tbuckley/cabot-search huggingface dataset:
External detection and visualization of myocardial ischemia with 11C-substrates in vitro and in vivo.
Authors: E S Weiss, E J Hoffman, M E Phelps, M J Welch, P D Henry, M M Ter-Pogossian, B E Sobel
Journal: Circulation Research (1976)

To characterize externally detectable changes in myocardial metabolism of free fatty acids (FFA) and glucose associated with ischemia, isovolumically beating rabbit hearts were perfused under conditions of selected flows with cyclotron-produced, short-lived (t1/2 - 20.4 minutes), 11C-labeled isotopes of glucose and FFA. Tension-time index decreased 83% and lactate production increased from 0.5 +/- 1.9 (SE) to 5.3 +/- 2.1 mumol/min per g of dry weight reflecting myocardial ischemia after flow was reduced from 20 to 5 ml/min. After 30 minutes of low flow the myocardial accumulation of 11C-octanoate, expressed as the extraction fraction, declined from 56 +/- 15% to 30 +/- 3%, reflecting metabolic suppression of FFA extraction during low flow. Effects attributable exclusively to prolonged residence time were excluded. Similar results were obtained with 11C-palmitate. The myocardial avidity for 11C-palmitate was demonstrable by rectilinear whole body scanning in dogs given 5 mCi of the agent intravenously. Diminished 11C-palmitate uptake in zones of myocardium rendered ischemic for 20 minutes prior to reflow in intact dogs was delineated by electrocardiographically gated positron-emission transaxial computer reconstruction tomography. Thus, diminished 11C-FFA extraction, externally detectable, accompanies decreased perfusion in isolated perfused hearts, and decreased 11C-FFA uptake reflecting myocardial ischemia in vivo can be evaluated noninvasively by positron-emission transaxial tomography.
Early afterdepolarizations and triggered activity induced by cocaine. A possible mechanism of cocaine arrhythmogenesis.
Authors: S Kimura, A L Bassett, H Xi, R J Myerburg
Journal: Circulation (1992)

Cocaine may produce life-threatening cardiac arrhythmias, but it is not clear whether this is an indirect effect of coronary vasoconstriction and ischemia or a direct myocardial effect of the substance. Except for its effects on the Na+ current as a local anesthetic, little is known about the direct electrophysiological actions on cardiac cells. Therefore, we studied the effects of cocaine on action potentials and membrane currents in isolated feline ventricular myocytes to test the hypothesis that cocaine-induced arrhythmogenesis may be based on cellular and ionic mechanisms.Action potentials and membrane currents were recorded using the patch clamp technique. Single cells were isolated from feline left ventricles by enzymatic digestion. Exposure to cocaine (10 or 50 microM) depressed the plateau phase of the action potential and prolonged action potential duration. Action potential duration measured at 90% repolarization (APD90) was increased from 280 +/- 12 msec to 325 +/- 17 msec (p less than 0.01) by 5-minute exposure to 10 mumol cocaine, when the cells were stimulated at 1 Hz. During exposure to 50 mumol cocaine, APD90 was markedly increased from 298 +/- 13 msec to 437 +/- 35 msec (p less than 0.01) in seven of 16 cells, and early afterdepolarizations (EADs) developed in these cells. The take-off potential and the amplitude of EADs were -28.3 +/- 2.3 mV and 16.8 +/- 1.2 mV, respectively. Triggered activity arising from EADs was induced in four of the seven cells. Addition of 1 nmol isoproterenol augmented EADs and induced sustained triggered activity, whereas they were suppressed by exposure to 2 microM verapamil. Whole-cell voltage clamp experiments revealed that cocaine (50 microM) reduced the peak L-type Ca2+ current from 1.03 +/- 0.13 nA to 0.79 +/- 0.11 nA (23% reduction, p less than 0.05). Cocaine also reduced the peak delayed rectifier K+ current from 362 +/- 51 pA to 113 +/- 32 pA (69% reduction, p less than 0.01). However, cocaine did not affect activation and inactivation kinetics of these channels. Cocaine had no effect on the inward rectifier K+ current.We conclude that cocaine can prolong action potential duration and induce EADs and triggered activity by blocking the delayed rectifier K+ current, and that cocaine-induced abnormalities of repolarization, modulated by its inhibitory effects on catecholamine reuptake, may play a role in the potential of cocaine for induction of acute fatal arrhythmias.
A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA–induced IL-12 production and Th cell differentiation
Authors: Kenji Sugimoto, Mutsuhiro Ohata, Jun Miyoshi, Hiroyoshi Ishizaki, Naotake Tsuboi, Akio Masuda, Yasunobu Yoshikai, Masaya Takamoto, Kazuo Sugane, Seiichi Matsuo, Yasuhiro Shimada, Tetsuya Matsuguchi
Journal: Journal of Clinical Investigation (2004)

