tbuckley/cabot-search huggingface dataset:
Acute Coronary Syndromes in the GUSTO-IIb Trial
Authors: Paul W. Armstrong, Yuling Fu, Wei-Ching Chang, Eric J. Topol, Christopher B. Granger, Amadeo Betriu, Frans Van de Werf, Kerry L. Lee, Robert M. Califf
Journal: Circulation (1998)

Recurrent ischemia after an acute coronary syndrome portends an unfavorable outcome and has major resource-use implications. This issue has not been studied systematically among the spectrum of patients with acute coronary presentations, encompassing those with and without ST-segment elevation.We assessed the 1-year prognosis of the 12 142 patients enrolled in the GUSTO-IIb trial by the presence (n=4125) or absence (n=8001) of ST-segment elevation. This latter group was further categorized into those with baseline myocardial infarction (n=3513) or unstable angina (n=4488). We also assessed the incidence of recurrent ischemia and its impact on outcomes. Recurrent ischemia was significantly rarer in those with ST-segment elevation (23%) than in those without (35%; P<0.001). Mortality at 30 days was greater among patients with ST-segment elevation (6.1% versus 3.8%; P<0.001) but less so at 6 months; by 1 year, mortality did not differ significantly (9.6% versus 8.8%). Patients with non-ST-segment-elevation infarction had higher rates of reinfarction at 6 months (9.8% versus 6.2%) and higher 6-month (8.8% versus 5.0%) and 1-year mortality rates (11.1% versus 7.0%) than such patients who had unstable angina.Refractory ischemia was associated with an approximate doubling of mortality among patients with ST-segment elevation and a near tripling of risk among those without ST elevation. This study highlights not only the substantial increase in late mortality and reinfarction with non-ST-segment-elevation infarction but also the opportunities for better triage and application of therapeutic strategies for patients with recurrent ischemia.
Spontaneous Neurinoma in an African Lungfish, &lt;italic&gt;Protopterus annectens&lt;/italic&gt;, and DNA Repair Studies on Normal and Neoplastic Tissues&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: T Ishikawa, P Masahito, N Nemoto, J Matsumoto, A Shima
Journal: JNCI Journal of the National Cancer Institute (1986)

Neurinomas developed in an African lungfish (Protopterus annectens), living in an aquarium in Western Japan. The 2 tumors, measuring 7.5 X 9.0 X 6.5 and 13 X 4 X 6 cm, were located on the skin. As shown by light microscopy, tumor cells were composed of spindle-shaped cells with huge pleomorphic nuclei, which were arranged in parallel rows or whorls in interlacing connective tissue. Long-term culture of these tumor cells was achieved in vitro at 25 degrees C with use of conditioned medium over a period of more than 4 months. The nuclear DNA contents of erythrocytes (normal diploids, 2C) and tumor cells dispersed from the fixed tumor tissues were measured by 4',6-diamidino-2-phenylindole hydrochloride-DNA microfluorometry by using mouse cerebellar small granule cells (normal diploids, 2C) as a reference. The 2C value of the lungfish was approximately 28-fold greater than that of the mouse. Furthermore, consistent with the nuclear pleomorphism observed by light microscopy, the nuclear DNA contents of tumor cells showed a wide distribution from hypo-2C to hyper-4C. DNA repair synthesis was measured autoradiographically in organ cultures of the tumor, lung, and skin, exposed to chemical carcinogens or UV radiation. Considerable repair was observed in the tumor and skin cells exposed to 1-methyl-1-nitrosourea (CAS: 684-93-5), N-methyl-N'-nitro-N-nitrosoguanidine (CAS: 70-25-7), or 254-nm or sunlamp UV light. Only traces of repair synthesis were detected in lung exposed to 1-methyl-1-nitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine. 4-Hydroxyaminoquinoline 1-oxide (CAS: 4637-56-3) did not induce repair in any of the three tissues. The observed values for repair, relative to the amount of DNA, were similar to those in other fishes.
The Swan Lady
Authors: Dick Ashford
Journal: BMJ (2006)

