tbuckley/cabot-search huggingface dataset:
Abstract 3810: Ovarian tumor-induced changes in macrophage phenotype are associated with tumor metastasis
Authors: Aparna Yellapa, Pincas Bitterman, Sameer Sharma, Sanjib Basu, Animesh Barua
Journal: Cancer Research (2018)

Abstract Background: Ovarian cancer (OVCA) differs from other gynecologic malignancies in its dissemination pattern where the tumor migrates in a diffuse intrapelvic and -abdominal manner. OVCA also triggers a variety of cellular and/or humoral immune responses to a variety of tumor-associated proteins. OVCA is mostly diagnosed at late stages where tumor has already metastasized, indicating an escape from immune responses. Despite several immune response factors, ovarian tumor metastasizing to omentum indicates presence of one or more immune evasion mechanisms. Immune system recognizes and eliminates pathogenic products and tumor cells and macrophages play a critical role in this process. Macrophages in tumor condition express anti-inflammatory cytokines that induce immune suppression. Cellular immune response maximizes killing efficacy of macrophages and proliferation of CD8+ T cells. M2 macrophages are tumor-associated macrophages involved in active growth and progression of tumors. However, the mechanism of ovarian tumor-induced changes in M1 macrophages to M2 phenotype is not well understood. Therefore, the goal of our study was to determine the tumor-induced changes in macrophage phenotype and cytotoxic T cells in association with OVCA metastasis. Materials and Methods: This study was performed in exploratory design using ovarian specimen from normal subjects (60-80 years, n=10) and ovarian malignant tumors at early (n=16, 4 from each histologic type of OVCA) and late stages (n =20) as well as omental tissues from normal (n=3) and OVCA patients (n= 3). Tissue specimen were processed for immunohistochemistry (IHC), Western blotting (WB) and gene expression studies. Expression of M1 and M2 macrophages, CD8 and PI3K was examined by immunohistochemistry (IHC), Western blotting (WB) and qPCR. Results: Compared with normal ovaries, more M1 and M2 macrophages were localized in tumor tissues. However, compared with early-stage OVCA, the frequency of M2 macrophages was significantly higher in ovarian tumors and omental tissues at late OVCA. Intensity of PI3K was also higher in ovarian tumors and omental tissues at late OVCA compared with normal ovarian tissues. Frequency of CD8+T cells was higher in tumor ovarian samples in comparison with normal ovarian tissues. Conclusion: Results of this study suggest that the growth and metastasis of ovarian tumors are associated with increased conversion of M1 macrophages to M2 phenotype. This change in macrophage phenotype may be mediated by the increase in PI3K expression. Support: Swim Across America. Citation Format: Aparna Yellapa, Pincas Bitterman, Sameer Sharma, Sanjib Basu, Animesh Barua. Ovarian tumor-induced changes in macrophage phenotype are associated with tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3810.
Abstract 3920: nfP2X7mediates survival of cancer cells in the tumor microenvironment
Authors: Simon Mark Gilbert, Christopher John Oliphant, Anne-Lise Peille, Peter Bronsert, Francesco Di Virgilio, Shaun McNulty, Romain Lara
Journal: Cancer Research (2018)

Abstract The purpose of this study was to demonstrate the effect of the tumor microenvironment (TME) on expression of nfP2X7, a cancer specific form of P2X7 involved in cancer cell survival. P2X7 is an ATP-gated receptor, involved in inflammation, cell death, cell proliferation and cell migration. Alterations in these cellular processes are associated with the development of cancer. P2X7 is characterized by its capacity to open a large molecular weight pore in response to prolonged ATP activation. A mechanism that triggers membrane depolarisation and cell death. The TME contains high concentrations of ATP sufficient to cause opening of the P2X7 pore, while ATP is almost undetectable in healthy tissue. Secretion by cancer cells and release of intracellular ATP from dying cells are thought to be the main source of extracellular ATP in the TME. Non-functional P2X7 (nfP2X7) is a cancer-specific receptor in which formation of the large molecular weight pore, has been abrogated. Acquisition of nfP2X7 enables tumor cells to survive in the presence of high ATP concentrations. Using antibodies raised against nfP2X7, we assessed the expression of the receptor in a panel of cancer types and analysed the effect of the high ATP concentrations on nfP2X7 expression. We further analyzed the effect of siRNA mediated nfP2X7 depletion on cancer cell lines' viability. Our data shows that nfP2X7 is broadly expressed at the surface of many cancer types and supports cancer cell survival. Furthermore, we demonstrate that exposure to a high ATP concentration, equivalent to those in the TME, drives nfP2X7 expression. These data demonstrate that nfP2X7 is a cancer therapeutic target, whose expression is driven by the TME. Citation Format: Simon Mark Gilbert, Christopher John Oliphant, Anne-Lise Peille, Peter Bronsert, Francesco Di Virgilio, Shaun McNulty, Romain Lara. nfP2X7 mediates survival of cancer cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3920.
Regional and Systemic Hemodynamic Patterns in Rabbits with Neurogenic Hypertension
Authors: Nataliealexander, VINCENTDeQUATTRO
Journal: Circulation Research (1974)

