tbuckley/cabot-search huggingface dataset:
Short citrullinated epitope of filaggrin is recognised by sera as well as antibodies produced in vitro by B cells of rheumatoid arthritis patients
Authors: E. Szarka, M. Adori, F. Babos, A. Magyar, F. Hudecz, G. Nagy, J. Pozsgay, G. Sarmay
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> Autoantibodies in about 70% of rheumatoid arthritis (RA) patients recognising citrullinated proteins (ACPA) are cross-reactive with citrullinated filaggrin epitopes. Although filaggrin is an epithelial protein and is not expressed in synovial tissues, so is probably not the in vivo target of ACPA, sysnthetic peptid epitopes of filaggrin are good tools for the early diagnosis of RA. Our main goals are to identify the optimal citrullinated epitope(s) applicable in highly sensitive diagnostic tests and also recognised by ACPA producing B cells, thus allowing phenotyping and functional studies of this population. <h3>Materials and methods</h3> The previously identified citrullinated epitopes were synthesised by SPPS, according to Fmoc/tBu strategy, biotinylated at either the C- or the N-terminal end respectively, and tested for their reactivity with sera of RA and other autoimmune patients by ELISA. B cells were isolated from peripheral blood by negative selection, cultured with TLR9 ligand, CpG oligodeoxynucleotide, and with B cell activating factor of TNF family (BAFF), then the citrullinated peptide specific antibody production was measured on day 7. <h3>Results</h3> 5-mer and 19-mer citrullinated filaggrin peptides were recognised by the RA sera, with a sensitivity and specificity that was comparable with the currently used tests. RA sera specifically recognised the C terminally, and not by the N-terminally biotinylated 5-mer peptide, while did not differentiate between C and N terminally biotinylated 19-mer peptide, suggesting that the N-terminal amino acids in the 5-mer peptide are crucial for recognition. The data obtained with both the 5-mer and the19-mer peptides showed significant correlation with the anti-CCP titers of commercial test. To see whether B cells from RA patients and normal individuals produce citrullinated peptide specific antibodies in vitro, purified B cells were stimulated via TLR9 by CpG in the presence of BAFF. B cells from RA patients synthesised a substantial amount of antibodies that specifically recognised the 5-mer citrullinated filaggrin peptide, while B cells from normal blood donors did not, indicating that autoreactive B cells that are specific for citrullinated proteins can be stimulated via TLR9 to produce anticitrullinated peptide antibodies. Such mechanism may contribute to the pathogenicity of ACPA. <h3>Conclusion</h3> The five-mer citrullinated filaggrin peptide as a well defined short epitope could be important for development of new diagnostic tools for RA, and also may facilitate to reveal phenotypic and functional differences of autoreactive and normal B cells.
Acute and definitive renal failure in progressive multiple myeloma treated with recombinant interferon alpha‐2a: Report on two patients
Authors: C. Noël, F. Vrtovsnik, T. Facon, M. P. Noël‐Walter, M. Hazzan, J. P. Jouet, F. Bauters, G. Lelièvre
Journal: American Journal of Hematology (1992)
Role of prostaglandin E2 in mediating the effects of pH on the hydroosmotic response to vasopressin in the toad urinary bladder.
Authors: J N Forrest, C J Schneider, D B Goodman
Journal: Journal of Clinical Investigation (1982)

