tbuckley/cabot-search huggingface dataset:
Abstract 976: Hypoxic microenvironment promotes breast cancer stem cells through regulation of Polycomb protein expression
Authors: Chun-Ju Chang, Mien-Chie Hung
Journal: Cancer Research (2011)

Abstract The microenvironment of solid tumors contains regions of poor oxygenation as a result of hypoxia, which is associated with high grade breast cancer and poor prognosis. However, critical regulatory mechanism linking tumor microenvironment to cancer progression remains unclear. Cancer stem cells (tumor initiating cells) are suggested to be responsible for initiation and aggressive progression of cancer. It is recently proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genomic/genetic mutations and drives cancer progression. Additionally, high expression of a Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to aggressive progression of breast cancer. Here, we discovered that hypoxic microenvironment upregulates HIF1α-mediated transcriptional activation of EZH2 in CD44+CD24−/low breast tumor initiating cells (BTICs) isolated from several human primary tumor samples. Enhanced EZH2 expression was required for the hypoxia-promoted BTICs, where hypoxia significantly increased BTIC abundance, tumor sphere formation and tumor growth in mammary fat pads implanted with less than 500 primary BTICs. Using cDNA expression array and genome wide SNP array analysis, we further identified a novel mechanism in which enhanced expression of EZH2 by hypoxia downregulates DNA damage repair proteins through H3K27 methylation and thereby allows the acquisition of recurrent genomic abnormalities such as RAF1 gene amplification in BTICs. Using proteomic analysis, we demonstrated that RAF1 amplification highly activates its downstream ERK-β-catenin signaling, which leads to enhanced survival and proliferation of the BTICs. Furthermore, using immunohistochemistry analysis in a cohort of breast tumor samples, we found that EZH2 expression is positively correlated with RAF1, p-ERK and β-catenin expression in the high grade, poorly-differentiated tumors but not in the low grade, well-differentiated tumors, suggesting EZH2-amplified RAF1-ERK-β-catenin signaling may contribute significantly to promote BTICs and aggravate breast cancer malignancy. Our data also reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, can significantly suppress EZH2-promoted BTICs. To the best of our knowledge, this is the first study that provides evidences linking a specific genomic aberration mediated by EZH2-impaired DNA damage response to expansion of BTICs. Together, this study elucidates a previously unidentified therapeutic effect of RAF1-ERK signaling inhibitors to prevent breast cancer progression by eliminating BTICs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 976. doi:10.1158/1538-7445.AM2011-976
EFFECTS OF CONCANAVALIN A ON MOUSE PERITONEAL MACROPHAGES
Authors: Paul J. Edelson, Zanvil A. Cohn
Journal: The Journal of Experimental Medicine (1974)

The half-time for the degradation of horseradish peroxidase (HRP) is increased from 14 h to 37 h in Con A-treated cells, while the half-time for the degradation of [(125)I]BSA is increased from 5.4 h to 14.8 h. This supports prior microscopic observations which suggested that Con A pinosomes showed a marked impairment in their ability to form phagolysosomes. Artifacts due to anomalous behavior of HRP-Con A complexes, or to inhibition of lysosomal hydrolases by Con A, could be excluded. These indications of impaired phagolysosome formation, as well as those described in the preceding paper, could be reversed by postincubation of the cells in mannose, but not in galactose. This reversal is accompanied by a dissociation of Con A-FITC from the inner surface of the pinosome membrane, into the vesicle contents. These observations may be relevant to the ability of Con A to affect several membrane characteristics, and are also of interest in relation to the impaired formation of phagolysosomes which has been described in certain in vitro parasitic infections of macrophages or other cells.
Intravenous and Oral Itraconazole versus Intravenous Amphotericin B Deoxycholate as Empirical Antifungal Therapy for Persistent Fever in Neutropenic Patients with Cancer Who Are Receiving Broad-Spectrum Antibacterial Therapy
Authors: Marc Boogaerts
Journal: Annals of Internal Medicine (2001)

Background: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting. Objective: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy. Design: An open randomized, controlled, multicenter trial, powered for equivalence. Setting: 60 oncology centers in 10 countries. Patients: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy. Intervention: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution. Measurements: Defervescence, breakthrough fungal infection, drug-related adverse events, and death. Results: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, −0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days. Conclusions: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity. *For other members of the Itraconazole Neutropenia Study Group, see the Appendix.
On Awakening Paralyzed During Surgery-Reply
Authors: John Archer
Journal: JAMA (1976)

