bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microinjection of kynurenic acid in the rostral nucleus of the tractus solitarius disrupts spatiotemporal aspects of mechanically induced tracheobronchial cough
Authors: Poliacek Ivan , Pitts Teresa , Rose Melanie J. , Davenport Paul W. , Simera Michal , Veternik Marcel , Kotmanova Zuzana , Bolser Donald C. 
Published: March 2017

The importance of neurons in the nucleus of the solitary tract (NTS) in the production of coughing was tested by microinjections of the nonspecific glutamate receptor antagonist kynurenic acid (kyn; 100 mM in artificial cerebrospinal fluid) in 15 adult spontaneously breathing anesthetized cats. Repetitive coughing was elicited by mechanical stimulation of the intrathoracic airway. Electromyograms (EMG) were recorded from inspiratory parasternal and expiratory transversus abdominis (ABD) muscles. Bilateral microinjections of kyn into the NTS rostral to obex [55 ± 4 nl total in 2 locations ( n = 6) or 110 ± 4 nl total in 4 locations ( n = 5)], primarily the ventrolateral subnucleus, reduced cough number and expiratory cough efforts (amplitudes of ABD EMG and maxima of esophageal pressure) compared with control. These microinjections also markedly prolonged the inspiratory phase, all cough-related EMG activation, and the total cough cycle duration as well as some other cough-related time intervals. In response to microinjections of kyn into the NTS rostral to the obex respiratory rate decreased, and there were increases in the durations of the inspiratory and postinspiratory phases and mean blood pressure. However, bilateral microinjections of kyn into the NTS caudal to obex as well as control vehicle microinjections in the NTS location rostral to obex had no effect on coughing or cardiorespiratory variables. These results are consistent with the existence of a critical component of the cough rhythmogenic circuit located in the rostral ventral and lateral NTS. Neuronal structures of the rostral NTS are significantly involved specifically in the regulation of cough magnitude and phase timing. NEW & NOTEWORTHY The nucleus of the solitary tract contains significant neuronal structures responsible for control of 1) cough excitability, 2) motor drive during cough, 3) cough phase timing, and 4) cough rhythmicity. Significant elimination of neurons in the solitary tract nucleus results in cough apraxia (incomplete and/or disordered cough pattern). The mechanism of the cough impairment is different from that for the concomitant changes in breathing.
Correlation Between Isocitrate Dehydrogenase Gene Aberrations and Prognosis of Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis
Authors: Xu Qingyu , Li Yan , Lv Na , Jing Yu , Xu Yihan , Li Yuyan , Li Wenjun , Yao Zilong , Chen Xiaosu , Huang Sai , Wang Lili , Li Yonghui , Yu Li 
Published: March 2017

Abstract
Purpose: Whether isocitrate dehydrogenase (IDH) gene aberrations affected prognosis of patients with acute myeloid leukemia (AML) was controversial. Here, we conducted a meta-analysis to evaluate their prognostic value.
Experimental Design: PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies exploring how IDH gene aberrations affected AML outcome. Pooled HRs and relative risks (RR) were calculated, along with 95% confidence intervals (CI).
Results: Thirty-three reports were included. IDH mutations seemed not to affect overall survival (OS: HR, 1.05; 95% CI, 0.89–1.23) and event-free survival (EFS: HR, 0.97; 95% CI, 0.80–1.18) when considered as a single factor, but improved accumulative incidence of relapse (CIR: HR, 1.44; 95% CI, 1.18–1.76) in patients with intermediate-risk karyotypes (IR-AML). However, IDH1 mutation conferred worse OS (HR, 1.17; 95% CI, 1.05–1.31) and EFS (HR, 1.29; 95% CI, 1.07–1.56), especially in patients with normal cytogenetics (OS: HR, 1.21; 95% CI, 1.01–1.46; EFS: HR, 1.56; 95% CI, 1.23–1.98). Prognosis of the IDH1 single-nucleotide polymorphism rs11554137 was also poor (OS: HR, 1.34; 95% CI, 1.03–1.75). IDH2 mutation improved OS (HR, 0.78; 95% CI, 0.66–0.93), particularly in IR-AML patients (OS: HR, 0.65; 95% CI, 0.49–0.86). The IDH2 (R140) mutation was associated with better OS among younger cases (HR, 0.64; 95% CI, 0.49–0.82). Treatment outcome was poor [RR for complete remission rates in IDH1 mutation: 1.21; 95% CI, 1.02–1.44; IDH2 (R172) mutation: 2.14; 95% CI, 1.61–2.85].
Conclusions: Various subtypes of IDH mutations might contribute to different prognosis and be allowed to stratify IR-AML further. Clin Cancer Res; 23(15); 4511–22. ©2017 AACR.
Abstract A29: The mechanism of differential effect of metformin on colorectal cancer stem cells: Metabolic alteration via glutamine metabolic pathway
Authors: Lee Kyoung Jin , Kim Jae Hyun , Kwon Ji-Hee , Seo Yoo Jung , Kim Tae Il 
Published: March 2017

