tbuckley/cabot-search huggingface dataset:
Abstract A10: Off-target toxicity in white blood cells by AG-012986, a pan-CDK inhibitor, is mediated through inhibition of p38 MAPK signaling pathway
Authors: Dong U. Lee, Bart Jessen
Journal: Clinical Cancer Research (2010)

Abstract Cyclin-dependent kinases (CDKs) have been an attractive target for cancer research because these kinases are predominantly active during cell division. AG-012986 is a small molecule pan-CDK inhibitor that has in vitro and in vivo antitumor properties. This compound was stopped during development due in part to rapid bone-marrow independent white blood cell toxicity in non-human primate and rodent species, and the potential for acute and delayed immunosuppression in humans. Because peripheral leukocytes are largely nonproliferating cells, it was hypothesized that the effects of AG-012986 was due to an off-target mechanism and not driven by the intended pharmacology. Using primary human peripheral blood mononuclear cells (PBMCs) and T-cells, we show that AG-012986 has a toxicity profile with greater specificity and more rapid cell death compared to the prototypical ATP-competitive kinase inhibitor, staurosporine. The cell toxicity mechanism was caspase-dependent and contained the hallmarks of apoptosis as indicated by cells staining double positive for propidium iodide and annexin-V. PBMCs or T-cells treated with AG-012986 and acutely stimulated either pharmacologically or through the T-cell receptor (TCR), exhibited decreased cellular toxicity compared to non-stimulated control cells. Interestingly under activating conditions with the pan-CDK compound, T-cells did not undergo significant cell division, as measured by BrdU incorporation, and were also rescued from apoptosis. This indicates that the pharmacology of AG-012986 was functioning as expected but that the toxicity due to its off-target effect had now been decoupled through cellular activation. Investigating the downstream signaling network showed that phosphorylation of p38 MAP kinase was impaired in the presence of AG-012986. Thus we hypothesize that AG-012986 may target the upstream kinase MKK3 and/or MKK6 for inhibition under basal conditions, leading to cell death in T cells and perhaps other white blood cells. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A10.
More Friction in the Hospitals — Doctors' and Nurses' Roles — True Story
Authors: John Lister
Journal: New England Journal of Medicine (1975)

ALTHOUGH there was no specific reference to the National Health Service (NHS) in the Queen's speech at the opening of the new Parliament, the omission was corrected during the debate on the speech,1 when Mrs. Barbara Castle, secretary of state at the Department of Health, returned to the topic of private beds in NHS hospitals with an announcement that the government would be phasing out these beds during the coming session. She furthermore reminded the House that the joint working party that she had set up under the chairmanship of her undersecretary, Dr. David Owen, was looking at the future . . .
Testing for Inherited Cancer Susceptibility
Authors: Judy E. Garber
Journal: JAMA (1996)

Testing for inherited cancer predisposition syndromes is becoming ever more widely available. In this transition period, health care professionals from many disciplines will be forced to integrate the rapidly evolving technologies and expanding knowledge base of cancer genetics into their patient care paradigms. They will also find it necessary to consider unfamiliar and complex issues with patients and their families while facing pressures to reduce time per patient visit and referral.  See also p 1885.  Many thoughtful and qualified lay and professional groups are concerned that the availability of predisposition testing outside the research setting may be premature: critical clinical questions have yet to be answered, clinicians appropriately educated, test characteristics adequately defined, and sufficient social protections put into place. 1-5 The risk of insurance and employment discrimination alone may prevent genetics from realizing its true potential for good. 6   The availability of commercial testing for common cancer susceptibility genes
New method for evaluating left ventricular wall motion by color-coded tissue doppler imaging: In vitro and in vivo studies
Authors: Kunio Miyatake, Masakazu Yamagishi, Norio Tanaka, Masaaki Uematsu, Nobuo Yamazaki, Yoshitake Mine, Akihiro Sano, Makoto Hirama
Journal: Journal of the American College of Cardiology (1995)
Updating guidelines on asthma in adults
Authors: B. Delaney
Journal: BMJ (2001)

The changes to the North of England evidence based guidelines on managing asthma in adults in primary care are not very great (see updated guidelines on bmj.com), but they are important and illustrate the need to keep guidelines updated if they are to continue to be useful in guiding doctors' clinical practice.

