneacetone)dipalladium(0)] for cancer therapy
Authors: Arora Loukik , Tan Chris Soon Heng , Sobota Radoslaw M. , Sethi Gautam
Published: August 2019

Cancer is complex disease involving complex genetic and epigenetic heterogeneity making it the second leading cause of death globally after heart disease. While conventional treatments like surgery, radiotherapy, chemotherapy are principal strategies, the focus is shifting to therapies that can target multiple pathways to treat cancers. In the present report, we hypothesized that Tris DBA, an organometallic compound, can inhibit proliferation, tumor growth, and induce apoptosis in multiple myeloma (MM) and hepatocellular carcinoma (HCC) cells, thereby potentially exhibiting significant anticancer effects. Our preliminary results clearly indicated that Tris DBA could substantially inhibit both constitutive as well as IL-6 inducible STAT3 activation and abrogate proliferation/survival in MM and HCC cells. A phospho-proteomic profiling revealed several key phosphorylation changes induced by Tris DBA treatment which further indicate broad anticancer potential of the compound. Additionally, the agent exhibited potent antitumor actvitiy in vivo, with little adverse effects. The ongoing work is aimed at investigating the possible binding target(s) of Tris DBA and further characterize the molecular mechanism(s) underlying STAT3 inhibitory effects of the drug.

Citation Format: Loukik Arora, Chris Soon Heng Tan, Radoslaw M. Sobota, Gautam Sethi. Identification of molecular targets of Tris DBA [Tris(dibenzylideneacetone)dipalladium(0)] for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1240.
Abstract 1470: Development & characterization of a new oncolytic immunotherapy platform based on herpes simplex virus type 1
Authors: Thomas Suzanne , Juncheria Linta , Roulstone Victoria , Kyula Joan N. , Kaufman Howard L. , Harrington Kevin J. , Coffin Robert S.
Published: August 2019

A number of oncolytic viruses have shown single agent clinical activity and evidence of clinical synergy with immune checkpoint blockade. However, not all patients respond, and as yet most of the promising clinical data have been generated in patients with melanoma. With the objective of maximally activating a patient's immune system against their own cancer which will then provide enhanced synergy with anti-PD1/L1 blockade, we developed a new oncolytic immunotherapy platform based on herpes simplex virus (HSV). This has the dual objectives of killing tumor to provide abundant release of tumor antigens, and potently activating immune responses against these antigens once released. To augment the natural ability of the virus to kill tumors and activate the immune system, these viruses are each armed with multiple therapeutic genes. Initially, we screened 29 new clinical strains of HSV isolated from volunteers who suffer from cold sores across a panel of human tumor cell lines to select a candidate for further development. This strain was then engineered to provide tumor selective replication (deletion of the genes encoding ICP34.5 and ICP47) and to express a potent fusogenic glycoprotein (GALV-GP R-). These modifications greatly enhance both local and systemic antitumor effects, increase immunogenic cell death, potently activate anti-tumor immunity, and are synergistic with PD-1 blockade in pre-clinical models. A virus expressing both GALV-GP R- and human GM-CSF is currently in a Phase 1/2 clinical trial in approximately 150 patients as a single-agent and combined with PD1 blockade in four solid tumor types. Further viruses express additional immune-activating proteins expected to act at the site of immune response initiation in tumors and draining lymph nodes, in particular an anti-CTLA-4 antibody-like molecule and immune co-stimulatory pathway-activating ligands. Each of these demonstrated increased activity in pre-clinical models, particularly an enhanced anenestic effect. The anti-CTLA-4 expressing virus (RP2) is targeted to enter clinical trials in the first half of 2019. Thus, a modular approach to oncolytic immunotherapy development can rapidly generate multiple clinical candidates with multiple mechanisms of action intended to act synergistically with other approaches to cancer therapy. The latest pre-clinical data utilizing this platform will be presented.

