tbuckley/cabot-search huggingface dataset:
Abstract P154: Systematic Review of Dietary Salt Reduction Policies: Evidence for an Effectiveness Hierarchy?
Authors: Lirije Hyseni, Alex Elliot-Green, Ffion Lloyd-Williams, Martin O’Flaherty, Chris Kypridemos, Rory McGill, Lois Orton, Helen Bromley, Francesco Cappuccio, Simon Capewell
Journal: Circulation (2016)

Background: Non-communicable disease (NCD) prevention strategies now prioritise four major risk factors: food, tobacco, alcohol and physical activity. Dietary salt intake is on average 5g/day higher than the recommended intake leading to high blood pressure, cardiovascular disease and gastric cancer. Substantial reductions in salt intake are therefore urgently needed. However, debate continues about the most effective approaches. We therefore systematically reviewed the evidence on possible interventions to inform future prevention programmes. We hypothesised an effectiveness hierarchy whereby “upstream structural” interventions targeting populations are more powerful than “downstream, agentic” interventions targeting individuals. Methods: We searched six electronic databases using a pre-piloted search strategy focussing on the effectiveness of population interventions to reduce salt intake. Retrieved papers were screened, appraised and graded for quality independently by two researchers. Extracted data were categorised using nine stages along the agentic/structural continuum, from “downstream”: dietary counselling (individuals, worksite and communities), through media campaigns, nutrition labelling, voluntary and mandatory reformulation, to the most “upstream” regulatory and fiscal interventions. We also considered comprehensive strategies involving multiple components. Results: After screening 2464 candidate papers, 65 were included in this systematic review (46 empirical and 19 modelling studies). Quality was variable. Multi-component strategies combining downstream with upstream interventions generally achieved the biggest reductions in salt consumption across an entire population, -3g/day in Finland, -4g/day in Japan and -1.5g/day recently in the UK. Tax interventions were considered in a few modelling studies; effects were mixed and modest. Mandatory reformulation achieved reductions of at least -1.45g/day, more than food labelling or worksite interventions (each typically -1.2g/day, but with a wide range). Smaller population benefits came from interventions in schools (-0.2g/day to -0.7g/day), and even smaller ones from health education media campaigns (-0.2g/day or less). Dietary advice achieved -2g/day reductions in compliant individuals in trials (representing an estimated population reduction of approximately -1g/day). Conclusions: Comprehensive strategies involving multiple components and “upstream” population-wide policies such as mandatory reformulation, and food labelling or worksite interventions appear to be most effective in achieving population-wide reductions in salt consumption. In conclusion, this ‘effectiveness hierarchy’ might deserve greater emphasis in future NCD prevention strategies, with correspondingly less emphasis on weaker ”downstream” individually-based interventions.
A phase I, open-label, first-time-in-patient dose escalation and expansion study to assess the safety, tolerability, and pharmacokinetics of nanoparticle encapsulated Aurora B kinase inhibitor AZD2811 in patients with advanced solid tumours.
Authors: Howard A. Burris, Judy Sing-Zan Wang, Melissa Lynne Johnson, Gerald Steven Falchook, Suzanne Fields Jones, Donald K Strickland, Carol Greenlees, Wolfram Brugger, Julie Charlton, Elizabeth Pease, Alexander MacDonald
Journal: Journal of Clinical Oncology (2017)

TPS2608 Background: Aurora kinase B performs key roles in the regulation of the cell cycle and represents a potential target for anticancer therapy. AZD2811, formerly designated AZD1152 hydroxy-quinazoline pyrazole anilide (AZD1152 hQPA), is a potent and selective inhibitor of Aurora B kinase activity and has been incorporated into a polymer nanoparticle carrier for intravenous (IV) administration. The phosphate pro-drug of AZD2811, known as AZD1152 (barasertib), reached Phase II of clinical development as a continuous IV infusion. While promising efficacy was seen with barasertib in elderly acute myeloid leukaemia (AML) patients ( Kantarjian HG et al., Cancer 2013;119:2611-19), continuous intravenous drug delivery precluded subsequent development in this disease setting and there were limited clinical responses in solid tumour patients due to dose-limiting myelotoxicity. AZD2811 nanoparticle has been designed to overcome these issues. Methods: Patients with relapsed advanced solid malignancies with no standard treatments are eligible for the part A dose escalation. Primary endpoint is to determine the maximum tolerated dose of AZD2811 nanoparticle using a 3+3 design. Patients with refractory/relapsed small cell lung cancer (SCLC) will be eligible for the part B expansion, where the safety, PK and anti-tumour activity of AZD2811 nanoparticle will be assessed as monotherapy and in combination with chemotherapy. Study enrolment is ongoing. Clinical trial information: NCT02579226.
Lack of Association Between Serum Immunoreactivity and Chlamydia pneumoniae Detection in the Human Aortic Wall
Authors: MassimoPorqueddu, RitaSpirito, AlessandroParolari, MarcoZanobini, GiulioPompilio, GianlucaPolvani, FrancescoAlamanni, DavideStangalini, ElenaTremoli, PaoloBiglioli
Journal: Circulation (2002)

