tbuckley/cabot-search huggingface dataset:
Hypermethylation and down-regulation of DLEU2 in paediatric acute myeloid leukaemia independent of embedded tumour suppressor miR-15a/16-1
Authors: Leah Morenos, Zac Chatterton, Jane L Ng, Minhee S Halemba, Mandy Parkinson-Bates, Francoise Mechinaud, Ngaire Elwood, Richard Saffery, Nicholas C Wong
Journal: Molecular Cancer (2014)

Acute Myeloid Leukaemia (AML) is a highly heterogeneous disease. Studies in adult AML have identified epigenetic changes, specifically DNA methylation, associated with leukaemia subtype, age of onset and patient survival which highlights this heterogeneity. However, only limited DNA methylation studies have elucidated any associations in paediatric AML. We interrogated DNA methylation on a cohort of paediatric AML FAB subtype M5 patients using the Illumina HumanMethylation450 (HM450) BeadChip, identifying a number of target genes with p <0.01 and Δβ >0.4 between leukaemic and matched remission (n = 20 primary leukaemic, n = 13 matched remission). Amongst those genes identified, we interrogate DLEU2 methylation using locus-specific SEQUENOM MassARRAY® EpiTYPER® and an increased validation cohort (n = 28 primary leukaemic, n = 14 matched remission, n = 17 additional non-leukaemic and cell lines). Following methylation analysis, expression studies were undertaken utilising the same patient samples for singleplex TaqMan gene and miRNA assays and relative expression comparisons. We identified differential DNA methylation at the DLEU2 locus, encompassing the tumour suppressor microRNA miR-15a/16-1 cluster. A number of HM450 probes spanning the DLEU2/Alt1 Transcriptional Start Site showed increased levels of methylation in leukaemia (average over all probes >60%) compared to disease-free haematopoietic cells and patient remission samples (<24%) (p < 0.001). Interestingly, DLEU2 mRNA down-regulation in leukaemic patients (p < 0.05) was independent of the embedded mature miR-15a/16-1 expression. To assess prognostic significance of DLEU2 DNA methylation, we stratified paediatric AML patients by their methylation status. A subset of patients recorded methylation values for DLEU2 akin to non-leukaemic specimens, specifically patients with sole trisomy 8 and/or chromosome 11 abnormalities. These patients also showed similar miR-15a/16-1 expression to non-leukaemic samples, and potential improved disease prognosis. The DLEU2 locus and embedded miRNA cluster miR-15a/16-1 is commonly deleted in adult cancers and shown to induce leukaemogenesis, however in paediatric AML we found the region to be transcriptionally repressed. In combination, our data highlights the utility of interrogating DNA methylation and microRNA in combination with underlying genetic status to provide novel insights into AML biology.
Paracetamol-induced acute renal failure.
Authors: A L Harris
Journal: BMJ (1982)

cell count is of no value in such situations in evaluating the probability of acute bacterial infection, as in a proportion of patients with infectious mononucleosis the first change evi- dent is a neutrophil leucocytosis.'To put my point in the language of clinical epidemiology, the positive predictive value of a neutrophil leucocytosis in diagnosing bacterial throat infection is low when the prevalence of infectious mononucleosis is high.This has obvious implications for those who care for young populations.Secondly, since this study was presumably designed to emphasise the importance of rational therapy of sore throats, I would like to ponder on the possible importance of irrational therapy in the dramatic reduction in poststreptococcal glomerulonephritis and rheu- matic fever which has taken place in the last three decades.Did wholesale prescription of antibiotics when they were available have a valuable role to play in the virtual dis- appearance of these diseases ?Is it only now that we can afford the luxury of a sophisticated rational therapy ?
Depressive Symptoms and Risk of Type 2 Diabetes in Women
Authors: Cassandra Arroyo, Frank B. Hu, Louise M. Ryan, Ichiro Kawachi, Graham A. Colditz, Frank E. Speizer, JoAnn Manson
Journal: Diabetes Care (2004)

