tbuckley/cabot-search huggingface dataset:
6-Bromoindirubin-3′-Oxime Inhibits JAK/STAT3 Signaling and Induces Apoptosis of Human Melanoma Cells
Authors: Lucy Liu, Sangkil Nam, Yan Tian, Fan Yang, Jun Wu, Yan Wang, Anna Scuto, Panos Polychronopoulos, Prokopios Magiatis, Leandros Skaltsounis, Richard Jove
Journal: Cancer Research (2011)

Abstract STAT3 is persistently activated and contributes to malignant progression in various cancers. Janus activated kinases (JAK) phosphorylate STAT3 in response to stimulation by cytokines or growth factors. The STAT3 signaling pathway has been validated as a promising target for development of anticancer therapeutics. Small-molecule inhibitors of JAK/STAT3 signaling represent potential molecular-targeted cancer therapeutic agents. In this study, we investigated the role of JAK/STAT3 signaling in 6-bromoindirubin-3′-oxime (6BIO)-mediated growth inhibition of human melanoma cells and assessed 6BIO as a potential anticancer drug candidate. We found that 6BIO is a pan-JAK inhibitor that induces apoptosis of human melanoma cells. 6BIO directly inhibited JAK-family kinase activity, both in vitro and in cancer cells. Apoptosis of human melanoma cells induced by 6BIO was associated with reduced phosphorylation of JAKs and STAT3 in both dose- and time-dependent manners. Consistent with inhibition of STAT3 signaling, expression of the antiapoptotic protein Mcl-1 was downregulated. In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the Akt and mitogen-activated protein kinase (MAPK) signaling proteins were not inhibited in cells treated with 6BIO. Importantly, 6BIO suppressed tumor growth in vivo with low toxicity in a mouse xenograft model of melanoma. Taken together, these results show that 6BIO is a novel pan-JAK inhibitor that can selectively inhibit STAT3 signaling and induces tumor cell apoptosis. Our findings support further development of 6BIO as a potential anticancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells. Cancer Res; 71(11); 3972–9. ©2011 AACR.
Teaching Medical Ethics-Reply
Authors: Edmund D. Pellegrino
Journal: JAMA (1979)

It is gratifying to see that a distinguished pathologist-administrator such as Dr McKee, far removed as he is from the problems of contemporary medical education and clinical medicine, should remain sufficiently interested in these problems to respond to our article and editorial. Dr McKee's letter is complex, but after considerable effort we think we have identified two of his major lines of criticism of our position. First, throughout his letter Dr McKee appears to distinguish "real" physicians from "medical phonies, posing as doctors, who are not physicians." Although Dr McKee never clarifies this distinction, we presume he intends to differentiate the merely technically competent practitioner from the humanistically sensitive, ethical, reflective physician of the Oslerian stamp. We consider it unfortunate that Dr McKee fails to perceive that that is precisely our concern as well. We do not share Dr McKee's pessimism that the product of medical school selection
Tetracycline and Staining of the Teeth-Reply
Authors: J. J. DiGiovanna
Journal: JAMA (1986)

In Reply.—  We appreciate Dr Grossman's interest in our article. He objects to our statement concerning tetracycline's ability to stain teeth only when administered before  age of 7  This information was derived from Goodman and Gilman's The Pharmacological Basis of Therapeutics . 1 In addition,  package insert for each tetracycline preparation, as listed in  Physicians' Desk Reference , 2 contains a warning concerning its use up to  age of 8 years. Another source 3 agrees with this age and adds that the stains resulting from tetracycline exposure during this period may not become visible for several years.  We do not know whether Dr Grossman is correct in his opinion that tetracycline... will continue to bind to  relatively unseen posterior teeth... until they have completed calcifying, years later. It is unfortunate that this speculation is not substantiated with data in either his letter or references. He states
Senate Committee Sees NIH/DOE Partnership in Genome Project
Authors: Beverly Merz
Journal: JAMA (1988)