The new guidelines draw on the reviews produced by the Cochrane airways collaborative review group1 since the first North of England guideline in 1996, as well as updating the literature searches and meta-analyses originally conducted by the group.2

The principal change in this useful updated guideline is the increasing role for long acting β2 agonists. These have replaced oral treatments as additional treatment when patients have nocturnal symptoms or need regular short acting β2 agonists in spite of inhaled steroids equivalent to beclomethasone 1000 μg daily. A recent Cochrane review of six trials comparing long acting β2 agonists with oral theophylline supports this recommendation.3 Patients taking salmeterol experienced fewer adverse events than those using theophylline …
The Concept of Motivation for Treatment
Authors: WILLIAM E. HOLT
Journal: American Journal of Psychiatry (1967)

The concept of motivation for treatment is of little practical value, principally because motivations are inseparable from the patient's infantile conflicts and defenses. A decision concerning therapy would be much better based on the patient's needs and capacities. The author feels it is unreasonable to insist that the psychiatric patient be made responsible for deciding he is in need of treatment.
Comparative Effects of Estrogen and Angiotensin-Converting Enzyme Inhibition on Plasminogen Activator Inhibitor-1 in Healthy Postmenopausal Women
Authors: Nancy J. Brown, Amira Abbas, Daniel Byrne, John A. Schoenhard, Douglas E. Vaughan
Journal: Circulation (2002)

Background — This study compares the effect of estrogens and ACE inhibition on plasminogen activator inhibitor-1 (PAI-1) concentrations in healthy postmenopausal women, genotyped for a 4G/5G polymorphism in the PAI-1 promoter, a polymorphism shown to influence PAI-1 concentrations. Methods and Results — Morning estradiol, PAI-1, tissue plasminogen activator, plasma renin activity, angiotensin II, and aldosterone were measured in 19 postmenopausal women (5G/5G:4G/5G:4G4G=5:10:4, respectively) at baseline and during randomized, single-blind, crossover treatment with conjugated equine estrogens 0.625 mg per os per day, ramipril 10 mg per os per day, and combination estrogens and ramipril. Estradiol ( P &lt;0.005) and angiotensin II ( P &lt;0.01) were significantly higher during estrogens. Plasma renin activity was significantly increased during ACE inhibition ( P &lt;0.05). Both conjugated estrogens [PAI-1 antigen from 12.5 (7.6, 17.4) [mean (95% CI)] baseline to 6.6 (2.6, 10.7) ng/mL, P &lt;0.01] and ACE inhibition [8.3 (4.9, 11.7) ng/mL, P &lt;0.005] decreased PAI-1 without decreasing tissue plasminogen activator. The effect of combined therapy on PAI-1 [5.6 (2.3, 8.8) ng/mL] was significantly greater than that of ramipril alone ( P &lt;0.05). There was a significant effect of PAI-1 4G/5G genotype on baseline PAI-1 concentrations ( P =0.001) and a significant interactive effect of 4G/5G genotype and treatment, such that genotype influenced the change in PAI-1 during ramipril ( P =0.011) or combined therapy ( P =0.006) but not during estrogens ( P =0.715). Conclusions — ACE inhibition with ramipril and conjugated estrogens similarly decrease PAI-1 antigen concentrations in postmenopausal women. Larger studies that use clinical outcomes are needed to determine whether PAI-1 4G/5G genotype should influence the choice of conjugated estrogens or ACE inhibition for the treatment of healthy postmenopausal women.
RESULTS FROM THE FENOFIBRIC ACID ON CAROTID INTIMA-MEDIA THICKNESS IN SUBJECTS WITH TYPE IIB DYSLIPIDEMIA WITH RESIDUAL RISK IN ADDITION TO ATORVASTATIN THERAPY (FIRST) TRIAL
Authors: Michael H. Davidson, Robert Rosenson, Kevin Maki, Stephen Nicholls, Christie Ballantyne, Theodore Mazzone, Laura Williams, Maureen Kelly, Heidi Camp, Aditya Lele, James Stolzenbach
Journal: Journal of the American College of Cardiology (2013)
Senators Call on State Governors to Expand Medicaid
Authors: Tracy Hampton
Journal: JAMA (2014)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Clinical Assessment of Norepinephrine Transporter Blockade Through Biochemical and Pharmacological Profiles
Authors: Simi Vincent, Peter R. Bieck, Emily M. Garland, Corina Loghin, Frank P. Bymaster, Bonnie K. Black, Celedon Gonzales, William Z. Potter, David Robertson
Journal: Circulation (2004)