Background— Only a few studies have focused the attention on the relation between elevated anti–Chlamydia pneumoniae (CP) antibodies and the detection of CP in the arterial wall. The aim of our study is thus to investigate the relationship between immune response to CP and detection of CP in the aortic walls of patients with abdominal aortic aneurysm. Methods and Results— A specimen of aortic wall was obtained from 102 consecutive patients who underwent abdominal aneurysm repair. The possible presence of CP was studied by polymerase chain reaction and confirmed by nonradioactive DNA hybridization. Antibody response to CP was studied (IgG, IgA titers). We found 33 patients (32.4%) with CP DNA+. No correlation between CP DNA detection and antibody titers was found (IgG P=0.52, IgA P=0.66). High correlation between IgG and IgA titer was observed (P<0.01). Endovascular presence of CP and antibody titers was not related to the age of the patient. Conclusions— CP antibody titers are not associated with the pres...
Abstract 5715: Monitoring immune cells-mediated cytolysis through impedance technology allows kinetic analysis of reagent efficacy
Authors: Fabio Cerignoli, Biao Xi, Garret Guenther, Lincoln Muir, Brandon Lamarche, Jason Shields, Yama Abassi
Journal: Cancer Research (2018)

Abstract In vitro characterization of immunotherapy reagents efficacy and combination synergies is necessary before moving to expensive animal models and clinical studies. Current standard assays like Chromium-51 release, ATP-based luminescence cell monitoring or flow cytometry are difficult to implement in a high throughput environment and are based on end point methodologies that are unable to capture the full dynamic of the immune response. Here we validate an impedance-based platform for monitoring cytotoxic activity of immune cells in the context of cancer immunotherapy assays. The technology detects cell death and proliferation of adherent cells by measuring changes in conductance of microelectrodes embedded in 96 and 384-wells cell culture plates, without the use of labeling or cell modification. We present a large set of validation including CD19 Car T models, EpCAM/CD3 BiTE antibodies and checkpoint combination therapies with anti PD-1/PD-L1 and CTLA-4 antibodies. Data comparison with Annexin V staining/Flow Cytometry shows perfect correlation between the drop in impedance signal and % of apoptotic cells. Long time monitoring (&amp;gt; 7 days) in combination with low effector:target ratios reveal the occurrence of resistance mechanisms in target cells and exhaustion in effector cells. Such dynamic response has been observed in animal models and patient clinical trials, but it is difficult to monitor in short time assays. Overall, our results demonstrate the value of such label-free approach in measuring the cytotoxic response across the temporal scale, an aspect that is otherwise very difficult to assess with more canonical end point assays but that is highly relevant when testing combinations. Thanks to the availability of 384-wells format and minimal sample handling, the technology is ideally suited for applications in large reagent validation screening or therapeutic protocol validation directly on patient samples. Citation Format: Fabio Cerignoli, Biao Xi, Garret Guenther, Lincoln Muir, Brandon Lamarche, Jason Shields, Yama Abassi. Monitoring immune cells-mediated cytolysis through impedance technology allows kinetic analysis of reagent efficacy [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 5715.
Abstract 17335: Dietary Carbohydrate Quality Affects Plasma Lipid Profile and the Microbiome
Authors: Nirupa R Matthan, Anne V Kane, William Evan Johnson, Solaiappan Manimaran, Tyler Faits, Alice H Lichtenstein
Journal: Circulation (2015)

