tbuckley/cabot-search huggingface dataset:
FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation
Authors: Wei Huang, Min Ye, Lian-ru Zhang, Qun-dan Wu, Min Zhang, Jian-hua Xu, Wei Zheng
Journal: Molecular Cancer (2014)

Heat shock protein 90 (Hsp90) is a promising therapeutic target and inhibition of Hsp90 will presumably result in suppression of multiple signaling pathways. FW-04-806, a bis-oxazolyl macrolide compound extracted from China-native Streptomyces FIM-04-806, was reported to be identical in structure to the polyketide Conglobatin. We adopted the methods of chemproteomics, computational docking, immunoprecipitation, siRNA gene knock down, Quantitative Real-time PCR and xenograft models on the research of FW-04-806 antitumor mechanism, through the HER2-overexpressing breast cancer SKBR3 and HER2-underexpressing breast cancer MCF-7 cell line. We have verified the direct binding of FW-04-806 to the N-terminal domain of Hsp90 and found that FW-04-806 inhibits Hsp90/cell division cycle protein 37 (Cdc37) chaperone/co-chaperone interactions, but does not affect ATP-binding capability of Hsp90, thereby leading to the degradation of multiple Hsp90 client proteins via the proteasome pathway. In breast cancer cell lines, FW-04-806 inhibits cell proliferation, caused G2/M cell cycle arrest, induced apoptosis, and downregulated Hsp90 client proteins HER2, Akt, Raf-1 and their phosphorylated forms (p-HER2, p-Akt) in a dose and time-dependent manner. Importantly, FW-04-806 displays a better anti-tumor effect in HER2-overexpressed SKBR3 tumor xenograft model than in HER2-underexpressed MCF-7 model. The result is consistent with cell proliferation assay and in vitro apoptosis assay applied for SKBR-3 and MCF-7. Furthermore, FW-04-806 has a favorable toxicity profile. As a novel Hsp90 inhibitor, FW-04-806 binds to the N-terminal of Hsp90 and inhibits Hsp90/Cdc37 interaction, resulting in the disassociation of Hsp90/Cdc37/client complexes and the degradation of Hsp90 client proteins. FW-04-806 displays promising antitumor activity against breast cancer cells both in vitro and in vivo, especially for HER2-overexpressed breast cancer cells.
Effect of measurement conditions on measured levels of peak exhaled nitric oxide
Authors: C. A. Byrnes, S. Dinarevic, C. A. Busst, E. A. Shinebourne, A. Bush
Journal: Thorax (1997)

BACKGROUND: It is possible to measure nitric oxide (NO) levels in exhaled air. The absolute concentrations of exhaled NO obtained by separate workers in similar patient groups and normal subjects with apparently similar techniques have been very different. A study was undertaken to determine whether changes in measurement conditions alter the concentration of exhaled NO. METHOD: NO concentrations measured by a chemiluminescence analyser (Dasibi Environmental Corporation) and carbon dioxide (CO2) measured by a Morgan capnograph were analysed in single exhalations from total lung capacity in healthy volunteers (mean age 35.9 years). Ten subjects performed five exhalations at four different expiratory flow rates, at four different expiratory mouth pressures, and before and after drinking hot (n = 5) or cold (n = 5) water. Three subjects performed five exhalations on a day of high background NO (mean NO level 134 ppb) before and after a set of five exhalations made while both the subject and analysers were sampling from a low NO/NO-free reservoir system. RESULTS: The mean peak concentration of NO decreased by 35 ppb (95% CI 25.7 to 43.4) from a mean (SE) of 79.0 (15.5) ppb at an expiratory flow rate of 250 ml/min to 54.1 (10.7) ppb at 1100 ml/min. The mean peak concentration of NO did not change significantly with change in mouth pressure. The mean (SE) peak NO concentration decreased from 94.4 (20.8) ppb to 70.8 (16.5) ppb (p = 0.002, 95% CI 12.9 to 33.1) with water consumption. The mean NO concentration with machine and subject sampling from the low NO reservoir was 123.1 (19.4) ppb, an increase from results obtained before (81.9 (10.2) ppb, p = 0.001, 95% CI -19.9 to -62.7) and after (94.2 (18.3) ppb, p = 0.017, 95% CI 6.0 to 51.8) sampling with high ambient NO. CONCLUSIONS: The measurement of exhaled NO must be performed in a carefully standardised manner to enable different teams of investigators to compare results.
Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors
Authors: Dariush Mozaffarian, RosaMaria Marfisi, Giacomo Levantesi, Maria G Silletta, Luigi Tavazzi, Gianni Tognoni, Franco Valagussa, Roberto Marchioli
Journal: The Lancet (2007)
The Induction of Labour: A Comparison of Some of the Methods, with Notes of Five Recent Cases
Authors: J. S. Sheill
Journal: BMJ (1905)

