bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceptual and categorical decision making: goal-relevant representation of two domains at different levels of abstraction
Authors: Shankar Swetha , Kayser Andrew S.
Published: March 2017

To date it has been unclear whether perceptual decision making and rule-based categorization reflect activation of similar cognitive processes and brain regions. On one hand, both map potentially ambiguous stimuli to a smaller set of motor responses. On the other hand, decisions about perceptual salience typically concern concrete sensory representations derived from a noisy stimulus, while categorization is typically conceptualized as an abstract decision about membership in a potentially arbitrary set. Previous work has primarily examined these types of decisions in isolation. Here we independently varied salience in both the perceptual and categorical domains in a random dot-motion framework by manipulating dot-motion coherence and motion direction relative to a category boundary, respectively. Behavioral and modeling results suggest that categorical (more abstract) information, which is more relevant to subjects’ decisions, is weighted more strongly than perceptual (more concrete) information, although they also have significant interactive effects on choice. Within the brain, BOLD activity within frontal regions strongly differentiated categorical salience and weakly differentiated perceptual salience; however, the interaction between these two factors activated similar frontoparietal brain networks. Notably, explicitly evaluating feature interactions revealed a frontal-parietal dissociation: parietal activity varied strongly with both features, but frontal activity varied with the combined strength of the information that defined the motor response. Together, these data demonstrate that frontal regions are driven by decision-relevant features and argue that perceptual decisions and rule-based categorization reflect similar cognitive processes and activate similar brain networks to the extent that they define decision-relevant stimulus-response mappings.

NEW & NOTEWORTHY Here we study the behavioral and neural dynamics of perceptual categorization when decision information varies in multiple domains at different levels of abstraction. Behavioral and modeling results suggest that categorical (more abstract) information is weighted more strongly than perceptual (more concrete) information but that perceptual and categorical domains interact to influence decisions. Frontoparietal brain activity during categorization flexibly represents decision-relevant features and highlights significant dissociations in frontal and parietal activity during decision making.
Fuzzy Logic Based Hardware Accelerator with Partially Reconfigurable Defuzzification Stage for Image Edge Detection
Authors: Kurdi Aous H. , Grantner Janos L. , Abdel-Qader Ikhlas M.
Published: March 2017

In this paper, the design and the implementation of a pipelined hardware accelerator based on a fuzzy logic approach for an edge detection system are presented. The fuzzy system comprises a preprocessing stage, a fuzzifier with four fuzzy inputs, an inference system with seven rules, and a defuzzification stage delivering a single crisp output, which represents the intensity value of a pixel in the output image. The hardware accelerator consists of seven stages with one clock cycle latency per stage. The defuzzification stage was implemented using three different defuzzification methods. These methods are the mean of maxima, the smallest of maxima, and the largest of maxima. The defuzzification modules are interchangeable while the system runs using partial reconfiguration design methodology. System development was carried out using Vivado High-Level Synthesis, Vivado Design Suite, Vivado Simulator, and a set of Xilinx 7000 FPGA devices. Depending upon the speed grade of the device that is employed, the system can operate at a frequency range from 83 MHz to 125 MHz. Its peak performance is up to 58 high definition frames per second. A comparison of this system’s performance and its software counterpart shows a significant speedup in the magnitude of hundred thousand times.
Urethral Reconstruction Using Mesothelial Cell-Seeded Autogenous Granulation Tissue Tube: An Experimental Study in Male Rabbits
Authors: Jiang Shiwei , Xu Zhonghua , Zhao Yuanyuan , Yan Lei , Zhou Zunlin , Gu Gangli
Published: March 2017

Objective. This study was to evaluate the utility of the compound graft for tubularized urethroplasty by seeding mesothelial cells onto autogenous granulation tissue.Methods. Silastic tubes were implanted subcutaneously in 18 male rabbits, of which nine underwent omentum biopsies simultaneously for in vitro expansion of mesothelial cells. The granulation tissue covering the tubes was harvested 2 weeks after operation. Mesothelial cells were seeded onto and cocultured with the tissue for 7 days. A pendulous urethral segment of 1.5 cm was totally excised. Urethroplasty was performed with mesothelial cell-seeded tissue tubes in an end-to-end fashion in nine rabbits and with unseeded grafts in others as controls. Serial urethrograms were performed at 1, 2, and 6 months postoperatively. Meanwhile, the neourethra was harvested and analyzed grossly and histologically.Results. Urethrograms showed cell-seeded grafts maintained wide at each time point, while strictures formation was found in unseeded grafts. Histologically, layers of urothelium surrounded by increasingly organized smooth muscles were observed in seeded grafts. In contrast, myofibroblasts accumulation and extensive scarring occurred in unseeded grafts.Conclusions. Mesothelial cell-seeded granulation tissue tube can be successfully used for tubularized urethroplasty in male rabbits.
Rapid Chondrocyte Isolation for Tissue Engineering Applications: The Effect of Enzyme Concentration and Temporal Exposure on the Matrix Forming Capacity of Nasal Derived Chondrocytes
Authors: Vedicherla Srujana , Buckley Conor Timothy
Published: March 2017