Citation Format: Suzanne Thomas, Linta Juncheria, Victoria Roulstone, Joan N. Kyula, Howard L. Kaufman, Kevin J. Harrington, Robert S. Coffin. Development & characterization of a new oncolytic immunotherapy platform based on herpes simplex virus type 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1470.
Abstract 1489: Increased levels of systemic LPS-positive bacterial extracellular vesicles in cancer patients with chemotherapy-induced intestinal barrier dysfunction
Authors: Tulkens Joeri , Wever Olivier De , Hendrix An
Published: August 2019

Bacterial extracellular vesicles (EV) are nanometer-sized membrane particles transporting nucleic acids, metabolites, proteins and endotoxins (lipopolysaccharide (LPS)). As such, bacterial EV that enter the systemic circulation may deliver and elicit a variety of immunological and metabolic responses in different organs including the brain. To date, the systemic presence and activity of bacterial EV in patients with intestinal barrier dysfunction have not been investigated. We combined size exclusion chromatography and density gradient (DG) centrifugation to fractionate plasma LPS in two dimensions to separate bacterial EV-associated LPS from other LPS products. We evaluated plasma from healthy donors asymptomatic of intestinal barrier dysfunction versus cancer patients with radiation- or chemotherapy (with or without gastrointestinal mucositis). We quantitatively measured bacterial EV-associated LPS and other LPS products by performing Limulus Amebocyte Lysate (LAL) and Toll-like receptor 4 (TLR4) reporter assays and qualitatively confirmed the results by immunoelectron microscopy. LAL analysis of DG fractions corresponding to the density of bacterial EV, demonstrated significantly increased LPS activity in patients diagnosed with therapy-induced gastrointestinal mucositis compared to respective controls. In accordance, we detected elevated amounts of microbial pattern recognition receptor (PRR) ligands by determining TLR4 agonistic activity. Immunoelectron microscopy confirmed bacterial EV-associated LPS. In conclusion, LPS-positive bacterial EV are present in plasma, and correlate with impaired barrier integrity in cancer therapy-induced intestinal mucositis. Further studies are needed to understand systemic functions of circulating bacterial EV in cancer patients and cancer therapy-induced conditions.

Citation Format: Joeri Tulkens, Olivier De Wever, An Hendrix. Increased levels of systemic LPS-positive bacterial extracellular vesicles in cancer patients with chemotherapy-induced intestinal barrier dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1489.
Abstract 1492: Evaluation of combinatorial chemotherapeutics nano-carriers at different dosage regimens in breast cancer model: Tumor immune signaling, inhibit angiogenesis and tumor growth
Authors: Fatease Adel Al , Shah Vidhi , Lopez Kalei , Cote Brianna , Rao Deepa , Alani Adam
Published: August 2019

The objective of this work is to evaluate the effect of individual & combinatorial delivery of Docetaxel (DTX) and Everolimus (EVR) in polymeric micelles at frequent dosing regimen below their maximum tolerated dose on angiogenesis, efficacy & immune signaling in breast cancer animal model. Based on previous in-vivowork in our lab, the maximum tolerated dose (MTDs) for EVR, DTX & combinatorial micelles is 50, 25 and 20 mg/kg respectively. To achieve our goal, two studies have been conducted. First, in-vivo assessment of anti-angiogenic effects of individual & dual DTX-EVR micelles in murine model at 10%, 30%, and 50% MTD, & MTD dose. Second, in-vivo efficacy evaluation of individual & dual DTX EVR micelles at 10%, 30%, 50% MTD, and MTD dose in orthotropic breast cancer murine model. Relative blood vessel invasion & increase in tumor growth will be evaluated for each dosing treatment. We observed that dual DTX EVR polymeric micelles showed significant inhibition of angiogenesis & tumor growth compared to individual agent. The effect of frequent lower dosing schedule is also currently being investigated for its effect immune signaling.

