tbuckley/cabot-search huggingface dataset:
Trimetrexate: Predictors of Severe or Life-Threatening Toxic Effects
Authors: E. A. Eisenhauer, B. C. Zee, J. L. Pater, W. R. Walsh
Journal: JNCI Journal of the National Cancer Institute (1988)

In four phase II trials of trimetrexate given iv daily for 5 days, we noted marked variability among patients in the development of severe or life-threatening toxic effects. In an effort to define which of 15 patients characteristics were associated with toxic effects of this degree, we have carried out single-factor and multifactor analyses on toxic effects during the first cycle of therapy in 68 patients. The final logistic regression model identified both low pretreatment serum protein levels and metastatic liver disease as significant correlates of severe toxic effects (P=.02 and P=.0005, respectively). While drug does was an important element of the best logistic model, its statistical significance was only borderline. Trimetrexate is extensively protein bound and is cleared primarily by hepatic metabolism, so it is not unreasonable to believe that alteration in protein binding of the drug or in metabolic capacity of the liver could produce enhanced toxic effects. Although the validity of these predictors should be confirmed, it seems prudent to recommend lower starting doses of trimetrexate for patients with metastatic liver disease and/or low protein levels and dose escalation if toxic effects allow it. [J Natl Cancer Inst 1988; 80: 1318–1322]
Adverse Events Among the Elderly Receiving Chemotherapy for Advanced Non–Small-Cell Lung Cancer
Authors: Elizabeth A. Chrischilles, Jane F. Pendergast, Katherine L. Kahn, Robert B. Wallace, Daniela C. Moga, David P. Harrington, Catarina I. Kiefe, Jane C. Weeks, Dee W. West, S. Yousuf Zafar, Robert H. Fletcher
Journal: Journal of Clinical Oncology (2009)

To describe chemotherapy use and adverse events (AEs) for advanced-stage, non-small-cell lung cancer (NSCLC) in community practice, including descriptions according to variation by age.We interviewed patients with newly diagnosed, stages IIIB and IV NSCLC in the population-based cohort studied by the Cancer Care Outcomes Research and Surveillance Consortium, and we abstracted the patient medical records. AEs were medical events occurring during chemotherapy. Using logistic regression, we assessed the association between age and chemotherapy; with Poisson regression, we estimated event rate ratios and adjusted the analysis for age, sex, ethnicity, radiation therapy, stage, histology, and presence and grade of 27 comorbidities.Of 1,371 patients, 58% (95% CI, 55% to 61%) received chemotherapy and 35% (95% CI, 32% to 38%) had AEs. After adjustment, 72% (95% CI, 65% to 79%) of those younger than 55 years and 47% (95% CI, 42% to 52%) of those age 75 years and older received chemotherapy. Platinum-based therapies were less common in the older-age groups. Pretreatment medical event rates were 18.6% for patients younger than 55 years and were only 9.2% for those age 75 years and older (adjusted rate ratio, 0.49; 95% CI, 0.26 to 0.91). In contrast, older adults were more likely to have AEs during chemotherapy. The adjusted rate ratios compared with age younger than 55 years were 1.70 for 65- to 74-year-olds (95% CI, 1.19 to 2.43) and 1.34 for those age 75 years and older (95% CI, 0.90 to 2.00).Older patients who received chemotherapy had fewer pretherapy events than younger patients and were less likely to receive platinum-based regimens. Nevertheless, older patients had more adverse events during chemotherapy, independent of comorbidity. Potential implicit trade-offs between symptom management and treatment toxicity should be made explicit and additionally studied.
The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor
Authors: Isabelle S. Lucet, Emmanuelle Fantino, Michelle Styles, Rebecca Bamert, Onisha Patel, Sophie E. Broughton, Mark Walter, Christopher J. Burns, Herbert Treutlein, Andrew F. Wilks, Jamie Rossjohn
Journal: Blood (2005)
Distribution of 1-(2-Deoxy-2-fluoro-β-<scp>d</scp>-arabinofuranosyl) Uracil in Mice Bearing Colorectal Cancer Xenografts
Authors: Julie L. Eiseman, Clive Brown-Proctor, Paul E. Kinahan, Jerry M. Collins, Lawrence W. Anderson, Erin Joseph, Deborah R. Hamburger, Su-shu Pan, Chester A. Mathis, Merrill J. Egorin, Raymond W. Klecker
Journal: Clinical Cancer Research (2004)

