tbuckley/cabot-search huggingface dataset:
EG-01 * EPIGENETIC INACTIVATION OF ARGININE BIOSYNTHESIS PATHWAY IN PAEDIATRIC HIGH GRADE GLIOMA
Authors: P. Channathodiyil, H. Kardooni, C. Khozoie, S. Nelofer, J. Darling, M. Morris, T. Warr
Journal: Neuro-Oncology (2014)

Aberrant cellular metabolism contributes significantly to the growth and proliferation of several tumour types. Identification of genes that control critical metabolic pathways is a major factor in the development of novel therapies that target metabolic defects in tumour cells. Our aim is to identify such genes in paediatric high grade glioma that are altered due to promoter hyper-methylation of cytosine residues in CpG dinucleotides. Genome wide DNA methylation profiling using Illumina infinium methylation 450K bead chip array was performed on 18 well-characterised short term cultures derived from paediatric high grade astrocytoma including 3 from diffuse intrinsic pontine glioma. Data analyses were based on beta scores of probes for each gene as measures of intensities of methylation. Genes were selected with beta scores of tumour > =0.70 and that of normal human astrocytes < =0.30. We identified that two vital genes involved in the regulation of arginine biosynthetic pathway, argininosuccinate synthetase 1(ASS1) and argininosuccinate lyase (ASL) were methylated in 9/18 (50%) cases. Hyper methylation was confirmed by methylation-specific PCR and up-regulation of gene expression following treatment with 2 µM 5-aza-2'-deoxyctidine. Down-regulation of ASS1 in hyper methylated samples was confirmed by Western blot analysis. Our findings report epigenetic deregulation of ASS1 and ASL in a subset of paediatric high grade glioma. The enzymes encoded by these genes are essential elements of urea cycle that function together in the de novo synthesis of arginine from citrulline. Tumour cells with deficient ASS1/ASL depend on external sources of arginine for survival and have been reported to be sensitive to autophagic cell death induced by arginine starvation. Therefore, further investigation may render the possibility of arginine-deprivation therapy in such sub type of paediatric high grade glioma. This therapeutic approach is of interest as tumour cells with abnormal expression of ASS1/ASL can be specifically targeted, while the normal cells can be spared.
TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis
Authors: Niklas Finnberg, Andres J.P. Klein-Szanto, Wafik S. El-Deiry
Journal: Journal of Clinical Investigation (2008)

Preclinical data support the potential of the death-signaling receptors for TRAIL as targets for cancer therapy. However, it is unclear whether these death-signaling receptors suppress the emergence and growth of malignant tumors in vivo. Herein we show that TNF-related apoptosis-inducing ligand receptor (TRAIL-R), the only proapoptotic death-signaling receptor for TRAIL in the mouse, suppresses inflammation and tumorigenesis. Loss of a single TRAIL-R allele on the lymphoma-prone Eμ-myc genetic background significantly reduced median lymphoma-free survival. TRAIL-R–deficient lymphomas developed with equal frequency irrespective of mono- or biallelic loss of TRAIL-R, had increased metastatic potential, and showed apoptotic defects relative to WT littermates. In addition, TRAIL-R–/– mice showed decreased long-term survival following a sublethal dose of ionizing radiation. Histological evaluation of moribund irradiated TRAIL-R–/– animals showed hallmarks of bronchopneumonia as well as tumor formation with increased NF-κB p65 expression. TRAIL-R also suppressed diethylnitrosamine-induced (DEN-induced) hepatocarcinogenesis, as an increased number of large tumors with apoptotic defects developed in the livers of DEN-treated TRAIL-R–/– mice. Thus TRAIL-R may function as an inflammation and tumor suppressor in multiple tissues in vivo.
Liver cell proliferation induced by nafenopin and cyproterone acetate is not associated with increases in activation of transcription factors NF-?B and AP-1 or with expression of tumor necrosis factor ?
Authors: M Menegazzi, A Carcereri-De Prati, H Suzuki, H Shinozuka, M Pibiri, R Piga, A Columbano, G M Ledda-Columbano
Journal: Hepatology (1997)