OBJECTIVE—To explore the relationship between depressive symptoms and incidence of type 2 diabetes in women. RESEARCH DESIGN AND METHODS—We conducted an analysis of 72,178 female nurses aged 45–72 years who did not have diagnosed diabetes and who answered the Medical Outcomes Study 36-Item Short-Form Health Status Survey (SF-36) at baseline in 1992. We calculated relative risks (RR) of type 2 diabetes for women with presence of depressive symptoms (i.e., Five-Item Mental Health Index [MHI-5] score &amp;gt;52). RESULTS—During 4 years of follow-up (282,317 person-years), 973 incident cases of type 2 diabetes were documented. Age-adjusted RR of developing type 2 diabetes for women with presence of depressive symptoms was 1.55 (95% CI 1.27–1.90). Additional adjustment for BMI resulted in a RR of developing type 2 diabetes of 1.36 (1.11–1.67). The multivariate RR of developing type 2 diabetes was 1.22 (1.00–1.50). After excluding women diagnosed with diabetes between 1992 and 1994, 472 incident cases of type 2 diabetes were documented for the follow-up period from 1994 to 1996 (148,889 person-years). The multivariate RR of developing type 2 diabetes for women with depressive symptoms was 1.29 (0.96–1.72). CONCLUSIONS—Our data suggest that depressive symptoms are associated with a modest increase in the risk of type 2 diabetes.
Clinical spectrum of CADASIL: a study of 7 families
Authors: H Chabriat, K Vahedi, M.G Bousser, M.T Iba-Zizen, A Joutel, A Nibbio, T.G Nagy, E Tournier Lasserve, M.O Krebs, J Julien, X Ducrocq, M Levasseur, J.L Mas, B Dubois, P Homeyer, O Lyon-Caen
Journal: The Lancet (1995)
Molecular Evolutionary Mechanisms Driving Functional Diversification of the HSP90A Family of Heat Shock Proteins in Eukaryotes
Authors: Lorenzo Carretero-Paulet, Victor A. Albert, Mario A. Fares
Journal: Molecular Biology and Evolution (2013)

The ubiquitous and conserved cytosolic heat-shock proteins 90 (HSP90A) perform essential functions in the cell. To understand the evolutionary origin of HSP90A functional diversification, we analyzed the distribution of HSP90A family from 54 species representing the main eukaryotic lineages. Three independent HSP90A duplications led to the paralog subfamilies HSP90AA (heat-stress inducible) and HSP90AB (constitutive) and trace back to key time points during vertebrate, seed plant, and yeast evolution. HSP90AA and HSP90AB present divergent selection pressures, positive selection (PS), and signatures of functional divergence (FD) after duplication. The differential evolutionary patterns support different mechanisms for HSP90A functional diversification in vertebrates and seed plants. Mapping of PS and FD residues onto the HSP90A structure suggests the acquisition of novel and/or specialized client protein and/or cochaperone binding functions. We propose these residues as targets for further experimental studies of HSP90A proteins, reported to be capacitors of rapid evolutionary change, and targets for anticancer therapeutics.
International Union of Pharmacology. LII. Nomenclature and Molecular Relationships of Calcium-Activated Potassium Channels
Authors: Aguan D. Wei, George A. Gutman, Richard Aldrich, K. George Chandy, Stephan Grissmer, Heike Wulff
Journal: Pharmacological Reviews (2005)

The second major group of six/seven transmembrane potassium-selective channels consists of the KCa channels (for reviews, see [Lingle, 2002][1]; [Magleby, 2003][2]; [Moczydlowski, 2004][3]; [Stocker, 2004][4]; [Cox, 2005][5]), and [Table 1][6] shows the International Union of Pharmacology (IUPHAR[1
Ascites and oedema in liver disease.
Authors: M S Losowsky, B B Scott
Journal: BMJ (1973)

1 Gil, D. G., Pediatrics, 1969, 44, Suppl., 857. ? Kempe, H. C., Archives of Disease in Childhood, 1971, 46, 28. * Jackson, G., British Medical Journal, 1972, 2, 756. 4 Hessel, S. J., New England Journal of Medicine, 1970, 283, 156. ? Rowe, D. S., New England Journal of Medicine, 1970, 283, 156. Brem, J., Pediatrics, 1970, 45, 894. 7 Oppe, T. E., Social Worker, 1973, 23 February. 8 Daily Telegraph, 5 February, 1973, p. 13. Kempe, H. C., Silverman, F. N., Steele, B. F., Droogemueller, N. D., and Silver, H. K., Journal of the American Medical Association, 1962, 181, 17. 10 Skinner, A. E., and Castle, R. L., 78 Battered Children. London, N.S.P.C.C., 1969.
Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes.
Authors: C F Nathan
Journal: Journal of Clinical Investigation (1987)