Acidosis inhibits the hydroosmotic response to vasopressin. Since prostaglandins are known to modulate vasopressin-stimulated water flow we investigated the role of endogenous prostaglandin E2(PGE2) production in the pH-dependent response of the toad urinary bladder to vasopressin. Graded acidification of the serosal medial resulted in a progressive decline in vasopressin-stimulated water flow from 26.6 +/- 0.5 mg/min at pH 8.4 to 1.7 +/- 0.6 at pH 6.9. In these bladders basal PGE2 synthesis increased from 5.09 +/- 0.51 pmol/min per g hemibladder at pH 8.4 to 18.8 +/- 2.8 at pH 6.9. The addition of that concentration of PGE2 produced by the bladder at pH 7.4 (4 nM) to bladders at pH 8.4 resulted in 62-71% of the inhibition usually seen at pH 7.4; these data suggest that basal PGE2 production per se and not other products of prostaglandin synthesis or other pH-dependent events is responsible for the effect of acidosis. Preincubation with prostaglandin synthesis inhibitors reversed in major part the effect of serosal acidification on the response to submaximal concentrations of vasopressin and completely abolished the effect of pH on near maximal concentrations of the hormone. An increase in PGE2 synthesis after vasopressin was not seen at any pH. These studies establish that increased basal PGE2 synthesis plays a critical role in the pH dependence of the hydroosmotic response to vasopressin and demonstrate that factors that modulate the response to vasopressin may exert this effect by changing the basal rate of prostaglandin synthesis.
Abstract 1248: Enhanced glutamine metabolism contributes to docetaxel resistance in DU145 prostate cancer cells
Authors: Kartik N. Rajagopalan, Calin O. Marian, Jerry W. Shay, Ralph J. DeBerardinis
Journal: Cancer Research (2011)

Abstract Chemotherapeutic resistance is one of the major factors contributing to cancer mortality. Although evidence supports a mechanistic link between metabolic enzyme polymorphisms and drug sensitivity, little is known about the metabolic changes tumor cells undergo when treated with a chemotherapeutic agent. Moreover, the metabolic consequences of exposure to these agents may provide essential adaptive functions contributing to chemotherapeutic resistance. Here we used metabolic flux analysis to identify metabolic changes accompanying and potentially accounting for docetaxel resistance in DU145 prostate cancer cells. We focused on the utilization of glucose and glutamine, the two most abundant extracellular nutrients, which together account for the bulk of carbon and nitrogen metabolism in tumor cells. Docetaxel resistant (DOCETR) cells consumed glutamine more avidly and secreted glutamate and ammonia at a greater rate than sensitive parental cells. Surprisingly, contribution of glutamine carbon into the TCA cycle was unchanged in DOCETR cells despite the higher glutamine utilization. Transfer of glutamine carbon into both the intracellular and extracellular glutamate pools, on the other hand, was higher in DOCETR cells, indicating that the DOCETR cells had an increased ability to convert glutamine to glutamate and then to secrete the glutamate. Accordingly, these cells also had increased expression and activity of glutaminase, the major enzyme responsible for glutamine deamidation. Because glutaminase activity does not yield energy unless the resulting glutamate is further oxidized, we hypothesized that this metabolic transition served a non-bioenergetic role, possibly supporting enhanced rates of glutathione synthesis for modification and secretion of docetaxel. Consistent with this idea, DOCETR cells displayed an increase in de novo synthesis of glycine, which is required for the production of glutathione. Importantly, a glutaminase inhibitor re-sensitized DOCETR cells to docetaxel, strongly suggesting that their enhanced glutamine metabolism was involved in resistance to the drug. We speculate that alterations in glutamine metabolism provide a general and targetable mechanism for xenobiotic resistance in cancer cells. 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 1248. doi:10.1158/1538-7445.AM2011-1248
Influence of Melanosome Dynamics on Melanoma Drug Sensitivity
Authors: Kevin G. Chen, Richard D. Leapman, Guofeng Zhang, Barry Lai, Julio C. Valencia, Carol O. Cardarelli, Wilfred D. Vieira, Vincent J. Hearing, Michael M. Gottesman
Journal: JNCI Journal of the National Cancer Institute (2009)