Our previous studies have shown a different pattern of immediate early gene and growth factor gene expression between compensatory liver regeneration occurring after cell loss/death and direct hyperplasia induced by primary mitogens. In the present study, modifications in the activation of two transcription factors, NF–κB and AP–1; steady– state levels of tumor necrosis factor α (TNF–α) messenger RNA (mRNA); and induction of the inducible nitric oxide synthase (iNOS) were examined in rat liver during different types of cell proliferation. Compensatory regeneration was induced in male Wistar rats by partial hepatectomy of two thirds (PH) or a necrogenic dose of CCl4 (2 mL/kg), whereas direct hyperplasia was induced by a single administration of the primary mitogens lead nitrate (LN, 100 micromol/kg), cyproterone acetate (CPA, 60 mg/kg), or nafenopin (NAF, 200 mg/kg). Liver regeneration after treatment with CCl4 was associated with an increase in steady–state levels of TNF–α mRNA, activation of NF–κB and AP–1, and induction of iNOS. A strong and prolonged activation of NF–κB but not of AP–1 was observed in LN–induced hyperplasia. LN also induced an increase in hepatic levels of TNF–α and iNOS mRNA. On the other hand, direct hyperplasia induced by two other primary mitogens, NAF and CPA, occurred in the complete absence of modifications in the hepatic levels of TNF–α mRNA, activation of NF–κB and AP–1, or induction of iNOS, although the number of hepatocytes entering S phase 18 to 24 hours after NAF was similar to that seen after PH. These results add further support to the hypothesis that cell proliferation occurring in the absence of cell loss/death may be triggered by unknown signaling pathways different from those responsible for the transition of hepatocytes from G0 to G1 after PH or cell necrosis.
The Immunosuppressive Surface Ligand CD200 Augments the Metastatic Capacity of Squamous Cell Carcinoma
Authors: Magda Stumpfova, Desirée Ratner, Edward B. Desciak, Yehuda D. Eliezri, David M. Owens
Journal: Cancer Research (2010)

Abstract CD200 (OX-2) is a cell surface glycoprotein that imparts immune privileges by suppressing alloimmune and autoimmune responses through its receptor, CD200R, expressed primarily on myeloid cells. The ability of CD200 to suppress myeloid cell activation is critical for maintaining normal tissue homeostasis but may also enhance the survival of migratory neoplastic cells. We show that CD200 expression is largely absent in well-differentiated primary squamous cell carcinoma (SCC) of the skin, but is highly induced in SCC metastases to the lymph node and other solid tissues. CD200 does not influence the proliferative or invasive capacity of SCC cells or their ability to reconstitute primary skin tumors. However, loss of CD200 impairs the ability of SCC cells to metastasize and seed secondary tumors, indicating that the survival of CD200+ SCC cells may depend on their ability to interact with CD200R+ immune cells. The predominant population of CD200R+ stromal cells was CD11b+Gr-1+ myeloid-derived suppressor cells, which release elevated levels of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor when in the presence of SCC cells in a CD200-dependent manner. Collectively, our findings implicate CD200 as a hallmark of SCC metastasis and suggest that the ability of CD200+ SCC keratinocytes to directly engage and modulate CD200R+ myeloid-derived suppressor cells is essential to metastatic survival. Cancer Res; 70(7); 2962–72
How to Achieve a High-Performance Health Care System in the United States
Authors: S. Ward Casscells, Elder Granger
Journal: Annals of Internal Medicine (2008)