500 YEARS AGO, a host of navigators were competing for Columbus' commission. Today, a good portion of the scientific community is vying for the same kind of opportunity—a government-funded exploration that should produce the ultimate map. In the 15th century, the map was to be of the world. In the 20th, it's to be of the human genome. There's no doubt that such a map, which would identify the chromosomal location of each of the 100 000 human genes, would be a boon to all of the biologic sciences, particularly to medicine (<i>JAMA</i>1987;258:1131-1132). The question now is how the map should be put together and who should put it together. The answer depends on who is talking. In recent months, there has been ample opportunity to hear from just about anyone with a stake in the quest, from representatives of the National Institutes of Health (NIH) and the Department
Polygenic susceptibility in rheumatoid arthritis.
Authors: P Wordsworth, J Bell
Journal: Annals of the Rheumatic Diseases (1991)

The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of μ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative crosstalk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified <i>in situ</i> in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, <i>in vivo</i> microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. <b>SIGNIFICANCE STATEMENT</b> The μ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel <i>in vitro</i> experiments in mammalian transfected cells and <i>in situ</i> and <i>in vivo</i> experiments in rat VTA we demonstrate that a significant population of these MOR form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.
A national training programme for gastroenterology and hepatology.
Authors: M J Farthing, R P Walt, R N Allan, C H Swan, I T Gilmore, C N Mallinson, J R Bennett, C J Hawkey, W R Burnham, A I Morris, C J Tibbs, T E Bowling, C Cobb, S Catnach, C Farrell, A Towle
Journal: Gut (1996)
Exposure to Concentrated Coarse Air Pollution Particles Causes Mild Cardiopulmonary Effects in Healthy Young Adults
Authors: Donald W. Graff, Wayne E. Cascio, Ana Rappold, Haibo Zhou, Yuh-Chin T. Huang, Robert B. Devlin
Journal: Environmental Health Perspectives (2009)

Background: There is ample epidemiologic and toxicologic evidence that exposure to fine particulate matter (PM) air pollution [aerodynamic diameter ≤ 2.5 µm (PM 2.5 )], which derives primarily from combustion processes, can result in increased mortality and morbidity.There is less certainty as to the contribution of coarse PM (PM 2.5-10 ), which derives from crustal materials and from mechanical processes, to mortality and morbidity.oBjective: To determine whether coarse PM causes cardiopulmonary effects, we exposed 14 healthy young volunteers to coarse concentrated ambient particles (CAPs) and filtered air.Coarse PM concentration averaged 89.0 µg/m 3 (range, 23.7-159.6µg/m 3 ).Volunteers were exposed to coarse CAPs and filtered air for 2 hr while they underwent intermittent exercise in a single-blind, crossover study.We measured pulmonary, cardiac, and hematologic end points before exposure, immediately after exposure, and again 20 hr after exposure.results: Compared with filtered air exposure, coarse CAP exposure produced a small increase in polymorphonuclear neutrophils in the bronchoalveolar lavage fluid 20 hr postexposure, indicating mild pulmonary inflammation.We observed no changes in pulmonary function.Blood tissue plasminogen activator, which is involved in fibrinolysis, was decreased 20 hr after exposure.The standard deviation of normal-to-normal intervals (SDNN), a measure of overall heart rate variability, also decreased 20 hr after exposure to CAPs.conclusions: Coarse CAP exposure produces a mild physiologic response in healthy young volunteers approximately 20 hr postexposure.These changes are similar in scope and magnitude to changes we and others have previously reported for volunteers exposed to fine CAPs, suggesting that both size fractions are comparable at inducing cardiopulmonary changes in acute exposure settings.
Effects of Intra-aortic Balloon Pumping on Coronary Flow and Metabolism in Man
Authors: ROBERT C. LEINBACH, MORTIMER J. BUCKLEY, W. GERALD AUSTEN, HARRY E. PETSCHEK, ARTHUR R. KANTROWITZ, CHARLES A. SANDERS
Journal: Circulation (1971)