<b>Background:</b> Because oxidative stress affects muscle function, the underlying mechanism to explain exercise induced peripheral muscle oxidative stress in patients with chronic obstructive pulmonary disease (COPD) is clinically relevant. This study investigated whether chronic hypoxaemia in COPD worsens peripheral muscle oxidative stress and whether an abnormal muscle inflammatory process is associated with it. <b>Methods:</b> Nine chronically hypoxaemic and nine non-hypoxaemic patients performed repeated knee extensions until exhaustion. Biopsy specimens were taken from the vastus lateralis muscle before and 48 hours after exercise. Muscle oxidative stress was evaluated by lipid peroxidation (lipofuscin and thiobarbituric acid reactive substances (TBARs)) and oxidised proteins. Inflammation was evaluated by quantifying muscle neutrophil and tumour necrosis factor (TNF)-α levels. <b>Results:</b> When both groups were taken together, arterial oxygen pressure was positively correlated with quadriceps endurance time (n = 18, <i>r</i> = 0.57; p&lt;0.05). At rest, quadriceps lipofuscin inclusions were significantly greater in hypoxaemic patients than in non-hypoxaemic patients (2.9 (0.2) <i>v</i> 2.0 (0.3) inclusions/fibre; p&lt;0.05). Exercise induced a greater increase in muscle TBARs and oxidised proteins in hypoxaemic patients than in non-hypoxaemic patients (40.6 (9.1)% <i>v</i> 10.1 (5.8)% and 51.2 (11.9)% <i>v</i> 3.7 (12.2)%, respectively, both p = 0.01). Neutrophil levels were significantly higher in hypoxaemic patients than in non-hypoxaemic patients (53.1 (11.6) <i>v</i> 21.5 (11.2) counts per fibre × 10<sup>−3</sup>; p&lt;0.05). Exercise did not alter muscle neutrophil levels in either group. Muscle TNF-α was not detected at baseline or after exercise. <b>Conclusion:</b> Chronic hypoxaemia was associated with lower quadriceps endurance time and worsened muscle oxidative stress at rest and after exercise. Increased muscle neutrophil levels could be a source of the increased baseline oxidative damage. The involvement of a muscle inflammatory process in the exercise induced oxidative stress of patients with COPD remains to be shown.
Learning How to Learn: The Goal of House Staff Training
Authors: J. Willis Hurst
Journal: JAMA (1986)

The two articles by Drs Shanke<sup>1</sup>and Mazzaferri<sup>1</sup>and Drs Parrino and Villanueva<sup>2</sup>on house staff training in this issue ofThe Journalshould be useful to anyone who is concerned about the quality of the next generation of physicians. They relate the results of surveys of teaching programs that indicate the perceived value of various cherished activities that, when added together, make up house staff training. Having observed the exciting scene known as house staff training for 30 years, I believe the following:<i>The objective of any educational system is to encourage those who are participating in the effort to learn how to learn and to be sensitive to interpersonal relationships</i>. House officers must learn how to learn medicine, and they must also learn how to deliver what they know to the satisfaction of their patients, colleagues, the public, and themselves. Furthermore, they must maintain these goals
Cardiopulmonary Bypass Induces Release of Soluble CD40 Ligand
Authors: Lisa Nannizzi-Alaimo, Mark H. Rubenstein, Veronica L. Alves, Gil Y. Leong, David R. Phillips, Herman K. Gold
Journal: Circulation (2002)

Cardiopulmonary bypass (CPB) is known to induce platelet activation, thrombosis, thrombocytopenia, and a systemic inflammatory response. It is known that CD40 ligand (CD40L) exists in platelets, that a soluble form of this protein (sCD40L) is released on platelet activation, that platelets are the primary source of sCD40L in blood, and that sCD40L is involved in thrombosis and inflammation. The present study was designed to determine whether sCD40L is released during CPB. Methods and Results- Blood was obtained from patients undergoing CPB-requiring surgery and analyzed for sCD40L, interleukin-6, and platelet factor 4 and beta-thromboglobulin (markers of platelet activation). Platelets were also isolated and analyzed for their levels of CD40L. Plasma levels of sCD40L increased >1.7-fold (from 0.29 to 0.51 ng/mL, P=0.001) within 1 hour on CPB and increased further to 3.7-fold (to 1.08 ng/mL, P=0.03) 2 hours after the procedure. Half of the released sCD40L was cleared in 2 hours, which allowed the sCD40L to return to approximately baseline levels 8 hours after the procedure. The platelet content of CD40L was decreased by 40% (2.675 to 1.64 ng/10(8) platelets, P=0.001) 1 hour after initiation of CPB and was similar to that observed for platelet factor 4 and beta-thromboglobulin. Interleukin-6, a marker of inflammation, also increased during CPB.The present study demonstrates that CPB causes an increase in the concentration of plasma sCD40L. The corresponding decrease in platelet CD40L suggests that this prothrombotic and proinflammatory protein was derived primarily from platelets and may contribute to the thrombotic and inflammatory complications associated with CPB.
Sarcoplasmic Reticulum Ca <sup>2+</sup> and Heart Failure
Authors: Donald M. Bers, David A. Eisner, Héctor H. Valdivia
Journal: Circulation Research (2003)