Letters6 May 2008How to Achieve a High-Performance Health Care System in the United StatesS. Ward Casscells, MD and Elder Granger, MC, USAS. Ward Casscells, MDFrom the Military Health System, the Pentagon, Washington, DC 20301.Search for more papers by this author and Elder Granger, MC, USAFrom the Military Health System, the Pentagon, Washington, DC 20301.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-148-9-200805060-00015 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:The recent position paper by the American College of Physicians (1) drew many lessons from international health care systems and the Veterans Administration and made several recommendations. In pointing out success stories, the article overlooked one of the largest health care systems in the United States, which covers more than 9 million men, women, and children: the U.S. Department of Defense's Military Health System (MHS) TRICARE health plan. The MHS is vigorously addressing the problems identified in caring for wounded warriors at Walter Reed Army Medical Center and across the system. Looking beyond those military-specific challenges, observers ...Reference1. Public Policy Committee of the American College of Physicians. Achieving a high-performance health care system with universal access: what the United States can learn from other countries. Ann Intern Med. 2008;148:55-75. [PMID: 18056654] LinkGoogle Scholar Author, Article, and Disclosure InformationAuthors: S. Ward Casscells, MD; Elder Granger, MC, USAAffiliations: From the Military Health System, the Pentagon, Washington, DC 20301.Disclosures: None disclosed. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAchieving a High-Performance Health Care System with Universal Access: What the United States Can Learn from Other CountriesHow to Achieve a High-Performance Health Care System in the United States Arvind R. Cavale How to Achieve a High-Performance Health Care System in the United States Richard S. Leff How to Achieve a High-Performance Health Care System in the United States Richard L. Cruess and Sylvia R. Cruess How to Achieve a High-Performance Health Care System in the United States Thomas James III How to Achieve a High-Performance Health Care System in the United States Harvey S. Zarren How to Achieve a High-Performance Health Care System in the United States Jack A. Ginsburg , Robert B. Doherty , and J. Fred Ralston Jr. Metrics Cited byCareer Satisfaction of Military Medical Officers 6 May 2008Volume 148, Issue 9Page: 708-709KeywordsArmed forcesChild healthChildrenHealth careHealth maintenance organizationsMedical servicesMilitary medicineMorbidityMortalityRural areas ePublished: 6 May 2008 Issue Published: 6 May 2008 Copyright & PermissionsCopyright © 2008 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Assessment of students.
Authors: S Lowry
Journal: BMJ (1993)

Therapeutic and toxic plasma concentrations of commonly measured drugs Concentration below Concentrationabove which a therapeutic which a toxic effect Drug effect is unlikely is more likely Aminoglycosides: Amikacin 34 ,umol/l (20 ,ug/ml) 55 ,umol/I (32 ,ug/ml) (at peak) (at peak) 17 ,imol/I (10,g/ml) (at trough) Gentamicin 5 ;Lg/ml (at peak) 12 ,ug/ml (at peak) 2,ug/ml (at trough) Kanamycin 50 ,umol/l (25 ,ug/ml) 80 ,umol/I (40 ,ug/ml) (at peak) (at peak) 20 jimol/I (10 ,ug/mI) (at trough) Cardiac glycosides: Digitoxin 20 nmol/I (15 ng/ml) 39 nmol/l (30 ng/ml) Digoxin 1.0 nmol/l (0-8 ng/ml) 3.8 nmol/l (3 ng/ml) Cyclosporin* 80-200 nmol/I 170-330 nmol/I (100-250 ng/mI) (200-400 ng/ml) Lithium 0.4 mmol/l 1-0 mmol/l Phenytoin 40 jimol/l (10 ,ug/ml) 80 ,umol/l (20 ,ug/ml) Theophylline 55 ,umol/I (10 jig/ml) 110 ,umol/l (20 ,ug/ml) *Measured in whole blood by specific radioimmunoassay or high performance liquid chromatography.The actual results depend on the laboratory in which the measurement is made.
The growth of Staphylococcus aureus and Escherichia coli in low-direct current electric fields
Authors: Dunya Zituni, Heidi Schütt-Gerowitt, Marion Kopp, Martin Krönke, Klaus Addicks, Christian Hoffmann, Martin Hellmich, Franz Faber, Wilhelm Niedermeier
Journal: International Journal of Oral Science (2013)

Electrical potentials up to 800 mV can be observed between different metallic dental restorations. These potentials produce fields in the mouth that may interfere with microbial communities. The present study focuses on the impact of different electric field strengths (EFS) on the growth of Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) in vitro. Cultures of S. aureus and E. coli in fluid and gel medium were exposed to different EFS. Effects were determined by calculation of viable counts and measurement of inhibition zones. In gel medium, anodic inhibition zones for S. aureus were larger than those for E. coli at all field strength levels. In fluid medium, the maximum decrease in the viable count of S. aureus cells was at 10 V⋅m−1. Field-treated S. aureus cells presented ruptured cell walls and disintegrated cytoplasm. Conclusively, S. aureus is more sensitive to increasing electric field strength than E. coli. The bacterium Staphylococcus aureus is more sensitive than Escherichia coli to disruption by low-voltage currents, researchers in Germany have found. Dental restorations made of different alloys can generate a direct, or galvanic, current in the mouth that is conducted through saliva. Typically, bacteria are negatively charged, so galvanic currents can alter their growth and behavior. Dunya Zituni and co-workers at Cologne University investigated the effect of low-voltage currents with electrical field strength of 2–27 V⋅m−1 on cultures of the common oral microbe S. aureus and the model organism E. coli. In solid medium, the currents inhibited larger zones of S. aureus than E. coli; and, in liquid culture, they ruptured a larger percentage of S. aureus's cells. The researchers conclude that dental restorations should consist of one alloy only to avoid altering oral microbial communities.
Postextrasystolic compliance of the left ventricle.
Authors: W H Gaasch, O H Bing, J S Cole, H G Hanley
Journal: Circulation (1977)