Citation Format: Adel Al Fatease, Vidhi Shah, Kalei Lopez, Brianna Cote, Deepa Rao, Adam Alani. Evaluation of combinatorial chemotherapeutics nano-carriers at different dosage regimens in breast cancer model: Tumor immune signaling, inhibit angiogenesis and tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1492.
Abstract 1502: KRAS RNAi therapy in preclinical models of pancreatic cancer sensitizes tumors to checkpoint blockade by affecting the tumor microenvironment
Authors: Ganesh Shanthi , Shui Serena , Craig Kevin , Wang Weimin , Brown Bob D. , Abrams Marc
Published: August 2019

KRAS is one of the most frequently mutated oncogenes in pancreatic cancer. Recent research has revealed that activation of KRAS in cancer cells causes recruitment of immunosuppressive molecules to the tumor microenvironment (TME) and blocks T-cell mediated cytotoxicity. Despite huge progress in our understanding of KRAS and its role in tumorigenesis, direct pharmacological targeting of KRAS has thus far not been achieved. In these studies, we inhibited KRAS directly in tumor-bearing mice, using a potent and specific Dicer substrate siRNA (DsiRNA) formulated in tumor-selective lipid nanoparticles. We demonstrate that intravenously-dosed KRAS DsiRNA treatment results in reduction of multiple immunosuppressive signaling molecules, affecting recruitment of myeloid cells and regulatory T cells (Tregs) to the TME. In addition, effective KRAS inhibition reversed MEK-inhibitor-induced resistance in a model of KRAS mutant human PDAC. These data suggest that KRAS DsiRNA has potential to sensitize treatment-refractory PDAC tumors to both immune checkpoint blockade as well as conventional targeted therapeutics

Note: This abstract was not presented at the meeting.

Citation Format: Shanthi Ganesh, Serena Shui, Kevin Craig, Weimin Wang, Bob D. Brown, Marc Abrams. KRAS RNAi therapy in preclinical models of pancreatic cancer sensitizes tumors to checkpoint blockade by affecting the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1502.
Abstract 151: Comprehensive characterization of gastric cancer at single-cell resolution
Authors: Chen Jiamin , Sathe Anuja , Grimes Sue , Greer Stephanie , Lau Billy , Renschler Ann , Poultsides George , Suarez Carlos , Ji Hanlee
Published: August 2019

The gastric carcinoma cells have complex interactions with diverse cell types in the associated tumor microenvironment. The tumor microenvironment plays important roles on gastric cancer development, progression and therapy response. In this study, we leveraged high-throughput single-cell RNA sequencing (scRNAseq) to characterize the diverse cell population in gastric tumors.

In total, we analyzed more than 30,000 single cells from eight gastric tumors and matched normal tissues. Cells were sequenced at an average depth of 70000 reads/cell to guarantee sufficient coverage for downstream analysis. Using graph-based cell clustering methods and known cell markers, we identified heterogenous epithelial cells (PGC+, MUC5AC+, TFF1+, EPCAM+, CDH1+), fibroblasts (ACTA2+, THY1+, COLA1+), endothelial cells (VWF+, PECAM1+), and a variety of immune cells including M1 and M2 macrophages (IL1A+, IL1B+, TNF+, MARCO+, MSR1+, CD68+), CD4 T cells (CD3D+, CD4+), CD8 T cells (CD8A+), Gamma Delta T cells (TRGC2+, TRDC+), B cells (CD79+), and plasma cells (CD19+, CD20+, IgG+). Specifically, gastric epithelial cancer cells demonstrated distinct CNVs inferred from single cell transcriptome files.

We established and characterized patient derived gastric cancer organoids from single tumor cells. The organoids recapitulate CNVs found in the original gastric tumors and displayed varied degree of drug responses. We identified specific molecular features of the tumor microenvironment that modulate cell growth and immune responses. For example, we identified heterogenous myofibroblast populations with distinct chemokine secretory profiles compared to normal gastric tissue. We characterized gene signatures associated with immune checkpoints on T cells and targetable molecules in innate cells. Using cell type specific expression profiles, we were able to establish a comprehensive signaling network of tumor-tumor, tumor-stromal, stromal-stromal and stromal-tumor signaling via receptor-ligand pairing.

