tbuckley/cabot-search huggingface dataset:
Potentiation of the Novel Topoisomerase I Inhibitor Indenoisoquinoline LMP-400 by the Cell Checkpoint and Chk1-Chk2 Inhibitor AZD7762
Authors: Sheena M. Aris, Yves Pommier
Journal: Cancer Research (2011)

Novel topoisomerase I (Top1) inhibitors are in clinical development to circumvent the drawbacks of camptothecins (CPT). Here, we report molecular investigations into LMP-400, an indenoisoquinoline Top1 inhibitor in phase 1 clinical trial, by itself and in combination with the cell-cycle checkpoint inhibitor AZD7762. We examined drug effects on DNA replication and killing of cancer cells and found that LMP-400 showed synergistic antiproliferative activity when combined with AZD7762 in human colon carcinoma cells. Inhibition of S-phase progression and bromodeoxyuridine incorporation were similarly induced by LMP-400 and CPT and were abrogated by AZD7762. Replication studied by single DNA molecule analyses and immunofluorescence microscopy (molecular combing) showed rapid inhibition of fork progression in response to LMP-400 treatment with subsequent recapitulation after AZD7762 addition. AZD7762 inhibited both the activation/autophosphosphorylation of Chk1 and Chk2 at nanomolar concentrations in LMP-400-treated cells. This potent dual inhibition of Chk1 and Chk2 by AZD7762 was below the drug concentrations required to abrogate cell-cycle inhibition and produce synergism with LMP-400. Also, the synergism was independent of Chk2 both in Chk2-complemented cells and Chk2 knockout cells, suggesting additional mechanisms for cell-cycle abrogation by AZD7762. Together, our findings show a rationale for combining cell-cycle checkpoint inhibitors with the novel non-CPT indenoisoquinoline Top1 inhibitors.
Health spending in England rises faster than in rest of UK
Authors: Bryan Christie
Journal: BMJ (2005)

Spending on the health service in England has increased at a faster rate than that in other countries of the United Kingdom over the past six years. As a result the gap between England Scotland, Wales, and Northern Ireland, which traditionally have all spent more per person than England, has narrowed.

At the same time devolution has led to greater divergence in health policy across the UK, as the four countries have pursued different priorities, challenging the widespread public expectation that standards of public services should be common across the UK.

A report produced by the Northern office …
Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia
Authors: Eli M. Roth, James M. McKenney, Corinne Hanotin, Gaelle Asset, Evan A. Stein
Journal: New England Journal of Medicine (2012)

Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation. REGN727/SAR236553 (designated here as SAR236553), a fully human PCSK9 monoclonal antibody, increases the recycling of LDL receptors and reduces LDL cholesterol levels.We performed a phase 2, multicenter, double-blind, placebo-controlled trial involving 92 patients who had LDL cholesterol levels of 100 mg per deciliter (2.6 mmol per liter) or higher after treatment with 10 mg of atorvastatin for at least 7 weeks. Patients were randomly assigned to receive 8 weeks of treatment with 80 mg of atorvastatin daily plus SAR236553 once every 2 weeks, 10 mg of atorvastatin daily plus SAR236553 once every 2 weeks, or 80 mg of atorvastatin daily plus placebo once every 2 weeks and were followed for an additional 8 weeks after treatment.The least-squares mean (±SE) percent reduction from baseline in LDL cholesterol was 73.2±3.5 with 80 mg of atorvastatin plus SAR236553, as compared with 17.3±3.5 with 80 mg of atorvastatin plus placebo (P<0.001) and 66.2±3.5 with 10 mg of atorvastatin plus SAR236553. All the patients who received SAR236553, as compared with 52% of those who received 80 mg of atorvastatin plus placebo, attained an LDL cholesterol level of less than 100 mg per deciliter, and at least 90% of the patients who received SAR236553, as compared with 17% who received 80 mg of atorvastatin plus placebo, attained LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter).In a randomized trial involving patients with primary hypercholesterolemia, adding SAR236553 to either 10 mg of atorvastatin or 80 mg of atorvastatin resulted in a significantly greater reduction in LDL cholesterol than that attained with 80 mg of atorvastatin alone. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01288469.).
Preoperative Pulmonary Function Testing
Authors: A. Jay Block
Journal: JAMA (1976)