eart failure (HF) is a leading cause of death and enormous effort has focused at understanding the molecular and cellular mechanisms of the decreased cardiac contractility.While changes of other components contribute, it is generally agreed that much of the contractile deficit is due to reduced myocyte Ca 2ϩ transients. 1,2Alterations in Ca 2ϩ current (I Ca ) and action potential characteristics are also seen in HF, but a central factor limiting Ca 2ϩ transient amplitude is a decrease of sarcoplasmic reticulum (SR) Ca 2ϩ content. 3-6HF is extremely complex, but it is easy to appreciate how reduced SR Ca 2ϩ content would reduce SR Ca 2ϩ release, myofilament activation, and contractility.Despite agreement that SR Ca 2ϩ content is reduced in HF, controversy exists about why SR content is low. Limitations of the RyR Hyperphosphorylation HypothesisThis is an important hypothesis but requires further testing.
Serum Monocyte Chemoattractant Protein-1 Concentrations Associate With Diabetes Status but Not Arterial Stiffness in Children With Type 1 Diabetes
Authors: Issam Zineh, Amber L. Beitelshees, Janet H. Silverstein, Michael J. Haller
Journal: Diabetes Care (2008)

The relationship between circulating markers of inflammation and arterial stiffness in children with type 1 diabetes is not well studied. We tested whether inflammatory monocyte chemoattractant protein (MCP)-1 concentrations correlate with arterial stiffness or type 1 diabetes status.MCP-1 concentrations and radial tonometry data were available for 98 children with type 1 diabetes and 55 healthy control subjects. Arterial stiffness was calculated as augmentation index corrected for a heart rate of 75 (AI75). Correlation between MCP-1 and AI75 and differences in MCP-1 concentrations between case and control subjects were tested.MCP-1 was significantly higher in children with type 1 diabetes than in control subjects (P < 0.001). However, there were no correlations between MCP-1 and AI75 in the overall sample or upon stratification by type 1 diabetes status (range P = 0.28-0.66).Circulating MCP-1 was not associated with arterial stiffness but was significantly elevated in children with type 1 diabetes, indicating a proinflammatory state in children as young as 10 years. The clinical significance of MCP-1 elevation in type 1 diabetes needs further investigation.
Abstract 151: Utilizing 3-D nuclear DNA methylation patterns for cell-based assays in epigenetic drug screening
Authors: Arkadiusz Gertych, Daniel L. Farkas, Jian Tajbakhsh
Journal: Cancer Research (2010)

Abstract The reversibility of epigenetic modifications, such as cytosine methylation, has gained much attraction in cancer therapy, with an emphasis on the development of anti-cancer drugs with demethylating potential to primarily reestablish tumor- suppressor gene functionality. The interest in the development of novel epigenetic drugs has increased the demand for cell-based assays to evaluate drug performance in the important pre-clinical phases of drug screening. Ideally a demethylating drug should reduce hypermethylation of tumor-suppressor genes for their reactivation, without creating unwanted effects: i.e. the hypomethylation of heterochromatin, of which a large percentage occurs in repetitive elements and can lead to genome instability. We have recently developed 3D quantitative DNA Methylation Imaging (3D-qDMI), an image-cytometrical approach, that can measure spatial nuclear distributions of methylated cytosine (MeC) and global DNA (gDNA) in addition to the nuclear MeC load in a high-throughput and cell-by-cell fashion to verify unwanted effects such as increased heterochromatin hypomethylation and decondensation that involve large-scale chromatin reorganization visualized by high-resolution confocal microscopy. Our novel approach succeeded in tracking differential changes of higher-order DNA organization due to drug-induced demethylation on a genomic scale, in human and mouse cancer cells. Our study showed that the differential distribution patterns of these two classes of DNA have the potential to be utilized as signatures for the characterization of different demethylating agents such as 5-azacytidine and zebularine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 151.
Air pollution and respiratory symptoms: results from three panel studies in Bangkok, Thailand.
Authors: N Vichit-Vadakan, B D Ostro, L G Chestnut, D M Mills, W Aekplakorn, S Wangwongwatana, N Panich
Journal: Environmental Health Perspectives (2001)