A serine/threonine protein kinase, Cot/Tpl2, is indispensable for extracellular signal–regulated kinase (ERK) activation and production of TNF-α and PGE2 in LPS-stimulated macrophages. We show here that Cot/Tpl2 is also activated by other Toll-like receptor (TLR) ligands. Bacterial DNA rich in the dinucleotide CG (CpG-DNA), unlike LPS or synthetic lipopeptide, activated ERK in a Cot/Tpl2–independent manner. Peritoneal macrophages and bone marrow–derived DCs from Cot/Tpl2–/– mice produced significantly more IL-12 in response to CpG-DNA than those from WT mice. Enhanced IL-12 production in Cot/Tpl2–/– macrophages is, at least partly, regulated at the transcriptional level, and the elevated IL-12 mRNA level in Cot/Tpl2–/– macrophages is accompanied by decreased amounts of IL-12 repressors, such as c-musculoaponeurotic fibrosarcoma (c-Maf) and GATA sequence in the IL-12 promoter–binding protein (GA-12–binding protein; GAP-12) in the nucleus. Consistently, Cot/Tpl2–/– mice showed Th1-skewed antigen-specific immune responses upon OVA immunization and Leishmania major infection in vivo. These results indicate that Cot/Tpl2 is an important negative regulator of Th1-type adaptive immunity, that it achieves this regulation by inhibiting IL-12 production from accessory cells, and that it might be a potential target molecule in CpG-DNA–guided vaccination.
Anthropometry, physical performance, and ultrasound patellar tendon abnormality in elite junior basketball players: a cross-sectional study
Authors: J L Cook, Z S Kiss, K M Khan, C R Purdam, K E Webster
Journal: British Journal of Sports Medicine (2004)

Patellar tendinopathy has been reported to be associated with many intrinsic risk factors. Few have been fully investigated. This cross-sectional study examined the anthropometric and physical performance results of elite junior basketball players with normal or abnormal patellar tendons to see if any measures were associated with changes in tendon morphology.Agility, leg strength, endurance, and flexibility were measured in 71 male and 64 female players. A blinded radiologist ultrasonographically examined their patellar tendons and athletes were grouped as having normal or abnormal tendons. One-way ANOVA was used to test for differences in anthropometric and physical performance data for athletes whose tendons were normal or abnormal (unilateral or bilateral tendinopathy) on ultrasound.Results show that females with abnormalities in their tendons had a significantly better vertical jump (50.9+/-6.8 cm) than those with normal tendons (46.1+/-5.4 cm) (p = 0.02). This was not found in males. In males, the mean sit and reach in those with normal tendons (13.2+/-6.7 cm) was greater (p<0.03) than in unilateral tendinopathy (10.3+/-6.2 cm) or in bilateral tendinopathy (7.8+/-8.3 cm). In females, those with normal tendons (13.3+/-4.8 cm) and bilateral tendinopathy (15.8+/-6.2 cm) were distinctly different from those with unilateral tendinopathy (7.9+/-6.6 cm).Flexibility and vertical jump ability are associated with patellar tendinopathy and the findings warrant consideration when managing young, jumping athletes.
Toll-like Receptor 7-Dependent Loss of B Cell Tolerance in Pathogenic Autoantibody Knockin Mice
Authors: Robert Berland, Luis Fernandez, Elina Kari, Jin-Hwan Han, Ina Lomakin, Shizuo Akira, Henry H. Wortis, John F. Kearney, Angelo A. Ucci, Thereza Imanishi-Kari
Journal: Immunity (2006)
Restricting HIV-1 pathways for escape using rationally designed anti–HIV-1 antibodies
Authors: Ron Diskin, Florian Klein, Joshua A. Horwitz, Ariel Halper-Stromberg, D. Noah Sather, Paola M. Marcovecchio, Terri Lee, Anthony P. West, Han Gao, Michael S. Seaman, Leonidas Stamatatos, Michel C. Nussenzweig, Pamela J. Bjorkman
Journal: The Journal of Experimental Medicine (2013)

