tbuckley/cabot-search huggingface dataset:
Abstract 15997: Cardioprotective Effects of Intracoronary Administration of 4-Chlorodiazepam in Small and Large Animal Models of Ischemia-Reperfusion
Authors: Chris Kapelios, Lampros Katsaros, Micheal Tsamatsoulis, Stella Vakrou, Vasilis Sousonis, Stefania Sventzouri, Despina Perrea, John Nanas, Konstantinos Malliaras
Journal: Circulation (2016)

Introduction:  The Translocator Protein (TSPO) of the mitochondrial membrane has been recognized as a potential therapeutic target for mitigation of myocardial ischemia-reperfusion injury. Administration of 4-chlorodiazepam (4-CLD), a TSPO ligand, has been shown to confer acute cardioprotective effects in small animals; however, long-term studies and studies in clinically-relevant large animal models are lacking. We investigated a potential cardioprotective effect of intracoronary administration of 4-CLD in small and large animal models of ischemia-reperfusion.   Methods:  Acute myocardial infarction (MI) was induced in 38 Wistar rats and 29 farm pigs by ligation of the left anterior descending coronary artery, followed by reperfusion. Animals were randomized to undergo intracoronary infusion of 2 μM 4-CLD or vehicle just prior (pigs) or immediately after (rats) reperfusion. Infarcted rats were euthanized either after 1 hour of reperfusion (for histological assessment of the “no reflow” area) or after 60 days (for serial evaluation of cardiac function and structure by echocardiography and histological assessment of infarct size). Infarcted pigs were euthanized after 2 hours of reperfusion for histological assessment of infarct size and “no reflow” area.   Results:  In infarcted rats, intracoronary infusion of 4-CLD resulted in acute reduction of the “no reflow” area and conferred durable long-term structural and functional benefits (reduction in infarct size, decreased end-diastolic and end-systolic volumes, improvement in ejection fraction at 60 days post-MI). In infarcted pigs, intracoronary infusion of 4-CLD was well-tolerated from a hemodynamic standpoint and resulted in acute reduction in infarct size (4-CLD: 78±13% of area at risk vs controls: 89± 10%, p=0.034), reduction in “no reflow” area (4-CLD: 7±5% of area at risk vs controls: 26±12%, p   Conclusions:  In a rat model of MI, intracoronary administration of 4-CLD attenuated the “no reflow” phenomenon and produced long-term structural and functional benefits. In a porcine model of MI intracoronary administration of 4-CLD did not raise safety concerns and conferred acute cardioprotective effects.
Prostaglandin E 2 suppresses human group 2 innate lymphoid cell function
Authors: Jovana Maric, Avinash Ravindran, Luca Mazzurana, Åsa K. Björklund, Aline Van Acker, Anna Rao, Danielle Friberg, Sven-Erik Dahlén, Akos Heinemann, Viktoria Konya, Jenny Mjösberg
Journal: Journal of Allergy and Clinical Immunology (2017)

BackgroundGroup 2 innate lymphoid cells (ILC2s) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. Prostaglandin (PG) E2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation.ObjectiveWe set out to investigate how PGE2 regulates human ILC2 function.MethodsThe effects of PGE2 on human ILC2 proliferation and intracellular cytokine and transcription factor expression were assessed by means of flow cytometry. Cytokine production was measured by using ELISA, and real-time quantitative PCR was performed to detect PGE2 receptor expression.ResultsPGE2 inhibited GATA-3 expression, as well as production of the type 2 cytokines IL-5 and IL-13, from human tonsillar and blood ILC2s in response to stimulation with a combination of IL-25, IL-33, thymic stromal lymphopoietin, and IL-2. Furthermore, PGE2 downregulated the expression of IL-2 receptor α (CD25). In line with this observation, PGE2 decreased ILC2 proliferation. These effects were mediated by the combined action of E-type prostanoid receptor (EP) 2 and EP4 receptors, which were specifically expressed on ILC2s.ConclusionOur findings reveal that PGE2 limits ILC2 activation and propose that selective EP2 and EP4 receptor agonists might serve as a promising therapeutic approach in treating allergic diseases by suppressing ILC2 function. Group 2 innate lymphoid cells (ILC2s) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. Prostaglandin (PG) E2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation. We set out to investigate how PGE2 regulates human ILC2 function. The effects of PGE2 on human ILC2 proliferation and intracellular cytokine and transcription factor expression were assessed by means of flow cytometry. Cytokine production was measured by using ELISA, and real-time quantitative PCR was performed to detect PGE2 receptor expression. PGE2 inhibited GATA-3 expression, as well as production of the type 2 cytokines IL-5 and IL-13, from human tonsillar and blood ILC2s in response to stimulation with a combination of IL-25, IL-33, thymic stromal lymphopoietin, and IL-2. Furthermore, PGE2 downregulated the expression of IL-2 receptor α (CD25). In line with this observation, PGE2 decreased ILC2 proliferation. These effects were mediated by the combined action of E-type prostanoid receptor (EP) 2 and EP4 receptors, which were specifically expressed on ILC2s. Our findings reveal that PGE2 limits ILC2 activation and propose that selective EP2 and EP4 receptor agonists might serve as a promising therapeutic approach in treating allergic diseases by suppressing ILC2 function.
Protein phosphatase 2A promotes DNA double-strand break repair through a non-homologous end joining pathway
Authors: Qinhong Wang, Xingming Deng
Journal: Cancer Research (2008)

