tbuckley/cabot-search huggingface dataset:
Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma
Authors: Jennifer A. Quinn, Sara Xiaoyin Jiang, David A. Reardon, Annick Desjardins, James J. Vredenburgh, Jeremy N. Rich, Sridharan Gururangan, Allan H. Friedman, Darell D. Bigner, John H. Sampson, Roger E. McLendon, James E. Herndon, Amy Walker, Henry S. Friedman
Journal: Neuro-Oncology (2009)

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O6-benzylguanine (O6-BG). Both TMZ and O6-BG were administered on days 1–5 of a 28-day treatment cycle. A bolus infusion of O6-BG was administered at 120 mg/m2 over 1 h on days 1, 3, and 5, along with a continuous infusion of O6-BG at 30 mg/m2/day. TMZ was administered at the end of the first bolus infusion of O6-BG and then every 24 h for 5 days during the continuous infusion of O6-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m2 on day 1 and 50 mg/m2/day on days 2–5; schedule 2, 50 mg/m2/day on days 1–5; and schedule 3, 50 mg/m2/day on days 1–5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O6-BG was schedule 1. This study provides the foundation for a phase II trial of O6-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.
The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer
Authors: Greg L. Shaw, Hayley Whitaker, Marie Corcoran, Mark J. Dunning, Hayley Luxton, Jonathan Kay, Charlie E. Massie, Jodi L. Miller, Alastair D. Lamb, Helen Ross-Adams, Roslin Russell, Adam W. Nelson, Matthew D. Eldridge, Andrew G. Lynch, Antonio Ramos-Montoya, Ian G. Mills, Angela E. Taylor, Wiebke Arlt, Nimish Shah, Anne Y. Warren, David E. Neal
Journal: European Urology (2015)

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression). This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.
Haemodynamics in children during rest and exercise: methods and normal values
Authors: M Rosenthal, A Bush
Journal: European Respiratory Journal (1998)

Measuring haemodynamic performance in children is either invasive, and thus unacceptable, or noninvasive when the measured variable is often remote from the true variable. Measuring only maximum performance variables relies too heavily on motivation, especially in disease groups. We describe a method for the measurement of haemodynamic performance using respiratory mass spectrometry during rest, exercise and recovery therefrom. One hundred and six healthy children (55 male, 51 female) aged 8-16.9 yrs underwent an identical exercise protocol. Following studies at rest, they initially bicycled at 25 W x m(-2), increasing every 3 min by 15 W x m(-2) until exhaustion, after which measurements were made during recovery. Effective pulmonary blood flow, stroke volume, oxygen consumption, arteriovenous oxygen difference and functional residual capacity (FRC) together with estimates of pulmonary capillary blood volume and transit time were assessed at every exercise stage using inert gas rebreathing techniques. Haemodynamic performance is highly dependent on surface area, age, gender and pubertal stage. Many parameters, for example transfer factor, demonstrate pubertal stage-dependent differences at identical workloads even after correction for size. Females have a lower capillary blood volume at rest compared to age and size-matched males, but it is equalized during exercise. FRC unexpectedly rose with exercise, and peak exercise was associated with a falling stroke volume in 91% (95% CI 84-96%) of children, a possible demonstration of Starling's law of the heart. Oxygen pulse (oxygen consumption/cardiac frequency) is a very poor marker for pulmonary blood flow. Normal values are provided for all haemodynamic parameters for rest and every exercise stage for all subgroups of children. This should allow accurate comparison of normal and disease groups in future.
Suppressor T cell memory. II. The role of memory suppressor T cells in tolerance to human gamma globulin.
Authors: R H Loblay, B Fazekas de St Groth, H Pritchard-Briscoe, A Basten
Journal: The Journal of Experimental Medicine (1983)