In Reply.—  My personal experience (234:24, 1975) may have relevance to some of the preceding letters and to Dr Blacher's article. A few months ago, I underwent the phenomenon of being awake and paralyzed during surgery.  The fact that I later had none of the psychiatric symptoms of Dr Blacher's patients may be in part because I had insight into the occurrence—at least to an adequate degree. I knew that my inability to move or communicate was the result of a muscle relaxant. I assumed incorrectly that my awareness indicated an anesthetic error; in fact, the operation was performed in an extreme emergency, and my condition was so poor during the early stages of surgery that the anesthesiologist judged that full anesthesia would be fatal.  At variance with the theories in Dr Larson's first paragraph, there is no question that my experience occurred during the surgery itself. I awoke after
Teaching the Epidemiological Concept
Authors: D. D. Reid
Journal: BMJ (1970)

erythropoietin to human disease is still ham- pered by the absence of an in vitro method of estimation.Few laboratories maintain the colonies of plethoric mice that are the cur- rent test animals, and it has been disap- pointing to find that erythropoietin activity in polycythaemia vera is apparently normal.But in the anaemia of uraemia one cause seems to be lack of this hormone and hence the suggestion for treatment by cobalt or testosterone, substances known to increase erythropoietin secretion.The reference list covers 104 pages, so it can be described as comprehensive.Certainly nothing has been missed, and this volume will be very useful to anyone inter- ested in the subject.
Residual Disease in Chronic Myeloid Leukemia after Induction of Molecular Remission
Authors: Thoralf Lange, Dietger W. Niederwieser, Michael W.N. Deininger
Journal: New England Journal of Medicine (2003)

To the Editor: Reliable assessment of molecular remission after allografting for chronic myeloid leukemia requires assays capable of detecting one BCR-ABL–positive cell among 105 to 106 BCR-ABL–negative cells1 — a sensitivity achieved with nested reverse-transcriptase polymerase chain reaction (PCR) but not with real-time quantitative PCR.2 Molecular remission after allografting predicts a low risk of relapse.1 On the basis of negative results on quantitative PCR testing, molecular remission has also been reported in some patients treated with imatinib.3,4 The sensitivity of any PCR assay is ultimately limited by the number of cells analyzed. Only a fraction of the . . .
CORONARY ARTERY DISEASE: A MAJOR DETERMINANT OF TIME-VARYING MYOCARDIAL PRESSURE-STRESS RELATIONSHIPS IN HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Sanjiv J. Shah, Z.J. Chai, Lauren Beussink, Sofia Podlusky, Amita Goyal, Daniel Schuster
Journal: Journal of the American College of Cardiology (2011)
Mice Transgenic for Baff Develop Lymphocytic Disorders along with Autoimmune Manifestations
Authors: Fabienne Mackay, Stephen A. Woodcock, Pornsri Lawton, Christine Ambrose, Manfred Baetscher, Pascal Schneider, Jurg Tschopp, Jeffrey L. Browning
Journal: The Journal of Experimental Medicine (1999)

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti–DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.
Think rationally rather than intuitively to avoid diagnostic errors, doctors are told
Authors: R. Coombes
Journal: BMJ (2010)

Diagnostic errors—the most common reason for patients to sue doctors—occur partly because doctors depend too much on their intuition when making clinical decisions, a conference on safety heard last week.

Pat Croskerry, professor in emergency medicine at Dalhousie University, Halifax, Nova Scotia, and a doctor of psychology, said that doctors were too quick to base their clinical decisions on intuition rather than on rational analysis. “Our intuition will always override analytical reasoning. We prefer to be in the intuitive mode; it is comfortably numb, but it gives you a misplaced feeling of security,” he said last week at a conference on patients’ safety hosted by Great Ormond Street Hospital for Children and supported by the BMJ .

“The diagnostic failure rate approaches 15%. This is staggering. …
947 EFFICACY OF AUTOLOGOUS MESENCHYMAL STEM CELL TRANSPLANTATION IN PATIENTS WITH LIVER CIRRHOSIS: THE PRELIMINARY RESULTS
Authors: M. Kantarcioglu, F. Avcu, A. Ozcan, I. Guvenc, A. Uygun, A.U. Ural, S. Bagci
Journal: Journal of Hepatology (2010)
Militating Against "Mitigated"
Authors: Seth L. Haber
Journal: JAMA (1963)