845   PP2A functions as a potent tumor suppressor but the mechanism(s) remain enigmatic. Here we discovered that PP2A promotes DNA double-strand break (DSB) repair by up-regulating Ku DNA binding and DNA-PK activities. Specific disruption of PP2A activity by either expression of SV40 small tumor antigen or depletion of endogenous PP2A/C by RNA interference results in decreased Ku DNA binding and DNA-PK activities, which leads to suppression of DSB repair and increased genetic instability ( i.e . chromosomal and chromatid breaks). In contrast, overexpression of the PP2A catalytic subunit (PP2A/C) enhances Ku and DNA-PK activities in association with accelerated DSB repair. PP2A co-localizes and interacts with Ku 70 and Ku 86. PP2A directly dephosphorylates Ku as well as DNA-PKcs  in vitro  and  in vivo , which promotes the formation of a functional Ku/DNA-PKcs complex. Intriguingly, PP2A promotes DSB repair in wild type  MEF cells but has no such effect in Ku deficient  MEF cells, suggesting that Ku 70/86 heterodimer is required for PP2A’s effect on DSB repair. Thus, PP2A promotion of DSB repair may occur in a novel mechanism by activating the non-homologous end-joining pathway, which may contribute to maintenance of genetic stability .
Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial
Authors: Sandra Andorf, Natasha Purington, Whitney M Block, Andrew J Long, Dana Tupa, Erica Brittain, Amanda Rudman Spergel, Manisha Desai, Stephen J Galli, Kari C Nadeau, R Sharon Chinthrajah
Journal: The Lancet. Gastroenterology & hepatology (2017)
Abstract 11690: Mineralocorticoid Receptor Antagonists Prevent or Reverse Abnormal Cardiopulmonary Hemodynamics in Two Animal Models of Pulmonary Arterial Hypertension
Authors: Bradley A Maron, Kevin White, Tim Hou, Joseph Loscalzo, Jane A Leopold
Journal: Circulation (2012)

Hyperaldosteronism (ALDO) associated with systemic hypertension contributes to vascular dysfunction by increasing vascular collagen deposition and fibrosis. In pulmonary arterial hypertension (PAH), the role of ALDO in mediating pulmonary vascular remodeling and dysfunction, however, is unknown. We hypothesized that in PAH, ALDO increases pulmonary arteriolar collagen levels to increase pulmonary vascular resistance and promote pulmonary hypertension. To test this hypothesis, we first demonstrated that plasma ALDO levels are elevated 4.2-fold (p<0.05) and 4.1-fold (p<0.05) in the rat Sugen-5416/Hypoxia (SU/Hyp) and monocrotaline (MCT) models of PAH, respectively. In a prevention study, rats were randomized to regular chow or the mineralocorticoid receptor antagonist eplerenone (0.6 gm/gm chow) initiated immediately following SU/Hyp initiation. Cardiac catheterization was performed 21 days later. Without affecting cardiac index (CI) or mean aortic pressure (MAP), eplerenone decreased pulmonary artery systo...
Neurosurgical referrals and opinions of neurosurgeons: a large-scale face-to-face survey of users of the online referral system
Authors: N. Kalyal, M. Amarouche, N. Adams, D. Curley, S. Deacon, F. Hafiz, T. Jayawardena, N. Khetani, D. Mathews, S. Mustoe, J. Neville, S. Okafor, O. Padfield, I. Rao, R. Samir, H. Tahir, B. Varghese, C. Tolias
Journal: International Journal of Surgery (2017)
Abstract B13: A growth of human choriocarcinoma cells was selectively inhibited by therapeutic neural stem cells expressing cytosine deaminase and interferon-β in cellular and xenograft models
Authors: Gyu-Sik Kim, Kyung-Chul Choi
Journal: Cancer Research (2017)