PREOPERATIVE pulmonary function testing is easy to perform. Setups for spirometry are cheap and simple, and automated systems are available to compute all varieties of measurement. Today's problems for the clinician are What does preoperative pulmonary function testing mean? and Who needs these studies? The patient with bronchogenic carcinoma often has concomitant obstructive airway disease, since cigarette smoking is a common factor. If a surgeon contemplates resection of the carcinoma, pneumonectomy looms as a possibility. If the possibility of removing an entire lung exists, the assessment of pulmonary function is mandatory. Consequently, much has been written about preoperative assessment of the pneumonectomy candidate.  Assessment for Pneumonectomy  The understanding of preoperative assessment for pneumonectomy has proceeded in three phases. First to be recognized was that reduction oftotalfunction made removal of a lung hazardous.1-3The amount of reduction (and by what test) and the hazard of the operation were
Hypersensitivity to pituitary snuff with miliary shadowing in the lungs.
Authors: W E Mahon, D J Scott, G Ansell, G L Manson, R Fraser
Journal: Thorax (1967)

<h3>Objective</h3> Intraosseous access is recommended as a reasonable alternative for vascular access during newborn resuscitation if umbilical access is unavailable, but there are minimal reported data in newborns. We compared intraosseous with intravenous epinephrine administration during resuscitation of severely asphyxiated lambs at birth. <h3>Methods</h3> Near-term lambs (139 days’ gestation) were instrumented antenatally for measurement of carotid and pulmonary blood flow and systemic blood pressure. Intrapartum asphyxia was induced by umbilical cord clamping until asystole. Resuscitation commenced with positive pressure ventilation followed by chest compressions and the lambs received either intraosseous or central intravenous epinephrine (10 μg/kg); epinephrine administration was repeated every 3 min until return of spontaneous circulation (ROSC). The lambs were maintained for 30 min after ROSC. Plasma epinephrine levels were measured before cord clamping, at end asphyxia, and at 3 and 15 min post-ROSC. <h3>Results</h3> ROSC was successful in 7 of 9 intraosseous epinephrine lambs and in 10 of 12 intravenous epinephrine lambs. The time and number of epinephrine doses required to achieve ROSC were similar between the groups, as were the achieved plasma epinephrine levels. Lambs in both groups displayed a similar marked overshoot in systemic blood pressure and carotid blood flow after ROSC. Blood gas parameters improved more quickly in the intraosseous lambs in the first 3 min, but were otherwise similar over the 30 min after ROSC. <h3>Conclusions</h3> Intraosseous epinephrine administration results in similar outcomes to intravenous epinephrine during resuscitation of asphyxiated newborn lambs. These findings support the inclusion of intraosseous access as a route for epinephrine administration in current guidelines.
Effects of HMG-CoA Reductase Inhibitors on Endothelial Function
Authors: R. Preston Mason, Mary F. Walter, Robert F. Jacob
Journal: Circulation (2004)

Certain pleiotropic activities reported for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are related to reductions in cellular cholesterol biosynthesis and isoprenoid levels. In endothelial cells, these metabolic changes contribute to favorable effects on nitric oxide (NO) bioavailability. Given the essential role of NO in preserving vascular structure and function, this effect of statins is of considerable therapeutic importance. Statins have been demonstrated to restore endothelial NO production by several mechanisms, including upregulating endothelial NO synthase (eNOS) protein expression and blocking formation of reactive oxygen species. In this article, we will discuss additional ways in which statins restore endothelial NO production and improve endothelial function. (1) Statins modulate membrane microdomain formation, resulting in reduced expression of proteins that specifically inhibit eNOS activation. (2) Statins reduce sterol biosynthesis, thus interfering with the formation of pathologic microdomains, including cholesterol crystalline structures. This observation has important implications for plaque stabilization, as these microdomains contribute to cholesterol crystal formation and endothelial apoptosis. Finally, (3) statins improve endothelial function by interfering with oxidative stress pathways through both enzymatic and nonenzymatic mechanisms. The relationships between membrane microdomains, cholesterol biosynthesis, and endothelial function will be discussed.
Reevaluating the Digital Divide: Current Lack of Internet Use Is Not a Barrier to Adoption of Novel Health Information Technology
Authors: Alice J. Watson, Alastair G. Bell, Joseph C. Kvedar, Richard W. Grant
Journal: Diabetes Care (2008)

Improving care for a growing population of complex patients with type 2 diabetes requires developing innovative strategies for clinical management (1,2). Currently, roughly 70% of the U.S. population uses the Internet (3,4). Disparities in Internet use across social and ethnic strata, however, have resulted in the well-publicized “digital divide” (5,6). Population segments less likely to be online, such as the elderly, nonwhite race/ethnic groups, and the poor, are also disproportionately affected by diabetes (7). It is unknown whether barriers to Internet use extend to the use of other health information technology (HIT) tools being developed to support diabetes care. We hypothesized that patients not currently online might nonetheless be receptive to adopting future technologies designed to support their diabetes care.

