tbuckley/cabot-search huggingface dataset:
Phase I and Pharmacokinetic Study of Pegylated Liposomal CKD-602 in Patients with Advanced Malignancies
Authors: William C. Zamboni, Suresh Ramalingam, David M. Friedland, Robert P. Edwards, Ronald G. Stoller, Sandra Strychor, Lauren Maruca, Beth A. Zamboni, Chandra P. Belani, Ramesh K. Ramanathan
Journal: Clinical Cancer Research (2009)

S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors.S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over 2 weeks and total (lactone+hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated+released) CKD602 measured by liquid chromatography-tandem mass spectrometry.Forty-five patients (21 males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m2, grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in two patients with refractory ovarian cancer (1.7 and 2.1 mg/m2). High interpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602.S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.
Life event research.
Authors: J W Paulley
Journal: Gut (1986)

<h3>Abstract</h3> <h3>Background</h3> Neurological disorders are the leading cause disability in Australia and the world. Combating the perceived difficulty of neurology or “neurophobia” and improving physician education is a key component in addressing this problem. We aim to conduct the first study to identify whether neurophobia exists in medical students and junior doctors in an Australian population and try to identify factors that may contribute to this in this population. <h3>Methods</h3> A 24 question online validated survey was distributed via email broadcast to all medical students and junior doctors at a metropolitan tertiary care centre in Australia. Responses were collected over 6 weeks with weekly reminder emails for 4 weeks after the initial invitation email. <h3>Results</h3> 114 medical students and junior doctors participated in the study. Participants perceived neurology as the most difficult medical speciality compared to 10 other medical specialties (p=0.001). The top three factors contributing to this perceived difficulty were: a lack of understanding of neuroanatomy, lack of diagnostic certainty and lack of clinical exposure. 65% of the participants stated that they had too little planned teaching in neurology with only 36% of the participants having performed a neurology rotation during medical school. <h3>Conclusion</h3> The prevalence of neurophobia in this Australian cohort of medical students and junior doctors is consistent with previous findings from around the world. This concerning finding requires further examination into the contributing factors in order to created trials of targeted interventions in order to resolve this.
Functional Expression of the Human Thiazide-Sensitive NaCl Cotransporter in Madin-Darby Canine Kidney Cells
Authors: Joke C. de Jong, Peter H.G.M. Willems, Lambertus P.W.J. van den Heuvel, Nine V.A.M. Knoers, René J.M. Bindels
Journal: Journal of the American Society of Nephrology (2003)

The thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is expressed on the apical membrane of epithelial cells lining the distal convoluted tubule, is responsible for the reabsorption of 5% to 10% of filtered Na(+) and Cl(-). To date, functional studies on the structural and regulatory requirements for localized trafficking and ion-transporting activity of NCC have been hampered by lack of a suitable cell system expressing this cotransporter. Reported here is the functional expression of human NCC (hNCC) in a polarized mammalian cell of renal origin-that is, the high-resistance Madin-Darby canine kidney (MDCK) cell. Western blot testing revealed that the cells predominantly expressed the complex glycosylated (approximately 140 kD) form of hNCC. hNCC was present primarily in the apical part of the cell. The functionality of hNCC was demonstrated by the gain of thiazide-sensitive Na(+) uptake and transepithelial transport activity. Na(+) uptake was significantly increased after short-term (15 min) treatment with forskolin, whereas cyclic guanosine monophosphate, wortmannin, phorbol 12-myriatate 13-acetate, and staurosporine were without effect. This indicates that hNCC activity is regulated through cyclic adenosine monophosphate, rather than via cyclic guanosine monophosphate, phospho-inositide 3-kinases or protein kinase C. Aldosterone did not alter Na(+) uptake in the short term (15 min) but significantly increased the transport activity in the long term (16 h). The latter effect of aldosterone was due to an effect on the cytomegalovirus promoter/enhancer driving the expression of hNCC. hNCC-MDCK cells are a good model for the study of the regulation of apical trafficking and ion-transporting activity of hNCC.
Raf-1 Antagonizes Erythroid Differentiation by Restraining Caspase Activation
Authors: Andrea Kolbus, Sandra Pilat, Zvenyslava Husak, Eva Maria Deiner, Gabriele Stengl, Hartmut Beug, Manuela Baccarini
Journal: The Journal of Experimental Medicine (2002)