Hastings Gilford says of his case,' of which I show you the illustration, that he was an infant as regards his generative organs; a child of 2 or 3 as regards his physiognomy and configuration of head; a little over 3 as regards height; about 6 or 7 as regards his epiphyses; and as regards his teeth, about iI.His actual age was 12.Our patient is also an example of primary asexual ateleiosis.Others, however, become sexually mature, and so are real dwarfs, as the well-known General Tom Thumb.Dr. Byrom Bramwell details a case due to defective pancDeas, of which a second case has been noted by Dr. Rentoul of Lisburn; also one associated with anaemia and enlargement of, spleen.Sporadic cretinism is a well-known cause of defective growth; and hereditary syphilis is given by Bramwell; our patient 'culty and survived but a short time.CASE IV.D. C., aged 27, g-para; about seven and a half months pregnant; ,contracted pelvis; true conjugate 6.8 cm.Wishes of patient also 7similar to those of Cases ii and iII.March 8th, 2905.Three No. 12 bougies passed, and, being left in for ,twenty-four hours, produced but a few feeble painful contractions.On ,being removed, three No. 14 bougies were with difficulty inserted, as the tbougies together were a tight fit for the os.Before inserting the larger lbougies the membranes were digitally separated from the lower uterine segment as far as could be reached.Some weak labour pains set in-Iew and far between.After six hours the bougles were removed, and Frommer's dilator inserted, and the os slowly dilated up to 3j cm.-diameter.Strong pains set in soon afterwards, and as the breech was dpresenting the ehild was delivered alive as an ordinary breech case.CASE V.March 15th, T905.K. B., aged 0, primipara; five and a half months ,pregnant; suffering from eclampsia; seven seizures.Patient had left 'kidney removed three years previously for (?) abscess.On admission great oedema present; urine scanty, with much albumen.Morphine and the usual measures successfully adopted.The fetal heart not being heard after careful auscultation, and as the flts had ceased, it was -decided to empty the uterus by induction of labour.March x6th.Os dilated by Hegar's dilators up to size I6, and three
An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway
Authors: Deliang Guo, Felicia Reinitz, Mary Youssef, Cynthia Hong, David Nathanson, David Akhavan, Daisuke Kuga, Ali Nael Amzajerdi, Horacio Soto, Shaojun Zhu, Ivan Babic, Kazuhiro Tanaka, Julie Dang, Akio Iwanami, Beatrice Gini, Jason DeJesus, Dominique D. Lisiero, Tiffany T. Huang, Robert M. Prins, Patrick Y. Wen, H. Ian Robins, Michael D. Prados, Lisa M. DeAngelis, Ingo K. Mellinghoff, Minesh P. Mehta, C. David James, Arnab Chakravarti, Timothy F. Cloughesy, Peter Tontonoz, Paul S. Mischel
Journal: Cancer Discovery (2011)

Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)-dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1-dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)-mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1-dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients.
SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance
Authors: Fabienne Niederer, Caroline Ospelt, Fabia Brentano, Michael O Hottiger, Renate E Gay, Steffen Gay, Michael Detmar, Diego Kyburz
Journal: Annals of the Rheumatic Diseases (2011)

Objective To analyse the expression of SIRT1 in synovial tissues and cells of patients with rheumatoid arthritis (RA) and to study the function of SIRT1 in inflammation and apoptosis in RA. Methods Levels of SIRT1 expression were analysed in synovial tissues and cells from patients with RA by real-time PCR and western blotting before and after stimulation with toll-like receptor ligands, tumour necrosis factor α (TNFα) and interleukin 1β (IL-1β). Immunohistochemistry was used to study the localisation of SIRT1. Fluorescence activated cell sorting analysis was performed to investigate the effect of SIRT1 on apoptosis. Peripheral blood monocytes and rheumatoid arthritis synovial fibroblasts (RASFs) were transfected with wild-type or enzymatically inactive SIRT1 expression vectors or with siRNA targeting SIRT1. Cytokine analysis of IL-6, IL-8 and TNFα were performed by ELISA to study the role of SIRT1 on proinflammatory mediators of RA. Results SIRT1 was found to be constitutively upregulated in synovial tissues and cells from patients with RA compared to osteoarthritis. TNFα stimulation of RASFs and monocytes resulted in further induced expression levels of SIRT1. Silencing of SIRT1 promoted apoptosis in RASFs, whereas SIRT1 overexpression protected cells from apoptosis. Inhibition of SIRT1 enzymatic activity by inhibitors, siRNA and overexpression of an enzymatically inactive form of SIRT1 reduced lipopolysaccharide-induced levels of TNFα in monocytes. Similarly, knockdown of SIRT1 resulted in a reduction of proinflammatory IL-6 and IL-8 in RASFs. Conclusion The TNFα-induced overexpression of SIRT1 in RA synovial cells contributes to chronic inflammation by promoting proinflammatory cytokine production and inhibiting apoptosis.
Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis
Authors: Roanne Keeton, Nasiema Allie, Ivy Dambuza, Brian Abel, Nai-Jen Hsu, Boipelo Sebesho, Philippa Randall, Patricia Burger, Elizabeth Fick, Valerie F.J. Quesniaux, Bernhard Ryffel, Muazzam Jacobs
Journal: Journal of Clinical Investigation (2014)