We conducted a mail survey of 4,024 patients with type 2 diabetes in eastern Massachusetts identified via our primary care network's administrative database. After excluding 102 ineligible subjects, our response rate was 29% (1,146 of 3,922). Excluding subjects who left blank the question about current Internet use, 952 responses remained for analysis (24% of eligible cohort). Compared with nonrespondents, survey respondents were somewhat older (65.8 vs. 64.2 years, P = 0.002), more often male (58 vs. 49%, P < 0.001), more often white (86 vs. 78%, P < 0.001), and lived in neighborhoods with slightly higher median family incomes ($49,746 vs. $44,101 based on annual tax returns by zip code, P < 0.001). However, the proportion of individuals insured by Medicare (50 vs. 53%) and the last …
Objective patient compliance in long-term use of nCPAP
Authors: B Fleury, D Rakotonanahary, C Hausser-Hauw, B Lebeau, C Guilleminault
Journal: European Respiratory Journal (1996)

Concerns remain regarding patient compliance with nasal continuous positive airway pressure (nCPAP). Poor objective compliance during the first months of treatment has been reported, but no data are available among chronically treated patients. Use of nCPAP, in 17 chronically treated obstructive sleep apnoea patients (820+/-262 days) was evaluated objectively using a pressure monitor (MC+; Sefam, France). Two consecutive recording periods of 30 sessions of treatment were scheduled at the patient's home. To minimize the potential bias caused by the introduction of the monitor, only the pressure data obtained at the end of the second period of recording (T2) were analysed. During the 28.1+/-2.6 monitored days, the mean effective daily rate of use was 7.1+/-1.1 h, 97% of the rate indicated by the standard in-built time counter. The prescribed pressure was observed during 95% of the machine run time. The nCPAP system was used for 94% of the monitored days. Sixty percent of the patients used their device every day. These preliminary results suggest that, contrary to reported compliance during the early period of the treatment, objective use of nasal continuous positive airway pressure therapy in chronically treated patients is satisfactory.
Constitutive and inducible secretion of platelet-derived growth factor analogs by human leukemic cell lines coexpressing erythroid and megakaryocytic markers.
Authors: T Papayannopoulou, E Raines, S Collins, B Nakamoto, M Tweeddale, R Ross
Journal: Journal of Clinical Investigation (1987)

We have examined the constitutive and inducible secretion of platelet-derived growth factor (PDGF)-like proteins in a variety of human hemopoietic cell lines. The highest levels of secreted protein were noted in four human erythroleukemia lines which, in addition to erythroid lineage markers, express one or more megakaryocytic lineage markers. Induction of these lines by 12-O-tetradecanoylphorbol-13-acetate enhanced the expression of megakaryocytic markers and increased secretion of PDGF-like proteins several fold. In concert with these changes, there was significant induction of c-sis/PDGF-B messenger RNA (mRNA) expression in all lines, whereas one line showed significant concurrent induction of PDGF-A mRNA expression. Whether PDGF-like secretion is part of the stem cell-like phenotype displayed by these lines or is secondary to their leukemic transformation remains to be determined. Nevertheless, these lines provide new cellular models for studying the expression and function of PDGF analogs in hemopoietic cells.
Self-regulation of procoagulant events on the endothelial cell surface.
Authors: D M Stern, I Bank, P P Nawroth, J Cassimeris, W Kisiel, J W Fenton, C Dinarello, L Chess, E A Jaffe
Journal: The Journal of Experimental Medicine (1985)