BackgroundMalignant melanomas are intrinsically resistant to many conventional treatments, such as radiation and chemotherapy, for reasons that are poorly understood. Here we propose and test a model that explains drug resistance or sensitivity in terms of melanosome dynamics.
Conserved noncoding sequences are selectively constrained and not mutation cold spots
Authors: Jared A Drake, Christine Bird, James Nemesh, Daryl J Thomas, Christopher Newton-Cheh, Alexandre Reymond, Laurent Excoffier, Homa Attar, Stylianos E Antonarakis, Emmanouil T Dermitzakis, Joel N Hirschhorn
Journal: Nature Genetics (2005)
Polymorphism in CYP1A1 and CYP2D6 genes: possible association with susceptibility to lung cancer.
Authors: A Hirvonen, K Husgafvel-Pursiainen, S Anttila, A Karjalainen, H Vainio
Journal: Environmental Health Perspectives (1993)

Polymorphism of CYP2D6 gene encoding for debrisoquine hydroxylase was determined genotypically for 94 controls and 77 lung cancer patients using a polymerase chain reaction-based application. Both of the point mutations that give rise to deficient alleles of the CYP2D6 gene are detectable by this method. Out of the 94 healthy controls, 3 individuals (3.2%) had poor metabolizer (PM) genotypes, whereas no PM genotypes were detected in the lung cancer patient group. We observed no difference in the allelic frequencies for either homozygous extensive metabolizers (EMs) or heterozygous EMs between the lung cancer patients and the healthy controls. However, the absence of the poor metabolizer genotype (0/77) in the lung cancer patients is compatible with the hypothesis that there is an increased risk of lung cancer for individuals who are extensive metabolizers of debrisoquine. Another member of the cytochrome P450 gene superfamily that has attracted interest for its potential role in human pulmonary carcinogenesis is the CYP1A1 gene. In CYP1A1 gene studies, a polymorphic site assessable to MspI gives rise to two different hybridizable fragments in a Southern blot analysis (alleles C1 and C2, respectively). The C2C2 genotype has previously been associated with an increased risk of lung cancer. So far 74 lung cancer patients, 30 patients with lung diseases other than cancer, and 118 healthy controls have been studied for CYP1A1 gene polymorphism. No association between the MspI restriction fragment length polymorphism in the CYP1A1 gene and lung cancer susceptibility has been found.
Tumor necrosis factor α regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats
Authors: Masayuki Ohta, Andrzej S. Tarnawski, Rabiha Itani, Rama Pai, Morimasa Tomikawa, Keizo Sugimachi, James I. Sarfeh
Journal: Hepatology (1998)

Anti-tumor necrosis factor α (TNF-α) treatment decreases nitric oxide (NO) synthesis and ameliorates the hyperdynamic circulation in portal hypertensive rats. We have recently demonstrated that nitric oxide synthase isoform 3 (NOS3) is overexpressed in portal hypertensive gastric mucosa and that resultant NO overproduction probably is responsible for the increased susceptibility of the mucosa to damage. In the present study, we examined whether TNF-α is overexpressed in portal hypertensive gastric mucosa and whether anti-TNF-α treatment affects gastric NOS3 messenger RNA (mRNA) and protein expression. We examined plasma concentrations of TNF-α and its protein expression in gastric specimens from portal hypertensive and sham-operated rats using Western blotting and immunohistochemistry. We also measured gastric mucosal blood flow, gastric expression of NOS3 mRNA and protein, and NOS3 enzyme activity in rats with and without TNF-α- neutralizing antibody treatment. The TNF-α protein levels in portal hypertensive stomachs were significantly increased by 57% compared with levels in sham-operated controls. TNF-α antibody treatment normalized gastric mucosal blood flow in portal hypertensive stomachs and significantly reversed overexpression of gastric NOS3 mRNA, protein, and its enzyme activity in portal hypertensive rats by 48%, 45%, and 33%, respectively. These results suggest that TNF-α may regulate NOS3 expression in the portal hypertensive stomach and that anti-TNF-α treatment may ameliorate the pathophysiological abnormalities of portal hypertensive gastric mucosa.
Expression of a Protein Kinase C Inhibitor in Purkinje Cells Blocks Cerebellar LTD and Adaptation of the Vestibulo-Ocular Reflex
Authors: Chris I. De Zeeuw, Christian Hansel, Feng Bian, Sebastiaan K.E. Koekkoek, Adriaan M. van Alphen, David J. Linden, John Oberdick
Journal: Neuron (1998)