In colorectal, breast, and head and neck cancers, response to 5-fluorouracil is associated with low expression of thymidylate synthase. In contrast, tumors with high expression of thymidylate synthase may be more sensitive to prodrugs such as 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil (FAU) that are activated by thymidylate synthase. These studies were designed to evaluate FAU as a potential therapeutic and diagnostic probe.[18F]-FAU and [3H]-FAU were synthesized with >97% radiochemical purity. [3H]-FAU or [18F]-FAU was administered intravenously to severe combined immunodeficient mice bearing either HT29 (low thymidylate synthase) or LS174T (high thymidylate synthase) human colon cancer xenografts. Four hours after [3H]-FAU dosing, tissue distribution of total radioactivity and incorporation of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) 5-methyluracil (FMAU), derived from thymidylate synthase activation of FAU, into tumor DNA was measured. Positron emission tomography (PET) images were obtained for 90 minutes after injection of [18F]-FAU. Thymidylate synthase activity was determined in vitro in tumors from untreated mice by [3H] release from [3H]dUMP. Each cell line was incubated in vitro with [3H]-FAU or [3H]-FMAU in the absence or presence of 5-fluoro-2'-deoxyuridine (FdUrd) and then was analyzed for incorporation of radiolabel into DNA.Thymidylate synthase enzymatic activity in LS174T xenografts was approximately 3.5-fold higher than in HT29 xenografts, and incorporation of radioactivity derived from [3H]-FAU into LS174T DNA was approximately 2-fold higher than into HT29 DNA. At 240 minutes, radioactivity derived from [3H]-FAU was approximately 2-fold higher in tumors than in skeletal muscle. At times up to 90 minutes, PET imaging detected only small differences in uptake of [18F]-FAU between the tumor types. Fluorine-18 in skeletal muscle was higher than in tumor for the first 90 minutes and plateaued earlier, whereas [18F] in tumor continued to increase during the 90-minute imaging period. For both cell lines in vitro, FdUrd decreased the rate of incorporation of [3H]-FAU into DNA, whereas the incorporation of [3H]-FMAU was increased.These results for FAU incorporation into DNA in vitro and in vivo further support clinical evaluation of FAU as a therapeutic agent in tumors with high concentrations of thymidylate synthase that are less likely to respond to 5-fluorouracil treatment. The high circulating concentrations of thymidine reported in mice may limit their utility in evaluating FAU as a PET probe.
Access to Surgical Care in Developing Countries
Authors: Tarik Sammour, Andrew G. Hill
Journal: JAMA Surgery (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Effect of triiodothyronine on mitochondrial energy coupling in human skeletal muscle
Authors: Vincent Lebon, Sylvie Dufour, Kitt Falk Petersen, Jianming Ren, Beat M. Jucker, Lori A. Slezak, Gary W. Cline, Douglas L. Rothman, Gerald I. Shulman
Journal: Journal of Clinical Investigation (2001)