The transient presence of suppressor T cell (Ts) activity in high-dose tolerance to human gamma globulin (HGG), and its (apparent) absence in low-dose tolerance, have been advanced as strong evidence against the concept that Ts play an important role in maintenance of immunological unresponsiveness. To analyze this question, CBA mice were exposed to high or low doses of deaggregated HGG (dHGG) and later challenged with HGG in immunogenic form (aHGG); their capacity to mount a primary or secondary suppressive response was assessed in an adoptive hapten-carrier system. Primary suppression reached a maximum 7 d after high-dose tolerance induction and gradually waned thereafter, being no longer detectable by day 30-35. Subsequent challenge of tolerant mice with aHGG, however, led to a rapid reactivation of suppression that bore the hallmarks of an anamnestic secondary response, and this effect was still demonstrable 135 d after tolerance induction. It was also shown that a single low dose of dHGG was capable of generating memory for suppression despite the absence of detectable primary suppression, indicating that the latter is not a prerequisite for induction of memory cells. The results were interpreted as indicating that tolerance, like immunity, is a manifestation of specific immunological memory. If tolerance to self-antigens is maintained by a similar mechanism, it would be expected that memory Ts could be induced during the early stages of fetal development. Mice were therefore exposed to tolerogen in utero by injection of their mothers with dHGG at day 7 of gestation, and were assessed at various times after birth for the capacity to exhibit primary or secondary suppression in adoptive transfer. Nonspecific suppression masked any specific effects during the first 5 wk of life. Antigen-specific, primary suppression was demonstrable subsequently until 10-12 wk of age, and if the animals were challenged with aHGG before transfer an anamnestic secondary suppressive response could be elicited up to 6 mo of age. These observations are consistent with the notion that memory Ts may play an important role in the maintenance of self-tolerance.
GENETICS OF BRAIN STRUCTURE AND INTELLIGENCE
Authors: Arthur W. Toga, Paul M. Thompson
Journal: Annual Review of Neuroscience (2005)

Genetic influences on brain morphology and IQ are well studied. A variety of sophisticated brain-mapping approaches relating genetic influences on brain structure and intelligence establishes a regional distribution for this relationship that is consistent with behavioral studies. We highlight those studies that illustrate the complex cortical patterns associated with measures of cognitive ability. A measure of cognitive ability, known as g, has been shown highly heritable across many studies. We argue that these genetic links are partly mediated by brain structure that is likewise under strong genetic control. Other factors, such as the environment, obviously play a role, but the predominant determinant appears to be genetic.
The Heart in Friedreich Ataxia
Authors: Frank Weidemann, Christian Rummey, Bart Bijnens, Stefan Störk, Ruta Jasaityte, Jan Dhooge, Aigul Baltabaeva, George Sutherland, Jörg B. Schulz, Thomas Meier
Journal: Circulation (2012)

Background— This cross-sectional study provides a practical approach for the clinical assessment of Friedreich ataxia (FA) cardiomyopathy (FA-CM). Methods and Results— A comprehensive cardiac assessment, including standard echocardiography, color Doppler myocardial imaging, cardiac magnetic resonance imaging, ECG, and exercise stress testing, was performed in 205 FA patients. To assess myocardial hypertrophy in FA-CM, the end-diastolic interventricular septal wall thickness (IVSTd) was found to be the best echocardiographic parameter compared with cardiac magnetic resonance imaging–determined left ventricular mass. With the use of this parameter, 4 groups of patients with FA-CM could be defined. Patients with normal values for IVSTd (31.7%) were classified as having no FA-CM. Patients with an IVSTd exceeding the predicted normal IVSTd were classified as having mild FA-CM (40%) if IVSTd exceeded the normal value by &lt;18% or as having intermediate FA-CM (16.1%) if IVSTd exceeded the normal value by ≥18%. Patients with ejection fraction &lt;50% were classified as having severe FA-CM (12.2%). In addition to increased myocardial mass, severe FA-CM was further characterized by dilatation of the left ventricle, reduced systolic strain rate of the posterior wall, and ECG abnormalities. Regional myocardial function correlated negatively with FA-CM groups. Younger patients had a tendency for more advanced FA-CM. Importantly, no clear correlation was found between FA-CM groups and neurological function. Conclusions— We provide and describe a readily applicable clinical grouping of the cardiomyopathy associated with FA based on echocardiographic IVSTd and ejection fraction data. Because no distinct interrelations between FA-CM and neurological status could be determined, regular follow-up of potential cardiac involvement in FA patients is essential in clinical practice. Clinical Trial Registration— https://www.clinicaltrials.gov . Unique identifier: NCT00905268.
Benefits and Risks of Abciximab Use in Primary Angioplasty for Acute Myocardial Infarction
Authors: James E. Tcheng, David E. Kandzari, Cindy L. Grines, David A. Cox, Mark B. Effron, Eulogio Garcia, John J. Griffin, Giulio Guagliumi, Thomas Stuckey, Mark Turco, Martin Fahy, Alexandra J. Lansky, Roxana Mehran, Gregg W. Stone
Journal: Circulation (2003)