Cerebellar long-term depression (LTD) is a model system for neuronal information storage that has an absolute requirement for activation of protein kinase C (PKC). It has been claimed to underlie several forms of cerebellar motor learning. Previous studies using various knockout mice (mGluR1, GluRδ2, glial fibrillary acidic protein) have supported this claim; however, this work has suffered from the limitations that the knockout technique lacks anatomical specificity and that functional compensation can occur via similar gene family members. To overcome these limitations, a transgenic mouse (called L7-PKCI) has been produced in which the pseudosubstrate PKC inhibitor, PKC[19–31], was selectively expressed in Purkinje cells under the control of the pcp-2(L7) gene promoter. Cultured Purkinje cells prepared from heterozygous or homozygous L7-PKCI embryos showed a complete blockade of LTD induction. In addition, the compensatory eye movements of L7-PKCI mice were recorded during vestibular and visual stimulation. Whereas the absolute gain, phase, and latency values of the vestibulo-ocular reflex and optokinetic reflex of the L7-PKCI mice were normal, their ability to adapt their vestibulo-ocular reflex gain during visuo-vestibular training was absent. These data strongly support the hypothesis that activation of PKC in the Purkinje cell is necessary for cerebellar LTD induction, and that cerebellar LTD is required for a particular form of motor learning, adaptation of the vestibulo-ocular reflex.
Real-time observation of ruptured right sinus of Valsalva aneurysm by high speed ultrasono-cardiotomography. Report of a case.
Authors: K Nishimura, N Hibi, T Kato, Y Fukui, T Arakawa
Journal: Circulation (1976)

A two-dimensional echocardiographic manifestation of a ruptured right sinus of Valsalva aneurysm is described in this case report. The ultrasono-cardiotomograms demonstrated the aneurysm cut longitudinally and protruding into the outflow tract of the right ventricle. The configuration of the aneurysm was consistent with the contrast medium-filled sinus demonstrated by angiocardiography. In systole, the aneurysmal sinus moved anteroinferiorly together with the aortic wall. The echocardiogram revealed an abnormal two-layered horizontal echo in the right ventricle which showed the aneurysm when the ultrasonic beam passed through the interventricular septum near the aortic root and mitral leaflets. During the operation, the protruding sinus and a small interventricular septal defect in the membranous septum under it were observed through the opened right ventricle. After the closure of the aneurysm, the two-dimensional echocardiogram no longer showed an abnormal configuration.
Echocardiography in Active Infective Endocarditis.
Authors: Richard D. Spangler
Journal: Annals of Internal Medicine (1973)

Meeting Abstracts1 May 1973Echocardiography in Active Infective Endocarditis.Richard D. Spangler, M.D., F.A.C.P., J. Thomas Okin, M.D., Michael L. Johnson, M.D., Joseph H. Holmes, M.D., F.A.C.P., S. Gilbert Blount Jr, M.D.Richard D. Spangler, M.D., F.A.C.P.Search for more papers by this author, J. Thomas Okin, M.D.Search for more papers by this author, Michael L. Johnson, M.D.Search for more papers by this author, Joseph H. Holmes, M.D., F.A.C.P.Search for more papers by this author, S. Gilbert Blount Jr, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-78-5-822_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptEchocardiograms were obtained in 9 patients with active infective endocarditis. Echocardiographic findings were confirmed by cardiac catheterization (6 patients) and cardiac surgery (6 patients). Echocardiography showed bacterial vegetations on the mitral leaflets in three patients with mitral stenosis. Open mitral commissurotomy showed multiple bacterial vegetations intermittently occluding a moderately narrowed mitral orifice. A 12-year-old patient presented with congestive heart failure and fever. Echocardiography showed congenital mitral valvular stenosis and questionable vegetations. Hemodynamic findings were confirmed by catheterization, and vegetations on the valve were seen at the time of prosthetic mitral-valve replacement. In two patients echocardiography showed bacterial vegetations on the... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: Richard D. Spangler, M.D., F.A.C.P.; J. Thomas Okin, M.D.; Michael L. Johnson, M.D.; Joseph H. Holmes, M.D., F.A.C.P.; S. Gilbert BlountJr, M.D.Affiliations: Denver, Colorado. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1973Volume 78, Issue 5Page: 822-822KeywordsCardiac surgeryCatheterizationEchocardiographyEndocarditisFeversHeart failureHemodynamicsMitral stenosisMitral valve replacementStenosis ePublished: 1 December 2008 Issue Published: 1 May 1973 PDF downloadLoading ...
Mediastinal Mass in a Sick Infant
Authors: David P. Colley
Journal: JAMA (1974)