To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process.Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study.These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.
Platelet injury during phototherapy
Authors: Harold M. Maurer, Joyce C. Haggins, W. J. S. Still
Journal: American Journal of Hematology (1976)

Abstract Phototherapy with blue fluorescent light is widely employed for treatment of neonatal hyperbilirubinemia. Functional, biochemical, and morphologic changes produced by blue fluorescent light in human platelets were identified and characterized. Platelet‐rich plasma was exposed for up to 170 min to amounts of light equivalent to that used in phototherapy of neonatal hyperbilirubinemia. Within 110 min of light exposure, platelets were essentially no longer aggregable by ADP and connective tissue suspension and were depleted of ADP, ATP, and glycogen. Electron photomicrographs revealed these platelets to be swollen, depleted of glycogen granules and organelles, and to have ill‐defined membranes. Platelet injury could be accelerated by adding a photosensitizing agent, hematoporphyrin, to platelet samples before exposure. In contrast, control platelets kept in the dark for 170 min or nonirradiated platelets resuspended in irradiated plasma maintained their integrity. The results indicate that platelets are damaged in vitro when exposed to amounts of blue light used in phototherapy.
Heart Disease and Rehabilitation
Authors: Albert Z. Kattus
Journal: JAMA (1980)

This is a big book, divided into eight chapters and containing 44 articles by a distinguished group of authors—all adding up to a comprehensive work on the current state of cardiac rehabilitation in the United States, Canada, and Sweden.  The book is a treasure of current information on the technical aspects of the rehabilitation process as practiced by some of the most eminent experts in the field. In addition, the underlying processes of heart disease are examined in detail with reference to their susceptibility to modification by rehabilitative measures. Thus, the epidemiologic, physiological, and therapeutic aspects of heart disease are extensively treated as the underpinnings of the rehabilitative process.  Experimental and intervention studies on coronary risk-factor modification are described and their implications for the rehabilitation concept are analyzed realistically.  Problems of financing are analyzed from the point of view of third-party insurers. The unanswered questions of whether the present procedures
Rapid Displacement of Vimentin Intermediate Filaments in Living Endothelial Cells Exposed to Flow
Authors: Brian P. Helmke, Robert D. Goldman, Peter F. Davies
Journal: Circulation Research (2000)