Coronary blood flow (CBF) and myocardial oxygen consumption (MVO 2 ), myocardial lactate extraction, blood gases, and hemodynamics were measured on and off intra-aortic balloon pumping (IABP) 14 times in 10 patients during treatment of cardiovascular collapse following myocardial infarction. At the time of study an average of 14 hours of IABP had elapsed and all but one patient had stabilized out of cardiogenic shock. With IABP, CBF fell in 7 instances, was unaffected in 3, and rose in 4. Changes in MVO 2 correlated closely with the observed effects on CBF. Lactate extraction and blood gases were not significantly affected. Systolic arterial pressure fell an average of 11 mm Hg with IABP, while mean diastolic pressure rose 8 mm Hg. These results suggest that the net result of IABP on coronary flow and metabolism depends on the interplay between increased blood flow to ischemic areas provided by increased diastolic perfusion pressure and diminution of blood flow to normal myocardium in which the oxygen requirements are reduced by diminished afterload.
U2AF1 mutations alter sequence specificity of pre-mRNA binding and splicing
Authors: Theresa Okeyo-Owuor, Brian S. White, Rakesh Chatrikhi, Dipika R. Mohan, Sanghyun Kim, Malachi Griffith, Li Ding, Shamika Ketkar-Kulkarni, Jasreet Hundal, Kholiswa M. Laird, Clara L. Kielkopf, Timothy J. Ley, Matthew J. Walter, Timothy A. Graubert
Journal: Leukemia (2014)
Migraine as a Sequel to Infection by L. icterohaemorrhagiae
Authors: J. B. Atkins
Journal: BMJ (1955)

Of recent years migraine has been attributed to a bewildering assortment of causes, ranging from heredity (Friedman and Wilson, 1947), through allergy (Crowe, 1946), and personality (Alvarez, 1947), to the compre- hensive list drawn up by von Storch (1947).The estimate of Scott (1941) that " much has been written and little has been established as to the aetiology of migraines" seems largely true to-day.The following observations, which were made in the course of a follow-up study of former cases of Weil's
Thalidomide and dexamethasone therapy of myeloma in a patient with previously untreated B‐chronic lymphocytic leukemia
Authors: James C. Barton
Journal: American Journal of Hematology (2003)

A 67-year-old woman with previously untreated lambda-positive B-chronic lymphocytic leukemia (CLL) had kappa-positive myeloma develop that was treated with daily thalidomide and intermittent dexamethasone. After 4 months, there was a marked reduction in marrow plasmacytosis, urine kappa chains, and peripheral blood and marrow lymphocytosis. She reduced her thalidomide (but not dexamethasone) doses after 6 months, because she had symptoms of peripheral neuropathy. Although blood lymphocyte concentrations remained normal, she had progression of myeloma and died. Thalidomide and dexamethasone therapy similar to that administered for myeloma alone may be effective treatment for myeloma in patients with preexisting B-CLL and may also have anti-B-CLL activity.
Systematic Review: Antimicrobial Urinary Catheters To Prevent Catheter-Associated Urinary Tract Infection in Hospitalized Patients
Authors: James R. Johnson, Michael A. Kuskowski, Timothy J. Wilt
Journal: Annals of Internal Medicine (2006)

Background: The efficacy of antimicrobial urinary catheters in hospitalized patients is poorly defined. Purpose: To assess currently marketed antimicrobial urinary catheters for preventing catheter-associated urinary tract infection (UTI). Data Sources: Electronic databases, conference proceedings, bibliographies, trialists, and catheter manufacturers (search dates, 1966 to June 2005). Study Selection: Randomized and quasi-randomized trials of nitrofurazone-coated or silver alloy–coated antimicrobial urinary catheter use for less than 30 days; no language restriction. Data Extraction: Study design, study sample, inclusion and exclusion criteria, allocation, blinding, UTI definition, ascertainment methods, and proportion developing symptomatic UTI (primary end point) or bacteriuria (secondary end point) were extracted by using a structured data collection instrument. Data Synthesis: Twelve qualifying trials (13 392 total participants or catheters) were identified. They compared nitrofurazone-coated silicone (n = 3) or silver-coated latex (n = 9) catheters with silicone or latex catheters. No study addressed symptomatic UTI. All trials suggested protection against bacteriuria with test catheter use. However, effect size varied considerably and postrandomization exclusions were very common. Effect size was greatest in trials of nitrofurazone-coated catheters (all post-1995) and in pre-1995 silver alloy–coated catheter trials and was smallest in post-1995 silver alloy–coated catheter trials. Control group bacteriuria rate, control catheter type (latex vs. silicone), and patient sample (urology vs. other) also predicted effect size. Few studies addressed secondary bloodstream infection, mortality, costs, or microbial resistance. Short-term adverse effects were minimal. Limitations: The study was limited by the number, size, and quality of studies and by lack of the following: intention-to-treat analyses, data on clinical end points, and trials comparing nitrofurazone-coated with silver alloy–coated catheters. Conclusions: According to fair-quality evidence, antimicrobial urinary catheters can prevent bacteriuria in hospitalized patients during short-term catheterization, depending on antimicrobial coating and several other variables. Older data probably lack current relevance. Cost implications and effect on infectious complications remain undefined.
Effects of antihypertensive drugs on heart and resistance vessels
Authors: H. Kobayashi, T. Sano, R. C Tarazi, F. M Fouad-Tarazi
Journal: Cardiovascular Research (1990)