Development of host protective immunity against Mycobacterium tuberculosis infection is critically dependent on the inflammatory cytokine TNF. TNF signals through 2 receptors, TNFRp55 and TNFRp75; however, the role of TNFRp75-dependent signaling in immune regulation is poorly defined. Here we found that mice lacking TNFRp75 exhibit greater control of M. tuberculosis infection compared with WT mice. TNFRp75–/– mice developed effective bactericidal granulomas and demonstrated increased pulmonary recruitment of activated DCs. Moreover, IL-12p40–dependent migration of DCs to lung draining LNs of infected TNFRp75–/– mice was substantially higher than that observed in WT M. tuberculosis–infected animals and was associated with enhanced frequencies of activated M. tuberculosis–specific IFN-γ–expressing CD4+ T cells. In WT mice, TNFRp75 shedding correlated with markedly reduced bioactive TNF levels and IL-12p40 expression. Neutralization of TNFRp75 in M. tuberculosis–infected WT BM-derived DCs (BMDCs) increased production of bioactive TNF and IL-12p40 to a level equivalent to that produced by TNFRp75–/– BMDCs. Addition of exogenous TNFRp75 to TNFRp75–/– BMDCs infected with M. tuberculosis decreased IL-12p40 synthesis, demonstrating that TNFRp75 shedding regulates DC activation. These data indicate that TNFRp75 shedding downmodulates protective immune function and reduces host resistance and survival; therefore, targeting TNFRp75 may be beneficial for improving disease outcome.
Identification of a Gene Signature for Rapid Screening of Oral Squamous Cell Carcinoma
Authors: Amy F. Ziober, Kirtesh R. Patel, Faizan Alawi, Phyllis Gimotty, Randall S. Weber, Michael M. Feldman, Ara A. Chalian, Gregory S. Weinstein, Jennifer Hunt, Barry L. Ziober
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Oral cancer is a major health problem worldwide and in the U.S. The 5-year survival rate for oral cancer has not improved significantly over the past 20 years and remains at ∼50%. Patients diagnosed at an early stage of the disease typically have an 80% chance for cure and functional outcome, however, most patients are identified when the cancer is advanced. Thus, a convenient and an accurate way to detect oral cancer early will decrease patient morbidity and mortality. The ability to noninvasively monitor oral cancer onset, progression, and treatment outcomes requires two prerequisites: identification of specific biomarkers for oral cancers as well as noninvasive access to and monitoring of these biomarkers that could be conducted at the point of care (i.e., practitioner's or dentist's office) by minimally trained personnel. Experimental Design: Here, we show that DNA microarray gene expression profiling of matched tumor and normal specimens can identify distinct anatomic site expression patterns and a highly significant gene signature distinguishing normal from oral squamous cell carcinoma (OSCC) tissue. Results: Using a supervised learning algorithm, we generated a 25-gene signature for OSCC that can classify normal and OSCC specimens. This 25-gene molecular predictor was 96% accurate on cross-validation, averaging 87% accuracy using three independent validation test sets and failing to predict non–oral tumors. Conclusion: Identification and validation of this tissue-specific 25-gene molecular predictor in this report is our first step towards developing a new, noninvasive, microfluidic-based diagnostic technology for mass screening, diagnosis, and treatment of pre-OSCC and OSCC.
T cell subsets defined by expression of Lyt-1,2,3 and Thy-1 antigens. Two-parameter immunofluorescence and cytotoxicity analysis with monoclonal antibodies modifies current views.
Authors: J A Ledbetter, R V Rouse, H S Micklem, L A Herzenberg
Journal: The Journal of Experimental Medicine (1980)