The Raf kinases are key signal transducers activated by mitogens or oncogenes. The best studied Raf isoform, Raf-1, was identified as an inhibitor of apoptosis by conventional and conditional gene ablation in mice. c-raf-1−/− embryos are growth retarded and anemic, and die at midgestation with anomalies in the placenta and fetal liver. Here, we show that Raf-1–deficient primary erythroblasts cannot be expanded in culture due to their accelerated differentiation into mature erythrocytes. In addition, Raf-1 expression is down-regulated in differentiating wild-type cells, whereas overexpression of activated Raf-1 delays differentiation. As recently described for human erythroid precursors, we find that caspase activation is necessary for the differentiation of murine fetal liver erythroblasts. Differentiation-associated caspase activation is accelerated in erythroid progenitors lacking Raf-1 and delayed by overexpression of the activated kinase. These results reveal an essential function of Raf-1 in erythropoiesis and demonstrate that the ability of Raf-1 to restrict caspase activation is biologically relevant in a context distinct from apoptosis.
Summaries of Key Journal Articles
Authors: Kim A. Eagle, Christopher P. Cannon, William F. Armstrong, David S. Bach, Ragavendra R. Baliga, Anna M. Booher, Timothy B. Cotts, Jennifer Cowger, Daniel T. Eitzman, James B. Froehlich, Caren S. Goldberg, Hitinder S. Gurm, Jennifer C. Hirsch, Elizabeth Anne Jackson, Fred Morady, Debabrata Mukherjee, Himanshu J. Patel, John E. Rectenwald, Melvyn Rubenfire
Journal: Journal of the American College of Cardiology (2012)
Mid-expiratory flow versus FEV1 measurements in the diagnosis of exercise induced asthma in elite athletes
Authors: J W Dickinson
Journal: Thorax (2005)

A fall in FEV(1) of > or =10% following bronchoprovocation (eucapnic voluntary hyperventilation (EVH) or exercise) is regarded as the gold standard criterion for diagnosing exercise induced asthma (EIA) in athletes. Previous studies have suggested that mid-expiratory flow (FEF(50)) might be used to supplement FEV(1) to improve the sensitivity and specificity of the diagnosis. A study was undertaken to investigate the response of FEF(50) following EVH or exercise challenges in elite athletes as an adjunct to FEV(1).Sixty six male (36 asthmatic, 30 non-asthmatic) and 50 female (24 asthmatic, 26 non-asthmatic) elite athletes volunteered for the study. Maximal voluntary flow-volume loops were measured before and 3, 5, 10, and 15 minutes after stopping EVH or exercise. A fall in FEV(1) of > or =10% and a fall in FEF(50) of > or =26% were used as the cut off criteria for identification of EIA.There was a strong correlation between DeltaFEV(1) and DeltaFEF(50) following bronchoprovocation (r = 0.94, p = 0.000). Sixty athletes had a fall in FEV(1) of > or =10% leading to the diagnosis of EIA. Using the FEF(50) criterion alone led to 21 (35%) of these asthmatic athletes receiving a false negative diagnosis. The lowest fall in FEF(50) in an athlete with a > or =10% fall in FEV(1) was 14.3%. Reducing the FEF(50) criteria to > or =14% led to 13 athletes receiving a false positive diagnosis. Only one athlete had a fall in FEF(50) of > or =26% in the absence of a fall in FEV(1) of > or =10% (DeltaFEV(1) = 8.9%).The inclusion of FEF(50) in the diagnosis of EIA in elite athletes reduces the sensitivity and does not enhance the sensitivity or specificity of the diagnosis. The use of FEF(50) alone is insufficiently sensitive to diagnose EIA reliably in elite athletes.
In vivo characterization of synthetic thromboxane A2 in canine myocardium.
Authors: H H Holzgrefe, L V Buchanan, S Bunting
Journal: Circulation Research (1987)

