bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decisions in motion: passive body acceleration modulates hand choice
Authors: Bakker Romy S. , Weijer Roel H. A. , van Beers Robert J. , Selen Luc P. J. , Medendorp W. Pieter 
Published: March 2017

In everyday life, we frequently have to decide which hand to use for a certain action. It has been suggested that for this decision the brain calculates expected costs based on action values, such as expected biomechanical costs, expected success rate, handedness, and skillfulness. Although these conclusions were based on experiments in stationary subjects, we often act while the body is in motion. We investigated how hand choice is affected by passive body motion, which directly affects the biomechanical costs of the arm movement due to its inertia. With the use of a linear motion platform, 12 right-handed subjects were sinusoidally translated (0.625 and 0.5 Hz). At 8 possible motion phases, they had to reach, using either their left or right hand, to a target presented at 1 of 11 possible locations. We predicted hand choice by calculating the expected biomechanical costs under different assumptions about the future acceleration involved in these computations, being the forthcoming acceleration during the reach, the instantaneous acceleration at target onset, or zero acceleration as if the body were stationary. Although hand choice was generally biased to use of the dominant hand, it also modulated sinusoidally with the motion, with the amplitude of the bias depending on the motion’s peak acceleration. The phase of hand choice modulation was consistent with the cost model that took the instantaneous acceleration signal at target onset. This suggests that the brain relies on the bottom-up acceleration signals, and not on predictions about future accelerations, when deciding on hand choice during passive whole body motion. NEW & NOTEWORTHY Decisions of hand choice are a fundamental aspect of human behavior. Whereas these decisions are typically studied in stationary subjects, this study examines hand choice while subjects are in motion. We show that accelerations of the body, which differentially modulate the biomechanical costs of left and right hand movements, are also taken into account when deciding which hand to use for a reach, possibly based on bottom-up processing of the otolith signal.
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.
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

AbstractWith 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.