The mechanism underlying the regulation of basal metabolic rate by thyroid hormone remains unclear. Although it has been suggested that thyroid hormone might uncouple substrate oxidation from ATP synthesis, there are no data from studies on humans to support this hypothesis. To examine this possibility, we used a novel combined 13C/31P nuclear magnetic resonance (NMR) approach to assess mitochondrial energy coupling in skeletal muscle of seven healthy adults before and after three days of triiodothyronine (T3) treatment. Rates of ATP synthesis and tricarboxylic acid (TCA) cycle fluxes were measured by 31P and 13C NMR spectroscopy, respectively, and mitochondrial energy coupling was assessed as the ratio. Muscle TCA cycle flux increased by approximately 70% following T3 treatment. In contrast, the rate of ATP synthesis remained unchanged. Given the disproportionate increase in TCA cycle flux compared with ATP synthesis, these data suggest that T3 promotes increased thermogenesis in part by promoting mitochondrial energy uncoupling in skeletal muscle.
Cumulative dose-response curves for assessing combined effects of salbutamol and ipratropium bromide in chronic asthma
Authors: BM Grandordy, V Thomas, D de Lauture, J Marsac
Journal: European Respiratory Journal (1988)

We investigated whether salbutamol (S) and ipratropium bromide (IB) exerted a true additive bronchodilator effect in asthma. In fifteen selected chronic asthmatics, individual cumulative dose-response curves to S and IB were performed on two separate days (linear regression of bronchodilator response (delta FEV1) between 20 and 80% of maximal response, versus log dose), and the dose of S equipotent to the IB dose giving the maximal bronchodilator effect (IBopt) was calculated by interpolation of each S curve. On two other days, each patient received IBopt or the equipotent S dose followed by an additional 400 micrograms S. On day 1 or 2, FEV1 reached 220 +/- 410 ml and 2410 +/- 380 ml (p less than 0.05) after the maximal dose of IB and S respectively. On day 3 or 4 after pretreatment by IB or S an additional 400 micrograms S gave a further increase, which was similar in both series (315 and 320 ml, respectively). FEV1 after combination treatment reached 238 +/- 350 ml and was not significantly different from the maximal effect of S (2440 +/- 290 ml). We conclude that S and IB exert a true pharmacological additive effect, since the combination effect is as great as the maximal effect of the most potent drug (S) and greater than the maximal effect of IB, and that the same additional dose of S gives the same increase after equipotent doses of S and IB.
Prospective Evaluation of Allogeneic Hematopoietic Stem-Cell Transplantation From Matched Related and Matched Unrelated Donors in Younger Adults With High-Risk Acute Myeloid Leukemia: German-Austrian Trial AMLHD98A
Authors: Richard F. Schlenk, Konstanze Döhner, Silja Mack, Michael Stoppel, Franz Király, Katharina Götze, Frank Hartmann, Heinz A. Horst, Elisabeth Koller, Andreas Petzer, Wolfgang Grimminger, Guido Kobbe, Axel Glasmacher, Hans Salwender, Heinz Kirchen, Detlef Haase, Stephan Kremers, Axel Matzdorff, Axel Benner, Hartmut Döhner
Journal: Journal of Clinical Oncology (2010)

Purpose To assess the impact of allogeneic hematopoietic stem-cell transplantation (HSCT) from matched related donors (MRDs) and matched unrelated donors (MUDs) on outcome in high-risk patients with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. Patients and Methods Between 1998 and 2004, 844 patients (median age, 48 years; range, 16 to 62 years) with AML were enrolled onto protocol AMLHD98A that included a risk-adapted treatment strategy. High risk was defined by the presence of unfavorable cytogenetics and/or by no response to induction therapy. Results Two hundred sixty-seven (32%) of 844 patients were assigned to the high-risk group. Of these 267 patients, 51 patients (19%) achieved complete remission but had adverse cytogenetics, and 216 patients (81%) had no response to induction therapy. Allogeneic HSCT was actually performed in 162 (61%) of 267 high-risk patients, after a median time of 147 days after diagnosis. Graft sources were as follows: MRD (n = 62), MUD (n = 89), haploidentical donor (n = 10), and cord blood (n = 1). The 5-year overall survival rates were 6.5% (95% CI, 3.1% to 13.6%) for patients (n = 105) not proceeding to HSCT and 25.1% (95% CI, 19.1% to 33.0%; from date of transplantation) for patients (n = 162) receiving HSCT. Multivariable analysis including allogeneic HSCT as a time-dependent covariable revealed that allogeneic HSCT significantly improved outcome; there was no difference in outcome between allogeneic HSCT from MRD and MUD. Conclusion Allogeneic HSCT in younger adults with high-risk AML has a significant beneficial impact on outcome, and allogeneic HSCT from MRD and MUD yields similar results.
Vascular Neointimal Formation and Signaling Pathway Activation in Response to Stent Injury in Insulin-Resistant and Diabetic Animals
Authors: Michael Jonas, Elazer R. Edelman, Adam Groothuis, Aaron B. Baker, Philip Seifert, Campbell Rogers
Journal: Circulation Research (2005)