Laboratory based processing and expansion to yield adequate cell numbers had been the standard in Autologous Disc Chondrocyte Transplantation (ADCT), Allogeneic Juvenile Chondrocyte Implantation (NuQu®), and Matrix-Induced Autologous Chondrocyte Implantation (MACI). Optimizing cell isolation is a key challenge in terms of obtaining adequate cell numbers while maintaining a vibrant cell population capable of subsequent proliferation and matrix elaboration. However, typical cell yields from a cartilage digest are highly variable between donors and based on user competency. The overall objective of this study was to optimize chondrocyte isolation from cartilaginous nasal tissue through modulation of enzyme concentration exposure (750 and 3000 U/ml) and incubation time (1 and 12 h), combined with physical agitation cycles, and to assess subsequent cell viability and matrix forming capacity. Overall, increasing enzyme exposure time was found to be more detrimental than collagenase concentration for subsequent viability, proliferation, and matrix forming capacity (sGAG and collagen) of these cells resulting in nonuniform cartilaginous matrix deposition. Taken together, consolidating a 3000 U/ml collagenase digest of 1 h at a ratio of 10 ml/g of cartilage tissue with physical agitation cycles can improve efficiency of chondrocyte isolation, yielding robust, more uniform matrix formation.
An Improved Model of Variable Fuzzy Sets with Normal Membership Function for Crane Safety Evaluation
Authors: Li Aihua , Zhao Zhangyan
Published: March 2017

Crane safety evaluation is significant for reducing the casualties and economic losses. Various evaluation methods have been applied to evaluate crane safety. However, when index standard with respect to every level is described in terms of intervals, existing crane safety evaluation models are not ideal. Although variable fuzzy sets (VFS) method has successfully solved similar problems, its evaluation processes are rather complex complicated and tedious. In this paper, we provided an improved VFS evaluation method with normal membership function for solving crane safety problem, in which the evaluation criteria are described in terms of intervals. To demonstrate our presented method, the improved variable fuzzy sets (IVFS) method was applied to two numerical cases including an application to crane safety assessment. It is shown that our proposed method possesses the merit to simplify assessment processes of traditional VFS and can be applied to assess crane safety when criteria values are defined as interval numbers.
Addison’s Disease and Possible Cannabis Withdrawal Syndrome Presenting as an Eating Disorder in a Thirty-Year-Old Female
Authors: Lazare Kimberly
Published: March 2017

A 30-year-old female with a history of anxiety, cannabis use, and Avoidant/Restrictive Food Intake Disorder presented for residential treatment of a Cannabis Use Disorder. Upon arrival, she had not eaten for two days and was found to be hypotensive with electrolyte disturbances. She was admitted to a nearby hospital, where the Internist diagnosed her with Addison’s disease. She was treated with corticosteroid therapy, with rapid normalization of her electrolytes, eating, and anxiety. This is the first published case of undiagnosed Addison’s disease presenting as an eating disorder, with cannabis use likely contributing to symptoms. This case elucidates the importance of ruling out other biologic and psychologic causes of clinical presentations before an eating disorder diagnosis can be made.
Physicochemical Characterization and Cyclodextrin Complexation of the Anticancer Drug Lapatinib
Authors: Tóth Gergő , Jánoska Ádám , Völgyi Gergely , Szabó Zoltán-István , Orgován Gábor , Mirzahosseini Arash , Noszál Béla
Published: March 2017

Lapatinib (LAP), the tyrosine kinase inhibitor drug with moderate bioavailability, was characterized in terms of physicochemical properties: acid-base characteristics, lipophilicity, and solubility. The highly lipophilic nature of the drug and its extremely low water solubility (S0=0.82 nM) limit the development of a parenteral formulation. In order to enhance solubility and bioavailability, inclusion complex formation with cyclodextrins (CDs) is a promising method of choice. Therefore, LAP-CD interactions were also studied by a multianalytical approach. The stability constants of LAP with native cyclodextrins, determined by UV spectroscopy, identified the seven-membered β-CD as the most suitable host. Continuous variation method (Job’s plot) by 1H NMR showed a 1 : 1 stoichiometry for the complexes. The geometry of the complex was elucidated by 2D ROESY NMR measurements and molecular modeling, indicating that the partial molecular encapsulation includes the fluorophenyl ring of LAP. Phase-solubility studies with four CDs, β-CD, (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), randomly methylated-β- (RAMEB-) cyclodextrin, and sulfobutylether-β-cyclodextrin (SBE-β-CD), show an AL type diagram and highly increased solubility via CD complexation. The results are especially promising with SBE-β-CD, exerting more than 600-fold gain in solubility. The equilibrium and structural information presented herein can offer the molecular basis for an improved drug formulation with enhanced bioavailability.
The Optimal Strategies of Risk-Averse Newsvendor Model for a Dyadic Supply Chain with Financing Service
Authors: Chen Jianxin
Published: March 2017