Recently identified broadly neutralizing antibodies (bNAbs) that potently neutralize most HIV-1 strains are key to potential antibody-based therapeutic approaches to combat HIV/AIDS in the absence of an effective vaccine. Increasing bNAb potencies and resistance to common routes of HIV-1 escape through mutation would facilitate their use as therapeutics. We previously used structure-based design to create the bNAb NIH45-46G54W, which exhibits superior potency and/or breadth compared with other bNAbs. We report new, more effective NIH45-46G54W variants designed using analyses of the NIH45-46–gp120 complex structure and sequences of NIH45-46G54W–resistant HIV-1 strains. One variant, 45-46m2, neutralizes 96% of HIV-1 strains in a cross-clade panel and viruses isolated from an HIV-infected individual that are resistant to all other known bNAbs, making it the single most broad and potent anti–HIV-1 antibody to date. A description of its mechanism is presented based on a 45-46m2–gp120 crystal structure. A second variant, 45-46m7, designed to thwart HIV-1 resistance to NIH45-46G54W arising from mutations in a gp120 consensus sequence, targets a common route of HIV-1 escape. In combination, 45-46m2 and 45-46m7 reduce the possible routes for the evolution of fit viral escape mutants in HIV-1YU-2–infected humanized mice, with viremic control exhibited when a third antibody, 10–1074, was added to the combination.
An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 study Ann Oncol 2002; 13: 1264–1274
Authors: G.M. Mead, M.R. Sydes, J. Walewski, A. Grigg, C.S. Hatton, P. Norbert, C. Guarnaccia, M.S. Lewis, J. McKendrick, S.P. Stenning, D. Wright
Journal: Annals of Oncology (2002)
Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression
Authors: Peter Kuehl, Jiong Zhang, Yvonne Lin, Jatinder Lamba, Mahfoud Assem, John Schuetz, Paul B. Watkins, Ann Daly, Steven A. Wrighton, Stephen D. Hall, Patrick Maurel, Mary Relling, Cynthia Brimer, Kazuto Yasuda, Raman Venkataramanan, Stephen Strom, Kenneth Thummel, Mark S. Boguski, Erin Schuetz
Journal: Nature Genetics (2001)
S36 The adhesion receptor CADM1 promotes human mast cell viability
Authors: E. P. Moiseeva, M. L. Leyland, P. Bradding
Journal: Thorax (2011)

<h3>Introduction and Objectives</h3> Cell adhesion molecule 1 (CADM1) contributes to cell–cell adhesion, proliferation and adhesion-induced degranulation in human lung mast cells. Previously we found that it is expressed as three alternatively spliced isoforms (major SP4 and SP1, and minor SP6) in human lung mast cells (HLMCs) and only SP4 in the cell line HMC-1, originating from mast cell leukaemia. Here we investigated the role of CADM1 in the viability of HLMCs and HMC-1. <h3>Methods</h3> Modulation of CADM1 expression was investigated using adenoviral delivery in both HMC-1 and HLMCs. Cell viability in the absence of survival factors was determined by measuring cell numbers and caspase-3/7 activity. <h3>Results</h3> Modulation of CADM1 expression in HMC-1 cells and HLMCs by overexpressing SP4 (exon 8/11) and SP1 (exon 8/9/11) and RNA interference was confirmed by FACS and Western blotting. Overexpression of SP4 did not affect HMC-1 viability (105%±7% of original number of cells) or caspase-3/7 activity (7.7±0.2 FU/cell) in IMDM only for 48 h vs GFP-transduced cells, but overexpression of SP1 reduced cell number (66%±1%) and increased caspase-3/7 activity (9.8±0.3 FU/cell). CADM1 knockdown reduced HMC-1 number (71%±2%) and increased caspase-3/7 activity (9.5±0.2 FU/cell) in these conditions. In contrast to HMC-1 cells, overexpression of SP4 in HLMCs enhanced cell survival (39%±3%) in IMDM alone after 72 h compared to non-transduced cells (31%±1%, whereas downregulation of CADM1 reduced cell number to 26%±2%. Caspase3/7 activity was increased in HLMCs with downregulated CADM1 (99±20 FU/cell) compared to SP4-overexpressing and non-transduced cells (40±4 FU/cell and 20±1 FU/cell respectively). HLMCs displayed lower basal levels of Mcl-1, parallelled with lower survival and higher caspase-3/7 activation compared to HMC-1 cells. CADM1 downregulation in HLMCs coincided with decreased basal expression of Kit and Mcl-1. <h3>Conclusions</h3> Modulation of CADM1 isoform expression or CADM1 downregulation in HMC-1 cells reduced survival. Conversely, SP4-overexpression or CADM1 downregulation in HLMCs resulted in increased survival or increased cell death, respectively. CADM1 modulation in HLMCs coincided with modulation of proteins related to survival. Hence, CADM1 promotes survival in human mast cells.
Exercise Training in Patients with Chronic Heart Failure Promotes Restoration of High-Density Lipoprotein Functional Properties
Authors: Volker Adams, Christian Besler, Tina Fischer, Meliana Riwanto, Friederike Noack, Robert Höllriegel, Andreas Oberbach, Nico Jehmlich, Uwe Völker, Ephraim B. Winzer, Karsten Lenk, Rainer Hambrecht, Gerhard Schuler, Axel Linke, Ulf Landmesser, Sandra Erbs
Journal: Circulation Research (2013)