Abstract
Background/Aim: There have been reports about cancer stem cells (CSCs) suppressing effect of metformin in several cancers. However, the differential effect of metformin on CSCs and its mechanism has not been reported. We identified various effect of metformin in suppression of colorectal CSCs and its molecular mechanism in colorectal cancer (CRC) cell lines.
Methods: Eight CRC cell lines including HT29 and SW620 cells were used. The CSC suppressing effects of metformin (10 mM), glutaminase inhibitor (compound 968, 10 μM), and combination of two drugs were measured by flow cytometry (CD133/44), and tumor sphere formation assay. AMPK and mTOR signaling were examined by Western blotting using anti-pAMPK and anti-pS6, and oxygen consumption rate was measured. The CSC inhibitory effects were also evaluated in xenografted nude mice of HT19 and SW620 cells, using immunohistochemical stain for CD133/CD44.
Results: CSCs decreased after treatment of metformin in HT29, DLD-1, and LoVo, and HCT116 cells, but not in SW620, WiDr, Colo205, and Caco-2 cells. Treatment of metformin induced pAMPK activation and pS6 suppression in HT29 cells (metformin-sensitive cells), but not in SW620 cells (metformin-resistant cells). Oxygen consumption rate was higher in HT29 cells than in SW620 cells, and showed more prominent decrease after metformin treatment in HT29 cells. In addition, SW620 cells became sensitive to metformin in CSC-suppressing effect in glutamine-depleted media, but not in low glucose media. Considering the alternative energy source of glutamine, which escapes the effect of metformin on tumor cells, we found that combination of metformin and compound 968 induced CSC-suppressing effect in SW620 cells, and enhanced that effect in HT29 cells. Further, SW620 cells showed higher expression of glutaminase and glutamine transporter than HT29 cells. In xenograft model of HT29 and SW620 cells, combined treatment of metformin and 968 also showed the same results with in vitro experiments.
Conclusion: The effect of metformin on CSCs of CRC cells is various depending on AMPK-mTOR pathway and glutamine metabolic pathway. Inhibition of glutamine pathway could enhance the CSC-suppressing effect of metformin, overcoming metformin-resistance.
Citation Format: Kyoung Jin Lee, Jae Hyun Kim, Ji-Hee Kwon, Yoo Jung Seo, Tae Il Kim. The mechanism of differential effect of metformin on colorectal cancer stem cells: Metabolic alteration via glutamine metabolic pathway. [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 A29.
Abstract B02: Blood-based epigenetic profiling of circulating cell free nucleosomes in 2000 FIT positive individuals: A novel approach to colorectal cancer detection
Authors: Herzog Marielle , Eccleston Mark , Pamart Dorian , Cuvelier Brieuc , Christensen Ib Jarle , Nielson Hans Jørgen , Micallef Jake , Terrell Jason 
Published: March 2017