Considerable data is available on the effect of carbohydrate (carb) quantity on CVD risk factors but data for carb quality is limited. Our objective was to determine the relative comparability for an isocaloric exchange of unrefined-carb (endosperm+germ+bran, e.g., whole wheat flour), refined-carb (endosperm only, e.g., white flour) and simple-carb (sucrose, e.g., high fructose corn syrup), on cardiometabolic risk factors and the gut microbiome. All foods/beverages (60%E total carb, 15%E protein, 27%E fat [7%E SFA, 10%E MUFA, 10%E PUFA], 80mg cholesterol/1000 kcal) were provided to study subjects (n=11 men and women, 65 years, BMI 27.5 kg/m 2 , LDL-C ≥100 mg/dL) for 5 weeks (randomized, single-blind, cross-over design). Body weight was maintained constant. At the end of each diet phase plasma lipid profile, inflammatory factors and glucose homeostasis were determined using standard methods. Fecal microbiota taxa was characterized by 16S rRNA sequencing and data analyzed using QIIME and PathoScope. Plasma LDL-C levels differed among diets (125 ± 29 mg/dL b , 129 ± 29 mg/dL a,b and 136 ± 24 mg/dL a , unrefined-, simple- and refined-carb , respectively). Carb quality had no significant effect on HDL-C, TG, FFA, glucose, insulin, CRP or IL-6 levels. There were 21 genera that had a mean relative abundance (RA) of ≥1% and 4 genera (Roseburia, Oscillospira, Ruminococcus and Coprococcus) varied significantly across diets but after multiple testing adjustment, only Roseburia RA variations remained significant ( 2.58% a , 0.99% b , and 0.81% b , unrefined-, simple- and refined-carb , respectively). Interesting trends were observed between the RA of the following genera and plasma lipids: Roseburia was negatively associated with LDL-C (r=0.28, p=0.097) and HDL-C (r=-0.39, p=0.022); Oscillospira was negatively associated with TG (r=-0.53, p=0.097), and Anaerostipes was positively associated with TG (r=0.40, p=0.0585) levels. These data suggest that carb quality alters the RA of butyrate-producing bacteria, presumably leading to higher short chain fatty acid production, with subsequent alterations in plasma lipids. This study provides novel information about the impact of carb quality on the phylogenetic structure and functional capacity of the fecal microbiome.
Aging and Disease as Modifiers of Efficacy of Cell Therapy
Authors: StefanieDimmeler, AnnarosaLeri
Journal: Circulation Research (2008)

Cell therapy is a promising option for treating ischemic diseases and heart failure. Adult stem and progenitor cells from various sources have experimentally been shown to augment the functional recovery after ischemia, and clinical trials have confirmed that autologous cell therapy using bone marrow—derived or circulating blood–derived progenitor cells is safe and provides beneficial effects. However, aging and risk factors for coronary artery disease affect the functional activity of the endogenous stem/progenitor cell pools, thereby at least partially limiting the therapeutic potential of the applied cells. In addition, age and disease affect the tissue environment, in which the cells are infused or injected. The present review article will summarize current evidence for cell impairment during aging and disease but also discuss novel approaches how to reverse the dysfunction of cells or to refresh the target tissue. Pretreatment of cells or the target tissue by small molecules, polymers, growth factors...
Abstract 11041: Use of Digoxin is Associated With Reduced Interstage Mortality: Results From the Pediatric Heart Network Single Ventricle Reconstruction Trial
Authors: Matthew Oster, Michael Kelleman, Courtney McCracken, Richard P Ohye, William T Mahle
Journal: Circulation (2015)