Using monoclonal antibodies and multiparameter fluorescence analyses, we show that the expression of Lyt-1, Lyt-2, and Lyt-3 on T cell subpopulations is more complex than was originally recognized by the cytotoxic depletion studies with conventional reagents that defined the Lyt-1+2+3+, Lyt-1+2-3-, and Lyt-1-2+3+ populations. We detect at least some Lyt-1 on all T (Thy-1-bearing) lymphocytes; however, in agreement with previous studies, we find that Lyt-2+3+ cells are more difficult to depelete with anti-Lyt-1 than Lyt-1+2-3- cells. Surprisingly, we found a small subpopulation of cells carrying relatively large amounts of Lyt-1 and no Thy-1 detectable by fluorescence-activated cell sorter analysis. We also detect cells with this phenotype histologically in B cell zones (primary follicles) and germinal centers in spleen and lymph nodes. In general, the Lyt-1 only population represents approximately 2% of spleen cells. The relative quantitative expression of Thy-1, Lyt-1, Lyt-2, and Lyt-3 changes systematically during T cell maturation. Among Lyt-1+2+3+ cells in the thymus, Thy-1 and Lyt-2 are high, whereas Lyt-1 is low. Among splenic T cells, in contrast, Thy-1 is low, Lyt-1 is high, and Lyt-2 and Lyt-3 are a little higher than in thymus. In general, Thy-1 expression is negatively correlated with Lyt-1. Thus, even among splenic and lymph node T cells subpopulations exist that tend to be either high Thy-1 and low Lyt-1 or vice versa. Lyt-2+3+ cells represent approximately 85% of thymocytes but only approximately 35% of splenic or lymph node T cells. The Lyt-2+3+ cells are found predominantly in the low Lyt-1, high Thy-1 subpopulation.
The effect of processing on inflammatory markers in induced sputum
Authors: R Louis, J Shute, K Goldring, B Perks, LC Lau, M Radermecker, R Djukanovic
Journal: European Respiratory Journal (1999)

The effects of the mucolytic agent, dithioerythritol (DTE), and the temperature at which sputum processing is conducted on cellular and biochemical markers in induced sputum was assessed. Samples from healthy and atopic asthmatic subjects were treated with either DTE or phosphate-buffered saline (PBS) at 22 or 37 degrees C and compared for cell counts and concentrations of histamine, tryptase, eosinophil cationic protein (ECP), free interleukin (IL)-8, immunoglobulin (Ig)A, IL-8/IgA complexes and secretory component (SC). In addition, the influence of DTE on in vitro mediator release from blood eosinophils, basophils and bronchoalveolar lavage (BAL) mast cells was studied. Processing with DTE improved cytospin quality and increased the cell yield and measurable ECP, tryptase, IgA and SC, but reduced levels of histamine in PBS-treated samples and had no effect on IL-8. Cell counts or mediator levels were similar when sputum was processed at 22 or 37 degrees C, even though DTE induced blood basophils and BAL mast cells to release histamine at 37 degrees C. In spiking experiments, recovery of added ECP, tryptase, total IL-8 and histamine from sputum was similar in DTE- and PBS-processed sputum, but reduced for free IL-8 in PBS-treated samples. In conclusion, dithioerythritol improves cell and mediator recovery without causing cell activation when sputum processing is conducted at room temperature. The extent of recovery depends on the mediator studied.
Histochemical study on the Paneth cell in the rat.
Authors: E O Riecken, A G Pearse
Journal: Gut (1966)