Abstract
Genome wide epigenetic signals are altered in cancer cells. In addition, circulating nucleosome bound DNA fragments contain the same mutations as matched cancer tissue samples suggesting a tumor origin for at least some circulating nucleosomes. We have developed ELISA tests for circulating nucleosomes (NuQ®) and show that the profile of epigenetic features, including histone modifications and variants, DNA modifications and adducts between nucleosomes and non-histone proteins can be correlated with clinical disease and overcomes a major limitation of simple nucleosome quantification for diagnostic and prognostic use.
Validation of this approach in a retrospective cohort of 4800 patients presenting with symptoms of Colorectal diseases generated a diagnostic NuQ® panel with sensitivity of 81% at a specificity of 80% in an age adjusted linear regression model for the detection of Colorectal cancer (CRC). In a subsequent pilot prospective study of 58 subjects, a sensitivity of 91% at 90% specificity was achieved for the detection of CRC.
We now present preliminary Nucleosomics® data from the first 2000 individuals of a 14 000 asymptomatic, average risk cohort as part of a prospective clinical comparison with a national Fecal Immunological Screening (FIT) program in Denmark. Successful validation of this approach would provide an affordable, accessible and easily implemented blood based testing alternative to address relatively low compliance of fecal testing.
Note: This abstract was not presented at the conference.
Citation Format: Marielle Herzog, Mark Eccleston, Dorian Pamart, Brieuc Cuvelier, Ib Jarle Christensen, Hans Jørgen Nielson, Jake Micallef, Jason Terrell. Blood-based epigenetic profiling of circulating cell free nucleosomes in 2000 FIT positive individuals: A novel approach to colorectal cancer detection. [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 B02.
Abstract IA03: Lessons from colorectal cancer
Authors: Kinzler Kenneth W. 
Published: March 2017

Abstract
Many of the fundamental tenets of cancer genetics have their origins in the study of colorectal cancer (CRC). This is, at least in part, due to several clinical features of CRC that make it a particularly attractive and amenable to study in humans. Some of these key features include the relative abundance of CRC and precursor adenomas in the general population, the ease of identifying and collecting adenomas through routine screening colonoscopies, the existence of well recognized histopathological classifications with defined clinical implications and the long standing description of several well defined inherited predispositions. As a result, studies in CRC have often proven to be seminal in defining the role of somatic mutations and germline variations in the initiation progression and resistance of human cancer. Moreover, studies of CRC have proven to be influential beyond the aforementioned areas helping to define the roles of diet, inflammation and the microbiome in human cancer and providing new paradigms for the prevention and management of cancer. How these findings inform our understanding of CRC and cancer in general will be discussed with special emphasis on emerging topics highlighted in this conference.
Citation Format: Kenneth W. Kinzler. Lessons from colorectal cancer. [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 IA03.
Abstract IA26: Changes in diet and microbiome that mitigate CRC risk in Native Africans vs. African Americans
Authors: O'Keefe Stephen J. 
Published: March 2017

Abstract
Colon cancer is an environmental disease associated with westernization, and it has been shown that it takes one generation for immigrants to change their risk of cancer. To investigate the role of the western diet in driving this change, we have switched the macronutrient composition of diets of groups of 20 healthy middle aged African Americans, who have the highest risk of colon cancer in the USA (~65:100,000) and rural Africans, who rarely get the disease (&lt;5:100,000) and measured its impact on mucosal biomarkers of cancer risk and the colonic microbiota that we hypothesize regulate this risk. Twenty healthy middle-aged volunteers from each community were housed for two weeks so that food could be prepared and consumed under close supervision. Americans were given a “traditional African” diet, high in fiber and low in meat and fat, while Africans were given a western diet, high in meat and fat, low in fiber. Mucosal biopsies taken from the proximal, mid and distal colon at colonoscopy before and after the dietary switch showed significant suppression of inflammation and proliferation cancer biomarkers in Americans and increases in Africans. In keeping with our hypothesis, these changes were associated with changes in bacterial co-occurrences, notably those of butyrate producers, and their metabolomic phenotypes. Targeted analysis of microbes associated with saccharolytic fermentation and their products, short chain fatty acids, showed that they were strongly associated with suppression of cancer biomarkers, whilst microbes associated with bile acid deconjugation and secondary bile acid production exhibited the reverse, providing a mechanism for the strong epidemiological evidence that fiber reduces risk and fat, by increasing the hepatic synthesis of bile acids, increases risk. In conclusion, our results build on the observation that the incidence of colon cancer changes within one generation of westernization by showing that the mucosal changes associated with carcinogenesis change within two weeks of switching to a western diet and provide evidence that the change is mediated by colonic microbial metabolism.
Citation Format: Stephen J. O'Keefe. Changes in diet and microbiome that mitigate CRC risk in Native Africans vs. African Americans. [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 IA26.
Abstract A15: Development of an in vitro 3D vessel-spheroid model for investigating cancer metastasis
Authors: Munoz Adam , Miller Joseph , Reinhart-King Cynthia A. 
Published: March 2017