Abstract —Hemodynamic shear stress at the endothelial cell surface induces acute and chronic intracellular responses that regulate vessel wall biology. The cytoskeleton is implicated by acting both as a direct connector to local surface deformation and as a distribution network for mechanical forces throughout the cell; however, direct observation and measurement of its position during flow have only recently become possible. In this study, we directly demonstrate rapid deformation of the intermediate filament (IF) network in living endothelial cells subjected to changes in hemodynamic shear stress. Time-lapse optical sectioning and deconvolution microscopy were performed within the first 3 minutes after the introduction of flow (shear stress, 12 dyn/cm 2 ). Spatial and temporal dynamics of green fluorescent protein–vimentin IFs in confluent endothelial cells were analyzed. The imposition of shear stress significantly increased the variability of IF movement throughout the cell in the x -, y -, and z -directions compared with the constitutive dynamics noted in the absence of flow. Acute polymerization and depolymerization of the IF network were absent. The magnitude and direction of flow-induced IF displacement were heterogeneous at the subcellular level. These qualitative and quantitative data demonstrate that shear stress acting at the luminal surface of the endothelium results in rapid deformation of a stable IF network.
Experimental rhinovirus 16 infection in moderate asthmatics on inhaled corticosteroids
Authors: P. T. Adura, E. Reed, J. Macintyre, A. del Rosario, J. Roberts, R. Pestridge, R. Beegan, C. B. Boxall, C. Xiao, T. Kebadze, J. Aniscenko, V. Cornelius, J. E. Gern, P. D. Monk, S. L. Johnston, R. Djukanovi 
Journal: European Respiratory Journal (2013)

neutrophilic airway inflammation.Our data indicate that the increase of a specific profile of DAMPs rather than that of HMGB1 alone, which has been implicated in COPD development [6], may be an important determinant of the susceptibility towards neutrophilic airway inflammation upon cigarette smoking.In future studies it will be of interest to confirm whether a similar DAMP release signature is present in COPD patients, whether this is related to the susceptibility of smoking individuals to develop COPD and whether this signature can be used for the early detection of susceptibility to or the presence of COPD.
Abstract 4802: Human breast carcinoma-associated mesenchymal stem cells from primary breast cancer metastasis promote proliferation, invasion and mammosphere formation in breast cancer
Authors: Maria E. Gonzalez, Kathy A. Toy, Celina G. Kleer
Journal: Cancer Research (2014)

Abstract Background: Accumulating evidence suggests that mesenchymal stem cells (MSCs) are recruited to the tumor microenvironment; however controversy exists regarding their role in solid tumors. In this study, we identified the presence of carcinoma-associated MSCs (CA-MSCs) isolated from breast cancer metastasis to a human lymph node (LNM) and liver (LM). Methods: Tissue harvesting and culture: CA-MSCs were isolated from fresh samples of lymph nodes and liver breast cancer metastasis obtained from the operating room. A portion of each specimen was mechanically dissected and digested with collagenase. Red cells were lysed with ACK buffer and cell suspensions were cultured in Human Epithelial Medium and isolated adherent CA-MSCs were subculture in MSC medium for up to 12 passages for each experiment. Another portion of the tumor samples were subjected to IHC for H&amp;E staining. Differentiation assays: For bone differentiation cells were plated in StemPro Osteogenesis differentiation or control medium and allowed to grow for 14 days, and then washed and stained with Alizarin Red S. For cartilage differentiation cells were pelleted and grown in 15 ml tubes for 21 days, immobilized in histogel and stained with Alizarin Blue. For adipose differentiation cells were plated in StemCell differentiation and control medium, after 21 days the cells were stained with 0.3% Oil Red O. Proliferation, invasion, mammosphere assays, cytokine array and RT-PCR for EMT signature were performed seeding the same number of cells and comparing the single culture of CA-MSCs with co-culture of CA-MSCs and a panel of breast cancer cells lines Results: CA-MSCs had spindle morphology, normal karyotype, were nontumorigenic, and possessed tri-lineage differentiation ability (osteoblast, adipocyte, and chondrocyte). When co-cultured with breast cancer cells, CA-MSCs promoted proliferation, invasion, and mammosphere formation, increased IL6 and IL8 secretion into the media, and induced a gene expression profile of EMT when compared to the single cultures. Conclusion: We successfully isolated and characterized CA-MSCs, confirming their presence in human breast metastasis. We found that they provide a favorable microenvironment for tumor cell growth, enhance mammosphere formation, and promote an EMT signature and invasion in breast cancer cells. Citation Format: Maria E. Gonzalez, Kathy A. Toy, Celina G. Kleer. Human breast carcinoma-associated mesenchymal stem cells from primary breast cancer metastasis promote proliferation, invasion and mammosphere formation in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4802. doi:10.1158/1538-7445.AM2014-4802
Insulin-like Growth Factors in Pygmies
Authors: Thomas J. Merimee, Jurgen Zapf, Barry Hewlett, L.L. Cavalli-Sforza
Journal: New England Journal of Medicine (1987)