The characteristic granules of this cell fulfil the enzymatic criterion of lysosomes.The function of the Paneth cell has more than once been investigated since its discovery in 1872 by Schwalbe.A complete review of available infor- mation was presented by Patzelt (1936).Various histochemical approaches have been made, but knowledge about the enzymatic content of these cells in the rat is restricted to reports on some enzymes in connexion with other investigations of the small intestine (Lojda and Fabry, 1959; Jervis, 1963; Liu and Baker, 1963).Studies on the heavy metal content of the Paneth cell in rats are frequent and have been carried out more recently by Midorikawa and Eder (1962).Investigations on the membrane of the Paneth cell granules have been performed by Taylor and Flaa (1964).The present investigation confirms and extends previous work, especially in respect of their enzyme content.MATERIAL Male, adult, M.R.C. hooded rats, kept on a standard laboratory diet and tap water, were starved for five hours and decapitated after stunning by a blow on the head.The time of sacrifice was strictly maintained constant.Various segments of the small intestine, 1 cm. in length, were quickly removed and processed in four different ways:-1 Tissue was placed on a block-holder and quenched immediately in liquid nitrogen.2 Tissue was fixed in cold 4 % formal calcium for 16 hours and frozen in the same way.3 Tissue was freeze-dried in a thermoelectric freezedryer (Pearse, 1963) and embedded in paraffin wax after formal-vapour fixation.4 Tissue was fixed in 70 % alcohol which was saturated with hydrogen sulphide gas, dehydrated, and embedded in paraffin.Sections, 8 t thick, were cut on a cold micro- tome from the unfixed frozen and formalin-fixed frozen blocks; the paraffin-embedded material was cut on an M.S.E.sledge microtome (6, thick sections).METHODS PROTEIN Amino groups were demonstrated by the DNFB reaction (Tranzer and Pearse, 1964) and by the Alloxan-Schiff reaction (Yasuma and Ichikawa, 1953); sulphydryl groups by the DDD-coupling method (Barr- nett and Seligman, 1952); arginine was shown by a on July 11,
Multiplexed Quantitative Analysis of CD3, CD8, and CD20 Predicts Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Jason R. Brown, Hallie Wimberly, Donald R. Lannin, Christian Nixon, David L. Rimm, Veerle Bossuyt
Journal: Clinical Cancer Research (2014)

Although tumor-infiltrating lymphocytes (TIL) have been associated with response to neoadjuvant therapy, measurement typically is subjective, semiquantitative, and unable to differentiate among subpopulations. Here, we describe a quantitative objective method for analyzing lymphocyte subpopulations and assessing their predictive value.We developed a quantitative immunofluorescence assay to measure stromal expression of CD3, CD8, and CD20 on one slide. We validated this assay by comparison with flow cytometry on tonsil specimens and assessed predictive value in breast cancer on a neoadjuvant cohort (n = 95). Then, each marker was tested for prediction of pathologic complete response (pCR) compared with pathologist estimation of the percentage of lymphocyte infiltrate.The lymphocyte percentage and CD3, CD8, and CD20 proportions were similar between flow cytometry and quantitative immunofluorescence on tonsil specimens. Pathologist TIL count predicted pCR [P = 0.043; OR, 4.77; 95% confidence interval (CI), 1.05-21.6] despite fair interobserver reproducibility (κ = 0.393). Stromal AQUA (automated quantitative analysis) scores for CD3 (P = 0.023; OR, 2.51; 95% CI, 1.13-5.57), CD8 (P = 0.029; OR, 2.00; 95% CI, 1.08-3.72), and CD20 (P = 0.005; OR, 1.80; 95% CI, 1.19-2.72) predicted pCR in univariate analysis. CD20 AQUA score predicted pCR (P = 0.019; OR, 5.37; 95% CI, 1.32-21.8) independently of age, size, nuclear grade, nodal status, ER, PR, HER2, and Ki-67, whereas CD3, CD8, and pathologist estimation did not.We have developed and validated an objective, quantitative assay measuring TILs in breast cancer. Although this work provides analytic validity, future larger studies will be required to prove clinical utility.
Mucosal Imprinting of Vaccine-Induced CD8 <sup>+</sup> T Cells Is Crucial to Inhibit the Growth of Mucosal Tumors
Authors: Federico Sandoval, Magali Terme, Mevyn Nizard, Cécile Badoual, Michel-Francis Bureau, Ludovic Freyburger, Olivier Clement, Elie Marcheteau, Alain Gey, Guillaume Fraisse, Cécilia Bouguin, Nathalie Merillon, Estelle Dransart, Thi Tran, Françoise Quintin-Colonna, Gwennhael Autret, Marine Thiebaud, Muhammad Suleman, Sabine Riffault, Tzyy-Choou Wu, Odile Launay, Claire Danel, Julien Taieb, Jennifer Richardson, Laurence Zitvogel, Wolf H. Fridman, Ludger Johannes, Eric Tartour
Journal: Science Translational Medicine (2013)

Mucosal vaccination induces targeted CD8 + T cell homing to inhibit mucosal tumors.
THE DICK TEST IN SCARLET FEVER
Authors: W. Brown
Journal: BMJ (1929)

THE-DICK TEST IN SC-ARLET FEVER.[MTzBBItiT 13It m1ay well be urged that mine is a very small ser'ies of ecases, aid that they have not been given nlearly enough timne -in wrhiih to relapse, nevertheless any small success in the treatment of this disfiguring condition is acceptable to mllost of us, and if others are encourLaged by this note to use the drug and to record their results its object will not have been missed.