tbuckley/cabot-search huggingface dataset:
SYNTHESIS OF ENDOGENOUS PYROGEN BY RABBIT LEUKOCYTES
Authors: Douglas M. Moore, Patrick A. Murphy, P. Joan Chesney, W. B. Wood
Journal: The Journal of Experimental Medicine (1973)

Rabbit ieukocytes from peritoneal exudates and from blood were stimulated to form leukocyte pyrogen in the presence of radiolabeled amino acids. The stimuli used were endotoxin, phagocytosis, and tuberculin. The crude leukocyte pyrogen samples were purified; pyrogen from exudate cells was rendered homogeneous; pyrogen from blood cells was still contaminated with other proteins. All the purified pyrogens were radioactive; and for all it was shown that radioactivity and pyrogenic activity coincided on electrophoresis at pH 3.5 and pH 9 in acrylamide and on isoelectric focusing in acrylamide. Furthermore, pyrogens obtained from exudate cells stimulated in different ways, or from blood cells and exudate cells stimulated with endotoxin, appeared to be identical. These results suggest that leukocyte pyrogen was synthesized de novo from amino acid precursors and that leukocytes made the same pyrogen whatever the stimulus used to activate them.
Should Early Acceleration of Heart Rate During Exercise Be Used to Risk Stratify Patients With Suspected or Established Coronary Artery Disease?
Authors: Bernard R. Chaitman
Journal: Circulation (2007)

xercise is one of the most common noninvasive stressors used to risk stratify patients with suspected or established coronary disease.Functional capacity, time to onset of demand-induced ischemic ST-segment shifts or angina, complex ventricular arrhythmias, a progressive fall in systolic blood pressure during exercise, and abnormal heart rate (HR) responses either during or after exercise are all well-established independent predictors of long-term outcome and, when used in combination, have the potential to identify prognostic high-risk patients who may be candidates for coronary angiography and coronary revascularization. 1 Among HR variables tested that are predictive of mortality, the most common include the ability to augment HR to age-predicted maximum (chronotropic response), the HR recovery response in the immediate postexercise phase, and the ST-segment response corrected for HR. 2,
Effects of Intracoronary Radiation on Thrombosis After Balloon Overstretch Injury in the Porcine Model
Authors: Yoram Vodovotz, Ron Waksman, Won-Ho Kim, Balram Bhargava, Rosanna C. Chan, Martin Leon
Journal: Circulation (1999)

Background —The main complications of PTCA remain thrombosis and restenosis. Recent studies have demonstrated reduction in the neointimal hyperplasia after intracoronary radiation (IR) with doses of 10 to 25 Gy of ionizing radiation delivered by either β- or γ-emitters to injured vessels. The purpose of this study was to examine the effect of ionizing radiation on the thrombosis rate (TR) of injured porcine coronary arteries. Methods and Results —Thirty-four juvenile swine (63 coronary arteries) were subjected to overstretch balloon injury followed by IR with doses of 0 to 18 Gy of either β- or γ-radiation. Two weeks after treatment, tissue sections were perfusion-fixed, stained with hematoxylin-eosin and Verhoeff–van Gieson’s stain, and analyzed for presence of a thrombus, thrombus morphology, and neointima formation by computer-assisted histomorphometry techniques. Although the overall TR increased dose-dependently from 0 to 18 Gy prescribed dose, luminal thrombi decreased. Thrombus area also decreased with increasing radiation dose, whether assessed at the prescription point or at the luminal surface, which corresponded to decreased intimal area. Furthermore, luminal thrombi present after IR tended to consist mostly of fibrin and thus were less organized than in controls. Conclusions —These results suggest that IR induces thrombosis but does not necessarily compromise the lumen. Strategies for reducing TR may further decrease intimal area as well as increasing the safety of this therapy.
Lethal reperfusion injury in acute myocardial infarction: facts and unresolved issues
Authors: D. Garcia-Dorado, M. Ruiz-Meana, H. M. Piper
Journal: Cardiovascular Research (2009)

### 1.1 Definitions

‘Reperfusion injury’ has been for some time an imprecise and controversial term referring to a variety of alterations occurring at the time of restoration of blood flow, from functional impairment to cell death. The term ‘lethal reperfusion injury’ specifically refers to cell death associated with transient ischaemia that can be prevented by interventions applied at the time of reperfusion.1 Therefore, it is the component of cell death occurring as a consequence of reperfusion. There are aspects of lethal reperfusion injury upon which there is general agreement based on solid information.