Recombinant tumor necrosis factor alpha (rTNF alpha) and beta (rTNF beta) did not trigger H2O2 release from PMN in suspension. However, when PMN were plated on polystyrene surfaces coated with serum, fibronectin, vitronectin, laminin, or human umbilical vein endothelial cells (HUVEC), rTNFs induced a massive, prolonged secretory response, similar to that elicited by phorbol myristate acetate (PMA) or bacteria. On serum-coated plates, the maximum sustained rate of H2O2 release in response to rTNF alpha was 2.6 +/- 0.2 nmol/min per 10(6) PMN, the same as that with PMA; release continued for 73 +/- 4 min. On laminin-coated surfaces or HUVEC, release of H2O2 in response to rTNFs was slower, but lasted approximately 3.5 h, reaching the same total (greater than 100 nmol/10(6) PMN). Not only was this response far longer and larger than for other soluble stimuli of the respiratory burst studied with PMN in suspension, but the concentration necessary to elicit a half-maximal response (EC50) for rTNF alpha was orders of magnitude lower (55 pM). Responses were similar with FMLP, but ranged from zero to small with recombinant IFN alpha, recombinant IFN beta, recombinant IFN gamma, platelet-derived growth factor, recombinant IL-1 beta, or bacterial lipopolysaccharide. Adherent monocytes did not secrete H2O2 in response to rTNFs. H2O2 secretion by adherent PMN was first detectable 15-90 min after addition of rTNFs or FMLP. This lag period was unaffected by prior exposure of PMN to rTNF alpha in suspension, by allowing PMN to adhere before adding rTNF alpha, or by incubating adherent PMN in medium conditioned by rTNF alpha-treated PMN. Cytochalasins abolished H2O2 secretion in response to rTNFs, but not FMLP, if added during, but not after, the lag period. Thus, H2O2 secretion from rTNF alpha-treated PMN appears to be a direct but delayed response that requires assembly of microfilaments during exposure to the cytokine. These results suggest that PMN adherent to intra- or extravascular surfaces may undergo a massive, prolonged respiratory burst at the command of macrophages and lymphocytes reacting to microbial products and antigens.
Persistent Activation of Dendritic Cells after Resolution of Allergic Airway Inflammation Breaks Tolerance to Inhaled Allergens in Mice
Authors: Leonie S. van Rijt, Nanda Vos, Monique Willart, Femke Muskens, Paul P. Tak, Corine van der Horst, Henk C. Hoogsteden, Bart N. Lambrecht
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Polysensitization of patients who are allergic is a common feature. The underlying immunologic mechanism is not clear. The maturation status of dendritic cells (DCs) is considered to be important for priming naive T cells in the draining lymph nodes. We hypothesized that chronic airway inflammation can induce an enhanced maturation of airway DCs and facilitate subsequent priming to neoallergens.To investigate whether chronic airway inflammation could induce an altered activation of airway DCs in mice and whether this influences the development of allergic sensitization.Balb/c mice were repeatedly challenged with DCs to induce a chronic airway inflammation. We evaluated (1) the induction of the main characteristic features of human asthma including persistent remodeling, (2) the maturation status of airway DCs 1 month after inflammation resolved, (3) whether this influences tolerance to inhaled neoallergen, and (4) what type of T helper response would be induced by DCs.Airway DCs displayed a mature phenotype after complete resolution of airway eosinophilia. Inhalation of a neoallergen without any adjuvant was able to induce airway inflammation in postinflammation lungs but not in control lungs. One month after inflammation, airway DCs were able to induce Th2 polarization in naive T cells consistent with the up-regulation of the Th2 skewing molecules Ym1/2 and OX-40L compared with DCs of control airways.This study provides evidence that sustained maturation of DCs after resolution of Th2-mediated inflammation can contribute to polysensitization.
Retinoblastoma RB94 Enhances Radiation Treatment of Head and Neck Squamous Cell Carcinoma
Authors: Koji Araki, Sidrah M. Ahmad, Guoyan Li, David A. Bray, Koichiro Saito, Daiyou Wang, Uwe Wirtz, Sunil Sreedharan, Bert W. O'Malley, Daqing Li
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To assess whether adenovirus-mediated retinoblastoma 94 (Ad-RB94) transgene expression enhances efficacy of radiation therapy (XRT) of human head and neck squamous cell carcinoma (HNSCC). Experimental Design: The HNSCC cell lines (JHU006 and JHU012) were treated in vitro and in a nude mouse xenograft model with Ad-RB94, Ad-DL312 control vector, or untreated as mock control. Cell viability and tumor growth were evaluated and combined RB94/XRT antitumor activity was analyzed by measuring DNA double-strand breaks, apoptosis-associated early DNA fragmentation, and levels of RB-regulated cell cycle progression E2F1 transcription factor. Results: Ad-RB94/XRT resulted in significant HNSCC cell growth inhibition compared with XRT alone or Ad-RB94 alone in vitro and caused significant tumor regression compared with XRT alone and Ad-DL312/XRT in JHU006 and with XRT alone, Ad-DL312/XRT and Ad-RB94 alone in JHU012 in vivo. Neutral comet analysis revealed that DNA damage was significantly elevated in cells treated with Ad-RB94 alone and Ad-RB94/XRT. Tumors treated with Ad-RB94 alone showed a striking increase in early apoptosis DNA fragmentation, and DNA fragmentation was further enhanced with XRT. In addition, levels of E2F1 were up-regulated by Ad-RB94/XRT combination, whereas Ad-RB94 alone did not affect E2F1 levels and XRT alone led to down-regulation of E2F1. Conclusions: A potent antitumor effect has been observed after Ad-RB94/XRT combination treatment in HNSCC xenograft tumors. Enhanced tumor regression correlated with increased apoptosis. Ad-RB94 treatment enhances the efficacy of XRT through tumor cell sensitization by arresting the cells at the radiation-sensitive G2-M cell cycle and via E2F1 up-regulation.
T cell growth factor receptors. Quantitation, specificity, and biological relevance
Authors: RJ Robb, A Munck, KA Smith
Journal: The Journal of Experimental Medicine (1981)