The hemodynamic basis of neurogenic hypertension was studied in unanesthetized rabbits 10 minutes to 30 days after sinoaortic denervation (SAD). The fractional distribution of 86Rb to body tissues was determined and used to calculate regional blood flow from the value of cardiac output obtained from an arterial dilution curve of the indicator. Sham-operated rabbits served as controls. Increased cardiac output was a major hemodynamic component of SAD hypertension in 69% of the rabbits studied 1-40 hours postoperatively (acutely) but in only 25% of those studied 3-30 days after surgery (chronically). In the majority of the chronic SAD rabbits, increased total peripheral resistance (TPR) was the basis of the hypertension. All SAD rabbits had increased heart rates. Acutely, most high-cardiac output hypertensive rabbits had increased splanchnic resistance with normal blood flow, whereas all of them had low or normal renal resistance with high blood flow. Flows were increased in other major regions. Acutely, in...
Abstract 5546: eFT508, a potent and highly selective inhibitor of MNK1 and MNK2, regulates T-cell differentiation promoting an antitumor immune response
Authors: Rajesh K. Sharma, Vikas K. Goel, Jocelyn Staunton, Maria Barrera, Ana Parra, Eric Sung, Gary G. Chiang, Kevin R. Webster
Journal: Cancer Research (2018)

Abstract An effective and durable T-cell response is a cornerstone of current immunotherapies. We show that eFT508, a potent, selective inhibitor of MNK1 and MNK2, establishes a regulatory program that promotes multiple steps in the cancer immunity cycle including expansion of memory T cells and prevention of T-cell exhaustion. Using OT-I and OT-II transgenic systems, we show that eFT508 shifts the distribution of T cells towards a CD62LhighCD44high central memory (CM) phenotype in both CD4 and CD8 T cells upon activation with SIINFEKL peptide in vitro without adverse effects on T-cell proliferation, interferon-γ production or cytotoxic function. Similar effects are seen in vivo, where eFT508 treatment also enriches the CM T-cell pool in a SIINFEKL vaccine-induced OT-I adoptive T-cell transfer model, which results in increased persistence as demonstrated by a higher memory-recall T-cell response upon rechallenge. In addition, the CM bias elicited by eFT508 remains dominant when combined with agonists of co-stimulatory molecules, such as 4-1BB, OX-40 and GITR, or checkpoint inhibitors, such as PD-1, PD-L1 and CTLA-4, suggesting that eFT508 can affect the rate of T-cell differentiation in these combinations. eFT508 treatment also reduces the expression of exhaustion markers such as PD-1, LAG3 and TIM3, leading to increased cytotoxic T-cell function. eFT508 is currently under evaluation as a single agent in two phase 1/2 clinical trials for patients with advanced solid tumors and patients with advanced lymphoma. In addition, a phase 2 study evaluating eFT508, alone or in combination with avelumab, a PD-L1 immune checkpoint inhibitor, in microsatellite stable relapsed or refractory CRC patients is ongoing. The preclinical studies presented here provide further evidence that eFT508 may combine well with additional immunotherapies beyond checkpoint blockade. Citation Format: Rajesh K. Sharma, Vikas K. Goel, Jocelyn Staunton, Maria Barrera, Ana Parra, Eric Sung, Gary G. Chiang, Kevin R. Webster. eFT508, a potent and highly selective inhibitor of MNK1 and MNK2, regulates T-cell differentiation promoting an antitumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5546.
Normal Values of Esophageal Distensibility and Distension-Induced Contractility Measured by Functional Luminal Imaging Probe Panometry
Authors: Dustin A. Carlson, Wenjun Kou, Zhiyue Lin, Monique Hinchcliff, Anjali Thakrar, Sophia Falmagne, Jacqueline Prescott, Emily Dorian, Peter J. Kahrilas, John E. Pandolfino
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract 2881: RET signaling in pancreatic cancer: A novel target by metformin to suppress cancer progression
Authors: Huailong Chang, Zhiyong Xiao, Tao Li, Lanjing Zhang, Yong Lin, Darren Carpizo, Xianglin Tan
Journal: Cancer Research (2018)