Introduction: Despite medical and surgical advances over the past few decades, mortality for infants with single ventricle congenital heart disease remains as high as 8-12% during the interstage period, the time between discharge after the Norwood procedure and before the stage II palliation. The objective of our study was to determine the effect of digoxin use on interstage mortality in infants with single ventricle congenital heart disease. Hypothesis: We hypothesized that digoxin would be associated with lower interstage mortality. Methods: We conducted a retrospective cohort study using the Pediatric Heart Network Single Ventricle Reconstruction Trial public use dataset, which includes data on infants with single right ventricle congenital heart disease randomized to receive either a Blalock-Taussig shunt or right ventricle-to-pulmonary artery shunt during the Norwood procedure at 15 institutions in North America from 2005-2008. Parametric survival models were used to compare the risk of interstage mortality between those discharged to home on digoxin vs. those discharged to home not on digoxin, adjusting for center volume, ascending aorta diameter, shunt type, and socioeconomic status. Further comparisons were made to compare the number of other adverse events in the two groups. Results: Of the 330 infants eligible for this study, 102 (31%) were discharged home on digoxin. Interstage mortality for those not on digoxin was 12.3%, compared to 2.9% among those on digoxin (Figure), with a number needed to treat of 11 patients to prevent one death. The adjusted hazard ratio was 3.5 (95%CI 1.1-11.7, p=0.04). There were no differences in complications between the two groups during the interstage period. Conclusions: Digoxin use in infants with single ventricle congenital heart disease is associated with significantly reduced interstage mortality and should be considered for all such infants unless otherwise contraindicated.
Abstract 19614: IL 10 Inhibits Fibroblast Progenitor Cells Mediated Cardiac Fibrosis in Pressure Overloaded Myocardium
Authors: Suresh K Verma, Venkata N Girikipathi, Prasanna Krishnamurthy, Cindy Benedict, Emily Nickoloff, David Goukassian, Raj Kishore
Journal: Circulation (2016)

Background: Activated fibroblasts (myoFBs) play critical role in cardiac fibrosis, however, their origin in diseased heart remains uncertain. Recent studies suggest the contribution of bone marrow fibroblasts progenitor cells (BM-FPC) in pressure overload (PO)-induced cardiac fibrosis. Previously we have shown that interleukin-10 suppress PO-induced cardiac fibrosis, however, its role on inhibition of BM-FPC-mediated fibrosis is not known. Thus, we hypothesized that IL-10 inhibits PO-induced homing and transition of BM-FPC to myoFBs and therefore, attenuates cardiac fibrosis. Methods and Results: Cardiac fibrosis was induced in Wild-type (WT) and IL-10-knockout (KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in KO mice. Systemic recombinant IL-10 administration markedly improved LV function and inhibited PO-induced cardiac fibrosis. PO-enhanced FPC (Prominin1+ cells) mobilization and homing in IL-10 KO mice compared to ...
Brief Antecedent Ischemia Enhances Recombinant Tissue Plasminogen Activator–Induced Coronary Thrombolysis by Adenosine-Mediated Mechanism
Authors: KarinPrzyklenk, PeterWhittaker
Journal: Circulation (2000)

Background—Clinical studies have implicated preinfarct angina (brief antecedent ischemia/reperfusion [I/R]) as a predictor of more rapid thrombolysis and lower rates of reocclusion. However, the effects of antecedent ischemia on the efficacy of thrombolysis have not been rigorously assessed. Using a canine model of coronary thrombosis, we aimed to (1) reproduce these clinical findings and (2) determine whether release of adenosine (a potent inhibitor of platelet aggregation via stimulation of platelet A2 receptors) during brief I/R contributes to this improved patency. Methods and Results—To address our first objective, we compared the time required to achieve lysis with recombinant tissue plasminogen activator and patency during the first 2 hours after lysis in dogs in which 1-hour thrombotic occlusion was preceded by brief I/R (10-minute coronary occlusion/10-minute reperfusion) versus 20-minute uninterrupted perfusion (controls). Time to lysis was accelerated in the I/R group versus the control group (...
Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive
Authors: Marton Keszei, Julien Record, Joanna S. Kritikou, Hannah Wurzer, Chiara Geyer, Meike Thiemann, Paul Drescher, Hanna Brauner, Laura Köcher, Jaime James, Minghui He, Marisa A.P. Baptista, Carin I.M. Dahlberg, Amlan Biswas, Sonia Lain, David P. Lane, Wenxia Song, Katrin Pütsep, Peter Vandenberghe, Scott B. Snapper, Lisa S. Westerberg
Journal: Journal of Clinical Investigation (2018)