To examine directly the hypothesis that T cell growth factor (TCGF) interacts with target cells in a fashion similar to polypeptide hormones, the binding of radiolabeled TCGF to various cell populations was investigated. The results indicate that TCGF interacts with activated T cells via a receptor through which it initiates the T cell proliferative response. Internally radiolabeled TCGF, prepared from a human T leukemia cell line and purified by gel filtration and isoelectric focusing, retained biological activity and was uniform with respect to size and charge. Binding of radiolabeled TCGF to TCGF-dependent cytolytic T cells occurred rapidly (within 15 rain at 37 degrees C) and was both saturable and largely reversible. In addition, at 37 degrees C, a receptor- and lysosome-dependent degradation of TCGF occurred. Radiolabeled TCGF binding was specific for activated, TCGF-responsive T cells. Whereas unstimulated lymphocytes of human or murine origin and lipopolysaccharide-activated B cell blasts expressed few if any detectable binding sites, lectin- or alloantigen-activated cells had easily detectable binding sites. Moreover, compared with lectin- or alloantigen-activated T cells, long-term TCGF-dependent cytolytic and helper T cell lines and TCGF-dependent neo-plastic T cell lines bound TCGF with a similar affinity (dissociation constant of 5-25 pM) and expressed a similar number of receptor sites per cell (5,000-15,000). In contrast, a number of TCGF-independent cell lines of T cell, B cell, or myeloid origin did not bind detectable quantities of radiolabeled TCGF. Binding of radiolabeled TCGF to TCGF-responsive cells was specific, in that among several growth factors and polypeptide hormones tested, only TCGF competed for binding. Finally, the relative magnitude of T cell proliferation induced by a given concentration of TCGF closely paralleled the fraction of occupied receptor sites. As the extent of T cell clonal expansion depends on TCGF and on the TCGF receptor, the dissection of the molecular events surrounding the interaction of TCGF and its receptor that these studies permit, should provide new insight into the hormonelike regulation of the immune response by this lymphokine.
Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4<b>+</b>CD25<b>+</b> regulatory T cells is interleukin 10 dependent
Authors: Jennifer Kearley, Jane E. Barker, Douglas S. Robinson, Clare M. Lloyd
Journal: The Journal of Experimental Medicine (2005)

Deficient suppression of T cell responses to allergen by CD4+CD25+ regulatory T cells has been observed in patients with allergic disease. Our current experiments used a mouse model of airway inflammation to examine the suppressive activity of allergen-specific CD4+CD25+ T cells in vivo. Transfer of ovalbumin (OVA) peptide–specific CD4+CD25+ T cells to OVA-sensitized mice reduced airway hyperreactivity (AHR), recruitment of eosinophils, and T helper type 2 (Th2) cytokine expression in the lung after allergen challenge. This suppression was dependent on interleukin (IL) 10 because increased lung expression of IL-10 was detected after transfer of CD4+CD25+ T cells, and regulation was reversed by anti–IL-10R antibody. However, suppression of AHR, airway inflammation, and increased expression of IL-10 were still observed when CD4+CD25+ T cells from IL-10 gene–deficient mice were transferred. Intracellular cytokine staining confirmed that transfer of CD4+CD25+ T cells induced IL-10 expression in recipient CD4+ T cells, but no increase in IL-10 expression was detected in airway macrophages, dendritic cells, or B cells. These data suggest that CD4+CD25+ T cells can suppress the Th2 cell–driven response to allergen in vivo by an IL-10–dependent mechanism but that IL-10 production by the regulatory T cells themselves is not required for such suppression.
Splenic Erythroid Response to Friend Polycythemia Virus: Time Course In Vitro After Infection In Vivo2
Authors: W. David Hankins, Paul Rosenblatt, Sanford B. Krantz
Journal: JNCI Journal of the National Cancer Institute (1977)