<h3>To the Editor:</h3> —It grieves me to observe that my idol,The Journal, "His legs of iron, his feet part of iron and part of clay," (Daniel 2:33) has literally been caught with his pants down. I refer to the article, "Mondor's Disease," by Drs. James E. Anthony and W. Frank Matthews, in the Sept 21 issue (<b>185</b>:972). Apparently, the editorial staff has condoned "... the lack of a well-defined elastic lamina mitigated against arterioles." I infer from<i>Webster's New International Dictionary, Second Edition</i>, that it is as incorrect "to mitigate against" something as it is to have "militating circumstances." Now, removing my tongue from my cheek, may I request that my name follow Abou ben Adhem's on the list of those to receive your soon to be released<i>Suggestions to Authors...?</i>
Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis
Authors: Victor L. Ruiz-Perez, Susan E. Ide, Tim M. Strom, Bettina Lorenz, David Wilson, Kathryn Woods, Lynn King, Clair Francomano, Peter Freisinger, Stephanie Spranger, Bruno Marino, Bruno Dallapiccola, Michael Wright, Thomas Meitinger, Mihael H. Polymeropoulos, Judith Goodship
Journal: Nature Genetics (2000)
Correction and Clarification: Factors Contributing to the Death of General Stonewall Jackson
Authors: Robert J. Turner
Journal: JAMA (1997)

<h3>To the Editor.</h3> —In the Medical News &amp; Perspectives article<sup>1</sup>discussing challenges in conducting clinical trials, Dr Harlan comments that General Stonewall Jackson "probably died because of bloodletting and not from any wound he received." It is a matter of record that General Jackson was dropped from the litter during his evacuation and had an amputation at the shoulder joint, but actually died of pneumonia. I am sure that the general received bloodletting as part of the treatment for the pneumonia and that this procedure did not help him. On the other hand, if it were not for the wound, he would not have developed pneumonia and would not have died; thus, the Confederacy would not have experienced its tremendous loss.
Sink or Swim: Training to Be an Obstetrician
Authors: Arthur G. King
Journal: JAMA (1988)

June 14,1928, my first obstetric delivery! In my just-completed second year at Harvard Medical School, the training had included only 12 lectures in obstetrics from "Chubby" Newell and an intense study of a mimeographed syllabus that might have been titled "How to Deliver a Baby." I had reported to the Boston Lying-In Hospital's "district" headquarters along with two classmates whose ignorance equaled mine, each of us armed with his self-prepared bag of instruments, gloves, cotton, and pans for sterilization by boiling water on the kitchen stove. For medication we each had an ounce of fluid extract of ergot that was replaced daily from the hospital with a freshly prepared supply. The patients had all been screened by the lordly interns who conducted the hospital's prenatal clinics, and the women, mostly multiparas, lived all over the eastern suburbs. When a telephone call came into the district headquarters, one of us would
Decreased Catecholamine Sensitivity and β-Adrenergic-Receptor Density in Failing Human Hearts
Authors: Michael R. Bristow, Robert Ginsburg, Wayne Minobe, Roger S. Cubicciotti, W. Scott Sageman, Keith Lurie, Margaret E. Billingham, Donald C. Harrison, Edward B. Stinson
Journal: New England Journal of Medicine (1982)

To identify the role of the myocardial β-adrenergic pathway in congestive heart failure, we examined β-adrenergic-receptor density, adenylate cyclase and creatine kinase activities, muscle contraction in vitro, and myocardial contractile protein levels in the left ventricles of failing and normally functioning hearts from cardiac-transplant recipients or prospective donors. Eleven failing left ventricles had a 50 to 56 per cent reduction in β-receptor density, a 45 per cent reduction in maximal isoproterenol-mediated adenylate cyclase stimulation, and a 54 to 73 per cent reduction in maximal isoproterenol-stimulated muscle contraction, as compared with six normally functioning ventricles (P<0.05 for each comparison). In contrast, cytoplasmic creatine kinase activity, adenylate cyclase activities stimulated by fluoride ion and by histamine, histamine-stimulated muscle contraction, and levels of contractile protein were not different in the two groups (P>0.05). We conclude that in failing human hearts a decrease in β-receptor density leads to subsensitivity of the β-adrenergic pathway and decreased β-agonist-stimulated muscle contraction. Regulation of β-adrenergic receptors may be an important variable in cardiac failure. (N Engl J Med. 1982; 307:205–11.)
HRT does not prevent chronic disease after menopause
Authors: Caroline White
Journal: BMJ (2004)

Hormone replacement therapy (HRT) should not be used to prevent chronic disease in women who have gone through the menopause. This is the conclusion from the latest trial in the US women's health initiative (WHI) study, published this week in JAMA (2004;291: 1701-12).

But HRT does have a role in the short term relief of menopausal symptoms, concludes an accompanying editorial ( JAMA 2004;291: 1769-71).