This paper studies the budget-constrained newsvendor problem under risk aversion with financing service and builds a two-stage supply chain decision model on the order quantity and wholesale price. The budget-constrained retailer as a newsvendor faces a nonnegative random demand and the financial institution provides the loan service for the retailer who is risk-averse. This paper first explores the impact of risk aversion on the decisions in financial supply chain. Different from the existing research, we analyze how the financing service of bank loan impacts the risk-averse newsvendor’s decision and how the risk-averse behavior of the retailer influences the optimal strategies in supply chain with CVaR risk measure criterion. It is found that the order quantity decreases in the degree of risk aversion. The optimal order quantity is decreasing in initial budget, wholesale price, and interest rate. It is worth noting that the financing service can improve the profit of the supply chain system when the retailer has a low initial wealth. Finally, to compare with the existing results the theoretical analysis and numerical examples are also illustrated.
A Secure Steganographic Algorithm Based on Frequency Domain for the Transmission of Hidden Information
Authors: Soria-Lorente A. , Berres S.
Published: March 2017

This contribution proposes a novel steganographic method based on the compression standard according to the Joint Photographic Expert Group and an Entropy Thresholding technique. The steganographic algorithm uses one public key and one private key to generate a binary sequence of pseudorandom numbers that indicate where the elements of the binary sequence of a secret message will be inserted. The insertion takes eventually place at the first seven AC coefficients in the transformed DCT domain. Before the insertion of the message the image undergoes several transformations. After the insertion the inverse transformations are applied in reverse order to the original transformations. The insertion itself takes only place if an entropy threshold of the corresponding block is satisfied and if the pseudorandom number indicates to do so. The experimental work on the validation of the algorithm consists of the calculation of the peak signal-to-noise ratio (PSNR), the difference and correlation distortion metrics, the histogram analysis, and the relative entropy, comparing the same characteristics for the cover and stego image. The proposed algorithm improves the level of imperceptibility analyzed through the PSNR values. A steganalysis experiment shows that the proposed algorithm is highly resistant against the Chi-square attack.
Recurrent Intrathoracic Locking of the Scapula after Lung Cancer Resection and Combined Rib Resection
Authors: Kimura Akinori , Sasanuma Hideyuki , Ajiki Takashi , Sekiya Hitoshi , Takeshita Katsushi
Published: March 2017

We report a case of recurrent locking of the scapula in the thorax after combined lobectomy and thoracic wall resection for advanced lung cancer. The patient was a 52-year-old man with advanced spindle cell carcinoma in his right lung. He had undergone right lung lobectomy and thoracic wall excision (Th1–5). Intrathoracic repair had not been performed to address the defect in the thoracic wall. Two months after the operation he experienced sudden acute pain in the right shoulder. Three-dimensional computed tomography revealed locking of the scapula intrathoracically. The diagnosis was recurrent locking of the scapula in the thorax. He underwent conservative treatment. Because his symptoms were not alleviated and he continued to experience recurrent locking, we performed partial resection of the inferior part of the scapula. Although scapular locking diminished after this procedure, there were still some pain and “catching” between the scapula and the thoracic wall (T6) when he undertook certain movements. No further surgery could be performed, however, because the cancer from the primary lesion had recurred near the previously operated thoracic wall. A procedure for recurrent intrathoracic locking of the scapula was not successful in this case.
Quantitative Analysis of the Security of Software‐Defined Network Controller Using Threat/Effort Model
Authors: Wu Zehui , Wei Qiang
Published: March 2017

SDN‐based controller, which is responsible for the configuration and management of the network, is the core of Software‐Defined Networks. Current methods, which focus on the secure mechanism, use qualitative analysis to estimate the security of controllers, leading to inaccurate results frequently. In this paper, we employ a quantitative approach to overcome the above shortage. Under the analysis of the controller threat model we give the formal model results of the APIs, the protocol interfaces, and the data items of controller and further provide our Threat/Effort quantitative calculation model. With the help of Threat/Effort model, we are able to compare not only the security of different versions of the same kind controller but also different kinds of controllers and provide a basis for controller selection and secure development. We evaluated our approach in four widely used SDN‐based controllers which are POX, OpenDaylight, Floodlight, and Ryu. The test, which shows the similarity outcomes with the traditional qualitative analysis, demonstrates that with our approach we are able to get the specific security values of different controllers and presents more accurate results.
Quantitative Analysis of Efficiency Improvement of a Propulsion Drive by Using SiC Devices: A Case of Study
Authors: Kumar Kundan , Bertoluzzo Manuele , Buja Giuseppe , Ortenzi Fernando
Published: March 2017