### 1.2 Existence and relevance

The existence of lethal myocardial reperfusion injury has been demonstrated by an overwhelming body of evidence obtained mainly in laboratory experiments, but also, and increasingly, in humans.2 Different interventions have consistently been shown to limit myocardial necrosis when applied at the time of reperfusion in a variety of models and preparations, and it is unquestionable that, at least under certain conditions, lethal myocardial reperfusion injury occurs. It is also clear from those studies that lethal reperfusion injury can be responsible for a significant proportion (one-third or more) of cell death caused by transient global or regional myocardial ischaemia.

### 1.3 Initial minutes after reperfusion

Many studies have shown a reduction of the protection afforded by several pharmacological interventions and postconditioning protocols when they are first applied only a few minutes later than reperfusion onset.3 Prolonging intracellular acidosis for only 3 min at the onset of reperfusion has a dramatic protective effect.4,5 These observations demonstrate that at least part of lethal reperfusion injury takes place very early after restoration of flow, and they are consistent with the fact that most changes associated with cell death, such as calcium oscillations, calpain activation, hypercontracture, oxidative stress, or mitochondrial permeability transition,6 occur during the very first minutes of reflow.

### 1.4 Necrosis

The rapid time course …
Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy
Authors: Sarah Picaud, Oleg Fedorov, Angeliki Thanasopoulou, Katharina Leonards, Katherine Jones, Julia Meier, Heidi Olzscha, Octovia Monteiro, Sarah Martin, Martin Philpott, Anthony Tumber, Panagis Filippakopoulos, Clarence Yapp, Christopher Wells, Ka Hing Che, Andrew Bannister, Samuel Robson, Umesh Kumar, Nigel Parr, Kevin Lee, Dave Lugo, Philip Jeffrey, Simon Taylor, Matteo L. Vecellio, Chas Bountra, Paul E. Brennan, Alison O'Mahony, Sharlene Velichko, Susanne Müller, Duncan Hay, Danette L. Daniels, Marjeta Urh, Nicholas B. La Thangue, Tony Kouzarides, Rab Prinjha, Jürg Schwaller, Stefan Knapp
Journal: Cancer Research (2015)

Abstract The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein–protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9+ acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers. Cancer Res; 75(23); 5106–19. ©2015 AACR.
Association Versus Causation Versus Quality Improvement: Setting Benchmarks for Lymph Node Evaluation in Colon Cancer
Authors: R. Ricciardi, N. N. Baxter
Journal: JNCI Journal of the National Cancer Institute (2007)

There has been substantial attention and interest directed toward improving the quality of medical care in the United States; the need for quality improvement has reached the consideration of policy makers, providers, payers, and patients. In response to congressional mandates, the Institute of Medicine launched the Redesigning Health Insurance Performance Measures, Payment, and Performance Improvement Project ( 1 ), with the goal of accelerating the diffusion and pace of quality improvement efforts. Specific policies have been promoted to improve care, including measurement and reporting of performance data, payment incentives, and quality improvement initiatives. Measures in oncology are under active development, and as this process evolves, it is likely that implementation of performance measures will become mandatory and that the scope will broaden. Lymph node evaluation is a frequently discussed potential quality measure for colon cancer, and benchmarks for adequacy of lymph node evaluation have been proposed. As Chang et al. ( 2 ) point out, “the number of lymph nodes recovered from a patient with colon cancer has been identified as a potentially important measure of the quality of cancer care by many organizations, including the American College of Surgeons, the American Society of Clinical Oncology, the National Comprehensive Cancer Network, the National Quality Forum, healthcare insurance providers, and others.” This paper, a systematic review of the evidence associating lymph node harvest in colon cancer and clinical outcomes is, therefore, both timely and topical. In a pooled analysis including more than 60 000 patients ( 2 ), the authors found that 16 of 17 national and international studies demonstrated improved survival as the number of lymph nodes evaluated increased in patients with stage II colon cancer. In addition, four of six studies reported a positive association between lymph node number and survival among patients with stage III colon cancer. The authors conclude that given the evidence, lymph node evaluation deserves consideration as a quality measure for colon cancer care. However, before lymph node benchmarks are established as a quality measure, two important questions must be addressed. First, who or what is being evaluated when we report lymph node counts — the surgeon, the pathologist, the hospital, the patient, or even the tumor?
Nitric oxide causes dysfunction of coronary autoregulation in endotoxemic rats
Authors: Jurgen A.M Avontuur, Hajo A Bruining, Can Ince
Journal: Cardiovascular Research (1997)