Citation Format: Jiamin Chen, Anuja Sathe, Sue Grimes, Stephanie Greer, Billy Lau, Ann Renschler, George Poultsides, Carlos Suarez, Hanlee Ji. Comprehensive characterization of gastric cancer at single-cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 151.
Abstract 1524: CD137 (4-1BB) engagement fine-tunes the synergistic IL-15- and IL-21-driven NK cell proliferation
Authors: Vidard Laurent , Dureuil-Sizaire Christine , Baudhuin Jérémy , Vescovi Lionel , Durand Laurence , Sierra Véronique , Parmantier Eric
Published: August 2019

To understand and dissect the mechanisms driving NK cell proliferation, we took advantage of the methodology used in cell therapy to numerically expand NK cells in the presence of K562-derived artificial Antigen Presenting Cells (aAPCs) and cytokines. For 9 consecutive weeks, high expression of CD137L by a K562-derived aAPC cell line was able to sustain NK cell expansion by 100 million-fold whereas low expression of CD137L by the parental K562 cell line supported the expansion by only 40,000-fold. The level of expression of CD137L, however, did not modulate the sensitivity of the K562 cell line to the intrinsic cytotoxicity of NK cells. Similarly, the low NK cell proliferation in the presence of the parental K562 cell line and cytokines was increased by adding agonistic anti-CD137 antibodies to levels similar to CD137L-expressing K562-derived aAPCs. Finally, the synergy between IL-15 and IL-21 was observed only upon CD137 engagement and the presence of aAPCs. Therefore, we conclude that NK cell proliferation requires cell-to-cell contact, the activation of CD137 axis, the presence of IL-15 (or its membranous form) and IL-21. By analogy with the three signals model required to activate T cells, we speculate, that the cell-to-cell contact represents “signal 1”, CD137 would be “signal 2” and cytokines would be “signal 3”. The precise nature of signal 1 remains to be defined.

Citation Format: Laurent Vidard, Christine Dureuil-Sizaire, Jérémy Baudhuin, Lionel Vescovi, Laurence Durand, Véronique Sierra, Eric Parmantier. CD137 (4-1BB) engagement fine-tunes the synergistic IL-15- and IL-21-driven NK cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1524.
Abstract 2302: Natural killer cell cancer therapy in mouse model
Authors: Huang Shih-Wen , Lai Yein-Gei , Wu Jen-Qi , Liou Yae-Huei , Liao Nan-Shih
Published: August 2019

Natural killer (NK) cells exert anti-tumor function through direct killing of tumor cells and indirect modulation of the function of other immune cells, such as T cells, dendritic cells and macrophages. However, the efficacy of adoptive NK cell transfer in cancer treatment has been limited, and only found in certain myeloid leukemia under allogeneic setting. The functional heterogeneity of NK cells and the immunosuppressive tumor microenvironment likely contribute to the limited efficacy. We establish a method to condition ex vivo expanded murine NK cells with anti-tumor activity. The conditioned NK cells are EOMES+CD127-DX5-CD49a+and CD11b+CD27+. Encountering with solid tumor cell lines in vitro enhances the production of IFN-γand triggers killing of the tumor cells by conditioned NK cells. In a syngeneic orthotopic EO771 breast cancer model, adoptive transfer of conditioned NK cells into tumor-bearing mice slows tumor progression and alters the composition and function of intra-tumor immune cells. To better imitate clinical condition, we transfer conditioned NK cells into tumor-resected mice, and found the therapy improved survival rate. We are investigating the anti-tumor mechanism of the conditioned NK cells.

Citation Format: Shih-Wen Huang, Yein-Gei Lai, Jen-Qi Wu, Yae-Huei Liou, Nan-Shih Liao. Natural killer cell cancer therapy in mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2302.