Recently, total chemical synthesis of thromboxane was achieved. The in vitro activity of synthetic thromboxane A2 is indistinguishable from biologically generated material. The present study describes the in vivo characterization of synthetic thromboxane A2 on the regional blood flow distribution of the canine heart. Local injections of synthetic thromboxane A2 into the coronary vasculature caused marked reductions in coronary blood flow, measured by both radiolabeled microsphere injection and an electromagnetic flow device. The threshold concentration required to bring about this effect varied greatly between dogs and ranged from 0.125 microgram/kg to 2.0 micrograms/kg. Similarly, the dose of thromboxane A2 required to aggregate dog platelets in vitro varied from 30 ng/ml to 1,000 ng/ml. Bolus injections of 2 micrograms/ml thromboxane A2 into the circumflex or left anterior coronary artery resulted in a simultaneous reduction in platelet count in coronary sinus blood of 83 +/- 5.2% (mean +/- SEM, n = 4, p = .0005). Both flow reduction and platelet effects were transient and localized. The time taken from onset to recovery of the response to control levels was 77 +/- 6.0 seconds (mean +/- SEM) for flow and 70-80 seconds for platelet count. Injections of thromboxane A2 caused a small but significant increase in heart rate with no change in systemic blood pressure. In conclusion, the in vivo actions of synthetic thromboxane A2 are consistent with the vasoconstrictor and platelet aggregatory effects seen in vitro, but dogs vary considerably in their sensitivity.
GRIEF REACTIONS IN LATER LIFE
Authors: KARL STERN, GWENDOLYN M. WILLIAMS, MIGUEL PRADOS
Journal: American Journal of Psychiatry (1951)

Grief reactions in later life have been studied in 25 subjects, 23 of whom attended an old age counselling service. The most striking features in this group were: a relative paucity of overt grief and of conscious guilt feelings, a preponderance of somatic illness precipitated or accentuated by the bereavement; a tendency to extreme exaggeration of the common idealization of the deceased with a blotting-out of all "dark" features; a tendency to self-isolation and to hostility against some living person. These features are discussed in the light of the psychoanalytic theories of mourning and depressions in general, as applied to the psychological dynamics of later life. A brief outline of the management of these cases is given.
Glucose-Lowering Effects and Low Risk of Hypoglycemia in Patients With Maturity-Onset Diabetes of the Young When Treated With a GLP-1 Receptor Agonist: A Double-Blind, Randomized, Crossover Trial
Authors: Signe H. Østoft, Jonatan I. Bagger, Torben Hansen, Oluf Pedersen, Jens Faber, Jens J. Holst, Filip K. Knop, Tina Vilsbøll
Journal: Diabetes Care (2014)

OBJECTIVE The most common form of maturity-onset diabetes of the young (MODY), hepatocyte nuclear factor 1α (HNF1A diabetes: MODY3) is often treated with sulfonylureas that confer a high risk of hypoglycemia. We evaluated treatment with GLP-1 receptor agonists (GLP-1RAs) in patients with HNF1A diabetes. RESEARCH DESIGN AND METHODS Sixteen patients with HNF1A diabetes (8 women; mean age 39 years [range 23–67 years]; BMI 24.9 ± 0.5 kg/m2 [mean ± SEM]; fasting plasma glucose [FPG] 9.9 ± 0.9 mmol/L; HbA1c 6.4 ± 0.2% [47 ± 3 mmol/mol]) received 6 weeks of treatment with a GLP-1RA (liraglutide) and placebo (tablets), as well as a sulfonylurea (glimepiride) and placebo (injections), in randomized order, in a double-blind, crossover trial. Glimepiride was up-titrated once weekly in a treat-to-target manner; liraglutide was up-titrated once weekly to 1.8 mg once daily. At baseline and at the end of each treatment period a standardized liquid meal test was performed, including a 30-min light bicycle test. RESULTS FPG decreased during the treatment periods (−1.6 ± 0.5 mmol/L liraglutide [P = 0.012] and −2.8 ± 0.7 mmol/L glimepiride [P = 0.003]), with no difference between treatments (P = 0.624). Postprandial plasma glucose (PG) responses (total area under the curve) were lower with both glimepiride (2,136 ± 292 min × mmol/L) and liraglutide (2,624 ± 340 min × mmol/L) compared with baseline (3,127 ± 291 min × mmol/L; P &amp;lt; 0.001, glimepiride; P = 0.017, liraglutide), with no difference between treatments (P = 0.121). Eighteen episodes of hypoglycemia (PG ≤3.9 mmol/L) occurred during glimepiride treatment and one during liraglutide treatment. CONCLUSIONS Six weeks of treatment with glimepiride or liraglutide lowered FPG and postprandial glucose excursions in patients with HNF1A diabetes. The glucose-lowering effect was greater with glimepiride at the expense of a higher risk of exclusively mild hypoglycemia.
Contrasting effects of nifedipine and adenosine on regional myocardial flow distribution and metabolism distal to a severe coronary arterial stenosis: observations in sedated, closed-chest, domestic swine.
Authors: H Gewirtz, S L Gross, D O Williams, A S Most
Journal: Circulation (1984)