Abstract Metformin has recently gained attention as an anti-cancer drug and/or a chemoprevention agent because of its roles in inhibiting mTOR, lowering hyperinsulinemia, modulating inflammatory responses, and selectively killing cancer stem cells. However, the key underlying molecular mechanisms for the inhibitory effects of metformin on pancreatic cancer progression remain largely unknown. RET (REarranged during Transfection), a single-pass transmembrane receptor tyrosine kinase and its ligand, glial cell-derived neurotrophic factor (GDNF), were strongly expressed in pancreatic cancer and correlated to invasion and worse survival after surgical resection. In this study, we investigated the roles of RET in the inhibitory effects of metformin on pancreatic cancer cell growth and migration. Real-time PCR and Western blot were used to determine mRNA and protein levels of molecular markers, respectively. siRNAs were adopted to specifically knockdown target genes. Boyden chamber assay was applied to assess cell migration in vitro. We observed that metformin treatment significantly reduced the mRNA and protein expression of RET in a dose-dependent manner in pancreatic cancer cells PANC-1 and MIA PaCa-2. The inhibitory effects of metformin on RET expression were not diminished when AMPK was knockdown by AMPK siRNA or the specific inhibitor, Compound C, suggesting that metformin may suppress RET in an AMPK-independent manner. Metformin treatment or RET knockdown by RET siRNA significantly decreased the phosphorylation of NF-κB and p70S6K, while modestly reduced the phosphorylation of the ERK, AKT, or STAT3. Furthermore, metformin treatment or RET knockdown significantly inhibited GDNF-induced cell migration. These data indicate that targeting RET with metformin may be an attractive and novel strategy for the prevention and treatment of pancreatic cancer progression and metastasis. Further in vitro and in vivo studies are warranted to investigate how metformin modulates RET signaling to inhibit the progression and metastasis of pancreatic cancer. Citation Format: Huailong Chang, Zhiyong Xiao, Tao Li, Lanjing Zhang, Yong Lin, Darren Carpizo, Xianglin Tan. RET signaling in pancreatic cancer: A novel target by metformin to suppress cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2881.
Abstract 2421: SOD1 is required for tumor maintenance in a genetically engineered KRAS/TP53 non-small cell lung cancer mouse model
Authors: Xiaowen Wang, Justin Wong, Holly Van Remmen, Jessie Yanxiang Guo, Eileen White, X. F. Steven Zheng
Journal: Cancer Research (2018)

Abstract Lung cancer is the second most common cancer and the primary cause of cancer-related mortality globally. Over half a million people are estimated living with lung and bronchus cancer with a 5-year survival rate of 18%. Identifying and studying new drug targets are important for improving lung cancer patient survival. 80% to 85% of lung cancers are Non-small cell lung cancer (NSCLC). Knocking down and small molecule inhibition of Superoxide dismutase 1 (SOD1) has been shown to be cytotoxic to cultured NSCLC cells and mouse tumors, suggesting that SOD1 is important for NSCLC survival, thus presenting a promising therapeutic strategy. SOD1 rapidly converts superoxide anion to hydrogen peroxide. It is a critical component of the cellular antioxidant defense system. In addition, our laboratory has recently demonstrated that SOD1 has a novel function as a transcription factor that regulates oxidative stress response genes. Currently, there are no selective SOD1 inhibitors available to study physiological functions of SOD1. In our study, we show that genetically knockout SOD1 resulted in reduced tumor burden in lung cancer mouse model. Using mouse tumor-derived primary cancer cells, we further show that SOD1 is critical for NSCLC cell proliferation and survival. This study reveals novel functions of SOD1 that are of biological and translational significance, and provide further support for SOD1 as a promising therapeutic target for NSCLC. Citation Format: Xiaowen Wang, Justin Wong, Holly Van Remmen, Jessie Yanxiang Guo, Eileen White, X. F. Steven Zheng. SOD1 is required for tumor maintenance in a genetically engineered KRAS/TP53 non-small cell lung cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2421.
Epiregulin as a Major Autocrine/Paracrine Factor Released From ERK- and p38MAPK-Activated Vascular Smooth Muscle Cells
Authors: MasanoriTakahashi, Ken’ichiroHayashi, KenjiYoshida, YasuyukiOhkawa, ToshiKomurasaki, AkiraKitabatake, AkiraOgawa, WataruNishida, MasahikoYano, MoritoMonden, KenjiSobue
Journal: Circulation (2003)