One of the emerging research topics in the propulsion drive of the electric vehicles is the improvement in the efficiency of its component parts, namely, the propulsion motor and the associated inverter. This paper is focused on the efficiency of the inverter and analyzes the improvement that follows from the replacement of the silicon (Si) IGBT devices with silicon carbide (SiC) MOSFETs. To this end, the paper starts by deriving the voltage-current solicitations of the inverter over the working torque-speed plane of the propulsion motor. Then, a proper model of the power losses in the inverter over a supply period of the motor is formulated for the two types of device, including the integrated freewheeling diode. By putting together the voltage-current solicitations and the device power losses, the efficiency maps of the Si IGBT and SiC MOSFET inverters are calculated and compared over the torque-speed plane. The results for the Si IGBT inverter are supported by measurements executed on a marketed C-segment compact electric car, while the SiC MOSFET loss model is validated by an on-purpose built test bench. Finally, the overall efficiency of the propulsion drive is calculated by accounting for the motor efficiency. Main outcomes of the paper is a quantitative evaluation of both the improvement in the efficiency achievable with the SiC MOSFETs and the ensuing increase in the electric car range.
Interplay between Immune Checkpoint Proteins and Cellular Metabolism
Authors: Lim Sangbin , Phillips Joshua B. , Madeira da Silva Luciana , Zhou Ming , Fodstad Oystein , Owen Laurie B. , Tan Ming
Published: March 2017

With the recent successes in immuno-oncology, renewed interest in the role of immune checkpoint modulators, such as the B7 family proteins, has escalated. The immune checkpoint proteins play a crucial role in the regulation of cellular immunity; however, their contribution to other aspects of cancer biology remains unclear. Accumulating evidence indicate that immune checkpoint proteins can regulate metabolic energetics of the tumor, the tumor microenvironment, and the tumor-specific immune response, leading to metabolic reprogramming of both malignant cells and immune cells involved in mounting and sustaining this response. Immune cell metabolism impacts the activation status of immune cells and ultimately the immune response in cancer. Tumor cells may deplete nutrients that immune cells require for optimal generation, expansion, and function. They may also generate toxic metabolites in the microenvironment or induce conserved inhibitory pathways that impair immune function and thus inhibit antitumor responses. In this review, we will discuss how cancer cells with altered expression of immune checkpoint proteins can potently inhibit immune function through the alteration of cellular and microenvironmental metabolism, providing a new perspective on the interplay between these pathways and offering a potential therapeutic intervention strategy in the treatment of malignant disease. Cancer Res; 77(6); 1245–9. ©2017 AACR.
Abstract B29: Reorganization of signaling modules revealed in human colorectal cancer using single-cell mass cytometry
Authors: Simmons Alan J. , Scurrah Cherie R. , McKinley Eliot T. , Herring Charles A. , Irish Jonathan M. , Washington Mary K. , Coffey Robert J. , Lau Ken S.
Published: March 2017

Cellular heterogeneity poses a significant challenge to understanding tissue level phenotypes, and confounds conventional bulk analyses. To facilitate the analysis of signaling at the single-cell level in human tissues, we, for the first time, applied mass cytometry using CyTOF (Cytometry Time-of-Flight) to formalin-fixed paraffin-embedded (FFPE) normal and diseased intestinal specimens. We developed and validated FFPE-DISSECT (Disaggregation for Intracellular Signaling in Single Epithelial Cells from Tissue), a single-cell approach for preserving and characterizing native signaling states from embedded solid tissue samples. We applied FFPE-DISSECT coupled to mass cytometry to demonstrate differential TNF-α signaling in intestinal enterocytes, goblet cells and enteroendocrine cells, implicating the role of the RAS-RAF-MEK-ERK signaling pathway in goblet cell identity. In addition, application of FFPE-DISSECT, mass cytometry, and data-driven computational analyses of human colorectal cancer specimens confirmed reduction of differentiation and revealed quantitative changes in inter- and intra-tumoral heterogeneity with regards to the modular regulation of signaling pathways. Our single-cell approach, applied in conjunction with genomic annotation such as microsatellite and K-Ras and B-RAF status, allows rapid and detailed characterization of cellular heterogeneity from clinical repositories of embedded human tissues.

