tbuckley/cabot-search huggingface dataset:
Enhanced Synthesis of the Oxysterol 24( <i>S</i> ),25-Epoxycholesterol in Macrophages by Inhibitors of 2,3-Oxidosqualene:Lanosterol Cyclase
Authors: Andrea H. Rowe, Carmen A. Argmann, Jane Y. Edwards, Cynthia G. Sawyez, Olivier H. Morand, Robert A. Hegele, Murray W. Huff
Journal: Circulation Research (2003)

Oxysterols are key regulators of lipid metabolism and regulate gene expression by activating the liver X receptor (LXR). LXR plays a vital role in macrophage foam cell formation, a central event in atherosclerosis. It is known that addition of exogenous oxysterols to cultured macrophages activates LXR, leading to increased expression of ABCA1 and cholesterol efflux. In this study, we tested the novel hypothesis that stimulation of endogenous oxysterol synthesis would block foam cell formation induced by atherogenic lipoproteins. Macrophage synthesis of 24( S ),25-epoxycholesterol, a potent LXR ligand, increased 60-fold by partial inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), a microsomal enzyme in both the cholesterol biosynthetic pathway and the alternative oxysterol synthetic pathway. When macrophages were challenged with human hypertriglyceridemic VLDL (HTG-VLDL), cellular cholesteryl ester accumulation increased 12-fold. This was reduced dramatically, by 65%, after preincubation with an OSC inhibitor (OSCi). The HTG-VLDL–induced accumulation of macrophage TG (70-fold) was unaffected by the OSCi or exogenous 24( S ),25-epoxycholesterol, an effect associated with suppression of SREBP-1 processing. By contrast, TO901317, a synthetic LXR agonist, increased cellular TG significantly and markedly increased SREBP-1 processing. OSC inhibition decreased HTG-VLDL uptake through downregulation of LDL-receptor expression, despite substantial inhibition of cholesterol synthesis. Furthermore, OSC inhibition significantly upregulated ABCA1 and ABCG1 expression, which led to enhanced macrophage cholesterol efflux, an effect mediated through LXR activation. Therefore, increased macrophage synthesis of endogenous oxysterols represents a new mechanism for the dual regulation of LXR- and SREBP-responsive genes, an approach that inhibits foam cell formation without detrimental effect on TG synthesis.
Effects of treatment with etanercept (Enbrel, TNRF:Fc) on rheumatoid arthritis evaluated by Doppler ultrasonography
Authors: L Terslev
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> to estimate and visualise the efficacy of treatment with etanercept (Enbrel) in patients with rheumatoid arthritis (RA) using colour Doppler and spectral Doppler ultrasonography to determine the possible changes in synovial perfusion during a one year observation period. <b>Methods:</b> Eleven patients from the European multicentre trial of the efficacy and safety of etanercept were included in this study when transferred into the open label, long term safety, and efficacy study. Before a scheduled dosage increase to 50 mg/week they were examined clinically, serologically, and by ultrasonography using the colour Doppler pixels and the spectral Doppler resistance index (RI) as indicators of inflammation. The patients were re-examined at two weeks and at one year follow up <b>Results:</b> The clinical activity decreased significantly from baseline to week 2, but no significant changes were seen from baseline to one year. The number of coloured pixels in each region of interest decreased from baseline to week 2 with a median reduction of 60% (p=0.005). This effect on the perfusion in the synovium could not be found after one year of treatment. During the initial treatment we detected an increase in synovial RI by spectral Doppler. The median increase in peripheral resistance from baseline to week 2 as estimated by the mean RI was 22.6% (p=0.005). The increase in peripheral resistance was maintained to some extent after one year (mean RI increased by 18.8% p=0.074). <b>Conclusion:</b> Ultrasonography seems to be a promising tool for the detection of treatment response using spectral Doppler and pixel estimation.
Keeping up with orthopaedic epidemics
Authors: J M. H Paterson
Journal: BMJ (1987)