Journal Article Effects of antihypertensive drugs on heart and resistance vessels Get access Hideo Kobayashi, Hideo Kobayashi Department of Heart and Hypertension, Cleveland Clinic Foundation, One Clinic Center/FF10-2b, 9500 Euclid Avenue, Cleveland, Ohio 44195-5069, USA Correspondence to: Dr Fouad-Tarazi Search for other works by this author on: Oxford Academic PubMed Google Scholar Toshio Sano, Toshio Sano Department of Heart and Hypertension, Cleveland Clinic Foundation, One Clinic Center/FF10-2b, 9500 Euclid Avenue, Cleveland, Ohio 44195-5069, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert C Tarazi, Robert C Tarazi Department of Heart and Hypertension, Cleveland Clinic Foundation, One Clinic Center/FF10-2b, 9500 Euclid Avenue, Cleveland, Ohio 44195-5069, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Fetnat M Fouad-Tarazi Fetnat M Fouad-Tarazi Department of Heart and Hypertension, Cleveland Clinic Foundation, One Clinic Center/FF10-2b, 9500 Euclid Avenue, Cleveland, Ohio 44195-5069, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 24, Issue 2, February 1990, Pages 137–143, https://doi.org/10.1093/cvr/24.2.137 Published: 01 February 1990 Article history Received: 27 April 1989 Accepted: 06 October 1989 Published: 01 February 1990
Empowerment is inappropriate for equal citizens
Authors: H. Thornton
Journal: BMJ (2013)

Do we really need a revolution to promote patient involvement and improve healthcare?1 Revolutions tend to throw out the good with the bad, whereas evolution takes a calmer approach. We should study the history of patient and public involvement. Much lively and useful activity is occurring in research, shared decision making, delivery, and organisation—locally, nationally, and …
DNA content of granulocytes, monocytes, and lymphocytes in the bone marrow smears of patients with myelodysplastic syndromes
Authors: Susanne Widell, Robert Hast, Christopher Cox, Gert Auer, John M. Bennett
Journal: American Journal of Hematology (2001)

Abstract Recently, we have reported a high incidence of DNA hypodiploidy defined as DNA index (DI) in blasts/promyelocytes from 39 patients with myelodysplastic syndromes (MDS) found to be without a relationship to cytogenetics. In the present study the DNA content (DI) in granulocytes, monocytes, and lymphocytes measured in the same bone marrow smears from the above patients are reported. DNA hypodiploidy was found in mature cells, not only in myeloid cells (granulocytes and monocytes) but also in lymphocytes. A lower mean DI in each cell type of patients compared to controls was found. Pairwise comparison of the mean DI (±SE) in 32 patients with normal ( n = 22) and abnormal ( n = 10) cytogenetics and controls ( n = 8) showed a significantly ( P &lt; 0.01) lower value for each group of patients, respectively, in all cell types. No difference was found between the two groups of patients. Presence of weak‐Feulgen stained nuclei (DI &lt; 0.40) in granulocytes and monocytes was more pronounced in patients expressing DNA hypodiploid immature cell populations, but only occasionally in lymphocytes, suggesting a link to an apoptotic event and intramedullary cell death. DNA hypodiploidy is shown to be a common feature even in mature cell populations in MDS bone marrows. Clonality, by means of DNA content, appears reasonable as regards the granulocytes and monocytes. DNA hypodiploid lymphocytes, on the other hand, might be small blasts (stem cells) or dying cell populations of unknown origin. Am. J. Hematol. 67:112–118, 2001. © 2001 Wiley‐Liss, Inc.
RECOGNITION OF TYPES OF ARTERIOSCLEROSIS BY OSCILLOMETRY
Authors: ALFRED FRIEDLANDER
Journal: JAMA (1935)