Citation Format: Alan J. Simmons, Cherie R. Scurrah, Eliot T. McKinley, Charles A. Herring, Jonathan M. Irish, Mary K. Washington, Robert J. Coffey, Ken S. Lau. Reorganization of signaling modules revealed in human colorectal cancer using single-cell mass cytometry. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B29.
Abstract IA07: Germline next-generation sequencing panels for detection of inherited colorectal cancer syndromes
Authors: Yurgelun Matthew B.
Published: March 2017

Background: Germline genetic testing for hereditary cancer predisposition syndromes can prevent cancer and save lives by identifying individuals who will benefit from enhanced surveillance, prophylactic surgery, and other risk-reduction strategies. Classically, hereditary cancer risk assessment has involved identification of individuals with clinical histories that fulfill specific criteria for a given syndrome followed by germline testing for mutations in the associated gene(s). Recent advances in next-generation sequencing technologies now allow individuals to undergo germline evaluation of numerous genes in parallel and a growing array of multigene panels are clinically available for such diagnostic testing.

Methods: This presentation will discuss updates in clinical genetic testing, specifically the growing availability of next-generation sequencing multigene panel testing for hereditary cancer risk assessment.

Findings: Data regarding next-generation sequencing multigene panel testing will be presented and will be contrasted with traditional, syndrome-specific hereditary colorectal cancer risk assessment strategies. Particular areas of focus in this talk will include: the detection of unexpected/off-target germline mutations by multigene panels (e.g. BRCA1/2 mutations in patients with colorectal cancer); cost-effectiveness considerations; the significance of moderate-penetrance cancer susceptibility gene mutations; germline variants of uncertain significance; and ways in which multigene panel testing results are expanding knowledge (and uncertainty) about both well- and poorly-defined colorectal cancer predisposition syndromes.

Conclusions: Next-generation sequencing multigene panels are rapidly growing in popularity and availability for assessing hereditary cancer risk, including the identification of germline mutations linked to inherited colorectal cancer risk. In order for patients considering such testing to receive optimal care, it is essential that both they and their providers have a clear understanding of the benefits and potential limitations of multigene panels, including the possibility of identifying unexpected and/or indeterminate germline results.

Citation Format: Matthew B. Yurgelun. Germline next-generation sequencing panels for detection of inherited colorectal cancer syndromes. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA07.
Abstract IA08: Polyposis beyond FAP (and APC)
Authors: Kuiper Roland P.
Published: March 2017

Familial adenomatous polyposis (FAP) is the most common high-penetrant Mendelian syndrome predisposing to adenomatous polyposis. FAP is caused by monoallelic germline mutations in the gene APC, and shows autosomal dominant inheritance. A somatic mutation in the remaining wild type APC allele results in loss of APC activity, which is one of the initiating events of adenoma development. The high proliferation rate in the colorectum increases the chance that an intestinal epithelium cell obtains this somatic second hit, which explains why FAP patients usually develop hundreds to thousands of adenomatous polyps and, if untreated, inevitably develop colorectal cancer (CRC).

Nevertheless, the majority of polyposis patients and families are not explained by mutations in APC. Since the discovery of FAP in 1991, several additional polyposis syndromes have been discovered, usually associated with lower number of polyps and somewhat less elevated risk of CRC. Many of the genes underlying these syndromes play a role in DNA repair and have a wider tumor spectrum. As becomes apparent from the somatic mutation profiles in tumors of these polyposis patients, these DNA repair deficiencies cause increased somatic mutation rates that affect proliferating tissues like the colon, and accelerate the formation of polyps and carcinomas. As an example, polymerase proofreading associated polyposis (PPAP) is a recently discovered autosomal dominant syndrome caused by mutations in the exonuclease domains of the polymerase genes POLE and POLD1. In addition, mutations in the base excision repair genes MUTYH and NTHL1, and the mismatch repair gene MSH3 underlie autosomal recessive polyposis syndromes. Notably, the incidences of these syndromes, particularly those recently discovered, are low. The question therefore arises how many more genes in which mutations cause high-penetrant polyposis still await their discovery. Here, I will present the latest findings on NTHL1-associated polyposis, it's expected incidence and its phenotypic characteristics. Furthermore, I will discuss the possible role of other DNA glycosylase genes of the base excision repair pathway in the development of polyposis and colorectal cancer.

Citation Format: Roland P. Kuiper. Polyposis beyond FAP (and APC). [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA08.
Abstract A34: Modeling and analysis of YAP/TAZ activity integrating mechanosensing and the Hippo pathway
Authors: Sun Meng , Spill Fabian , Zaman Muhammad
Published: March 2017

With the recent enormous progress in uncovering the roles of YAP/TAZ in cell proliferation, differentiation, tissue organization and tumorgenesis, the crosstalk of YAP/TAZ mechanical regulators and the Hippo pathway regulators (the cell-cell adhesion) remains largely elusive. To bridge the current gap in our understanding, we present a computational model predicting YAP/TAZ activity depending on ECM mechanical properties, cell-cell adhesions, and more importantly, the crosstalk between the two. We propose a mechanism of the interaction between LIMK and LATS to explain the unresolved synergistic effect of YAP/TAZ activity between the mechano-sensing and the Hippo pathways. Using this computational model, we are able to analyze the synergistic effects of YAP/TAZ driven by the LIMK-LATS mechanism or by the AMOT mechanism, which is another key candidate for the crosstalk.