Trials of platelet glycoprotein IIb/IIIa inhibitors as adjuncts to primary percutaneous coronary intervention for acute myocardial infarction (MI) have shown improved early clinical and angiographic outcomes with treatment. However, variations in trial designs, modest sample sizes, and limited long-term follow-up have precluded these studies from being definitive.As a prespecified secondary analysis of the CADILLAC trial, we compared early and late outcomes by abciximab assignment among 2082 patients randomized in an open-label, 2x2 factorial-design trial of primary stenting versus angioplasty and abciximab treatment (n=1052) versus no abciximab treatment (n=1030). Baseline characteristics were balanced between groups. Abciximab treatment was associated with a significant reduction in the composite end point of death, MI, ischemia-driven target-vessel revascularization (TVR), or disabling stroke at 30 days (4.6% versus 7.0%; relative risk, 0.65; 95% CI, 0.46 to 0.93; P=0.01). Subacute thrombosis also was significantly reduced with abciximab treatment. At 12 months, however, rates of the composite end point did not differ significantly (18.4% for controls versus 16.9% for abciximab-treated patients; relative risk, 0.92; 95% CI, 0.76 to 1.10; P=0.29), reflecting a decrease in the relative difference in TVR rates (ie, no effect of abciximab on reducing restenosis). In an angiographic substudy (n=656), myocardial salvage, restenosis, and infarct-artery reocclusion at 7 months were unaffected by abciximab treatment. There was no significant interaction between stenting and abciximab treatment.Adjunctive abciximab treatment during primary percutaneous coronary intervention significantly enhanced 30-day event-free survival, predominantly by reducing ischemia-driven TVR. Abciximab treatment did not affect the composite end point at 1 year, reflecting a lack of effect on restenosis.
Oxidant Stress Leads to Impaired Regulation of Renal Cortical Oxygen Consumption by Nitric Oxide in the Aging Kidney
Authors: Stephen Adler, Harer Huang, Michael S. Wolin, Pawel M. Kaminski
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Structural and functional changes occur in the kidney with aging. Previous studies have suggested that loss of nitric oxide production contributes to these changes. The authors therefore explored regulation of renal cortical oxygen consumption, a nitric oxide mediated effect, in tissue from Fischer 344 rats at different ages (4, 13, and 23 mo) to characterize changes in renal nitric oxide production with age. Bradykinin, enalaprilat, and amlodipine significantly suppressed cortical oxygen consumption in 4-mo-old rats (bradykinin: −2.5 ± 0.9% to −21 ± 1.5%; enalaprilat: −0.7 ± 0.5% to −26 ± 1.2%; amlodipine: −1.3 ± 0.9% to −18 ± 1.2%; P < 0.05). Similar results were obtained in 13-mo-old animals. However, in 23-mo-old animals, the responses to bradykinin and enalaprilat were attenuated (bradykinin: 0 ± 0% to −13 ± 0.9%; enalaprilat: −0.3 ± 0.3% to −17 ± 2.1%; P < 0.05), whereas the response to an NO donor was unaffected, suggesting decreased bioavailability of NO. Addition of the superoxide radical scavenger tempol restored the ability of bradykinin, enalaprilat, and amlodipine to suppress oxygen consumption in tissue from 23-mo-old animals to levels seen in younger animals, suggesting NO destruction by superoxide as the reason for decreased NO availability. Apocynin, an inhibitor of NAD(P)H oxidase, similarly restored the ability of all three drugs to suppress oxygen consumption, suggesting NAD(P)H oxidase as the enzyme responsible for enhanced superoxide production in aging. Levels of eNOS protein, assessed by immunoblotting, did not change significantly with age. These results suggest that NO availability is decreased in the aging kidney and that this is due to scavenging of NO by superoxide produced by NAD(P)H oxidase. Oxidant stress, by depleting NO, may contribute to the structural and hemodynamic changes characteristic of the aging kidney. E-mail: [email protected]
Inhibition of Cancer Cell Proliferation by PPARγ Is Mediated by a Metabolic Switch that Increases Reactive Oxygen Species Levels
Authors: Nishi Srivastava, Rahul K. Kollipara, Dinesh K. Singh, Jessica Sudderth, Zeping Hu, Hien Nguyen, Shan Wang, Caroline G. Humphries, Ryan Carstens, Kenneth E. Huffman, Ralph J. DeBerardinis, Ralf Kittler
Journal: Cell Metabolism (2014)
Asthma Severity Is Associated with Body Mass Index and Early Menarche in Women
Authors: Raphaëlle Varraso, Valérie Siroux, Jean Maccario, Isabelle Pin, Francine Kauffmann
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Asthma severity in relation to body mass index (BMI) has rarely been studied. The relation between BMI and asthma severity was studied by sex in 366 adults with asthma from the Epidemiological Study on the Genetics and Environment of Asthma, a case-control and family study on asthma. Factors related to asthma severity and BMI such as smoking, FEV(1), bronchial hyperresponsiveness, and dyspnea were taken into account. The influence of early menarche was studied to assess the potential role of hormonal factors. Clinical asthma severity in the last 12 months was assessed by a score (0-7) based on the frequency of asthma attacks, persisting symptoms between attacks, and hospitalization. Asthma severity, which was unrelated to sex, increased with BMI in women (p = 0.0001) but not in men (p = 0.3). In women, the association remained after adjustment for age, FEV(1), smoking habits, and BMI-adjusted dyspnea and taking into account familial dependence (p = 0.0001). The association between BMI and severity was stronger in women with early menarche than in women without early menarche (p interaction = 0.02). Findings support the hypothesis of hormonal factors involved in the severity of asthma.
Renal Function in High-Output Heart Failure in Rats
Authors: ROLAND WILLENBROCK, INES PAGEL, MICHAELA SCHEUERMANN, KLAUS HÖHNEL, HARALD S. MACKENZIE, BARRY M. BRENNER, RAINER DIETZ
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The physiologic and pathophysiologic importance of natriuretic peptides (NP) has been imperfectly defined. The diminished renal responses to exogenous atrial NP in heart failure have led to the perception that the endogenous NP system might be less effective and thus contribute to renal sodium retention in heart failure. This study tests the hypothesis that in experimental heart failure, the renal responses to an acute volume load are still dependent on the NP system. The specific antagonist HS-142-1 was used to block the effects of NP in a model of high-output heart failure induced by an aortocaval shunt. Plasma cGMP levels and renal cGMP excretion were significantly lower in shunted and sham-operated rats receiving HS-142-1, compared with vehicle-treated controls, indicating effective blockade of guanylate cyclase-coupled receptors. Baseline sodium excretion and urine flow rate were lower in HS-142-1-treated sham-operated rats (15.2 ± 1.1 μl/min versus 27.5 ± 3.1 μl/min with vehicle, P &lt; 0.001) and in HS-142-1-treated shunted rats (8.1 ± 1.3 μl/min versus 19.9 ± 2.3 μl/min with vehicle, P &lt; 0.001). After an acute volume load, the diuretic and natriuretic responses were attenuated by HS-142-1 in control and shunted rats. The renal responses were reduced by HS-142-1 to a significantly greater extent in shunted rats than in control rats. HS-142-1 did not induce any significant systemic hemodynamic changes in either group, nor did it alter renal blood flow. However, the GFR in HS-142-1-treated shunted rats was lower than that in vehicle-treated shunted rats, both at baseline (0.6 ± 0.3 ml/min versus 2.1 ± 0.4 ml/min with vehicle, P &lt; 0.05) and after an acute volume load (1.2 ± 0.4 ml/min versus 2.6 ± 0.4 ml/min with vehicle, P = 0.01), whereas no such effect was observed in control rats. These data indicate that the maintenance of basal renal function and the responses to acute volume loading are dependent on the NP system. The NP seem to be of particular importance for the maintenance of GFR in this model of experimental heart failure. These observations provide new insights into the importance of the renal NP system in heart failure.
hsa-miR-191 Is a Candidate Oncogene Target for Hepatocellular Carcinoma Therapy
Authors: Eran Elyakim, Einat Sitbon, Alexander Faerman, Sarit Tabak, Eve Montia, Liron Belanis, Avital Dov, Eric G. Marcusson, C. Frank Bennett, Ayelet Chajut, Dalia Cohen, Noga Yerushalmi
Journal: Cancer Research (2010)