Data on 1,618 male and 1,669 female adults aged 40-69 yrs, from China in the Beijing Respiratory Health Study, were analysed to investigate the gender differences in effects of smoking on pulmonary function. Smoking was characterized by total smoking-years, smoking status (former, transitional and constant), smoking type (cigarette, cigar and others). The effects of smoking on height-standardized forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were assessed by multiple regressions adjusting for age, education level, use of an indoor coal stove for heating, passive smoking, occupational dust and gas/fume exposure, and residence. Prediction equations were derived from nonsmoking asymptomatic subjects. As compared to women, men had a much higher smoking prevalence (78 vs 35%) but a lower quitting rate (14 vs 23%). Female lifetime nonsmokers had greater mean percentage predicted lung function values than male lifetime nonsmokers, whilst female cigarette smokers had lower values than their male counterparts. In both sexes, the highest mean percentage predicted lung function values were found in lifetime nonsmokers, whilst the lowest values were found among former smokers, the second lowest among transitional smokers, and constant smokers actually had greater values than both former and transitional smokers. These findings were confirmed by sex-specific regression analyses. A global test on the interactions between smoking and sex was highly significant. This study suggests that adverse smoking effects on pulmonary function were greater in women than in men.(ABSTRACT TRUNCATED AT 250 WORDS)
Induction of hypomagnesemia during amsacrine treatment
Authors: John F. Seymour
Journal: American Journal of Hematology (1993)

Serious cardiac arrhythmias and QT interval prolongation have been reported following Amsacrine chemotherapy. The underlying mechanism is unknown. In this study, electrolyte and electrocardiographic parameters were prospectively studied in patients with acute myeloid leukemia (AML) treated with an Amsacrine containing combination chemotherapy regime. Data were collected immediately before and at 20 (+20) and 90 (+90) min after commencement of Amsacrine administration. Sixteen episodes were studied in six consecutive patients over a continuous 9 month period. One patient developed asymptomatic ventricular tachycardia during administration. Results from +20 and +90 min were compared with baseline by Wilcoxon matched pairs test. There was no significant change in potassium, albumin, or ionized calcium concentration at +20 or +90 min. The magnesium concentration at +20 min was significantly reduced (mean -0.04 mmol/liter; P < 0.05) but not so at +90 min. Sodium concentration at +20 min was significantly reduced (mean - 1.9 mmol/liter; P < 0.01). Electrocardiographic analysis showed no significant alteration in PR interval or QRS duration. Heart rate fell significantly from baseline, mean change -10 and -8 min-1 at +20 and +90 min, respectively (P < 0.01 for both). Corrected QT interval (QTc) was significantly prolonged at +20 min (+0.05) and +90 min (+0.05) (P = 0.0001 and P < 0.0001, respectively). This study confirms the high incidence of QTc prolongation with Amsacrine administration and suggests that transient hypomagnesemia may contribute to the risk of cardiac arrhythmia in this setting.
Epstein-Barr virus–specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential
Authors: Padraic J. Dunne, Jeffery M. Faint, Nancy H. Gudgeon, Jean M. Fletcher, Fiona J. Plunkett, Maria Vieira D. Soares, Andrew D. Hislop, Nicola E. Annels, Alan B. Rickinson, Mike Salmon, Arne N. Akbar
Journal: Blood (2002)
DISEASE ACCOMPANYING <i>IN UTERO</i> VIRAL INFECTION
Authors: Michael B. A. Oldstone, Frank J. Dixon
Journal: The Journal of Experimental Medicine (1972)

Early, after in utero infection with LCM virus, SWR/J and HA/ICR mice developed manifestations of immune complex disease. Observations based on nursing such mice with virus-infected, immune, or noninfected mouse mothers indicated that maternal antiviral antibody was responsible for the early immune complex glomerulonephritis. Despite comparable viral persistance, in utero-infected offspring failed to develop glomerulonephritis when nursed by noninfected mouse mothers, but did when suckled by virus-infected mouse mothers. Nursing by mouse mothers carrying high titers of anti-LCM viral antibody markedly enhanced the Ig glomerular deposits and the resultant nephritis.
Acute megakaryoblastic leukemia following transient myeloproliferative disorder in a patient without down syndrome
Authors: Mark D. Brissette, Bertrand J. Duval‐Arnould, Bruce G. Gordon, James D. Cotelingam
Journal: American Journal of Hematology (1994)

Abstract Transient myeloproliferative disorder (TMD) and subsequent acute myeloid leukemia (AML) occur with increased frequency in infants and children with Down syndrome. TMD can also occur in phenotypically normal newborns. We describe the second case of a non‐Down syndrome child with TMD who subsequently developed AML. Trisomy 21 karyotype was restricted to hematopoietic cells in the blood and bone marrow. No other karyotypic abnormalities were found. Leukemic blasts showed megakaryoblastic features with immunophenotyping. This case shows that TMD in a child without Down syndrome may not be entirely benign. Close follow‐up is warranted. © 1994 Wiley‐Liss, Inc.
Sodium nitroprusside enhances in vivo left ventricular function in β-adrenergically stimulated rabbit hearts
Authors: P. A. De Mulder, S. G. De Hert, R. J. Van Kerckhoven, H. F. Adriaensen, T. C. Gillebert
Journal: Cardiovascular Research (1998)

