tbuckley/cabot-search huggingface dataset:
High Levels of Costimulatory Receptors OX40 and 4-1BB Characterize CD4 <sup>+</sup> CD28 <sup>null</sup> T Cells in Patients With Acute Coronary Syndrome
Authors: Ingrid E. Dumitriu, Paramita Baruah, Caroline J. Finlayson, Ian M. Loftus, Ricardo F. Antunes, Pitt Lim, Nicholas Bunce, Juan Carlos Kaski
Journal: Circulation Research (2012)

Rationale: Patients with acute coronary syndrome (ACS) predisposed to recurrent coronary events have an expansion of a distinctive T-cell subset, the CD4 + CD28 null T cells. These cells are highly inflammatory and cytotoxic in spite of lacking the costimulatory receptor CD28, which is crucial for optimal T cell function. The mechanisms that govern CD4 + CD28 null T cell function are unknown. Objective: Our aim was to investigate the expression and role of alternative costimulatory receptors in CD4 + CD28 null T cells in ACS. Methods and Results: Expression of alternative costimulatory receptors (inducible costimulator, OX40, 4–1BB, cytotoxic T lymphocyte associated antigen-4, programmed death-1) was quantified in CD4 + CD28 null T cells from circulation of ACS and stable angina patients. Strikingly, in ACS, levels of OX40 and 4-1BB were significantly higher in circulating CD4 + CD28 null T cells compared to classical CD4 + CD28 + T lymphocytes. This was not observed in stable angina patients. Furthermore, CD4 + CD28 null T cells constituted an important proportion of CD4 + T lymphocytes in human atherosclerotic plaques and exhibited high levels of OX40 and 4-1BB. In addition, the ligands for OX40 and 4-1BB were present in plaques and also expressed on monocytes in circulation. Importantly, blockade of OX40 and 4-1BB reduced the ability of CD4 + CD28 null T cells to produce interferon-γ and tumor necrosis factor-α and release perforin. Conclusions: Costimulatory pathways are altered in CD4 + CD28 null T cells in ACS. We show that the inflammatory and cytotoxic function of CD4 + CD28 null T cells can be inhibited by blocking OX40 and 4-1BB costimulatory receptors. Modulation of costimulatory receptors may allow specific targeting of this cell subset and may improve the survival of ACS patients.
Effects of external pH on ionic currents in smooth muscle cells from the basilar artery of the guinea pig.
Authors: G A West, D C Leppla, J M Simard
Journal: Circulation Research (1992)

pHo is an important determinant of vascular tone in cerebral blood vessels. We investigated the effects of changes in pHo on isolated smooth muscle cells from the basilar artery of the guinea pig. Single cells contracted rapidly in response to an elevation in pHo (constant CO2), and contraction was blocked by nifedipine, suggesting a role for dihydropyridine-sensitive Ca2+ channels. In whole-cell patch-clamp experiments, changes in pHo (pHo 5.7-8.1, pHi 7.2 with 10 mM HEPES) strongly affected the amplitude of the peak Ca2+ channel current (10 mM Ba2+, +15 mV, holding potential of -55 mV), with an apparent pK of 6.9. The current-voltage curves were minimally shifted, indicating no important effect of surface charge. To separate the slowly inactivating L-type Ca2+ channel current from the more rapidly inactivating B-type current, the decaying portions of inward currents from cells studied with repetitive 1-second pulses (+15 mV, holding potential of -55 mV) were fit to a two-component model. Titration curves for the L-type and B-type currents indicated maximum increases by factors of 3.65 and 1.28 at alkaline pHo and gave apparent pK values of 7.71 and 6.47 (Hill coefficient unity). The time constant of inactivation for the B-type current at +15 mV was little affected by pHo, whereas that for the L-type current increased somewhat with increasing pHo. Additional experiments showed no significant effect of pHo on holding current or on voltage-activated outward currents (pCai 7 with 11 mM EGTA). Our results provide additional evidence for participation of Ca2+ channels in regulating basal tone in cerebral smooth muscle and indicate that pHo regulates current through slowly inactivating, dihydropyridine-sensitive L-type Ca2+ channels.
859 THREE SINGLE NUCLEOTIDE POLYMORPHISMS HAPLOTYPE OF ANGIOTENSINOGEN GENE ASSOCIATED WITH THE PREVALENCE OF JAPANESE NASH
Authors: M. Ono, T. Ochi, K. Munekage, M. Ogasawara, A. Hirose, Y. Nozaki-Fujimura, M. Takahashi, N. Okamoto, S. Iwasaki, Y. Eguchi, T. Saibara
Journal: Journal of Hepatology (2011)
Effect of Endothelin-1 on Actomyosin ATPase Activity
Authors: George McClellan, Andrea Weisberg, Saul Winegrad
Journal: Circulation Research (1996)