Rationale: High-density lipoprotein (HDL) exerts endothelial-protective effects via stimulation of endothelial cell (EC) nitric oxide (NO) production. This function is impaired in patients with cardiovascular disease. Protective effects of exercise training (ET) on endothelial function have been demonstrated. Objective: This study was performed to evaluate the impact of ET on HDL-mediated protective effects and the respective molecular pathways in patients with chronic heart failure (CHF). Methods and Results: HDL was isolated from 16 healthy controls (HDL healthy ) and 16 patients with CHF-NYHA-III (HDL NYHA-IIIb ) before and after ET, as well as from 8 patients with CHF-NYHA-II (HDL NYHA-II ). ECs were incubated with HDL, and phosphorylation of eNOS-Ser 1177 , eNOS-Thr 495 , PKC-βII-Ser 660 , and p70S6K-Ser 411 was evaluated. HDL-bound malondialdehyde and HDL-induced NO production by EC were quantified. Endothelial function was assessed by flow-mediated dilatation. The proteome of HDL particles was profiled by shotgun LC-MS/MS. Incubation of EC with HDL NYHA-IIIb triggered a lower stimulation of phosphorylation at eNOS-Ser 1177 and a higher phosphorylation at eNOS-Thr 495 when compared with HDL healthy . This was associated with lower NO production of EC. In addition, an elevated activation of p70S6K, PKC-βII by HDL NYHA-IIIb , and a higher amount of malondialdehyde bound to HDL NYHA-IIIb compared with HDL healthy was measured. In healthy individuals, ET had no effect on HDL function, whereas ET of CHF-NYHA-IIIb significantly improved HDL function. A correlation between changes in HDL-induced NO production and flow-mediated dilatation improvement by ET was evident. Conclusions: These results demonstrate that HDL function is impaired in CHF and that ET improved the HDL-mediated vascular effects. This may be one mechanism how ET exerts beneficial effects in CHF.
High incidence of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based pacing in the Mode Selection Trial (MOST)
Authors: Mark S Link, Anne S Hellkamp, N.A.Mark Estes, E.John Orav, Kenneth A Ellenbogen, Bassiema Ibrahim, Arnold Greenspon, Carlos Rizo-Patron, Lee Goldman, Kerry L Lee, Gervasio A Lamas
Journal: Journal of the American College of Cardiology (2004)
The CD3 chains of the T cell antigen receptor associate with the ZAP-70 tyrosine kinase and are tyrosine phosphorylated after receptor stimulation.
Authors: D B Straus, A Weiss
Journal: The Journal of Experimental Medicine (1993)

Recent work indicates that signaling events resulting from stimulation of the T cell antigen receptor (TCR) can be initiated by the CD3 complex (gamma, delta, epsilon) as well as the zeta chains of the receptor. To help characterize the signaling function of CD3 we examined its associated tyrosine kinase activity since induction of tyrosine phosphorylation is one of the earliest signaling events. Our results indicate that at least two kinases, lck and ZAP-70, contribute to the CD3-associated kinase activity. A likely target of this activity is the CD3 complex itself since we observed that TCR stimulation resulted in rapid tyrosine phosphorylation of the CD3 epsilon and delta chains. To examine the function of the CD3 epsilon chain in particular, we constructed a chimera that fused the extracellular and transmembrane domains of CD8 to the cytoplasmic domain of CD3 epsilon. This chimera demonstrated that CD3 epsilon was independently capable of associating with proteins having tyrosine kinase activity, including ZAP-70. Our results show that the kinase activity that associates with the CD3 complex has characteristics that are quite similar to the previously characterized zeta-associated kinase activity. This finding suggests that both these components of the TCR initiate signaling events using a common mechanism. However, differences in their signaling function could result from recognition of distinct substrates.
Interleukin 4 Reduces Expression of Inhibitory Receptors on B Cells and Abolishes CD22 and FcγRII-mediated B Cell Suppression
Authors: Elizabeth U. Rudge, Antony J. Cutler, Nicholas R. Pritchard, Kenneth G.C. Smith
Journal: The Journal of Experimental Medicine (2002)