Cancer cell lines that have downregulated E-cadherin expression overcoming the LATS-dependent YAP/TAZ contact inhibition regulation, and the mechanical sensing of YAP/TAZ serves as an important checkpoint for regulating tumor progression. We are able to quantitatively predict the YAP/TAZ activity as a function of mechanical ECM properties (stiffness response function) in these systems. Our model aims to bridge the gap by including mechano-to-biochemical signal conversion by adhesion molecules, intracellular signal transmission, cytoskeleton dynamics, and regulation of effectors relevant to directing transcriptional programs, such as YAP/TAZ activity. Such an integrated molecular model predicts effects of molecular inhibitors or changes in mechanical propertiesin silico, and the difference in 2D and 3D. For example, adhesion molecules such as FAK can shift the stiffness response function horizontally, such that FAK overexpression rescues YAP/TAZ activity in soft environments. The model also predicts that the sensitivity of YAP/TAZ activity to ECM mechanical properties is higher than the one of SRF/MAL, which is another important regulator of differentiation and regulated by cytoskeleton dynamics.

Overall, our model provides a novel platform of studying YAP/TAZ activity in the context of integrating different signaling pathways. This platform can be used to gain new fundamental insights into the role of key molecular and mechanical regulators on development, tissue engineering or tumor progression.

Citation Format: Meng Sun, Fabian Spill, Muhammad Zaman. Modeling and analysis of YAP/TAZ activity integrating mechanosensing and the Hippo pathway. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A34.
Abstract A40: A novel, biosynthetic 3D hydrogel system for breast cancer mechanobiology studies
Authors: Blatt Amy Elissa , Carrion Bita , Coleman Rhima M.
Published: March 2017

Breast tumor cell-extracellular matrix (ECM) interactions drive malignant transformation, invasion, and metastasis of breast cancer cells and contribute to treatment resistance. The tumor microenvironment, composed of multiple ECM components, activate mechanochemical pathways associated with breast cancer progression and signaling of runt-related transcription factor 2 (Runx2). There is an urgent need to model these interactions in physiologically relevant three-dimensional (3D) models in vitro. We recently demonstrated that we can create 3D PEG hydrogel systems, containing type I collagen, Arg-Gly-Asp (RGD), and hyaluronic acid, whose stiffness can be tuned independent of the number of ECM components incorporated. In this study, we demonstrate that these hydrogels can be utilized to mimic the in vivo tumor microenvironment. We examined the behavior of breast cancer cell lines MDA-MB-231 (invasive) and MCF7 (non-invasive) as well as MCF10A (non-tumorigenic mammary epithelial cells) in our novel, biosynthetic hydrogel systems. We showed that these hydrogels supported growth for each cell line and formation of acinar structures over a 23-day period in vitro. In future studies, we will assess the migratory behaviors of these cell lines in vitro using microfluidic devices as well as Runx2 expression and activity to determine the influence of matrix physiochemical properties on the invasive potential of breast tumor cells. This novel, biosynthetic system represents a reproducible framework where tumor cell behavior may be quantified as a function of a complex system in which combined microenvironmental parameters, including matrix stiffness, ECM composition, and their interactions, are systematically varied.

Citation Format: Amy Elissa Blatt, Bita Carrion, Rhima M. Coleman. A novel, biosynthetic 3D hydrogel system for breast cancer mechanobiology studies. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A40.
Abstract B40: P-selectin is a nanotherapeutic delivery target to the tumor microenvironment
Authors: Heller Daniel A.
Published: March 2017

Disseminated tumors are poorly accessible to nanoscale drug delivery systems due to the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases using this property. We found unexpectedly that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we employed a polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK inhibitor at tumor sites in both primary and metastatic models, resulting in superior anti-tumor efficacy. On non-expressing tumors, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon in unirradiated tumors, suggesting a potential strategy to target disparate drug classes to almost any tumor.