Abstract Endothelin is a powerful inotropic peptide that increases isometric force in isolated papillary muscle and the extent of shortening in isolated single cardiac myocytes. Its mechanism of action has been variously attributed to increased Ca 2+ activation, increased Ca 2+ sensitivity of the contractile proteins, and increased intracellular pH, but the physiological function of the changes in cardiac performance remains obscure. In this study, the effects of endothelin-1 on both force development and the kinetics of contraction have been examined. Isometric force, actomyosin ATPase activity, and unloaded shortening velocity were measured. The effects were dose dependent. From 1 to 50 pmol/L endothelin-1 did not alter force development in isolated trabeculae with intact endothelial cells, but actomyosin ATPase activity was increased. Between 100 pmol/L and 10 nmol/L endothelin-1 raised isometric force, decreased actomyosin ATPase activity, and decreased unloaded shortening velocity. The reduction in ATPase activity was progressively enhanced as sarcomere length was increased from 1.9 to 2.4 μm. These results indicate that the effects of endothelin-1 on the force of contraction and the rate of ATP hydrolysis are not tightly coupled and are changed in the opposite directions by endothelin-1 over most of its effective-dose range. This raises the possibility that endothelin-1 may increase the economy of contraction. A novel function of endothelin may be the modulation of the efficiency of contraction, particularly when increased preload raises the contractile work of the heart.
CG0070, a Conditionally Replicating Granulocyte Macrophage Colony-Stimulating Factor–Armed Oncolytic Adenovirus for the Treatment of Bladder Cancer
Authors: Nagarajan Ramesh, Ying Ge, David L. Ennist, Mingzhu Zhu, Mervat Mina, Shanthi Ganesh, P. Seshidhar Reddy, De-Chao Yu
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The purpose of this study was to examine the tumor specificity, cytotoxicity, and granulocyte macrophage colony-stimulating factor expression of CG0070, a conditionally replicating oncolytic adenovirus, in human bladder transitional cell carcinoma (TCC) cell lines and determine its antitumor efficacy in bladder TCC tumor models. Experimental Design: Virus yield and cytotoxicity assays were used to determine tumor specificity and virus replication-mediated cytotoxicity of CG0070 in a panel of human bladder TCC cell lines and primary cells in vitro. Two s.c. and one orthotopic bladder TCC xenograft tumor models were used to assess antitumor activity of CG0070. Results: In a matched isogenic pair of cell lines with differing retinoblastoma (Rb) pathway status, CG0070 showed selective E1a and granulocyte macrophage colony-stimulating factor (GM-CSF) expression in Rb pathway–defective cells. CG0070 replicated in Rb-defective bladder TCC cell lines as efficiently as wild-type adenovirus but produced 100-fold less virus in normal human cells. CG0070 was up to 1,000-fold more cytotoxic in Rb pathway–defective bladder TCC cells in comparison with normal human cells. Antitumor activity of CG0070 was shown in two bladder TCC s.c. xenograft tumor models following intratumoral injections and intravesical treatment in an orthotopic xenograft tumor model when compared with PBS treatment. Conclusions: In vitro and in vivo studies showed the selective replication, cytotoxicity, GM-CSF production, and antitumor efficacy of CG0070 in several bladder TCC models, suggesting a potential utility of this oncolytic agent for the treatment of bladder cancer. Further studies are warranted to show the role of human GM-CSF in the antitumor efficacy of CG0070.
Similar RANTES levels in healthy and asthmatic airways by immunoassay and in situ hybridization.
Authors: J V Fahy, D J Figueroa, H H Wong, J T Liu, J S Abrams
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

To determine if RANTES expression is unregulated in the airways of asthmatic subjects, we performed bronchial mucosal biopsies and airway lavage in seven atopic asthmatic subjects and eight healthy subjects. Immunohistochemistry was used to reveal RANTES protein expression in the airway biopsies. An ELISA was used to quantitate RANTES in lavage. In three subjects in each group, we also used in situ hybridization to reveal mRNA for RANTES in airway biopsies. We found that the mean (+/- SD) percent expression for RANTES in the epithelium and submucosa was 26 +/- 9% and 26 +/- 10% in the asthmatic and healthy tissue samples, respectively. RANTES mRNA was demonstrable in the bronchial mucosa of both healthy and asthmatic subjects, predominantly in the epithelial cells but also in the submucosa. We also found that there was no significant difference in the median RANTES concentrations between the groups (healthy: 2.9 pg/ml [range: 0.0 to 28.7 pg/ml]; asthma: 1.8 pg/ml [range: 0.0 to 82.1 pg/ml], p > 0.05) despite a trend for higher concentrations of eosinophil cationic protein (ECP) in the asthmatic group (p = 0.08). In summary, this study confirms that cells in airway mucosal tissue produce RANTES but that the level of production in mild stable asthma is not different from that of healthy control subjects.
CCR2 expressing CD4+ T lymphocytes are preferentially recruited to the ileum in Crohn's disease
Authors: S J Connor
Journal: Gut (2004)