Diabetes and insulin resistance are associated with increased disease risk and poor outcomes from cardiovascular interventions. Even drug-eluting stents exhibit reduced efficacy in patients with diabetes. We now report the first study of vascular response to stent injury in insulin-resistant and diabetic animal models. Endovascular stents were expanded in the aortae of obese insulin-resistant and type 2 diabetic Zucker rats, in streptozotocin-induced type 1 diabetic Sprague-Dawley rats, and in matched controls. Insulin-resistant rats developed thicker neointima (0.46±0.08 versus 0.37±0.06 mm 2 , P =0.05), with decreased lumen area (2.95±0.26 versus 3.29±0.15 mm 2 , P =0.03) 14 days after stenting compared with controls, but without increased vascular inflammation (ED1+ tissue macrophages). Insulin-resistant and diabetic rat vessels did exhibit markedly altered signaling pathway activation 1 and 2 weeks after stenting, with up to a 98% increase in p-ERK (anti-phospho ERK) and a 54% reduction in p-Akt (anti-phospho Akt) stained cells. Western blotting confirmed a profound effect of insulin resistance and diabetes on Akt and ERK signaling in stented segments. p-ERK/p-Akt ratio in stented segments uniquely correlated with neointimal response ( R 2 =0.888, P =0.04) in insulin-resistant and type 1 and 2 diabetic rats, but not in lean controls. Transfemoral aortic stenting in rats provides insight into vascular responses in insulin resistance and diabetes. Shifts in ERK and Akt signaling related to insulin resistance may reflect altered tissue repair in diabetes accompanied by a shift in metabolic:proliferative balance. These findings may help explain the increased vascular morbidity in diabetes and suggest specific therapies for patients with insulin resistance and diabetes.
Development of Complement-Fixing 19S, Anti-Heart Mitochondria Autoantibody, Following Myocardial Infarction in Dogs
Authors: R. Neol Pinckard, Merle S. Olson, Robert A. O'Rourke, John D. Palmer, Robert E. Kelley, Samuel Goldfein
Journal: Circulation Research (1971)

The development of anti-heart autoantibody following experimental myocardial infarction in dogs was studied with respect to (1) the subcellular localization of the heart autoantigen(s), (2) the incidence of autoantibody following myocardial infarction, and (3) the temporal development of the autoantibody and its relation to serum enzyme elevations and electrocardiographic changes. Complement-fixing anti-heart autoantibody developed following myocardial infarction induced by either two-stage coronary artery ligation or by the injection of microspheres directly into the coronary circulation. The autoantibody was directed toward an autoantigen residing in the mitochondrial fraction of myocardial tissue and was found to be associated with the 19S class of immunoglobulin. Eighteen of 20 dogs with infarction produced anti-heart mitochondria autoantibody 10 days following induction of myocardial damage; the autoantibody persisted 4 to 6 weeks thereafter. In these dogs the presence of anti-heart mitochondria autoantibody was diagnostic of myocardial infarction at times when the serum enzymes and electrocardiograms were within normal limits. Our studies indicate that a serologic test, based on the detection of complement-fixing anti-heart mitochondria autoantibody, may be a valuable adjunct to tests currently available for diagnosing recent myocardial infarction.
A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease
Authors: Donald P. Tashkin, Bartolome Celli, Stephen Senn, Deborah Burkhart, Steven Kesten, Shailendra Menjoge, Marc Decramer
Journal: New England Journal of Medicine (2008)

Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease (COPD) led us to examine the long-term effects of tiotropium therapy.In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with a forced expiratory volume in 1 second (FEV(1)) of 70% or less after bronchodilation and a ratio of FEV(1) to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV(1) before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. George's Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality.Of a total of 5993 patients (mean age, 65+/-8 years) with a mean FEV(1) of 1.32+/-0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2987 to the tiotropium group and 3006 to the placebo group. Mean absolute improvements in FEV(1) in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (P<0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV(1) before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure.In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1). (ClinicalTrials.gov number, NCT00144339.)
The insulin-like growth factor I receptor is overexpressed in psoriatic epidermis, but is differentially regulated from the epidermal growth factor receptor.
Authors: J F Krane, A B Gottlieb, D M Carter, J G Krueger
Journal: The Journal of Experimental Medicine (1992)

Insulin-like growth factor I (IGF-I)/somatomedin C is an important mediator of keratinocyte growth in vitro, and the expression of IGF-I receptors in the basal layer of normal epidermis suggests that this growth pathway may function in the regulation of keratinocyte growth in vivo as well. The pattern of IGF-I receptor expression in normal skin is distinct from that of the epidermal growth factor (EGF) receptor, suggesting that these receptors might be differentially regulated. The purpose of this study was to obtain a better understanding of IGF-I receptor function in the skin by examining IGF-I receptor expression in psoriatic epidermis and in cultured human keratinocytes. Our findings indicate that IGF-I receptor expression is increased in psoriasis as measured by protein tyrosine kinase assays of biopsy extracts and by immunohistochemical staining with an IGF-I receptor-specific monoclonal antibody. Unlike EGF receptor expression, which is also increased in psoriatic epidermis, the pattern of IGF-I receptor expression corresponds closely with the increased size of the keratinocyte proliferative compartment in psoriasis. Biochemical agents that diminish EGF receptor ligand binding (phorbol ester or calcium ionophore treatment) produce opposite effects on the IGF-I receptor. These results suggest that cellular expression and differential regulation of both growth factor receptor systems may control critical aspects of epidermal proliferation or function.
Cyclin-Dependent Kinase-3–Mediated c-Jun Phosphorylation at Ser63 and Ser73 Enhances Cell Transformation
Authors: Yong-Yeon Cho, Faqing Tang, Ke Yao, Chengrong Lu, Feng Zhu, Duo Zheng, Angelo Pugliese, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2008)

Abstract c-Jun is a component of the activator protein-1 (AP-1) complex, which plays a crucial role in the regulation of gene expression, cell proliferation, and cell transformation, as well as cancer development. Herein, we found that cyclin-dependent kinase (Cdk)-3, but not Cdk2 or c-Jun NH2-terminal kinase, is a novel kinase of c-Jun induced by stimulation with growth factors such as epidermal growth factor (EGF). Cdk3 was shown to phosphorylate c-Jun at Ser63 and Ser73 in vitro and ex vivo. EGF-induced Cdk3 activation caused c-Jun phosphorylation at Ser63 and Ser73, resulting in increased AP-1 transactivation. Ectopic expression of Cdk3 resulted in anchorage-independent cell transformation of JB6 Cl41 cells induced by EGF and foci formation stimulated by constitutively active Ras (RasG12V), which was mediated by AP-1 in NIH3T3 cells. These results showed that the Cdk3/c-Jun signaling axis plays an important role in EGF-stimulated cell proliferation and cell transformation. [Cancer Res 2009;69(1):272–81]