Citation Format: Daniel A. Heller. P-selectin is a nanotherapeutic delivery target to the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B40.
Abstract B48: Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance
Authors: Ven Anne L. van de , Tangutoori Shifalika , Baldwin Paige , Qiao Ju , Gharagouzloo Codi , Seitzer Nina , Clohessy John , Korideck Houari , Makrigiorgos G. Mike , Cormack Robert , Pandolfi Pier Paolo , Sridhar Srinivas
Published: March 2017

Prostate cancers with PTEN deletions are promising candidates for DNA repair inhibitors such as olaparib and talazoparib. Here we show that radiation-resistant cells and tumors derived from Ptenpc-/-;Trp53pc-/- mice are rendered radiation-sensitive following pre-treatment with liposomal nanoOlaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to nanoformulated Olaparib alone. In animals, twice-weekly intravenous administration of nanoOlaparib alone results in significant tumor growth inhibition. When nanoOlaparib is administered prior to radiation, we find that a single dose of radiation is sufficient to increase mouse survival time by as much as 10 weeks (study duration = 13 weeks). Using ferumoxytol as a surrogate nanoparticle, magnetic resonance imaging (MRI) studies revealed that nanoOlaparib administration enhances the ability of nanoparticles to accumulate in tumors. Compared to untreated and radiation-only controls, nanoOlaparib-treated tumors showed 18-fold higher nanoparticle accumulation, suggesting that the in vivo efficacy of nanoOlaparib may be potentiated by its ability to enhance its own accumulation in tumors.

Citation Format: Anne L. van de Ven, Shifalika Tangutoori, Paige Baldwin, Ju Qiao, Codi Gharagouzloo, Nina Seitzer, John Clohessy, Houari Korideck, G. Mike Makrigiorgos, Robert Cormack, Pier Paolo Pandolfi, Srinivas Sridhar. Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B48.
Abstract B56: Breaching endosomal barriers for carried-mediated intracellular delivery of messenger RNA
Authors: Patel Siddhrath , Sahay Gaurav
Published: March 2017

RNA therapeutics represents a new class of modern medicine for targets considered undruggable. Lipid based nanoparticles (LNPs) based platforms remain the most advanced in clinical trials for RNA based drugs. Yet, the lack of mechanistic insights into the cellular trafficking and endosomal escape of nanoparticles has become a major hurdle for efficient intracellular delivery. We have 1) Dissected the productive sites for endosomal escape by utilizing an CRISPR/Cas9 based genetically altered cells targeted against endosomal proteins, that direct nanoparticles towards the early, recycling, late or lysosomal delivery. The disruption of key steps in endocytic trafficking revealed the active sites for endosomal escape 2) Identified novel compounds that improve escape from productive endocytic compartments. These molecules were selected based on their properties of influencing endo/lysosomal system that can trigger endosomal escape. Our investigation reveals that endo/lysosomal transport drives intracellular delivery of LNP delivered mRNA and we were able to pinpoint key stages of endosomal escape using genetically altered cells. Novel compounds that can improve cytosolic delivery of mRNA have been identified and are being further interrogated for their ability to breach endosomal barriers. Our goal is to unlock the mechanisms of carrier-mediated intracellular delivery, unravel productive sites of endosomal escape and identify compounds that enable intracellular mRNA delivery for the treatment of various devastating disorders including cancer.

Citation Format: Siddhrath Patel, Gaurav Sahay. Breaching endosomal barriers for carried-mediated intracellular delivery of messenger RNA. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B56.
Abstract PR09: Polymeric mechanical amplifiers of tumor apoptosis
Authors: Mitchell Michael John , Langer Robert
Published: March 2017

Regulation of receptor-mediated phenomenon at the nanoscale in a controlled manner remains a challenge for a broad range of fields, including cell biology, medicine, and bioengineering. Fluid forces play a crucial role in receptor-mediated signaling necessary for physiological function, while materials such as nanoparticles have demonstrated potential for spatiotemporal control of cellular signaling. Here, we have developed polymeric mechanical amplifiers that tether to the cell surface and increase receptor-mediated apoptosis in the presence of physiological fluid flow. The mechanical amplifiers consist of both non-degradable and biodegradable polymer nanoparticles that are tethered to the surface of tumor cells via polyethylene glycol (PEG) linkers. Tethered nanoparticles, in the presence of fluid shear forces observed in vivo, increased the therapeutic effect of a TNF superfamily death ligand (TRAIL) on colon and prostate tumor cells by as much as 50% compared to soluble TRAIL treatment alone, while exerting negligible toxic effects on normal cells. Increasing the number of nanoparticles conjugated to the tumor cell surface enhanced TRAIL-mediated apoptosis under fluid shear exposure, while the therapeutic effect under static conditions was not altered. Our results suggest that the enhanced therapeutic response using polymeric nanoparticles is both receptor-mediated apoptosis-specific and does not affect doxorubicin efficacy. Inhibition studies indicate the response is caspase signaling-dependent, and increased tumor cell death receptor expression in the presence of shear forces is also observed. We show that targeted polymeric nanoparticles delivered to tumor cells in vivo mechanically amplified a subsequent treatment of soluble TRAIL, and reduced both circulating tumor cells in blood and overall tumor cell burden in vivo by over 90%. We conclude that surface-bound polymeric nanoparticles enhance receptor-mediated apoptosis in the presence of physiological shear forces, and represents a potentially new application for a broad range of nanotechnologies to maximize the capacity of receptor-mediated signaling and function in the presence of a ligand.