Objective: This study tested the hypothesis that overproduction of endogenous nitric oxide (NO) during endotoxemia may modulate coronary autoregulation and myocardial reactive hyperemia. Methods: Hearts of endotoxin-pretreated rats and controls were isolated and arranged for perfusion in a Langendorff preparation. Autoregulation was studied by examining flow–pressure relations during stepwise changes in perfusion pressure. The contribution of nitric oxide was examined by perfusion with Nω-nitro-l-arginine (NNLA), an inhibitor of nitric oxide synthesis and methylene blue (MB), an inhibitor of soluble guanylate-cyclase. Results: Endotoxin-treated hearts showed massive coronary vasodilatation and autoregulatory function was impaired at perfusion pressures from 20 to 60 mmHg. Both NNLA and MB reduced coronary flow, improved autoregulation and eliminated differences in coronary flow and autoregulation between the control and endotoxin-treated group. Vasoconstriction with vasopressin, a direct smooth muscle constrictor, could not eliminate differences in autoregulation between groups. Reactive hyperemia following coronary occlusion in endotoxin-treated hearts showed decreased duration, flow repayment and repayment ratio. In the presence of NNLA or MB, however, no significant differences in reactive hyperemic flow patterns were present. Conclusions: These observations suggest that massive coronary vasodilatation due to increased myocardial NO synthesis can result in autoregulatory dysfunction and altered myocardial reactive hyperemia during endotoxemia.
Expression of intercellular adhesion molecule 1 (ICAM-1, CD54) in colonic epithelial cells.
Authors: W Dippold, B Wittig, W Schwaeble, W Mayet, K H Meyer zum Buschenfelde
Journal: Gut (1993)

The expression of intercellular adhesion molecule-1 (ICAM-1, CD54) was examined in 16 surgically removed colonic tumours and two colonic carcinoma cell lines. Immunohistochemistry showed a varying percentage of ICAM-1 positive colonic carcinoma cells in 9/16 tissue specimens, while normal colonic tissue (apart from a slight reactivity of endothelial cells) was not stained. The presence of the ICAM-1 molecule on the cell surface and the expression of ICAM-1 mRNA were investigated for two colonic carcinoma cell lines. It was possible to enhance the expression of ICAM-1 considerably by incubating the cells in the presence of inflammatory cytokines in HT-29 and CaCo-2 cells. The responsiveness to either interferon alpha (IFN-alpha), tumour necrosis factor alpha (TNF-alpha), or interleukin 1 beta (IL-1 beta) treatment was different in each cell line. Interestingly, ICAM-1 is shed by colonic carcinoma cells because soluble sICAM-1 was detected in the cell culture supernatants. In comparison with normal serum samples, the mean value of sICAM-1 in 63 samples of patients with colonic carcinoma and in 20 cases of active inflammatory bowel disease is raised about twofold. It remains to be clarified what part both forms of ICAM-1 play in the course of colonic cancer, ulcerative colitis, and Crohn9s disease.
Autoimmune thyroid disease is associated with a diagnosis of secondary Sjogren's syndrome in familial systemic lupus
Authors: R Hal Scofield, G. R Bruner, J. B Harley, B. Namjou
Journal: Annals of the Rheumatic Diseases (2006)