The importance of the concept of cardiovascular disease as a clinical entity is fully understood today. Emphasis has been placed, and properly so, on the recognition of cardiac abnormalities of various types. Recently the necessity of obtaining information as to the condition of the vascular tree has begun to be stressed. It is not believed today that arteriosclerosis is merely an expression of aging of the arteries. As Aschoff1has said, Arteriosclerosis is not merely a change or transformation attending the process of aging; it is not a mere infirmity of old age, but rather a disease of the vessels manifesting itself mainly during senescence. The clinical recognition of arteriosclerosis thus becomes a matter of import, because the type and the degree of arteriosclerosis present in a given individual have distinct prognostic significance. Any method of clinical examination that gives reliable information as to the condition of the vascular
Combination Angiostatin and Endostatin Gene Transfer Induces Synergistic Antiangiogenic Activity in Vitro and Antitumor Efficacy in Leukemia and Solid Tumors in Mice
Authors: Frank A. Scappaticci, Richard Smith, Anjali Pathak, Derrick Schloss, Bert Lum, Yihai Cao, Frances Johnson, Edgar G. Engleman, Garry P. Nolan
Journal: Molecular Therapy (2001)

Angiostatin and endostatin are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vivo and tumor growth in mice. However, tumor shrinkage requires chronic delivery of large doses of these proteins. Here we report synergistic antitumor activity and survival of animals when these factors are delivered in combination to tumors by retroviral gene transfer. We have demonstrated this efficacy in both murine leukemia and melanoma models. Complete loss of tumorigenicity was seen in 40% of the animals receiving tumors transduced by the combination of angiostatin and endostatin in the leukemia model. The synergy was also demonstrated in vitro on human umbilical vein endothelial cell differentiation and this antiangiogenic activity may suggest a mechanism for the antitumor activity in vivo. These findings imply separate pathways by which angiostatin and endostatin mediate their antiangiogenic effects. Together, these data suggest that a combination of antiangiogenic factors delivered by retroviral gene transfer may produce synergistic antitumor effects in both leukemia and solid tumors, thus avoiding long-term administration of recombinant proteins. The data also suggest that novel combinations of antiangiogenic factors delivered into tumors require further investigation as therapeutic modalities.
BASIC COUNTERPOINT: Mechanisms and Pathways of Gonadal Steroid Modulation of Growth Hormone Secretion*
Authors: WILLIAM B. WEHRENBERG, ANDREA GIUSTINA
Journal: Endocrine Reviews (1992)

IT IS with great interest that we follow the continued expansion and refinement of Harris' classical concept concerning the neuroendocrine control of pituitary gland function (1). A critical expansion of this concept came in 1970 when Dierschke and colleagues (2) observed in the primate that pituitary LH secretion was pulsatile in nature. This was soon followed by other reports which demonstrated that pituitary hormones, including GH, are secreted episodically. The significance of this pulsatile GH secretion and how it is modulated by gonadal steroids during childhood and adolescent growth is the subject of the accompanying paper by Kerrigan and Rogol (3). Their clinical review provides important insight concerning gonadal steroids and GH secretion, but due to the constraints of human research many questions remain. One of the most intriguing is: By which pathways and mechanisms do the gonadal steroids modulate GH secretion? To answer such questions investigators have focused their attention on numerous animal models. This counterpoint will attempt to summarize our current understanding of the effects of the gonadal steroids on GH secretion in the rat, investigating their effects on somatostatin and GH-releasing hormone (GHRH) at the hypothalamic level and on GH at the pituitary level. Our review primarily focuses on the neonatal through pubertal period, since we have attempted to parallel the clinical review of Kerrigan and Rogol (3). Readers are encouraged to refer to the work of Jansson et al. (4) and Millard et al. (5) for additional details concerning the effects of gonadal steroids on adult GH secretion in rats.