Several studies in North American cities have reported associations between air pollution and respiratory symptoms. Replicating these studies in cities with very different population and weather characteristics is a useful way of addressing uncertainties and strengthening inferences of causality. To this end we examined the responses of three different panels to particulate matter (PM) air pollution in Bangkok, Thailand, a tropical city characterized by a very warm and humid climate. Panels of schoolchildren, nurses, and adults were asked to report daily upper and lower respiratory symptoms for 3 months. Concentrations of daily PM(10) (PM with a mass median aerodynamic diameter less than 10 microm) and PM(2.5) (airborne particles with aerodynamic diameters less than 2.5 microm) were collected at two sites. Generally, associations were found between these pollution metrics and the daily occurrence of both upper and lower respiratory symptoms in each of the panels. For example, an interquartile increase of 45 microg/m(3) in PM(10) was associated with about a 50% increase in lower respiratory symptoms in the panel of highly exposed adults, about 30% in the children, and about 15% in the nurses. These estimates were not appreciably altered by changes in the specification of weather variables, stratification by temperature, or inclusion of individual characteristics in the models; however, time trends in the data cause some uncertainty about the magnitude of the effect of PM on respiratory symptoms. These pollutants were also associated with the first day of a symptom episode in both adult panels but not in children. The estimated odds ratios are generally consistent with and slightly higher than the findings of previous studies conducted in the United States.
Nitroglycerin-Induced S-nitrosylation and Desensitization of Soluble Guanylyl Cyclase Contribute to Nitrate Tolerance
Authors: Nazish Sayed, David D. Kim, Xavier Fioramonti, Toru Iwahashi, Walter N. Durán, Annie Beuve
Journal: Circulation Research (2008)

Nitrates such as nitroglycerin (GTN) and nitric oxide donors such as S-nitrosothiols are clinically vasoactive through stimulation of soluble guanylyl cyclase (sGC), which produces the second messenger cGMP. Development of nitrate tolerance, after exposure to GTN for several hours, is a major drawback to a widely used cardiovascular therapy. We recently showed that exposure to nitric oxide and to S-nitrosothiols causes S-nitrosylation of sGC, which directly desensitizes sGC to stimulation by nitric oxide. We tested the hypothesis that desensitization of sGC by S-nitrosylation is a mechanism of nitrate tolerance. Our results established that vascular tolerance to nitrates can be recapitulated in vivo by S-nitrosylation through exposure to cell membrane-permeable S-nitrosothiols and that sGC is S-nitrosylated and desensitized in the tolerant, treated tissues. We next determined that (1) GTN treatment of primary aortic smooth muscle cells induces S-nitrosylation of sGC and its desensitization as a function of GTN concentration; (2) S-nitrosylation and desensitization are prevented by treatment with N-acetyl-cysteine, a precursor of glutathione, used clinically to prevent development of nitrate tolerance; and (3) S-nitrosylation and desensitization are reversed by cessation of GTN treatment. Finally, we demonstrated that in vivo development of nitrate tolerance and crosstolerance by 3-day chronic GTN treatment correlates with S-nitrosylation and desensitization of sGC in tolerant tissues. These results suggest that in vivo nitrate tolerance is mediated, in part, by desensitization of sGC through GTN-dependent S-nitrosylation.
Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015)
Authors: Susan M. Blaney, Mark Bernstein, Kathleen Neville, Jill Ginsberg, Brenda Kitchen, Terzah Horton, Stacey L. Berg, Mark Krailo, Peter C. Adamson
Journal: Journal of Clinical Oncology (2004)