Abstract In this study, human neural stem cells (hNSCs) expressing Escherichia coli cytosine deaminase (CD) and human interferon-β (IFN-β) was used to cancer treatment strategy for human choriocarcinoma cancer. Prodrug 5-fluorocytosine (5-FC) is converted to 5-fluorouacil (5-FU) by CD, which induces an effect of killing the tumor cells through DNA synthesis inhibition. Also, IFN-β suppresses tumor growth through the apoptotic process. To manufacture animal models xenografted with choriocarcinoma, CMFDA pre-labeled JEG-3 cells (2×106) were injected intravenously (i.v.) into the tail vein of athymic nude mice (group A) and injected subcutaneously (s.c.) into the back of the mice (group B). Subcutaneously injected cancer cells were mixed with Matrigel (BD Biosciences, Bedford, MA, USA) at 1:1 volume ratio of Matrigel to PBS in 100 μl. On group A, CM-dil pre-labeled hNSCs (2×106) were injected intravenously after a week. On group B, when the tumor volume reached at 100mm3, CM-Dil pre-labeled hNSCs (2×106) were injected subcutaneously adjacent to the tumor mass. Every mice received i.p. injections of 5-FC (500 mg/kg/day) every day for 21 days. In a modified trans-well migration assay, NSCs selectively migrated to JEG-3 choriocarcinoma cells. It was revealed that the tumor-tropic properties of engineered NSCs were attributed to chemoattractant factors (CXCR4, SCF, SDF-1a, VEGF) secreted by JEG-3 cells. When JEG-3 cells co-cultured with engineered NSCs in the presence of 5-FC, the viability of JEG-3 cells was markedly decreased. The present results suggested that NSCs expressing CD gene and IFN-β gene have a potential therapeutic effect against choriocarcinoma. Consequently, hNSC therapy may be a clinically effective tool for the treatment of human choriocarcinoma cancer. In addition, we are currently studying on an in vivo model to demonstrate that selective anti-tumor effect of NSCs. Note: This abstract was not presented at the conference. Citation Format: Gyu-Sik Kim, Kyung-Chul Choi. A growth of human choriocarcinoma cells was selectively inhibited by therapeutic neural stem cells expressing cytosine deaminase and interferon-β in cellular and xenograft models [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B13.
Perioperative Management of Extremity Soft Tissue Sarcomas
Authors: Rick L. Haas, Alessandro Gronchi, Michiel A.J. van de Sande, Elizabeth H. Baldini, Hans Gelderblom, Christina Messiou, Eva Wardelmann, Axel Le Cesne
Journal: Journal of Clinical Oncology (2017)

Surgery is potentially curative for primary nonmetastatic extremity soft tissue sarcomas. After surgery alone, patients may remain at risk for local recurrences and/or metastatic disease. To reduce the likelihood of a local relapse, the addition of radiotherapy (RT) to limb-sparing surgery may result in higher local control rates of at least 85%. Generally, it can be stated that local control after both preoperative and postoperative RT is comparable, but that preoperative RT comes with a more favorable toxicity profile after prolonged follow-up, albeit at the cost of a higher wound complication rate. Furthermore, recent data suggest that preoperative RT is more cost effective. To reduce the risk of subsequent metastatic disease, systemic chemotherapy can be introduced early during the primary management of these patients. These systemic chemotherapy regimens can also be applied both preoperatively and postoperatively. Finally, with the aim of increasing the antitumor response of perioperative RT, these agents may even be combined with RT, concurrently and sequentially. While designing new preoperative combination regimens, responses should be carefully monitored by both sophisticated radiologic and pathologic evaluations. This article reviews all these aspects, in addition to limb-sparing surgery.
Illicit Fentanyl Driving Opioid Overdose Deaths
Authors: Rita Rubin
Journal: JAMA (2017)