We measured the serum concentrations of insulin-like growth factors (IGF) I and II and testosterone in pygmy children, adolescents, and adults, as well as in controls, to determine more precisely the role of these factors in controlling growth. We had previously shown that growth hormone levels were normal in pygmies. Prepubertal pygmy children and controls did not differ in linear growth or in serum concentrations of IGF I and II. In pygmy adolescent boys, the mean (+/- SEM) serum concentration of IGF I was only one third that in control adolescents, who were similar to the pygmies in age and Tanner stage of development (154 +/- 22 vs. 435 +/- 37 ng per milliliter; P less than 0.01). A similar difference in IGF I concentration was observed in girls (278 +/- 18 vs. 570 +/- 25 ng per milliliter; P less than 0.01). IGF II and testosterone levels were normal in all groups. There was a significant difference in growth between controls and pygmies only during puberty. There was a marked acceleration of growth in the controls during adolescence, but such an acceleration was absent or blunted in the pygmies. These findings suggest that the short stature of adult pygmies is due primarily to a failure of growth to accelerate during puberty. We postulate that IGF I is the principal factor responsible for normal pubertal growth and that testosterone does not accelerate growth appreciably in the absence of an increase in the level of IGF I.
Uremic Serum and Solutes Increase Post–Vascular Interventional Thrombotic Risk Through Altered Stability of Smooth Muscle Cell Tissue Factor
Authors: Vipul C. Chitalia, Sowmya Shivanna, Jordi Martorell, Mercedes Balcells, Irene Bosch, Kumaran Kolandaivelu, Elazer R. Edelman
Journal: Circulation (2012)

Background— Stent thrombosis (ST), a postinterventional complication with a mortality rate of 50%, has an incidence that rises precipitously in patients at risk. Chronic renal failure and end-stage renal disease have emerged as particularly strong ST risk factors, yet the mechanism remains elusive. Tissue factor (TF) is a crucial mediator of injury-related thrombosis and has been implicated for ST. We posit that uremia modulates TF in the local vessel wall to induce postinterventional thrombosis in patients with end-stage renal disease. Methods and Results— As a model of the de-endothelialized, postinterventional state, we exposed primary human vascular smooth muscle cells (vSMCs) pretreated with uremic serum (obtained from ESRD patients on hemodialysis) to coronary-like blood flow. vSMC TF expression, activity, stability, and posttranslational modification were examined after vSMCs were treated with uremic serum or solutes. We found significantly greater clot formation after uremic serum exposure, which was substantially reduced with the prior treatment with anti-TF neutralizing antibody. Uremic sera induced 2- to 3-fold higher TF expression and activity in vSMCs independent of diabetes mellitus. Relevant concentrations of isolated uremic solutes such as indole-3-acetic acid (3.5 μg/mL), indoxyl sulfate (25 μg/mL), and uric acid (80 μg/mL) recapitulated these effects in cell culture and the flow loop model. We show further that TF undergoes ubiquitination at baseline and that uremic serum, indole-3-acetic acid, and indoxyl sulfate significantly prolong TF half-life by inhibiting its ubiquitination. Conclusions— The uremic milieu is profoundly thrombogenic and upregulates vSMC TF levels by increasing TF stability and decreasing its ubiquitination. Together, these data demonstrate for the first time that the posttranslational regulation of TF in uremia may have a causative role in the increased ST risk observed in uremic patients. These data suggest that interventions that reduce vSMC TF may help to prevent ST and that uremic solutes should be considered as novel risk factors for ST in patients with chronic renal failure.