Abstract
During metastasis, cells break free from the primary tumor, migrate through the stroma and enter either the vascular or lymph systems to disseminate into secondary sites. To better understand this process, many groups have developed in vitro models of cancer metastasis using microfluidic based platforms to mimic the tumor microenvironment and the intravasation/extravasation of tumor cells. While these models have provided significant new insights into the mechanisms by which metastatic cells move across the endothelium, they are most often focused on the movement of single cells. Notably, there is significant clinical evidence to suggest that tumor cells can travel collectively though the stroma and can circulate as cell aggregates in the vasculature. Recent advances in the understanding of cancer metastasis have shown that cancer may move more aggressively as a collection of cell when traversing the extracellular matrix (ECM) of the tumor microenvironment as opposed to more studied singular cellular motif. To better mimic these collective movements, we have developed a model that incorporates the following essential elements that exist in the tumor microenvironment: a cylindrical channel lined with a confluent monolayer of endothelial cells, a metastatic tumor analog in close proximity to the channel, the ability to incorporate flow with tunable properties to simulate shear stress due to blood flow, and a tunable collagen microenvironment. Briefly, in a 3D printed cube, Type 1 collagen is added at physiological stiffness. As the collagen is polymerizing in the device, a metastatic tumor analog (spheroid) consisting of labeled MDA-MB-231 cells is placed in proximity of the vessel that is lined with endothelial cells. The platform allows for the visualization of metastatic cell intravasation using confocal microscopy. Notably, this model is easy to build and implement with fairly accessible tools and without the use of a clean room or microfabrication facilities. Importantly, going forward this model has the ability to study the cellular behavior post-intravasation due to the incorporation of physiological flows within the channel.
Citation Format: Adam Munoz, Joseph Miller, Cynthia A. Reinhart-King. Development of an in vitro 3D vessel-spheroid model for investigating cancer metastasis. [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 A15.
Abstract A60: Hyaluronan and cancer cell derived swelling of solid tumors and implications for cancer therapy
Authors: Voutouri Chrysovalantis , Polydorou Christiana , Papageorgis Panagiotis , Stylianopoulos Triantafyllos 
Published: March 2017