Autoimmune thyroid disease is common in systemic lupus erythematosus (SLE). About 20% of patients with SLE have secondary Sjögren's syndrome.Families with more than one patient with SLE were identified. All patients met the revised classification criteria, although SLE-unaffected relatives were confirmed not to satisfy these criteria. Diagnosis of autoimmune thyroid disease and Sjögren's syndrome was made on the basis of a review of medical records, interview and questionnaire administered to patients with SLE, and by a questionnaire administered to SLE-unaffected subjects.Of a total of 1138 patients with SLE, 169 had a diagnosis of Sjögren's syndrome. Of these 50 (29.6%) patients also had autoimmune thyroid disease. Of the 939 patients with SLE with no diagnosis of Sjögren's syndrome, 119 (12.7%) had autoimmune thyroid disease (chi2 = 20.1, p = 0.000009). There was no association of a diagnosis of hypertension with secondary Sjögren's syndrome (42% vss 47%). Among 2291 SLE-unaffected relatives, 44 had diagnosed primary Sjögren's syndrome and 16 (36.3%) of these also had autoimmune thyroid disease. 265 of 2247 (11.8%) subjects had autoimmune thyroid disease but no Sjögren's syndrome (chi2 = 24.2, p<0.001).Autoimmune thyroid disease is found in excess among patients with SLE with a diagnosis of secondary Sjögren's syndrome, as well as among their SLE-unaffected relatives with a diagnosis of primary Sjögren's syndrome.
Specific IgE Responses To Lipid Transfer Protein (LTP) And Profilin Have Interactive Effects On The Outcome Of Double-blind Placebo-controlled Food Challenges (DBPCFC) With Apple In Allergic Patients From Spain
Authors: M FERNANDEZRIVAS, L BARREALES, E GONZALEZMANCEBO, L ZUIDMEER, C MILLS, K HOFMANNSOMMERGRUBER, C FERNANDEZ, R VANREE
Journal: Journal of Allergy and Clinical Immunology (2008)
Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction.
Authors: R A Liddle, I D Goldfine, M S Rosen, R A Taplitz, J A Williams
Journal: Journal of Clinical Investigation (1985)

A sensitive and specific bioassay for the measurement of cholecystokinin (CCK) in human plasma was developed to determine the molecular forms of CCK in circulation, CCK responses to feeding, and the physiologic role of CCK in gallbladder contraction. First, plasma was quantitatively extracted and concentrated with octadecylsilylsilica, and the extracts were then assayed for their ability to stimulate amylase release from isolated rat pancreatic acini. Acini were highly sensitive to CCK whereas gastrin reacted only weakly in this system. With the assay, plasma levels of cholecystokinin octapeptide (CCK-8) bioactivity as low as 0.2 pM were detectable. CCK bioactivity in plasma was inhibited by the CCK antagonist, bibutyryl cyclic guanosine monophosphate, and was eliminated by immunoadsorption with an antibody directed against the carboxyl terminus of CCK. Detection of fasting levels of CCK was possible in all individuals tested and averaged 1.0 +/- 0.2 pM (mean +/- SE, n = 22) CCK-8 equivalents. Plasma CCK biological activity was normal in patients with gastrin-secreting tumors. After being fed a mixed liquid meal, CCK levels rose within 15 min to 6.0 +/- 1.6 pM. The individual food components fat, protein, and amino acids were all potent stimulants of CCK secretion; in contrast, glucose caused a significant but smaller elevation in plasma CCK levels. Gel filtration studies identified three major forms of CCK bioactivity in human plasma: an abundant form that eluted with CCK-33, a smaller form that eluted with CCK-8, and an intermediate form that eluted between CCK-33 and CCK-8. Ultrasonic measurements of gallbladder volume indicated that this organ decreased 51% in size 30 min after feeding a mixed liquid meal. This contraction occurred coincidentally with the increase in plasma CCK levels. Next CCK-8 was infused to obtain CCK levels similar to postprandial levels. This infusion caused a decrease in gallbladder volume, similar to that seen with a meal. The present studies indicate, therefore, that CCK can be bioassayed in fasting and postprandial human plasma. These studies also suggest that CCK may be an important regulator of gallbladder contraction.
Estrogen Receptor α Gene Polymorphisms and Risk of Myocardial Infarction
Authors: Stephanie C. E. Schuit, Hok-Hay S. Oei, Jacqueline C. M. Witteman, Corine H. Geurts van Kessel, Joyce B. J. van Meurs, Rogier L. Nijhuis, Johannes P. T. M. van Leeuwen, Frank H. de Jong, M. Carola Zillikens, Albert Hofman, Huibert A. P. Pols, André G. Uitterlinden
Journal: JAMA (2004)