Congenital neutropenia is characterized by low absolute neutrophil numbers in blood, leading to recurrent bacterial infections, and patients often require life-long granulocyte CSF (G-CSF) support. X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich syndrome protein (WASp). To understand the pathophysiology in XLN and the role of WASp in neutrophils, we here examined XLN patients and 2 XLN mouse models. XLN patients had reduced myelopoiesis and extremely low blood neutrophil number. However, their neutrophils had a hyperactive phenotype and were present in normal numbers in XLN patient saliva. Murine XLN neutrophils were hyperactivated, with increased actin dynamics and migration into tissues. We provide molecular evidence that the hyperactivity of XLN neutrophils is caused by WASp in a constitutively open conformation due to contingent phosphorylation of the critical tyrosine-293 and plasma membrane localization. This renders WASp activity less dependent on regulation by PI3K. Our data show that the amplitude of WASp activity inside a cell could be enhanced by cell-surface receptor signaling even in the context in which WASp is already in an active conformation. Moreover, these data categorize XLN as an atypical congenital neutropenia in which constitutive activation of WASp in tissue neutrophils compensates for reduced myelopoiesis.
Neutrophil cytoplasts induce T <sub>H</sub> 17 differentiation and skew inflammation toward neutrophilia in severe asthma
Authors: Nandini Krishnamoorthy, David N. Douda, Thayse R. Brüggemann, Isabell Ricklefs, Melody G. Duvall, Raja-Elie E. Abdulnour, Kimberly Martinod, Luciana Tavares, Xiao Wang, Manuela Cernadas, Elliot Israel, David T. Mauger, Eugene R. Bleecker, Mario Castro, Serpil C. Erzurum, Benjamin M. Gaston, Nizar N. Jarjour, Sally Wenzel, Eleanor Dunican, John V. Fahy, Daniel Irimia, Denisa D. Wagner, Bruce D. Levy
Journal: Science Immunology (2018)

Neutrophil cytoplasts promote T H 17 inflammation.
Abstract 3809: T-cell activation through the inhibition of tumor-expressed IDO1 activity in tryptophan metabolism pathway
Authors: Chunlan Dong, Ying Wang, Kefeng Gong, Frank Xing, Qian Shi
Journal: Cancer Research (2018)

Abstract Indoleamine 2,3-dioxygenase-1 (IDO1) has been described as a major mechanism of immunosuppression in tumors. Despite histologic evidence showing that most human tumor tissues have extensive infiltration by various pro-inflammatory and immune cells, expression of IDO1 by tumor cells results in aggressive tumor growth and resistance to T cell-targeting immunotherapies. To de-suppress T-cell function through inhibition of IDO1-mediated tryptophan metabolism pathway, we established an in vitro assay system allowing robust detection of production level of tryptophan metabolism product N-formyl-kynurenine (Kyn) in culture medium, plasma and tumor tissue through ELISA and LC-MS/MS. We screened a panel of human and murine tumor cell lines for IDO1 expression with and without INFg induction. Our data suggest that a few of these models constitutively express IDO1; about half of the tumor cell models in the panel express IDO1 in an IFNg-dependent manner while the others do not respond to the cytokine stimulation at all. The mechanism underlying the lack of response to cytokine induction on IDO1 production is under investigation. We next tested the reduction of kynurenine in culture medium through inhibition of IDO1 enzymatic activity. After 24h stimulation by IFNg, a murine cell model was treated by INCB024360 (Incyte) for 48h and 72h. Cell-free supernatants were then collected, followed by Kyn detection by LC-MS/MS. The results showed that longer compound treatment (72h) offered a more robust detection window (1,500 ng/mL Kyn down to 2,00 ng/mL), compared to 48h results (350 ng/mL Kyn down to 100 ng/mL). This reproducible assay offers a reliable platform for initial IDO compound screening. To correlate effective reduction of kynurenine production to reactivation of T-cell activity, a co-culture system was established in that T-cell proliferation and cytokine production (IL2) were examined upon IDO1 inhibition in a time course. To achieve maximal therapeutic effect, a combination of INCB024360 and aPD1 antibody was applied in a T cell-mediated tumor cell killing assay. Detailed data will be discussed. Citation Format: Chunlan Dong, Ying Wang, Kefeng Gong, Frank Xing, Qian Shi. T-cell activation through the inhibition of tumor-expressed IDO1 activity in tryptophan metabolism pathway [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 3809.