Interleukin 1 (IL-1) is a potent mediator of inflammatory and immunologic phenomena. In addition, IL-1 may be intimately involved in the regulation of hemostasis, since interaction of IL-1 with endothelial cells has been reported to induce tissue factor activity. We demonstrate that perturbation of the endothelial cell induces augmented IL-1 release. Human umbilical vein endothelial cells perturbed by treatment with lipopolysaccharide produced enhanced amounts of IL-1 activity. IL-1 activity from lipopolysaccharide-treated endothelial cell supernatants could be absorbed by an antibody to IL-1 coupled to Sepharose. Elaboration of IL-1 activity was dependent on the dose of lipopolysaccharide and occurred in a time-dependent manner. Addition of cycloheximide blocked generation of IL-1 activity. A physiological vessel wall perturbant, the coagulation enzyme thrombin, induced comparable amounts of IL-1 activity in endothelial cell cultures. This effect was specific for the enzyme, since active site-blocked thrombin and prothrombin had no effect on IL-1. In addition, IL-1-containing supernatants from thrombin-stimulated endothelial cells induced tissue factor procoagulant activity in fresh endothelial cell cultures. Thus, in contrast to the multiple, known inhibitory mechanisms that block thrombin procoagulant activity, these data suggest a circle of interaction in which thrombin induces endothelial cell elaboration of IL-1, a mediator of endothelial cell procoagulant activity. Endothelial cell production of IL-1 in response to perturbation allows these cells to play an integral role in the regulation of the inflammatory and coagulation systems.
Recent research on nickel carcinogenesis.
Authors: F W Sunderman
Journal: Environmental Health Perspectives (1981)

Research on nickel carcinogenesis from 1975 to March 1980 is reviewed. Epidemiological studies have strengthened the evidence that workers in nickel refineries have increased risks of cancers of the nasal cavities and lungs. Clinical investigations have resulted in improved diagnosis, classification, and management of cancers of respiratory organs in nickel refinery workers. Carcinogenicity tests have demonstrated the carcinogenicity of nickel subsulfide (alpha-Ni3S2) in rodents following administration by a variety of parenteral routes. Radiotracer studies and x-ray diffractometry have clarified the metabolism of alpha-Ni3S2 in rodents. In vitro exposures of mammalian cells to certain nickel compounds have been shown to inhibit cellular uptake of thymidine-3H, and to induce chromosomal aberrations, somatic mutations, and morphological transformation. Mutagenicity tests of nickel compounds in bacterial systems have consistently been negative. Ni(II) has beeb reported to impair the fidelity of viral and bacterial DNA polymerases for in vitro replication of synthetic nucleotide templates.
Antioxidant Supplementation and Lung Functions among Children with Asthma Exposed to High Levels of Air Pollutants
Authors: Isabelle Romieu, Juan José Sienra-Monge, Matiana Ramírez-Aguilar, Martha María Téllez-Rojo, Hortensia Moreno-Macías, Norma Isabel Reyes-Ruiz, Blanca Estela del Río-Navarro, María Xóchitl Ruiz-Navarro, Gary Hatch, Ralph Slade, Mauricio Hernández-Avila
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

To evaluate whether acute effects of ozone, nitrogen dioxide, and particulates with mass median diameter less than 10 micro m could be attenuated by antioxidant vitamin supplementation, we conducted a randomized trial using a double-blinded design. Children with asthma (n = 158) who were residents of Mexico City were randomly given a daily supplement of vitamins (50 mg/day of vitamin E and 250 mg/day of vitamin C) or a placebo and were followed from October 1998 to April 2000. Pulmonary function tests were carried out twice a week in the morning. During the follow-up observation period, the mean 1-hour maximum ozone level was 102 ppb (SD = 47), and the mean 24-hour average PM(10) level was 56.7 micro g/m(3) (SD = 27.4). In children with moderate and severe asthma, ozone levels 1 day before spirometry were inversely associated significantly with forced expiratory flow (FEF(25-75)) (-13.32 ml/second/10 ppb; p = 0.000), FEV(1) (-4.59 ml/10 ppb; p = 0.036), and peak expiratory flow (PEF) (-15.01 ml/second/10 ppb; p = 0.04) in the placebo group after adjusting for potential confounding factors. No association between ozone and lung functions was observed in the supplement group. We observed significant differences in lung function decrements between groups for FEF(25-75) and PEF. Our results suggest that supplementation with antioxidants might modulate the impact of ozone exposure on the small airways of children with moderate to severe asthma.
Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b-245.
Authors: J H Wandall
Journal: Gut (1992)