Hepatocellular carcinoma (HCC) is generally a fatal disease due to a paucity of effective treatment options. The identification of oncogenic microRNAs that exert pleiotropic effects in HCC cells may offer new therapeutic targets. In this study, we have identified the human microRNA miR-191 as a potential target for HCC therapy. Inhibition of miR-191 decreased cell proliferation and induced apoptosis in vitro and significantly reduced tumor masses in vivo in an orthotopic xenograft mouse model of HCC. Additionally, miR-191 was found to be upregulated by a dioxin, a known liver carcinogen, and was found to be a regulator of a variety of cancer-related pathways. Our findings offer a preclinical proof of concept for miR-191 targeting as a rational strategy to pursue for improving HCC treatment.
A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk
Authors: Peter Broderick, Luis Carvajal-Carmona, Alan M Pittman, Emily Webb, Kimberley Howarth, Andrew Rowan, Steven Lubbe, Sarah Spain, Kate Sullivan, Sarah Fielding, Emma Jaeger, Jayaram Vijayakrishnan, Zoe Kemp, Maggie Gorman, Ian Chandler, Elli Papaemmanuil, Steven Penegar, Wendy Wood, Gabrielle Sellick, Mobshra Qureshi, Ana Teixeira, Enric Domingo, Ella Barclay, Lynn Martin, Oliver Sieber, David Kerr, Richard Gray, Julian Peto, Jean-Baptiste Cazier, Ian Tomlinson, Richard S Houlston
Journal: Nature Genetics (2007)
Effect of Acute Isovolemic Anemia on Cardiac Output and Estimated Hepatic Blood Flow in the Conscious Dog
Authors: GASTON CHAMORRO, JOSE A. RODRIGUEZ, BARRY DZINDXIO, ELLIOT RAPAPORT
Journal: Circulation Research (1973)