Inhibitory receptors CD22, FcγRII (CD32), CD72, and paired immunoglobulin-like receptor (PIR)-B are critically involved in negatively regulating the B cell immune response and in preventing autoimmunity. Here we show that interleukin 4 (IL-4) reduces expression of all four on activated B cells at the level of messenger RNA and protein. This reduced expression is dependent on continuous exposure to IL-4 and is mediated through Stat6. Coligation of FcγRII to the B cell receptor (BCR) via intact IgG increases the B cell activation threshold and suppresses antigen presentation. IL-4 completely abolishes these negative regulatory effects of FcγRII. CD22 coligation with the BCR also suppresses activation — this suppression too is abolished by IL-4. Thus, IL-4 is likely to enhance the B cell immune response by releasing B cells from inhibitory receptor suppression. By this coordinate reduction in expression of inhibitory receptors, and release from CD22 and FcγRII-mediated inhibition, IL-4 is likely to play a role in T cell help of B cells and the development of T helper cell type 2 responses. Conversely, B cell activation in the absence of IL-4 would be more difficult to achieve, contributing to the maintenance of B cell tolerance in the absence of T cell help.
Induction of antibodies by Staphylococcus aureus nasal colonization in young children
Authors: N.J. Verkaik, A. Lebon, C.P. de Vogel, H. Hooijkaas, H.A. Verbrugh, V.W.V. Jaddoe, A. Hofman, H.A. Moll, A. van Belkum, W.J.B. van Wamel
Journal: Clinical Microbiology and Infection (2009)
Sensitivity to Sunburn Is Associated with Susceptibility to Ultraviolet Radiation–Induced Suppression of Cutaneous Cell–Mediated Immunity
Authors: Deirdre A. Kelly, Antony R. Young, Jane M. McGregor, Paul T. Seed, Christopher S. Potten, Susan L. Walker
Journal: The Journal of Experimental Medicine (2000)

Skin cancer incidence is highest in white-skinned people. Within this group, skin types I/II (sun sensitive/tan poorly) are at greater risk than skin types III/IV (sun tolerant/tan well). Studies in mice demonstrate that ultraviolet radiation (UVR)-induced suppression of cell-mediated immune function plays an important role in the development of skin cancer and induces a susceptibility to infectious disease. A similar role is suspected in humans, but we lack quantitative human data to make risk assessments of ambient solar exposure on human health. This study demonstrates that ambient levels of solar UVR, typically experienced within 1 h of exposure to noonday summer sunlight, can suppress contact hypersensitivity (CHS) responses in healthy white-skinned humans in vivo (n = 93). There was a linear relationship between increase in erythema and suppression of CHS (P &amp;lt; 0.001), and a moderate sunburn (two minimal erythema doses [2 MED]) was sufficient to suppress CHS in all volunteers by 93%. However, a single suberythemal exposure of either 0.25 or 0.5 MED suppressed CHS responses by 50 and 80%, respectively, in skin types I/II, whereas 1 MED only suppressed CHS by 40% in skin types III/IV. The two- to threefold greater sensitivity of skin types I/II for a given level of sunburn may play a role in their greater sensitivity to skin cancer.
CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer
Authors: Shouyu Wang, Xuming Wu, Jianbing Zhang, Yansu Chen, Jin Xu, Xiaowei Xia, Song He, Fulin Qiang, Aiping Li, Yongqian Shu, Oluf Dimitri Røe, Gang Li, Jianwei W Zhou
Journal: Gut (2012)

<h3>Objective</h3> CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC). <h3>Methods</h3> The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo. <h3>Results</h3> CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor κB (NF-κB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-κB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-κB activity and inhibiting IL-8-induced angiogenesis, which correlated with subsequent tumour metastasis. <h3>Conclusions</h3> Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target.