Abstract
A solid tumor is an aberrant tissue made of cancer cells and a variety of host cells—all embedded in an extracellular matrix—nourished by blood vessels and drained by lymphatic vessels. Rapid tumor growth in the confined space of the host tissue results in the accumulation of mechanical forces within structural components of the tumor, and between the tumor and the host. These forces can shape the tumor microenvironment and determine in large part tumor progression and response to treatment. Despite the important role that mechanical forces play in tumor growth, the contribution of swelling to tumor mechanics remains unexplored. Tumors rich in hyaluronan exhibit a highly negative fixed charge density. Repulsive forces among these negative charges cause swelling of the tumor and development of swelling solid stress. Additionally, fixed negative charges attract free cations from the tumor interstitial space creating an imbalance of ion distribution and a Donnan osmotic fluid pressure. Furthermore, it has been shown that tumor swelling can be produces not only by hyaluronan but also cancer cells swell due to osmotic regulation, which is required for their survival under compressive forces. In this study, we design an experimental set up to measure hyaluronan derived swelling solid stress in two orthotopic breast tumor models of different extracellular matrix composition. We also calculate the Donnan osmotic pressure and the solid stress owing to interactions with the host tissue, utilizing the experimental data and developing a triphasic biomechanical mathematical model. The mathematical model accounts for the fluid and the solid phase of a tumor and the transport of anions and cations. Furthermore, we measure the swelling of cancer cell spheroids under compressive mechanical forces in order to quantify cell derived tumor swelling. We will present data showing that swelling stress contributes significantly to tumor mechanics, whereas Donnan osmotic pressure is negligible. Interestingly, histological analysis revealed a linear correlation between swelling stress and the ratio of hyaluronan to collagen content. Our analysis further suggested an inverse relation of swelling stress to vessel diameter and tumor perfusion. These results provide guidelines for emerging therapeutic strategies that target the tumor microenvironment to alleviate swelling stress and improve perfusion and drug delivery.
Citation Format: Chrysovalantis Voutouri, Christiana Polydorou, Panagiotis Papageorgis, Triantafyllos Stylianopoulos. Hyaluronan and cancer cell derived swelling of solid tumors and implications for cancer therapy. [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 A60.
Abstract B06: Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells
Authors: Rong Fan , Emery Travis , Zhang Yongguo , Xia Yuxuan , Sun Jun , Wan Jiandi 
Published: March 2017

Abstract
During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a physiologically relevant circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viability decreased with the increase of circulating time, but increased with the magnitude of shear stress. Proliferation of cells survived from circulation could be maintained when physiologically relevant shear stresses were applied. High shear stress (60.5 dyne/cm2), however, led to decreased cell proliferation at long circulating time (1 h). We further showed that the expression levels of β-catenin and c-myc, proliferation regulators, were significantly enhanced by increasing shear stress. These data provided molecular based explanation for the observed cell viability at high shear. The presented study provides a new insight to the roles of circulatory shear stress in cellular responses of circulating tumor cells in a physiologically relevant model, and thus will be of interest for the study of cancer cell mechanosensing and cancer metastasis.
Citation Format: Fan Rong, Travis Emery, Yongguo Zhang, Yuxuan Xia, Jun Sun, Jiandi Wan. Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells. [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 B06.
Abstract B07: Visualization of the mechanisms of metastasis within a biomimetic engineered tumor microenvironment encompassing a perfusable cylindrical 3D microvessel
Authors: Wong Andrew D. , Silvestri Vanesa , Ewald Andrew J. , Searson Peter C. 
Published: March 2017

Abstract
Metastasis is responsible for the majority of cancer related deaths; however, many of the biological and physical details surrounding the critical steps (e.g. invasion and intravasation) are largely unknown, in part due to the difficulty in recapitulating and visualizing these dynamic processes. To elucidate these mechanisms, we have developed an in vitro model of invasion and intravasation that comprises tumor cells embedded within an extracellular matrix (ECM) surrounding an engineered microvessel. The microvessel is cylindrical, 150 μm in diameter, and lined with endothelial cells forming a functional barrier that is maintained under constant perfusion at a shear stress of 2-8 dyne cm-2. Using this biomimetic tumor-microvessel platform, we have previously visualized invasion and intravasation of single MDA-MB-231 breast cancer cells into the microvessel and escape into flow. Here, we present mechanistic details of intravasation from both single tumor cells (MDA-MB-231) and mouse mammary tumor organoids (MMTV-PyMT). For single cells, we observe a mitosis-mediated mechanism of intravasation where tumor cell entry into flow is prefaced by cell division at the ECM-vessel interface. For tumor organoids, we see vascular deformation and destabilization from growing tumors that impinge upon proximal vessels, and that bulk intravasation is mediated by shear stress and tumor cell adhesion. As we characterize the various ways in which tumor cells interact with the vessel endothelium and intravasate, we can explore strategies involving the tumor vasculature and clinically relevant drugs to inhibit critical steps in the metastatic cascade.
Citation Format: Andrew D. Wong, Vanesa Silvestri, Andrew J. Ewald, Peter C. Searson. Visualization of the mechanisms of metastasis within a biomimetic engineered tumor microenvironment encompassing a perfusable cylindrical 3D microvessel. [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 B07.