This study tested the hypothesis that intrinsic negative inotropic effects of a drug used to induce coronary vasodilation distal to a severe coronary arterial stenosis may influence the extent of redistribution of transmural flow and its metabolic consequences. To test this hypothesis, studies were conducted in eight closed-chest, sedated swine with severe (82% reduction in luminal diameter) coronary arterial stenoses. Measurement of hemodynamic parameters, regional myocardial blood flow (microsphere technique), lactate metabolism, and oxygen consumption were made (1) under control conditions, (2) after 10 min of intracoronary infusion of a vasodilator distal to the stenosis, and (3) under repeat control conditions. Each animal received both intracoronary adenosine (400 micrograms/min) and nifedipine (50 micrograms/min). The order of drug infusion was chosen at random and a control period separated administration of each. In response to nifedipine there was no significant change in the group mean (+/- SD) value of endocardial flow (1.21 +/- 0.34 to 1.29 +/- 0.61 ml/min X g-1) distal to the stenosis. In contrast, epicardial flow increased in comparison with control in response to nifedipine (1.30 +/- 0.58 to 1.79 +/- 0.74 ml/min X g-1; p less than .05). Regional myocardial oxygen consumption (MVO2) declined in comparison with control in response to nifedipine (14.0 +/- 4.2 to 11.1 +/- 5.0 ml/min X 100 g-1; p less than .05). Regional lactate extraction did not change in comparison with control during infusion of nifedipine (18.2 +/- 22.4 vs 11.7 +/- 16.8). In response to adenosine, endocardial blood flow distal to the stenosis declined in comparison with control (1.25 +/- 0.53 to 1.07 +/- 0.38 ml/min X g-1; p less than .05), while epicardial flow increased (1.31 +/- 0.55 to 2.26 +/- 0.59 ml/min X g-1; p less than .01). Regional MVO2 also tended to decline in comparison with control in response to adenosine (13.4 +/- 4.9 to 11.7 +/- 2.9 ml/min X 100 g-1) and was significantly (p less than .05) reduced in comparison with postintervention control (14.6 +/- 4.2 ml/min X 100 g-1). In contrast to nifedipine, adenosine caused a significant decline in regional lactate extraction in comparison with control (12.7 +/- 23.2% to -40.6 +/- 55.0%; p less than .01). Thus, administration of nifedipine, a negative inotropic agent, resulted in (1) a decline in regional MVO2, (2) increased epicardial blood flow with variable effects on endocardial flow distal to the stenosis, and (3) no evidence of de novo or worsening ischemia, even in animals in which endocardial flow decreased.(ABSTRACT TRUNCATED AT 400 WORDS)
Intratracheal Recombinant Surfactant Protein D Prevents Endotoxin Shock in the Newborn Preterm Lamb
Authors: Machiko Ikegami, Karen Carter, Kimberly Bishop, Annuradha Yadav, Elizabeth Masterjohn, William Brondyk, Ronald K. Scheule, Jeffrey A. Whitsett
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: The susceptibility of neonates to pulmonary and systemic infection has been associated with the immaturity of both lung structure and the immune system. Surfactant protein (SP) D is a member of the collectin family of innate immune molecules that plays an important role in innate host defense of the lung.Objectives: We tested whether treatment with recombinant human SP-D influenced the response of the lung and systemic circulation to intratracheally administered Escherichia coli lipopolysaccharides.Methods: After intratracheal lipopolysaccharide instillation, preterm newborn lambs were treated with surfactant and ventilated for 5 h.Measurement: Survival rate, physiologic lung function, lung and systemic inflammation, and endotoxin level in plasma were evaluated.Main Results: In control lambs, intratracheal lipopolysaccharides caused septic shock and death associated with increased endotoxin in plasma. In contrast, all lambs treated with recombinant human SP-D were physiologically stable and survived. Leakage of lipopolysaccharides from the lungs to the systemic circulation was prevented by intratracheal recombinant human SP-D. Recombinant human SP-D prevented systemic inflammation and decreased the expression of IL-1β, IL-8, and IL-6 in the spleen and liver. Likewise, recombinant human SP-D decreased IL-1β and IL-6 in the lung and IL-8 in the plasma. Recombinant human SP-D did not alter pulmonary mechanics following endotoxin exposure. Recombinant human SP-D was readily detected in the lung 5 h after intratracheal instillation.Conclusions: Intratracheal recombinant human SP-D prevented shock caused by endotoxin released from the lung during ventilation in the premature newborn.
Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy
Authors: Eric A. Reits, James W. Hodge, Carla A. Herberts, Tom A. Groothuis, Mala Chakraborty, Elizabeth K.Wansley, Kevin Camphausen, Rosalie M. Luiten, Arnold H. de Ru, Joost Neijssen, Alexander Griekspoor, Elly Mesman, Frank A. Verreck, Hergen Spits, Jeffrey Schlom, Peter van Veelen, Jacques J. Neefjes
Journal: The Journal of Experimental Medicine (2006)