The effects of a single premature contraction (PC) on left ventricular diastolic distensibility was studied in man, in the conscious chronically instrumented dog, and in the isolated (isovolumic) blood perfused dog heart. In the isolated dog heart at a constant volume, there was no difference in end-diastolic pressure when control diastolic pressure was compared to that following a PC. In man and conscious dogs, there was no difference between the overall pressure-volume or pressure-length plots when control diastolic data were compared to data from the diastole immediately following a PC (no change in the modulus of chamber stiffness). In the intact circulation of man dog, increased filling during the post PC pause causes the ventricle to operate higher on the steep (stiffer) portion of its pressure-volume or pressure-length curve (decrease in preload-dependent compliance). Thus, although a PC does not alter the modulus of chamber stiffness, a preload-dependent change in compliance may occur during post PC diastole.
Intensive Care: Medical Ethics and the Medical Profession
Authors: Kenneth V. Iserson
Journal: JAMA (1992)

In  Hollow Men, T. S. Eliot wrote, Between the idea and the reality, between the motion and the act, falls the shadow. The shadow of intensive care, as Zussman describes it, is not only its impact on hospital-based medicine but also the way the intensive care unit culture obscures the role of its ICU physicians and nurses and their decision-making process. His book follows in the tradition of other University of Chicago Press classics in medical sociology such asForgive and Remember(Charles L. Bosk, 1972) andBoys in White(Howard S. Becker, Blanche Geer, Everett C. Hughes, Anselm L. Strauss, 1961) that lent insight into medical practice through outsiders' observations. Zussman spent several years rounding with medical teams, talking to staff, patients, and families, and evaluating data in two major teaching hospital intensive care units. The result is a perceptive insight into the differences between ideals and reality
Genetic heterogeneity of β‐thalassemia in southeast sicily
Authors: G. Schilirò, F. di Gregorio, P. Samperi, E. Mirabile, R. Liang, M. A. Cürük, Z. Ye, T. H. J. Huisman
Journal: American Journal of Hematology (1995)

Abstract In this study we have defined the spectrum of the β‐thalassemia mutations, the β‐thalassemia haplotypes, and the genotype‐to‐phenotype correlations in a large number of patients with different β‐thalassemia conditions. Seventeen different (β‐thalassemia mutations were detected which included one chromosome each with Hb Dhonburi and Hb Lepore. Five alleles, namely, codon 39 (C→T), IVS‐l‐110 (G→A), IVS‐l‐6 (T C), IVS‐ll‐745 (C→G), and IVS‐l‐1 (G→A), account for 90% of all β‐thalassemia mutations in 846 thalassemic chromosomes studied. Haplotyping for a large number of subjects showed that the five common mutations are linked to a few haplotypes. The presence of milder mutations, mainly IVS‐l‐6 (T C), in about 19% of our patients explains some of the clinical variables. Among the 37 patients with thalassemia of intermediate severity, only 6 were homozygous or compound heterozygous for two severe alleles. The type of β‐thalassemia is the main factor responsible for differences in the phenotypic expression of the disease in patients with Hb S‐β‐thalassemia; patients with Hb S‐β + ‐thalassemia are less severely affected than those with Hb S‐β°‐thalassemia. The five most frequent mutations have comparable distributions all Over Sicily. ©1995 Wiley‐Liss, Inc.
Abstract 2903: Therapeutic targeting of leukemia and lymphoma with a neuropilin-1 binding pro-apoptotic peptide
Authors: Katja Karjalainen, Diana E. Jaalouk, Carlos E. Bueso-Ramos, Amado J. Zurita, Akihiko Kuniyasu, Bedrich L. Eckhardt, Frank C. Marini, Benjamin Lichtiger, Susan O'Brien, Hagob M. Kantarjian, Jorge E. Cortes, Erkki Koivunen, Wadih Arap, Renata Pasqualini
Journal: Cancer Research (2012)