Background— The coordinated activation of extracellular signal–regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non–heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs). Methods and Results— We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent V...
Abstract 269: How Much Exposure to Resuscitation Do Emergency Medical Services Personnel Get?
Authors: KylieDyson, JanetBray, KarenSmith, StephenBernard, LahnStraney, JudithFinn
Journal: Circulation (2014)

Objectives: The exposure of emergency medical service personnel (paramedics) to out-of-hospital cardiac arrest (OHCA) and resuscitation procedures could be an important factor in skill maintenance and quality of care. This study aims to describe paramedic exposure to OHCA resuscitation in the state of Victoria, Australia (population 5.8 million). Methods: We extracted and linked data from the Victorian Ambulance Cardiac Arrest Registry (VACAR) and Ambulance Victoria’s employment dataset for the period 2003-2012. Paramedics were considered to have ‘exposure’ to OHCA if they attended a case where resuscitation was attempted. Individual rates were calculated for annual exposure (number of OHCA exposures for each paramedic/years employed in study period) and days between exposures (total paramedic days/total number of exposures). Results: Over the 10-year period, there were 49,107 OHCAs and 5,673 paramedics employed. Resuscitation was attempted in 44% of patients. An average of 3.2 (SD±1.1) paramedics attende...
Response of Intra-acinar Pulmonary Microvessels to Hypoxia, Hypercapnic Acidosis, and Isocapnic Acidosis
Authors: KazuhiroYamaguchi, KoichiSuzuki, KatsuhikoNaoki, KazumiNishio, NagatoSato, KeiTakeshita, HiroyasuKudo, TakuyaAoki, YukioSuzuki, AtsushiMiyata, HarukuniTsumura
Journal: Circulation Research (1998)

Abstract—To elucidate the differential reactivity of pulmonary microvessels in the acini to hypoxia, excessive CO2, and increased H+, we investigated changes in the diameter of precapillary arterioles, postcapillary venules, and capillaries in isolated rat lungs on exposure to normocapnic hypoxia (2% O2), normoxic hypercapnia (15% CO2), and isocapnic acidosis (0.01 mol/L HCl). Microvascular diameters were precisely examined using a real-time confocal laser scanning luminescence microscope coupled to a high-sensitivity camera with an image intensifier. Measurements were made under conditions with and without indomethacin or Nω-nitro-l-arginine methyl ester to assess the importance of vasoactive substances produced by cyclooxygenase (COX) or NO synthase (NOS) as it relates to the reactivity of pulmonary microvessels to physiological stimuli. We found that acute hypoxia contracted precapillary arterioles that had diameters of 20 to 30 μm but did not constrict postcapillary venules of similar size. COX- and N...
Randomized Double-Blind Comparison of Two Doses of Hirulog With Heparin as Adjunctive Therapy to Streptokinase to Promote Early Patency of the Infarct-Related Artery in Acute Myocardial Infarction
Authors: PierreThéroux, FélixPérez-Villa, DavidWaters, JacquesLespérance, FaryalaShabani, RaoulBonan
Journal: Circulation (1995)

Background An improved survival rate is a consequence of successful reperfusion of the infarct-related artery. This double- blind, randomized trial investigated the potential of Hirulog, a direct thrombin inhibitor, to improve the early patency rates obtained with streptokinase and aspirin. Methods and Results Angiographic patency of the culprit coronary artery lesion was assessed 90 and 120 minutes after the initiation of streptokinase and aspirin and again after 4±2 days in 68 patients with acute myocardial infarction. Patients were randomized to Hirulog 0.5 mg/kg per hour for 12 hours followed by 0.1 mg/kg per hour (low dose), Hirulog 1.0 mg/kg per hour for 12 hours followed by placebo (high dose), or to heparin 5000 U bolus followed by 1000 U/h titrated to an activated partial thromboplastin time (aPTT) 2 to 2.5 times control after 12 hours. At 90 minutes, TIMI flow grade 2 or 3 was observed in 96% of patients treated with the low dose of Hirulog, in 79% with the high dose, and in 46% with heparin (P=...
Downregulation of the Na+-Creatine Cotransporter in Failing Human Myocardium and in Experimental Heart Failure
Authors: StefanNeubauer, HelgaRemkes, MatthiasSpindler, MichaelHorn, FrankWiesmann, JürgenPrestle, BerndWalzel, GeorgErtl, GerdHasenfuss, TheoWallimann
Journal: Circulation (1999)