Objective: Sodium nitroprusside (SNP) is an activator of soluble guanylate cyclase, which depresses myocardial contractility. These exclusively negative inotropic effects of SNP were recently challenged by in vitro data. In isolated rat ventricular myocytes, a moderate increase of cGMP improved the contractile response at baseline and in isoprenaline-stimulated conditions. The present study evaluated in vivo the inotropic effects of SNP at baseline and during administration of low dose dobutamine. Methods: Anesthetized open-chest rabbits (n=18) were instrumented with micromanometers, ultrasound crystals and atrial pacing wires. Measurements were obtained during caval occlusion with ventilation suspended at end-expiration. Systolic function was assessed with dP/dtmax and the slope Ees of the end-systolic pressure–volume relation. Diastolic function was assessed with the time constant τ and the stiffness constant Kc of the diastolic pressure–volume relation. SNP (0.02, 0.08, 0.32 μg·kg−1·min−1) was administered at baseline and during low dose dobutamine. Results: At baseline, SNP reduced dP/dtmax from 3750±88 to 3470±88 mmHg/s (mean±s.e.m.) and Ees from 148±16 to 103±13 mmHg/ml (P<0.01). During dobutamine infusion, SNP increased dP/dtmax from 4340±125 to 4681±230 mmHg/s and Ees from 148±19 to 190±30 mmHg/ml (P<0.01). Effects of SNP on dP/dtmax and Ees were different at baseline and during dobutamine (interaction P<0.01). SNP did not alter Kc at baseline nor during dobutamine. Conclusions: SNP enhances in vivo systolic function in β-adrenergically stimulated rabbits.
Multicenter, Phase II Study of Cetuximab in Combination With Carboplatin in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma
Authors: Anthony T.C. Chan, Mow-Ming Hsu, Boon C. Goh, Edwin P. Hui, Tsang-Wu Liu, Michael J. Millward, Ruey-Long Hong, Jacqueline Whang-Peng, Brigette B.Y. Ma, Ka F. To, Matthias Mueser, Nadia Amellal, Xiao Lin, Alex Y. Chang
Journal: Journal of Clinical Oncology (2005)

To evaluate efficacy and toxicity of cetuximab plus carboplatin in recurrent or metastatic nasopharyngeal carcinoma (NPC) resistant to platinum treatment.A multicenter, open-label, single-arm, phase II study in patients with epidermal growth factor receptor-expressing NPC who progressed on or within 12 months after termination of platinum-based chemotherapy for recurrent or metastatic disease. Cetuximab was administered at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Carboplatin area under the curve 5 was administered every 3 weeks up to a maximum of eight cycles.Sixty patients were enrolled (46 males, 14 females; median age, 44.5 years; range, 23 to 64 years), and all patients were included in the intent-to-treat and safety analyses. Of the 59 patients assessable for efficacy, there were seven partial responses (11.7%), 29 patients (48.3%) with stable disease, and 23 patients (38.3%) with progressive disease, giving an overall response rate of 11.7% (95% CI, 4.8% to 22.6%). The median time to progression was 81 days in all patients and was longest in the group of patients with a confirmed response (173 days). The median overall survival time was 233 days in all patients. Six patients (10%) experienced serious treatment-related adverse events. Grade 3 or 4 toxicities occurred in 31 patients (51.7%); of these patients, only 19 (31.7%) were considered to have toxicity related to cetuximab.Cetuximab in combination with carboplatin demonstrates clinical activity and an acceptable safety profile in heavily pretreated patients with recurrent or metastatic NPC who had previously experienced treatment failure with platinum-based therapy.
Endogenous Sex Hormones and Prostate Cancer: A Collaborative Analysis of 18 Prospective Studies
Authors: Endogenous Hormones
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundSex hormones in serum have been hypothesized to influence the risk of prostate cancer. We performed a collaborative analysis of the existing worldwide epidemiologic data to examine these associations in a uniform manner and to provide more precise estimates of risks.
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Authors: Rafael Rosell, Teresa Moran, Cristina Queralt, Rut Porta, Felipe Cardenal, Carlos Camps, Margarita Majem, Guillermo Lopez-Vivanco, Dolores Isla, Mariano Provencio, Amelia Insa, Bartomeu Massuti, Jose Luis Gonzalez-Larriba, Luis Paz-Ares, Isabel Bover, Rosario Garcia-Campelo, Miguel Angel Moreno, Silvia Catot, Christian Rolfo, Noemi Reguart, Ramon Palmero, José Miguel Sánchez, Roman Bastus, Clara Mayo, Jordi Bertran-Alamillo, Miguel Angel Molina, Jose Javier Sanchez, Miquel Taron
Journal: New England Journal of Medicine (2009)