This abstract is also being presented as Poster B35.

Citation Format: Michael John Mitchell, Robert Langer. Polymeric mechanical amplifiers of tumor apoptosis. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR09.
Abstract BS2-2: PTEN loss by exosomal microRNA primes brain metastasis outgrowth
Authors: Yu D
Published: March 2017

Of 1.6 million newly diagnosed breast cancer patients per year, about 10-16% will develop brain metastases. Among the different subtypes of breast cancer, HER2-overexpressing (HER2+) and triple-negative breast cancers (TNBC) have the highest incidence of brain metastasis. Recently, advances in targeted therapies for breast cancer (e.g., trastuzumab, T-DM1, and lapatinib) have prolonged patient survival through better control of the systemic disease. However, when patients have disease recurrence, their brain metastasis incidence doubles, which represents an imposing challenge. Current treatment options are limited and merely palliative for those patients with brain-metastatic breast cancer, and their one year survival is less than 20%. To develop effective treatments for brain metastasis, we strived to gain global understanding of the mechanisms of brain metastasis to guide rapid development of novel and clinically applicable targeted therapies.

We recently found that the brain astrocytes secrete exosomes that contain PTEN-targeting miR-19a, among other biomolecules. After brain metastatic tumor cells uptake these astrocytes-derived exosomes, miR-19a reversibly downregulates PTEN expression in metastatic tumor cells, thereby increasing Akt and NF-kB signaling, leading to an increased secretion of CCL2 cytokine. CCL2 then recruits CCR2 positive and Iba1 positive myeloid cells that promote proliferation and inhibit apoptosis of brain metastatic tumor cells and facilitate metastatic tumor outgrowth to symptomatic brain metastasis. Importantly, inhibition of exosome secretion or stable ablation of CCL2 inhibits brain metastasis outgrowth in vivo, demonstrating the potential of exosome- and CCL2-targeting for therapeutic intervention of life-threatening brain metastases (Nature, 11/2015). Currently, we are exploring the clinical potential by systematic preclinical testing in animal models.

Citation Format: Yu D. PTEN loss by exosomal microRNA primes brain metastasis outgrowth [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr BS2-2.
Abstract CS1-1: The genomics of metastatic breast cancer: What are we learning?
Authors: Wagle N
Published: March 2017

Over the past decade, genomic characterization of tumors from cancer patients obtained through large-scale sequencing projects has shed enormous light on the molecular underpinnings of cancer. These discoveries have, in turn, led to the development of novel therapies and preventive measures that have already revolutionized cancer care. Despite this tremendous progress, our understanding of the genomics of metastatic breast cancer – and in particular cancers that have developed resistance to therapies – remains incomplete. In this presentation, we will discuss recent and ongoing studies that focus on the genomics of metastatic breast cancer, and how the learnings from these studies are influencing precision medicine strategies for patients with advanced breast cancer. We will focus on how genomic and molecular characterization of metastatic tumor samples from patients can shed light on the biology of metastatic breast cancer and can enable the development of strategies to overcome or prevent drug resistance. We will discuss the landscape of mutations in metastatic breast cancer, the potential clinical impact of genomic profiling, and the incorporation of genomic information into clinical care and clinical trials. We will also discuss how partnering directly with patients, in projects such as The Metastatic Breast Cancer Project (mbcproject.org), enables rapid identification of large numbers of patients willing to share tumors, saliva, and medical records to accelerate this research.

Citation Format: Wagle N. The genomics of metastatic breast cancer: What are we learning? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr CS1-1.
Abstract ES4-2: Ex vivo and in vivo approaches to studying the immune tumor microenvironment
Authors: Lee PP
Published: March 2017

Tumors consist not only of cancer cells, but also stromal and immune cells that constitute the tumor microenvironment (TME). Clinical outcome and response to therapy depend on the complex interplay between these cell populations within the TME. Cancer drug development has traditionally relied on screening against cancer cell lines on plastic dishes before in vivo testing. It is increasingly clear that cancer cell lines in 2D do not fully reflect the biology of primary cancer cells within the complex 3D TME. In the new era of cancer immunotherapy, models also need to incorporate immune cells. In this educational session, we will discuss new ex vivo and in vivo approaches to studying the immune tumor microenvironment and response to therapy. These include patient-derived tumor organoids (PDO), patient-derived xenografts (PDX), and humanized mouse models to evaluate cancer immunotherapies.

Citation Format: Lee PP. Ex vivo and in vivo approaches to studying the immune tumor microenvironment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES4-2.