Abstract Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short cell-internalizing peptide ligands that bind to specific cell surface receptors on malignant hematopoietic cells. Such targeting motifs could also serve as vehicles for preferential delivery of cytotoxic agents to leukemias and lymphomas. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence FF/YXLRS, which bound to human leukemia and lymphoma cell lines as well as to primary human acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) bone marrow specimens obtained from patients. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, the functional relevance of this internalizing receptor was evaluated in the context of disease progression via the targeted delivery of a pro-apoptotic peptidomimetic to leukemia and lymphoma cells, and a potent anti-leukemia cell effect was observed both with cell lines and patient samples when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D(KLAKLAK)2. Markedly, the pro-apoptotic peptide did not have an effect on purified mononuclear cells from normal bone marrow cells. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with ALL or AML compared to normal bone marrow specimens. Taken together, our results indicate that NRP-1 could, potentially, be used as a target for ligand-directed therapy in human leukemias and lymphomas - as well as in many human solid tumors, which are also know to over-express NRP-1 - and that the prototype CGFYWLRSC-GG-D(KLAKLAK)2 is a promising drug candidate in this setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2903. doi:1538-7445.AM2012-2903
Murder she wrote
Authors: T. Dalrymple
Journal: BMJ (2010)

Literature, like the living world, can be divided into kingdoms, orders, families, genera, species, and even subspecies. For example, there is the kingdom prose; the order fiction; the family novels; the genus murder detection; the species the English golden age of detective stories; and the subspecies murders that take place in prep schools.

No doubt a Freudian might say that the very existence of such a subspecies is indicative of English attitudes to children or to education—or, of course, to both.

One detective story in which the murder takes place in a prep school is Murder at Half-Term , first published in 1939, by Josephine Bell, the pen …
Setting Health Care Priorities in Oregon
Authors: Duncan S. MacLean
Journal: JAMA (1991)

To the Editor.  —Dr Hadorn1has lucidly articulated the Rule of Rescue, the principle that saving a patient from imminent death has priority over any other medical duty. I commend him for effectively reintroducing this important value into the discourse about reforming the American health system.  However, the Rule of Rescue and clinical epidemiologic cost-effectiveness methodology are not irreconcilable, as Hadorn claims. Philosopher Paul Menzel has convincingly propounded the willingness-to-pay method of pricing life-saving interventions.2Using this method, which extrapolates from such data as wage differentials for high-risk occupations and from US emissions standards, he has demonstrated that the cost society is willing to pay to save the next year of a person's life is $25 000 to $100 000 in current dollars. This conclusion squares with our common-sense intuition that the lengths to which we will go to save a particular person's life are indeed—and should be—finite,
Adverse Effect of Nitrous Oxide in a Child with 5,10-Methylenetetrahydrofolate Reductase Deficiency
Authors: Rebecca R. Selzer, David S. Rosenblatt, Renata Laxova, Kirk Hogan
Journal: New England Journal of Medicine (2003)

Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B12, inhibiting the cobalamin-dependent enzyme methionine synthase, which has a key role in many biochemical reactions that involve the nervous system. This case report concerns the neurologic deterioration and death of a child anesthetized twice, over a short period, with nitrous oxide before an inherited deficiency in 5,10-methylenetetrahydrofolate reductase (MTHFR), which is critical in similar metabolic pathways, was diagnosed.
905-59 Preoperative Dobutamine Stress Echocardiography Predicts Intra-operative Myocardial Ischemia in Patients Undergoing Aortic Surgery
Authors: Marc E.R.M. van Daele, Theo Greenland, Mariarosaria Amesa, Don Poldermans, Paolo M. Fioretti, Nico J. Dubois, Hero van Urk, Jos R.T.C. Roelandt
Journal: Journal of the American College of Cardiology (1995)