Activating mutations in the epidermal growth factor receptor gene (EGFR) confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non–small-cell lung cancer. We evaluated the feasibility of large-scale screening for EGFR mutations in such patients and analyzed the association between the mutations and the outcome of erlotinib treatment.
Essential Features of Designating Out-of-Hospital Cardiac Arrest as a Reportable Event
Authors: Graham Nichol, John Rumsfeld, Brian Eigel, Benjamin S. Abella, Darwin Labarthe, Yuling Hong, Robert E. O’Connor, Vincent N. Mosesso, Robert A. Berg, Barbara “Bobbi” Leeper, Myron L. Weisfeldt
Journal: Circulation (2008)

The 2010 impact goal of the American Heart Association is to reduce death rates from heart disease and stroke by 25% and to lower the prevalence of the leading risk factors by the same proportion. Much of the burden of acute heart disease is initially experienced out of hospital and can be reduced by timely delivery of effective prehospital emergency care. Many patients with an acute myocardial infarction die from cardiac arrest before they reach the hospital. A small proportion of those with cardiac arrest who reach the hospital survive to discharge. Current health surveillance systems cannot determine the burden of acute cardiovascular illness in the prehospital setting nor make progress toward reducing that burden without improved surveillance mechanisms. Accordingly, the goals of this article provide a brief overview of strategies for managing out-of-hospital cardiac arrest. We review existing surveillance systems for monitoring progress in reducing the burden of out-of-hospital cardiac arrest in the United States and make recommendations for filling significant gaps in these systems, including the following: 1. Out-of-hospital cardiac arrests and their outcomes through hospital discharge should be classified as reportable events as part of a heart disease and stroke surveillance system. 2. Data collected on patients' encounters with emergency medical services systems should include descriptions of the performance of cardiopulmonary resuscitation by bystanders and defibrillation by lay responders. 3. National annual reports on key indicators of progress in managing acute cardiovascular events in the out-of-hospital setting should be developed and made publicly available. Potential barriers to action on cardiac arrest include concerns about privacy, methodological challenges, and costs associated with designating cardiac arrest as a reportable event.
In vitro and in vivo assessment of targeting lipid-based nanoparticles to the epidermal growth factor-receptor (EGFR) using a novel Heptameric ZEGFR domain
Authors: S. Rahima Benhabbour, J. Christopher Luft, Dongwook Kim, Anekant Jain, Saurabh Wadhwa, Matthew C. Parrott, Rihe Liu, Joseph M. DeSimone, Russell J. Mumper
Journal: Journal of Controlled Release (2011)
Host S-nitrosylation inhibits clostridial small molecule–activated glucosylating toxins
Authors: Tor C Savidge, Petri Urvil, Numan Oezguen, Kausar Ali, Aproteem Choudhury, Vinay Acharya, Irina Pinchuk, Alfredo G Torres, Robert D English, John E Wiktorowicz, Michael Loeffelholz, Raj Kumar, Lianfa Shi, Weijia Nie, Werner Braun, Bo Herman, Alfred Hausladen, Hanping Feng, Jonathan S Stamler, Charalabos Pothoulakis
Journal: Nature Medicine (2011)
Clinical Research in the United States at a Crossroads
Authors: William F. Crowley, Jr, Louis Sherwood, Patricia Salber, David Scheinberg, Hal Slavkin, Hugh Tilson, E. Albert Reece, Veronica Catanese, Stephen B. Johnson, Adrian Dobs, Myron Genel, Allan Korn, Nancy Reame, Robert Bonow, Jack Grebb, David Rimoin
Journal: JAMA (2004)