When spleen cells removed from plethoric BALB/c mice shortly after infection with Friend polycythemia virus were cultured, they subsequently increased their rate of hemoglobin synthesis in vitro without the addition of the hormone erythropoietin. The increased 59Fe incorporation into hemoglobin in vitro was part of a well-defined single wave unlike the progressive increase in hemoglobin synthesis that occurs in vivo. The peak occurred within the same total time (85-105 hr after infection), irrespective of either the virus dose or time after infection when the cells were removed from the animal and cultured. However, the magnitude of the peak increased with an increase in either of these two variables. Medium change experiments indicated that the time during which the peak occurred was not artificially determined by depletion of some medium component or the accumulation of an inhibitor. This system may be useful in separating the early events of Friend virus infection from the late effects on erythroid differentiation.
Internists' Attitudes about Clinical Practice Guidelines
Authors: Sean R. Tunis
Journal: Annals of Internal Medicine (1994)

Objective: To assess internists' familiarity with, confidence in, and attitudes about practice guidelines issued by various organizations. Design: Cross-sectional, self-administered survey. Participants: Questionnaires were mailed to a stratified random sample of 2600 members of the American College of Physicians (ACP) in 1992. Of the 2513 internists who met our eligibility criteria, 1513 responded (60%). Measurements and Results: Familiarity with guidelines varied from 11% of responders for the ACP guideline on exercise treadmill testing to 59% of responders for the National Cholesterol Education Program guideline. Confidence was reported in ACP guidelines by 82% of responders but by only 6% for Blue Cross and Blue Shield guidelines. Subspecialists had greatest confidence in guidelines developed by their own subspecialty organizations. It was thought that guidelines would improve the quality of health care by 70% of responders, increase health care costs by 43%, be used to discipline physicians by 68%, and make practice less satisfying by 34%. More favorable attitudes were held by internists who were paid a fixed salary, saw patients for less than 20 hours per week, had recently graduated from medical school, or were not in private practice. Conclusions: Although most ACP members studied recognized the potential benefits of practice guidelines, many were concerned about possible effects on clinical autonomy, health care costs, and satisfaction with clinical practice.
Arterial Wall Vibration Distal to Stenoses in Isolated Arteries of Dog and Man
Authors: JOHN E. K. FOREMAN, KENNETH J. HUTCHISON
Journal: Circulation Research (1970)

It has been suggested that poststenotic weakening of arterial walls is caused by arterial wall vibration and structural fatigue initiated by pressure disturbances in turbulent blood flow. We examined the frequency spectra of wall vibration downstream from experimental arterial stenoses and compared them with the natural resonant vibration characteristics of the artery walls. Spectra of arterial wall displacement of isolated perfused dog and human arteries were measured with a noncontacting capacitance transducer during conditions of fluid flow through the artery; resonant vibration characteristics were determined during pure sine and random sound stimulation of the artery walls in the absence of flow. It is concluded that fluid flow through isolated arteries with an experimental stenosis excites the artery wall to vibrate over a wide range of frequencies within which are discrete frequencies that coincide with the resonant frequencies of the artery wall.
Subcellular localization and heterogeneity of neutral proteases in neutrophilic polymorphonuclear leukocytes.
Authors: B Dewald, R Rindler-Ludwig, U Bretz, M Baggiolini
Journal: The Journal of Experimental Medicine (1975)

The subcellular localization of elastase and of neutral proteases hydrolyzing histone and casein was determined in human and rabbit polymorphonuclear leukocytes using fractionation by isopycnic centrifugation. Granule-rich fractions obtained by this technique were extracted and analyzed by acrylamide gel electrophoresis, and proteolytic activity on the gels was demonstrated by staining with either N-acetyl-D,L-alanine alpha-naphthyl ester or naphthol AS-D acetate as substrate. In both species, all neutral proteases assayed were found to be localized exclusively in the azurophil granules. Specific activities were about 10-30 times higher in human than in rabbit preparations. In extracts of human azurophil granules up to 10 proteins exhibiting esterolytic activity could be demonstrated after electrophoretic separation. Three major and two or three minor components of these esterases were shown to possess elastase activity. Similar zymograms prepared with extracts from rabbit azurophil granules revealed only one major elastase band. The electrophoretic analysis further showed that the most strongly cationic proteins of both human and rabbit PMNs were also confined to the azurophil granules.