The role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor alpha (ESR1) gene may influence IHD risk, but the role of common sequence variations in the ESR1 gene is unclear.To determine whether the ESR1 haplotype created by the c.454-397T>C (PvuII) and c.454-351A>G (XbaI) polymorphisms is associated with myocardial infarction (MI) and IHD risk.In 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment between 1989-1993 and follow-up to January 2000), a population-based, prospective cohort study of participants aged 55 years and older, ESR1 c.454-397T>C and c.454-351A>G haplotypes were determined. Detailed interviews and physical examinations were performed, blood samples were obtained, and cardiovascular risk factors were assessed.The primary outcome was MI and IHD defined as MIs, revascularization procedures, and IHD mortality.Approximately 29% of women and 28.2% of men were homozygous carriers of the ESR1 haplotype 1 (-397 T and -351 A) allele, 49% of women and 50% of men were heterozygous carriers, and 22% of women and 21.4% of men were noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women; 170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97 were fatal. After adjustment for known cardiovascular risk factors, female heterozygous carriers of haplotype 1 had an increased risk of MI (event rate, 2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed a similar association. In women, the effect of haplotype 1 on fatal IHD was larger than on nonfatal IHD. In men, the ESR1 haplotypes were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93; 95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82; 95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event rate, 5.8%) and were not associated with an increased risk of IHD.In this population-based, prospective cohort study, postmenopausal women who carry ESR1 haplotype 1 (c.454-397 T allele and c.454-351 A allele) have an increased risk of MI and IHD, independent of known cardiovascular risk factors. In men, no association was observed.
<i>RNASEL</i> Gene Polymorphisms and the Risk of Prostate Cancer: a Meta-analysis
Authors: Huihua Li, Bee Choo Tai
Journal: Clinical Cancer Research (2006)

Studies revealing conflicting results on the role of RNASEL polymorphisms Glu265X, Arg462Gln, and Asp541Glu on prostate cancer risk led us to perform a meta-analysis to investigate the association of these polymorphisms and prostate cancer risk.Relevant studies were selected by searching PubMed from January 1996 to August 2005 using keywords "RNASEL gene AND prostate cancer." For each study, odds ratio (OR) with 95% confidence interval (95% CI) was calculated to estimate the gene effect. Pooled estimates of the OR were computed using the random effects model.Ten studies were included in the meta-analysis. The overall results suggested no major influence of these variants on prostate cancer risk. However, analysis of the Asp541Glu polymorphism by ethnic populations showed that Asp/Glu (familial cases versus control: OR, 1.38; 95% CI, 1.04-1.82; sporadic cases versus control: OR, 1.26; 95% CI, 1.07-1.48; prostate cancer versus control: OR, 1.29; 95% CI, 1.12-1.48) and Asp/Glu + Glu/Glu (familial cases versus control: OR, 1.37; 95% CI, 1.10-1.70; sporadic cases versus control: OR, 1.24; 95% CI, 1.07-1.44; prostate cancer versus control: OR, 1.27; 95% CI, 1.13-1.44) increased prostate cancer risk in Caucasians, thus suggesting a dominant model for the Glu variant.Compared with the genotype Asp/Asp, the Glu variant at the Asp541Glu polymorphism increases prostate cancer risk by <2-fold in Caucasians, regardless of family history of the disease. This suggests that genuine genetic effects of this polymorphism may account for only a part of prostate cancer in the Caucasian population.