The study, a randomised, double blind, placebo controlled trial of unopposed oestrogen—0.625 …
Bony metastases in desmoplastic pleural mesothelioma.
Authors: T Machin, E T Mashiyama, J A Henderson, W T McCaughey
Journal: Thorax (1988)

Desmoplastic mesothelioma is an unusual variant of diffuse malignant mesothelioma in which much of the tumour is fibrous and which on this account may be difficult to distinguish from fibrous pleurisy.'2The clinical course is often rapid with metastases not infrequently occurring in liver, lung, adrenal, and kidney.Metastases in bone have only rarely been noted in desmoplastic mesothelioma,3 though they are known to occur in a small proportion ofcases of the closely related sarcomatous mesothelioma.34In this report we describe two cases of desmoplastic mesothelioma in which the pleural biopsy material resembled tissue with a reactive fibrosis, and which were unique in that osseous metastases were the first clinical evidence of tumour dissemination. Case reports CASE 1A 78 year old man presented with a left pleural effusion.Thoracotomy showed pleural thickening of up to I10 cm.Biopsy specimens were interpreted as showing fibrous pleur- isy.Ten months later lytic lesions were found in the pelvic bones and the spine.An open biopsy of iliac crest showed
Clinical Decision Analysis
Authors: John F. Schneider
Journal: Annals of Internal Medicine (1991)

Letters1 January 1991Clinical Decision AnalysisJohn F. Schneider, MD, PhDJohn F. Schneider, MD, PhDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-114-1-98_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editors:The article by Drs. Detsky and Naglie (1) provides an excellent description of the process of cost-effectiveness analysis. The authors emphasize the use of cost-effectiveness analysis in political decision making and the need for involvement in and understanding of this activity by physicians. However, I believe the authors incorrectly minimized the value of cost-effectiveness analysis for physicians making decisions about care of individual patients. In Canada, national health insurance protects all patients from personal costs when they receive care. In the United States, however, monetary costs can be expected to influence a patient's decision on therapy. A...Reference1. DetskyNaglie AI. A clinician's guide to cost-effectiveness analysis. Ann Intern Med. 1990;113:147-54. LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: John F. Schneider, MD, PhDAffiliations: University of Chicago Medical Center Chicago, IL 60637 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 January 1991Volume 114, Issue 1Page: 98-98KeywordsDecision analysisDecision makingHealth insurancePatients ePublished: 1 December 2008 Issue Published: 1 January 1991 PDF downloadLoading ...
Role of peripheral autonomic neurones in maintaining adequate cardiac function
Authors: M HORACKOVA
Journal: Cardiovascular Research (1995)

This review has focused on the putative effects that peripheral autonomic neurones exert on cardiac myocytes. Through data obtained by the use of in situ and in vitro models, the unique synaptology and chemical sensitivities of the various types of neurones in intrinsic cardiac and extracardiac intrathoracic ganglia are becoming evident. The intrathoracic nervous system acts as a distributive network, processing in a complex fashion information that arises not only from cardiac, vascular and pulmonary tissues but also from extrathoracic tissues, to maintain adequate cardiac function. In challenging the current understanding of cardiac regulation, this view provides novel opportunities to develop pharmacological and surgical strategies to manipulate cardiac function in disease states.
Haematoma of the Rectus Abdominis
Authors: G. H. Moore
Journal: BMJ (1948)

The 17-ketosteroids are end-products of steroid metabolism, their source being the adrenal cortex.The daily urinary 17-ketosteroid output is fairly constant-3.5-14.6 mg. in 24 hours for adult normal women and 9.4-20 mg. in 24 hours for adult normal men (Patterson, McPhee, and Greenwood, 1942).Hemphill, MacLeod, and Reiss (1942) investigated the 17-ketosteroid values before and after brain operations, in particular bilateral prefrontal leucotomy (lobotomy), in six cases, and found that after the third post-operative month the urinary 17-ketosteroid excretion rises, indicating an increased steroid metabolism.Com- menting on their results, they advanced the theory that an interference with the nervous pathways between the frontal lobes and the hypothalamus may influence the anterior pituitary, which in its turn alters the pituitary adreno-gonadal functions.The cerebral control of steroid metabolism is of clinical as well as physiological importance, and the above-quoted' conclusions have been reinvestigated in 12 cases.All the patients were' females at the period of sexual maturity, and all had undergone bilateral prefrontal leucotomy, per- formed with a rotating-blade leucotome of 25 mm.cutting diameter.The urinary 17-ketosteroid output was followed up fortnightly for three to four months, except in the case of one patient who, after leaving the hospital, was inacces- sible for the repeated investigations.The pre-operative and 3-4-monthly post-operative values are tabulated below.17-Ketosteroids in mg./24 hours Cae No.