In the last half of 2016, fentanyl, a synthetic opioid 50 to 100 times more potent than morphine, was detected in 56.3% of the opioid overdose deaths in the 10 states that make up the CDC’s Enhanced State Opioid Overdose Surveillance program, according to a recent CDC report.
Divergent PD-1 expression in tissue and circulating CD8 lymphocytes defines an immune profile predictive of the response to nivolumab in advanced NSCLC
Authors: G. Mazzaschi, D. Madeddu, M. Veneziani, F. Sogni, G. Armani, C. Frati, C. Lagrasta, A. Falco, B. Lorusso, R. Vilella, C. Mangiaracina, G. Bocchialini, E.M. Silini, F. Facchinetti, A. Ardizzoni, G. Missale, M. Tiseo, F. Quaini
Journal: Annals of Oncology (2017)
Intensive Blood Pressure Lowering in Patients With and Patients Without Type 2 Diabetes: A Pooled Analysis From Two Randomized Trials
Authors: Tom F. Brouwer, Jim T. Vehmeijer, Deborah N. Kalkman, Wouter R. Berger, Bert-Jan H. van den Born, Ron J. Peters, Reinoud E. Knops
Journal: Diabetes Care (2017)

OBJECTIVE The Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) study did not find a significant beneficial effect of intensive systolic blood pressure (SBP) lowering on cardiovascular events in hypertensive patients with type 2 diabetes mellitus (T2DM), while the Systolic Blood Pressure Intervention Trial (SPRINT) did find a significant beneficial effect in patients without T2DM. The objective of this analysis was to assess the effect of both T2DM and baseline cardiovascular disease risk on the treatment effect of intensive blood pressure lowering. RESEARCH DESIGN AND METHODS The individual patient data from the ACCORD-BP and SPRINT studies were pooled and follow-up durations harmonized. Both studies randomized hypertensive patients to an SBP target of &amp;lt;120 mmHg or a target of &amp;lt;140 mmHg. The composite primary end point consisted of unstable angina, myocardial infarction, acute heart failure, stroke, and cardiovascular death. The interaction between intensive blood pressure lowering and both T2DM and 10-year cardiovascular risk was assessed using Cox proportional hazards models. RESULTS The cohort consisted of 14,094 patients with mean age 66 ± 8.9 years and mean baseline SBP 139.5 ± 15.6 mmHg; 33.6% had T2DM. The hazard ratio for the primary composite end point was 0.82 (95% CI 0.73–0.93), P = 0.0017. The interaction between intensive blood pressure lowering and T2DM was nonsignificant (P = 0.13). The 10-year cardiovascular risk was higher in primary prevention patients with T2DM, but risk did not interact with the treatment effect (P = 0.84). CONCLUSIONS Intensive blood pressure lowering may have a similar favorable effect and appears to decrease cardiovascular events in both patients with and patients without T2DM.
Abstract IA5: Aspirin for precision chemoprevention of colorectal cancer
Authors: Andrew T. Chan
Journal: Cancer Research (2017)

Abstract Remarkably consistent experimental and epidemiologic evidence demonstrates that aspirin is associated with a lower risk of colorectal cancer. These studies have been complemented by compelling data from randomized controlled trials (RCTs). Five placebo-controlled RCTs among individuals with a history of colorectal adenoma or cancer showed that aspirin reduced the risk of recurrent adenomas, the precursors of the vast majority of cancers. Data from long-term follow-up of the CAPP2 trial, a RCT of aspirin among individuals with the Lynch hereditary colorectal cancer syndrome and the Women's Health Study, a RCT of aspirin among women for primary prevention of cardiovascular disease and cancer demonstrated that randomized aspirin treatment was associated with a lower risk of colorectal cancer. Finally, secondary analyses of RCTs of aspirin for cardiovascular prevention have shown that aspirin reduces incidence of and mortality from colorectal cancer. As a reflection of the strength of the evidence, the U.S. Preventive Services Task Force (USPSTF) updated its primary prevention guidelines for aspirin in 2016. The USPSTF now recommends low-dose aspirin (81 mg/day) for chronic disease prophylaxis, including colorectal cancer prevention, among U.S. adults between ages 50-59, and possibly ages 60-69, with a greater than 10% ten-year risk of cardiovascular events. The new USPSTF recommendation represents a significant milestone for the field of preventive medicine. With the exception of tamoxifen for women at high-risk for breast cancer, this is the first medication broadly recommended for cancer prevention by the USPSTF. Despite this advance, wider scale efforts to implement aspirin chemoprevention are limited by concerns about risk-benefit profile in view of the established association of aspirin with gastrointestinal bleeding. In concert with broader efforts to tailor prevention strategies, our group has led several studies into the mechanistic basis of aspirin's anti-cancer effect that has led to the development of intratumoral, colonic, germline, and circulating molecular correlates of outcomes. Such biomarkers can be exploited for risk stratification to more effectively target aspirin chemoprevention for those with more favorable risk-benefit profiles. In this presentation, we will review the evidence supporting a role for aspirin in the prevention of colorectal cancer, with a focus on novel methods for molecular risk stratification. Such a precision chemoprevention strategy could play a role in global efforts for chronic disease prevention and control. Citation Format: Andrew T. Chan. Aspirin for precision chemoprevention of colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA5.
Accreditation Readiness in US Multidisciplinary Rectal Cancer Care: A Survey of OSTRICH Member Institutions
Authors: Lawrence Lee, David W. Dietz, Fergal J. Fleming, Feza H. Remzi, Steven D. Wexner, David Winchester, John R. T. Monson
Journal: JAMA Surgery (2017)