The effects of omeprazole on polymorphonuclear neutrophil (PMN) chemotaxis, superoxide generation, degranulation and translocation of cytochrome b-245 were investigated. Omeprazole (10(-6) - 5 x 10(-3) mol/l) reduced chemotaxis under agarose in a dose dependent manner, and the effect was irreversible. Superoxide anion generation was inhibited 50% at a concentration of 2.5 x 10(-5) mol/l and completely abolished at 5 x 10(-3) mol/l. Acid degraded omeprazole also inhibited O2- generation. Omeprazole did not scavenge O2- generated in a cell free xanthin-xanthine oxidase system. Degranulation by PMNs was inhibited only by omeprazole in concentrations above 10(-4) mol/l. Translocation of cytochrome b-245, essential for generation of O2-, was not affected by omeprazole. In conclusion, the anti-ulcer agent omeprazole in concentrations obtained during intravenous administration may inhibit the function of PMNs in vitro.
Can Guideline-defined Asthma Control Be Achieved?
Authors: Eric D. Bateman, Homer A. Boushey, Jean Bousquet, William W. Busse, Tim J. H. Clark, Romain A. Pauwels, Søren E. Pedersen
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

For most patients, asthma is not controlled as defined by guidelines; whether this is achievable has not been prospectively studied. A 1-year, randomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Treatment was stepped-up until total control was achieved (or maximum 500 microg corticosteroid twice a day). Significantly more patients in each stratum (previously corticosteroid-free, low- and moderate-dose corticosteroid users) achieved control with salmeterol/fluticasone than fluticasone. Total control was achieved across all strata: 520 (31%) versus 326 (19%) patients after dose escalation (p < 0.001) and 690 (41%) versus 468 (28%) at 1 year for salmeterol/fluticasone and fluticasone, respectively. Asthma became well controlled in 1,071 (63%) versus 846 (50%) after dose escalation (p < 0.001) and 1,204 (71%) versus 988 (59%) at 1 year. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone. Across all strata, 68% and 76% of the patients receiving salmeterol/fluticasone and fluticasone, respectively, were on the highest dose at the end of treatment. Exacerbation rates (0.07-0.27 per patient per year) and improvement in health status were significantly better with salmeterol/fluticasone. This study confirms that the goal of guideline-derived asthma control was achieved in a majority of the patients.
Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study
Authors: M. Paulussen, S. Ahrens, M. Lehnert, D. Taeger, H.W. Hense, A. Wagner, J. Dunst, D. Harms, A. Reiter, G. Henze, C. Niemeyer, U. Göbel, B. Kremens, U.R. Fölsch, W.E. Aulitzky, P.A. Voûte, A. Zoubek, H. Jürgens
Journal: Annals of Oncology (2001)
Abstract 3503: Enhanced delivery of T cells to tumor after chemotherapy using membrane-anchored, apoptosis-targeted peptide
Authors: Xiaofeng He, Eun-Kyu Lee, In-San Kim, Byung-Heon Lee
Journal: Cancer Research (2012)

Abstract Chemotherapy-induced apoptosis of tumor cells enhances the antigen presentation and sensitizes tumor cells to T cell-mediated cytotoxicity. Here we harnessed the apoptosis of tumor cells as a homing signal for the delivery of T cells to tumor. Jurkat T cells were anchored with ApoPep-1, an apoptosis-targeted peptide ligand, using the biocompatible anchor for membrane (BAM), an oleyl acid derivative. The ApoPep-1-BAM conjugate was efficiently anchored to cell membrane, while little anchoring was obtained with ApoPep-1 alone. The retention period of the ApoPep-1-BAM conjugate on cells was approximately 40 and 20 minutes in the absence and presence of serum, respectively. The apoptosis-targeted T cells that were anchored with the ApoPep-1-BAM preferentially bound to apoptotic tumor cells over living cells. When intravenously injected into tumor-bearing mice, the number of the apoptosis-targeted T cells and in vivo fluorescence signals by the homing of the cells to doxorubicin-treated tumor were higher than those of untargeted T cells. These results suggest that the chemotherapy-induced apoptosis and subsequent enhancement of T cell delivery to tumor by the membrane anchoring of the apoptosis-targeted peptide could be a novel strategy for cancer immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3503. doi:1538-7445.AM2012-3503