The effect of acute isovolemic anemia induced by Dextran 70 exchange (40 ml/kg body weight) on estimated hepatic blood flow, cardiac output, and related variables was studied in 27 experiments on 24 unsedated dogs. Experiments were performed 5-10 days after implantation of an electromagnetic flow transducer around the aorta and catheters in the hepatic vein, jugular vein, and carotid artery. Bromsulphalein infusion was used to measure estimated hepatic blood flows, and electromagnetic measurements of stroke volume and cardiac output were calibrated using a simultaneous dye-dilution curve. With a mean fall in hematocrit from 34.8 to 17.0 ml/100 ml, estimated hepatic blood flow rose from 53.6 ± 15.3 (SD) to 76.3 ± 21.1 ml/min kg -1 and splanchnic vascular resistance fell from 119 ± 41 to 93 ± 38 mm Hg/liter min -1 ( P &lt;0.01). These changes were proportionately smaller than the increase in cardiac output (182 ± 80 to 350 ± 146 ml/min kg -1 ) and the fall in systemic vascular resistance (37.0 ± 4.9 to 21.7 ± 4.9 mm Hg/liter min -1 ), leading to a fall in the ratio of estimated hepatic blood flow to cardiac output from 34.3 to 25.7%. Bromsulphalein extraction ratio was significantly decreased, but Bromsulphalein clearance increased 44%. Splanchnic oxygen consumption did not change. β-receptor blockade in 6 dogs (propranolol 0.5 mg/kg body weight) failed to prevent or attenuate the increase in estimated hepatic blood flow or cardiac output when the blocking agent was given before induction of acute isovolemic anemia. Sixty minutes after accomplishment of anemia, estimated hepatic blood flow and cardiac output had returned toward but not to control levels. Induction of β-receptor blockade in the anemic dog did not influence the effects of time on estimated hepatic blood flow or cardiac output. We concluded that acute isovolemic anemia leads to a significant increase in estimated hepatic blood flow that is essentially independent of β-receptor stimulation.
Decreased Tonic Inhibition in Cerebellar Granule Cells Causes Motor Dysfunction in a Mouse Model of Angelman Syndrome
Authors: Kiyoshi Egawa, Kyoko Kitagawa, Koichi Inoue, Masakazu Takayama, Chitoshi Takayama, Shinji Saitoh, Tatsuya Kishino, Masatoshi Kitagawa, Atsuo Fukuda
Journal: Science Translational Medicine (2012)

Ube3a deficiency causes a decrease in cerebellar tonic inhibition by preventing degradation of GABA transporter 1 in a mouse model of Angelman syndrome.