Radiotherapy is one of the most successful cancer therapies. Here the effect of irradiation on antigen presentation by MHC class I molecules was studied. Cell surface expression of MHC class I molecules was increased for many days in a radiation dose-dependent manner as a consequence of three responses. Initially, enhanced degradation of existing proteins occurred which resulted in an increased intracellular peptide pool. Subsequently, enhanced translation due to activation of the mammalian target of rapamycin pathway resulted in increased peptide production, antigen presentation, as well as cytotoxic T lymphocyte recognition of irradiated cells. In addition, novel proteins were made in response to γ-irradiation, resulting in new peptides presented by MHC class I molecules, which were recognized by cytotoxic T cells. We show that immunotherapy is successful in eradicating a murine colon adenocarcinoma only when preceded by radiotherapy of the tumor tissue. Our findings indicate that directed radiotherapy can improve the efficacy of tumor immunotherapy.
Caregivers report a wide variety of early signs and symptoms of impending asthma exacerbations that are not different between preschool and school-aged children
Authors: Katherine Rivera-Spoljaric, Matthew Jaenicke, Sid Sridhar, Melissa J. Krauss, Jane M. Garbutt, Leonard B. Bacharier, Robert C. Strunk
Journal: Journal of Allergy and Clinical Immunology (2011)
Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial.
Authors: N E Lane, S Sanchez, G W Modin, H K Genant, E Pierini, C D Arnaud
Journal: Journal of Clinical Investigation (1998)

Corticosteroid-induced osteoporosis is the most common secondary cause of osteoporosis. We conducted a 12-mo, randomized clinical trial of human parathyroid hormone 1-34 (hPTH 1-34) in postmenopausal women (mean age was 63 yr) with osteoporosis who were taking corticosteroids and hormone replacement therapy. Response to the treatment was assessed with bone mineral density (BMD) measurements of the lumbar spine by quantitative computed tomography (QCT); BMD measurements of the lumbar spine, hip, and forearm by dual-energy x-ray absorptiometry (DXA); and biochemical markers of bone turnover. The mean (+/-SE) changes in BMD of the lumbar spine by QCT and DXA in the PTH group were 35+/-5.5% and 11+/-1.4%, respectively, compared with a relatively small change of 1.7+/-1.8% and 0+/-0.9% in the estrogen-only group. The differences in mean percentage between the groups at 1 yr were 33.5% for the lumbar spine by QCT (P < 0.001) and 9.8% for the lumbar spine by DXA (P < 0.001). The changes in the hip and forearm were not significantly different between or within the groups. During the first 3 mo of PTH treatment, markers of bone formation increased to nearly 150%, whereas markers of bone resorption increased only 100%, suggesting an early uncoupling of bone turnover in favor of formation. These results suggest that parathyroid hormone dramatically increases bone mass in the central skeleton of postmenopausal women with corticosteroid- induced osteoporosis who are taking hormone replacement.