This article presents a survey of 328 member health care centers by a consortium focused on improving quality in rectal cancer surgery.
CALR mutational status identifies different disease subtypes of essential thrombocythemia showing distinct expression profiles
Authors: Roberta Zini, Paola Guglielmelli, Daniela Pietra, Elisa Rumi, Chiara Rossi, Sebastiano Rontauroli, Elena Genovese, Tiziana Fanelli, Laura Calabresi, Elisa Bianchi, Simona Salati, Mario Cazzola, Enrico Tagliafico, Alessandro M. Vannucchi, Rossella Manfredini
Journal: Blood Cancer Journal (2017)

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia-negative myeloproliferative neoplasms (MPNs) characterized by erythrocytosis and thrombocytosis, respectively. Approximately 95% of PV and 50–70% of ET patients harbor the V617F mutation in the exon 14 of JAK2 gene, while about 20–30% of ET patients carry CALRins5 or CALRdel52 mutations. These ET CALR-mutated subjects show higher platelet count and lower thrombotic risk compared to JAK2-mutated patients. Here, we showed that CALR-mutated and JAK2V617F-positive CD34+ cells display different gene and miRNA expression profiles. Indeed, we highlighted several pathways differentially activated between JAK2V617F- and CALR-mutated progenitors, i.e., mTOR, MAPK/PI3K, and MYC pathways. Furthermore, we unveiled that the expression of several genes involved in DNA repair, chromatin remodeling, splicing, and chromatid cohesion are decreased in CALR-mutated cells. According to the low risk of thrombosis in CALR-mutated patients, we also found the downregulation of several genes involved in thrombin signaling and platelet activation. As a whole, these data support the model that CALR-mutated ET could be considered as a distinct disease entity from JAK2V617F-positive MPNs and may provide the molecular basis supporting the different clinical features of these patients.
A Highly Selective 3D Spiked Ultraflexible Neural (SUN) Interface for Decoding Peripheral Nerve Sensory Information
Authors: Jiahui Wang, Xin Yuan Thow, Hao Wang, Sanghoon Lee, Kai Voges, Nitish V. Thakor, Shih‐Cheng Yen, Chengkuo Lee
Journal: Advanced Healthcare Materials (2017)

Artificial sensors on the skin are proposed as a way to capture information that can be used in intracortical microstimulation or peripheral intraneural stimulation to restore sensory feedback to persons with tetraplegia. However, the ability of these artificial sensors to replicate the density and complexity of the natural mechanoreceptors is limited. One relatively unexplored approach is to make use of the signals from surviving tactile and proprioceptive receptors in existing limbs by recording from their transmitting axons within the primary sensory nerves. Here, a novel spiked ultraflexible neural (SUN) interface that is implanted into the peripheral nervous system to capture sensory information from these mechanoreceptors in acute rat experiments is described. The novel 3D design, which integrates spiked structures for intrafascicular nerve recording with an ultraflexible substrate, enables a unique conformal interface to the target nerve. With the high-quality recording (average signal-to-noise-ratio of 1.4) provided by the electrode, tactile from proprioceptive stimuli can be differentiated in terms of the firing rate. In toe pinching experiments, high spatial resolution classification can be achieved with support vector machine classifier. Further work remains to be done to assess the chronic recording capability of the SUN interface.
LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor
Authors: Xuecai Ge, Hong Yang, Maria A. Bednarek, Hadas Galon-Tilleman, Peirong Chen, Michael Chen, Joshua S. Lichtman, Yan Wang, Olivier Dalmas, Yiyuan Yin, Hui Tian, Lutz Jermutus, Joseph Grimsby, Cristina M. Rondinone, Anish Konkar, Daniel D. Kaplan
Journal: Cell Metabolism (2017)