<b>Background and aims:</b> Chemokine receptors are key determinants of leucocyte trafficking. While the chemokine receptor CCR9 and its chemokine ligand CCL25 (TECK) mediate lymphocyte homing to the healthy small intestine, the chemokine receptors important for recruitment during intestinal inflammation are undefined. Animal studies have suggested potential roles for CCR2 and CCR5 in inflammatory bowel disease (IBD). The aim of this study was to understand the role of CCR2 in human IBD. <b>Methods:</b> Resections of ileum or colon were obtained from patients undergoing surgery for small bowel Crohn's disease (SBCD; n = 10), Crohn's colitis (n = 5), ulcerative colitis (n = 6), and non-IBD related conditions (control ileum n = 11; control colon n = 11). Expression of CCR2 by lamina propria lymphocytes (LPLs) was determined by both flow cytometry and immunohistochemistry. As a functional correlate, chemotaxis assays using the CCR2 ligand, CCL2 (MCP-1), were performed. Expression of CCR2 by peripheral blood lymphocytes was determined by flow cytometry. <b>Results:</b> There were greater than 30-fold more CCR2<sup>+</sup> LPLs in SBCD than in control ileum (29.3% (19.9–55.1) <i>v</i> 0.9% (0.4–11.5); p = 0.0007). Specifically, CCR2<sup>+</sup>CD4<sup>+</sup> LPLs were increased (p = 0.002) whereas CCR2<sup>+</sup>CD8<sup>+</sup> LPLs were not. Increased expression included both memory (CD45RO<sup>+</sup>; p = 0.005) and naïve (CD45RO<sup>−</sup>; p = 0.01) CCR2<sup>+</sup> populations. The increase in CCR2<sup>+</sup> LPLs in SBCD was confirmed by both immunohistochemistry (p = 0.0002) and enhanced chemotactic responses to CCL2. CCR2 expression was not increased in the peripheral blood of patients with SBCD, suggesting ongoing recruitment of the CCR2<sup>+</sup> population to the ileum. In contrast with SBCD, there was no significant increase in CCR2<sup>+</sup> LPLs in Crohn's colitis or ulcerative colitis samples. <b>Conclusions:</b> The chemokine receptor CCR2 appears to be an important contributor to accumulation of CD4<sup>+</sup> T lymphocytes in the ileum in small bowel Crohn's disease. Blockade of CCR2 may provide a novel therapeutic alternative.
Understanding of Prognosis Among Parents of Children With Cancer: Parental Optimism and the Parent-Physician Interaction
Authors: Jennifer W. Mack, E. Francis Cook, Joanne Wolfe, Holcombe E. Grier, Paul D. Cleary, Jane C. Weeks
Journal: Journal of Clinical Oncology (2007)

Patients often overestimate their chances of surviving cancer. Factors that contribute to accurate understanding of prognosis are not known. We assessed understanding of likelihood of cure and functional outcome among parents of children with cancer and sought to identify factors that place parents at risk for overly optimistic beliefs about prognosis.We conducted a cross-sectional survey of 194 parents of children with cancer (response rate, 70%) who were treated at the Dana-Farber Cancer Institute and Children's Hospital in Boston, MA, and the children's physicians. Parent and physician expectations for likelihood of cure and functional outcome were compared. In 152 accurate or optimistic parents, we determined factors associated with accurate understanding of likelihood of cure compared with optimism.The majority of parents (61%) were more optimistic than physicians about the likelihood of cure. Parents' beliefs about other outcomes of cancer treatment were similar (quality-of-life impairment, P = .70) or more pessimistic (physical impairment, P = .01; intellectual impairment, P = .01) than physicians' beliefs. Parents and physicians were more likely to agree about chances of cure when physicians had confidence in knowledge of prognosis (odds ratio [OR] = 2.55, P = .004) and allowed parents to take their preferred decision-making role (OR = 1.89, P = .019).Parents of children with cancer are overly optimistic about chances of cure but not about other outcomes of cancer therapy. Parents tend to be overly optimistic about cure when physicians have little confidence and when the decision-making process does not meet parents' preferences. These findings suggest that physicians are partly responsible for parents' unrealistic expectations about cure.
The imaginary fundamentalists: The unshocking truth about Bayesian cognitive science
Authors: Nick Chater, Noah Goodman, Thomas L. Griffiths, Charles Kemp, Mike Oaksford, Joshua B. Tenenbaum
Journal: Behavioral and Brain Sciences (2011)