The clinical research infrastructure of the United States is currently at a critical crossroads. To leverage the enormous biomedical research gains made in the past century efficiently, a drastic need exists to reengineer this system into a coordinated, safe, and more efficient and effective enterprise. To accomplish this task, clinical research must be transformed from its current state as a cottage industry to an enterprise-wide health care pipeline whose function is to bring the novel research from both government and private entities to the US public. We propose the establishment of a unique public-private partnership termed the National Clinical Research Enterprise (NCRE). Its agenda should consist of informed public participation, supportive information technologies, a skilled workforce, and adequate funding in clinical research. Devoting only 0.25% of the budgets from all health care stakeholders to support the NCRE would permit adequate funding to build the infrastructure required to address these problems in an enterprise fashion. All participants in the US health care delivery system must come together to focus on system-wide improvements that will benefit the public.
The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a
Authors: Therese M Becker, Sebastian Haferkamp, Menno K Dijkstra, Lyndee L Scurr, Monika Frausto, Eve Diefenbach, Richard A Scolyer, David N Reisman, Graham J Mann, Richard F Kefford, Helen Rizos
Journal: Molecular Cancer (2009)

CDKN2A/p16INK4a is frequently altered in human cancers and it is the most important melanoma susceptibility gene identified to date. p16INK4a inhibits pRb phosphorylation and induces cell cycle arrest, which is considered its main tumour suppressor function. Nevertheless, additional activities may contribute to the tumour suppressor role of p16INK4a and could help explain its specific association with melanoma predisposition. To identify such functions we conducted a yeast-two-hybrid screen for novel p16INK4a binding partners.We now report that p16INK4a interacts with the chromatin remodelling factor BRG1. We investigated the cooperative roles of p16INK4a and BRG1 using a panel of cell lines and a melanoma cell model with inducible p16INK4a expression and BRG1 silencing. We found evidence that BRG1 is not required for p16INK4a-induced cell cycle inhibition and propose that the p16INK4a-BRG1 complex regulates BRG1 chromatin remodelling activity. Importantly, we found frequent loss of BRG1 expression in primary and metastatic melanomas, implicating this novel p16INK4a binding partner as an important tumour suppressor in melanoma.This data adds to the increasing evidence implicating the SWI/SNF chromatin remodelling complex in tumour development and the association of p16INK4a with chromatin remodelling highlights potentially new functions that may be important in melanoma predisposition and chemoresistance.
p53 Heterozygosity Results in an Increased 2-Acetylaminofluorene-Induced Urinary Bladder but not Liver Tumor Response in DNA Repair-Deficient <b> <i>Xpa</i> </b> Mice
Authors: Esther M. Hoogervorst, Conny Th. M. van Oostrom, Rudolf B. Beems, Jan van Benthem, Siska Gielis, Jolanda P. Vermeulen, Piet W. Wester, Joseph G. Vos, Annemieke de Vries, Harry van Steeg
Journal: Cancer Research (2004)

Abstract Both nucleotide excision repair (NER) and the p53 tumor suppressor protein play crucial roles in the prevention of cells becoming cancerous. This is clearly demonstrated by the fact that NER-deficient xeroderma pigmentosum patients and Li-Fraumeni patients who carry a germ-line p53 mutation are highly tumor prone. The NER-deficient Xpa and the p53+/− mouse models clearly mimic their human counterparts, because they are both tumor prone as well. The aim of the study presented here was to analyze the relative contribution of these two pathways in tumor suppression and to analyze a possible link between NER and p53 activation in vivo. For this, we exposed Xpa, p53+/−, and Xpa/p53+/− mice to 2-acetylaminofluorene (2-AAF). We show that 2-AAF-induced urinary bladder tumor suppression is dependent on p53 status, because p53+/− mice were highly tumor prone. Xpa/p53+/− mice were even more tumor prone, whereas no increased tumor response was found in Xpa mice. Short-term assays revealed a decreased apoptotic response in Xpa/p53+/− mice, pointing in vivo toward a link between NER and p53-mediated apoptosis. In contrast, liver tumor response was primarily dependent on appropriate DNA repair, because Xpa-deficient mice were liver tumor prone. p53 heterozygosity had no influence on liver tumor incidences, in line with the results obtained from the short-term 2-AAF studies revealing no altered cellular response in p53+/− or Xpa/p53+/− mice. Interestingly, however, mice completely deficient in both NER and p53 (Xpa/p53−/− mice) showed a dramatic increase of hepatocellular proliferation accompanied by lacZ reporter gene mutations.