Background—The failing myocardium is characterized by depletion of phosphocreatine and of total creatine content. We hypothesized that this is due to loss of creatine transporter protein. Methods and Results—Creatine transporter protein was quantified in nonfailing and failing human myocardium (explanted hearts with dilated cardiomyopathy [DCM; n=8] and healthy donor hearts [n=8]) as well as in experimental heart failure (residual intact left ventricular tissue, rats 2 months after left anterior descending coronary artery ligation [MI; n=8] or sham operation [sham; n=6]) by Western blotting. Total creatine content was determined by high-performance liquid chromatography. Donor and DCM hearts had total creatine contents of 136.4±6.1 and 68.7±4.6 nmol/mg protein, respectively (*P<0.05); creatine transporter protein was 25.4±2.2 optical density units in donor and 17.7±2.5 in DCM (*P<0.05). Total creatine was 87.5±4.2 nmol/mg protein in sham and 65.7±4.2 in MI rats (*P<0.05); creatine transporter protein was ...
Abstract 6214: Comparison of Adiponectin Levels in Healthy Americans and Japanese: Results from Framingham and Fukuoka
Authors: Tsunehisa Koga, Norihiro Furusyo, Masumi Ai, Seiko Otokozawa, Bela F Asztalos, Charles C White, Serkalem D Banjaw, L A Cupples, Katsuyuki Nakajima, Ernst J Schaefer, Jun Hayashi
Journal: Circulation (2008)

Background and Objectives: Adiponectin is an adipocytokine with insulin-sensitizing and anti-atherosclerotic effects. Serum adiponectin levels have been reported to be negatively correlated with body weight and waist circumference (WC). Low plasma adiponectin levels are known to predispose to the development of insulin resistance and type 2 diabetes mellitus. Adiponectin levels may vary according to ethnic group. The aim of this study was to investigate potential differences in plasma adiponectin levels between Japanese and Americans. Methods: Subjects consisted of 2,060 healthy American male and female participants in exam 6 of the Framingham Offspring Study (mean age 57.0 ± 9.0 years, 57.4 ± 10.5 years, respectively), and 1131 healthy Japanese male and female participants in the Fukuoka Study (mean age 56.3 ± 5.5 years, 55.6 ± 5.4 years, respectively). Frozen plasma samples (at −80 degree C) from both studies were shipped to Tufts University, Boston. Plasma concentrations of direct LDL-C, fasting plasma glucose and adiponectin were measured using the same assay kits on the same machine (Hitachi 911) by the same staff. Anthropometric measurements including weight, height, body mass index (BMI) and WC, were also used in the analysis. Results: Plasma adiponectin levels were significantly and inversely correlated with BMI, WC, glucose, insulin, triglycerides, and systolic and diastolic blood pressure. Moreover adiponectin levels were significantly and positively correlated with HDL-C in both populations. Mean BMI and WC of Japanese men and women were significantly lower (23.8 kg/m 2 and 22.1 kg/m 2 , 86.0 cm and 78.7 cm, respectively) than in US men and women (28.2 kg/m 2 and 27.0 kg/m 2 , 100.4 cm and 92.8 cm, respectively) (all p&lt;0.05). However, mean adiponectin levels (± SD) in Japanese men and women were significantly lower (9.3 ± 4.5 micro g/mL and 14.7 ± 7.3 micro g/mL, respectively) than in US men and women (10.3 ± 5.2 micro g/mL and 16.3 ± 7.7 micro g/mL, respectively)(p&lt;0.05). Conclusion: Our data indicate a substantially lower prevalence of adiposity, but not higher adiponectin levels, in a healthy Japanese population as compared to an American population. The data indicate that population specific norms may have to be used for different ethnic groups.