Abstract If Bayesian Fundamentalism existed, Jones &amp; Love's (J&amp;L's) arguments would provide a necessary corrective. But it does not. Bayesian cognitive science is deeply concerned with characterizing algorithms and representations, and, ultimately, implementations in neural circuits; it pays close attention to environmental structure and the constraints of behavioral data, when available; and it rigorously compares multiple models, both within and across papers. J&amp;L's recommendation of Bayesian Enlightenment corresponds to past, present, and, we hope, future practice in Bayesian cognitive science.
Origin of the Mesozoa inferred from 18S rRNA gene sequences
Authors: J. Pawlowski, J. I. Montoya-Burgos, J. F. Fahrni, J. Wuest, L. Zaninetti
Journal: Molecular Biology and Evolution (1996)

The phylum Mesozoa comprises small, simply organized wormlike parasites of marine invertebrates and is composed of two classes, the Rhombozoa and the Orthonectida. The origin of Mesozoa is uncertain; they are classically considered either as degenerate turbellarians or as primitive multicellular animals related to ciliated protists. In order to precisely determine the phylogenetic position of this group we sequenced the complete 18S rRNA gene of one rhombozoid, Dicyema sp., and one orthonectid, Rhopalura ophiocomae. The sequence analysis shows that the Mesozoa branch early in the animal evolution, closely to nematodes and myxozoans. Our data indicate probably separate origins of rhombozoids and orthonectids, suggesting that their placement in the same phylum needs to be revised.
Triggering infections in reactive arthritis.
Authors: V V Valtonen, M Leirisalo, P J Pentikainen, T Rasanen, I Seppala, U Larinkari, M Ranki, S Koskimies, M Malkamaki, P H Makela
Journal: Annals of the Rheumatic Diseases (1985)

Certain microbes like yersinia, salmonella, shigella, campylobacter, chlamydia, and possibly gonococcus can trigger reactive arthritis especially in patients of the HLA-B27 type. In the present study we have used serological and culture methods to identify the probable triggering infection in 50 consecutive HLA-B27 positive patients diagnosed as having reactive arthritis. The two most common triggering agents thus identified were Yersinia enterocolitica (12 patients) and Chlamydia trachomatis (11 patients). In addition six patients had high antistreptolysin O titres and two high teichoic acid antibody titres suggesting group A streptococci and Staphylococcus aureus as triggering agents. In 13 patients no preceding infection could be identified. The identity of the infective agent seems to have very little effect on the clinical picture of the reactive arthritis - the only difference between the various aetiological groups in the present material was absence of fever in the patients with a preceding C. trachomatis infection, of whom only one out of 11 had a temperature greater than or equal to 38 degrees C, whereas 13 of 16 patients with a preceding enterobacterial, and five of the eight patients with a streptococcal or staphylococcal infection had raised temperatures.
Treatment of Helicobacter pylori infection: management of patients with ulcer disease by general practitioners and gastroenterologists
Authors: G N J Tytgat
Journal: Gut (1998)

Knowledge of the importance of Helicobacter pylori infection is still fragmentary.Currently only a minority of patients with ulcers receive adequate eradication therapy.Ideally there should be no diVerence in the level of knowledge between general practitioners and gastroenterologists.Yet in practice there is a substantial difference.The results obtained in highly selected clinical trials do not reflect results of practice in the real world.The gap can only be narrowed through careful mass education.The role of testing for H pylori infection in primary care practice needs to be clarified and the problem of erratic treatment by general practitioners and specialists needs to be resolved.Adequate response to these problems will require the creation of "regional platforms" where both primary care physicians and specialists decide on empirical therapy, eradication strategy and referral of dyspeptic patients.
Haemodynamic Responses to Exercise in Hypertension: Place of the Sympathetic Nervous System Evaluated by a New Selective Cardiac Beta-adrenergic Blocking Agent ICI 50,172
Authors: Elliot Shinebourne, James Fleming, John Hamer
Journal: Cardiovascular Research (1968)