To determine the maximum-tolerated dose, dose-limiting toxicity (DLT), and pharmacodynamics of the proteasome inhibitor bortezomib (formerly PS-341) in children with recurrent or refractory solid tumors.An intravenous bolus of bortezomib was administered twice weekly for 2 consecutive weeks at either 1.2 or 1.6 mg/m2/dose followed by a 1-week rest. The pharmacodynamics of bortezomib were evaluated by measurement of whole blood 20S proteasome activity.Fifteen patients, 11 assessable, were enrolled between November 2001 and February 2003. Dose-limiting thrombocytopenia, which prevented administration of a complete course (four doses in 2 weeks) of therapy, occurred in two of five assessable children enrolled at the 1.6 mg/m2 dose level. There were no other DLTs. Inhibition of 20S proteasome activity seemed to be dose dependent. The average inhibition 1 hour after drug administration on day 1 was 67.2% +/- 7.6% at the 1.2 mg/m2/dose and 76.5% +/- 3.3% at the 1.6 mg/m2/dose. There were no objective antitumor responses.Bortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m2/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break.
Novel Aspects of Degradation of T Cell Receptor Subunits from the Endoplasmic Reticulum (ER) in T Cells: Importance of Oligosaccharide Processing, Ubiquitination, and Proteasome-dependent Removal from ER Membranes
Authors: Mei Yang, Satoshi Omura, Juan S. Bonifacino, Allan M. Weissman
Journal: The Journal of Experimental Medicine (1998)

Expression of the T cell antigen receptor (TCR) on the surface of thymocytes and mature T cells is dependent on the assembly of receptor subunits into TCRs in the endoplasmic reticulum (ER) and their successful traversal of the secretory pathway to the plasma membrane. TCR subunits that fail to exit the ER for the Golgi complex are degraded by nonlysosomal processes that have been referred to as “ER degradation”. The molecular basis for the loss of the TCR CD3-δ and TCR-α subunits from the ER was investigated in lymphocytes. For CD3-δ, we describe a process leading to its degradation that includes trimming of mannose residues from asparagine-linked (N-linked) oligosaccharides, generation of ubiquitinated membrane-bound intermediates, and proteasome-dependent removal from the ER membrane. When either mannosidase activity or the catalytic activity of proteasomes was inhibited, loss of CD3-δ was markedly curtailed and CD3-δ remained membrane bound in a complex with CD3-ε. TCR-α was also found to be degraded in a proteasome-dependent manner with ubiquitinated intermediates. However, no evidence of a role for mannosidases was found for TCR-α, and significant retrograde movement through the ER membrane took place even when proteasome function was inhibited. These findings provide new insights into mechanisms employed to regulate levels of TCRs, and underscore that cells use multiple mechanisms to target proteins from the ER to the cytosol for degradation.
Place and Provision of Palliative Care for Children With Progressive Cancer: A Study by the Paediatric Oncology Nurses’ Forum/United Kingdom Children's Cancer Study Group Palliative Care Working Group
Authors: Jan Vickers, Anne Thompson, Gary S. Collins, Margaret Childs, Richard Hain
Journal: Journal of Clinical Oncology (2007)

The purpose of this study was to describe and show effectiveness of the outreach team model of palliative care (PC) in allowing home death for children with incurable cancer.Over 7 months, 185 children from 22 United Kingdom oncology centers were recruited to a prospective questionnaire survey.One hundred sixty-four children from 22 centers died (median age, 8.7 years; 88 boys, 76 girls). One hundred twenty-six families completed two or more questionnaires. One hundred twenty (77%) of 155 with complete data died at home. Preference for home death was recorded in 90 (68%) of 164 and 132 (80%) 164 at study entry and last month of life, respectively. Death occurred in preferred place for 84 (80%) of 105 with recorded preference at entry. Forty-one (25%) of 164 and 68 (41.5%) of 164 needed no outpatient or inpatient hospital visits, respectively. A named individual provided on-call PC advice by phone or home visit in 22 (100%) and 18 (82%) of 22 oncology centers, respectively. As PC progressed, involvement of oncologist and social worker appeared less, whereas pediatric oncology outreach nurse specialists (POONSs) remained prominent.Preference for home death expressed by families in our study is similar to others, but the proportion of children actually able to die there is higher. Home death is facilitated by this model. Key components are POONSs, pediatric palliative and/or oncology specialist, and general practitioner. Professional roles change during PC and after death. An ongoing role for the oncology team in bereavement support is highlighted.