Intravenous administration of a new cardio-selective β-adrenergic blocking agent with intrinsic sympathetic activity, but, unlike propranolol, with no quinidine-like activity, produced insignificant haemodynamic effects at rest. On treadmill exercise, however, blood pressure, heart rate, cardiac output, and left ventricular work were reduced, peripheral resistance remaining unaltered.
PWE-012 In vitro characterisation of aberrantly glycosylated MUC1 binding-PS1 photoimmunoconjugates for oesophageal adenocarcinoma targeted photodynamic therapy in primary and metastatic disease: Abstract PWE-012 Figure 1
Authors: M A Butt, H Pye, I Stamati, G Yahioglu, R J Haidry, D Oukrif, M R Novelli, M P Deonarain, L B Lovat
Journal: Gut (2012)

<h3>Introduction</h3> Most patients with oesophageal adenocarcinoma (OA) are unfit for curative treatment but are fit for photodynamic therapy (PDT). PDT has been limited by poor tumour selectivity, poor tissue penetration of light and protracted side effects. These restrictions may be overcome with targeted PDT. We have previously demonstrated aberrantly glycosylated MUC1 (AG-MUC1), bound by humanised anti-human milk-fat globule-1 (Hu-HMFG1) antibody is significantly expressed in Barrett9s epithelium (BE) with high grade dysplasia and OA. In this study, we characterise photoimmunoconjugates (PIC) of Hu-HMFG1 with the photosensitisers (PS) pyropheophorbide-α (PPa), and PS1, a water-soluble derivative of PPa activated in the near infra-red. <h3>Methods</h3> PPa succinimidyl ester (PPA-SE) and PS1 were first synthesised (PhotoBiotics) from PPa. Both PS were then conjugated with Hu-HMFG1. The resulting PICs were dialysed, centrifuged and the supernatant and resultant pellet were resuspended in PBS and retained for spectroscopic and SDS-Page gel analysis. Fluorescence of PICs in the gels were photographed and the gels stained with Coomasie to confirm accurate loading. AIDA image analyser software was used for densitometry measurement. <h3>Results</h3> HuHMFG1:PPa PICs, although well conjugated by fluorescent photography of SDS-page gels, were very insoluble. Further characterisation was limited to PS1 PICs. UV/Vis analysis of the soluble HuHMFG1:PS1 PIC supernatant, suitable for subsequent in vitro testing, confirmed maximum absorption at 683 nm (Abstract PWE-012 figure 1). SDS page analysis indicated up to 52% of PS1 photosensitiser was conjugated in the supernatant mixture post-dialysis. AIDA image analysis confirmed that in those antibodies conjugated, a loading ratio of PS1:HuHMFG1 of up to 7:1 was achieved. <h3>Conclusion</h3> This pilot study is the first to successfully conjugate HuHMFG1 with the photosensitisers PPa and PS1. These PICs could potentially selectively target photosensitisers to tissues of interest preserving the surrounding architecture during PDT. HuHMFG1:PS1 PICs have shown enhanced absorption in the red spectral region which will translate clinically into deeper tissue penetration than currently licenced photosensitisers. Further experiments are needed to both optimise the conjugation protocol and purify the product to GLP standards prior to clinical studies. <h3>Competing interests</h3> None declared.
Avoidance of reperfusion injury after cardioplegia.
Authors: A H Brown, G N Morritt, M Hammo
Journal: Thorax (1982)

Myocardial damage incurred by ischaemia appears during and seems to be accelerated by reperfusion, which restores recoverable cells and disrupts badly damaged ones. Vicious cycles of oedema, calcium accumulation, acidosis, oxygen toxicity, fibrillation and air and platelet emboli contribute to the reperfusion injury. The philosophy of cool low-pressure reperfusion gradually restoring temperature and pressure to normal is here contrasted experimentally with that of immediate normothermic, normotensive perfusion after 90 minutes of ischaemic cool, cardioplegic arrest. The preparation was a canine heart which was treated according to the usual clinical protocol except that one group was reperfused at normal temperature and pressure, and the other group started reperfusion cool and at a low pressure and over the next 10 minutes pressure and temperature were restored to normal. Isovolumic ventricular function studies were done before ischaemia and after recovery and showed statistically significant differences between the groups in favour of the immediate restoration of normal temperature and pressure of perfusion. Contractile velocity and systolic pressure showed very highly significant (p = less than 0.005) differences, wall stress significant (p = less than 0.025) and compliance not significant differences between the groups. Reperfusion with optimal conditions may prevent "vicious cycle" changes in ischaemically damaged but recoverable myocardium. We have shown that a step in this direction is reperfusion with blood at normal temperature and pressure rather than initially at lowered temperature and pressure.