<h3>History</h3> Cough and slight fever developed in a 3-month-old infant. The physical examination gave normal results. A chest roentgenogram was obtained. <h3>Diagnosis</h3> Normal chest roentgenogram with normal thymic shadow. Discussion: The chest roentgenogram shows normal bony structures, lung fields, and pleura. The heart is not enlarged, but there is a shadow projecting superiorly and laterally to the right of the heart and mediastinum (Fig 1, top). This shadow has a subtle, wavy lateral margin with indentations exactly opposite the anterior ends of the ribs (Fig 1, bottom). This is the thymic "wave sign," first described by Mulvey,<sup>1</sup>which indicates that the shadow in question is the thymus. Intimate contact between the lateral border of normal soft thymic tissue and the anterior ends of the ribs (or their chondral extensions) creates this characteristic roentgenographic appearance. Thymic tumors or other masses in the anterior mediastinum are generally firmer and not positioned
Synergistic Antitumor Activity of Recombinant Human Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) in Combination with Carboplatin and Pemetrexed in Malignant Pleural Mesothelioma
Authors: Giulia Pasello, Loredana Urso, Micol Silic-Benussi, Marco Schiavon, Ilaria Cavallari, Giuseppe Marulli, Nazarena Nannini, Federico Rea, Vincenzo Ciminale, Adolfo Favaretto
Journal: Journal of Thoracic Oncology (2014)
An increasingly complex code
Authors: Hugh T. Spotswood, Bryan M. Turner
Journal: Journal of Clinical Investigation (2002)

The nucleosome core particle is the fundamental unit of chromatin structure in all eukaryotes. It comprises eight core histones (two each of H2A, H2B, H3, and H4) around which are wrapped 146 bp of DNA, and its structure has been defined at 2.8 Å resolution by x-ray crystallography (1). Since it was first described, it has been assumed that the function of the core particle is to package DNA into the interphase cell nucleus and metaphase chromosomes. Wrapping DNA around the histone octamer in left-handed supercoils results in an approximately sevenfold reduction in its length. Although this is only a small fraction of the several-thousand-fold length reduction required for compaction into metaphase chromosomes, it is presumably an essential first step that enables higher-order structures to assemble.

The nucleosome’s rather mundane packaging job became more interesting with the realization that compaction of DNA into chromatin is a crucial element in eukaryotic gene regulation (2). Appropriately located nucleosomes can hinder assembly of transcription initiation complexes and polymerase progression, and over recent years, whole families of chromatin-remodeling enzymes have been identified whose primary purpose is to reorganize histone-DNA interactions so as to facilitate (or repress) transcription (3). These enzymes disrupt the nucleosome in an ATP-dependent manner that often results in movement of the histone core relative to the DNA, thereby exposing recognition sequences for DNA-binding activators or repressors. However, even these insights still left the nucleosome as a passive inhibitor of transcription, something to be moved aside so transcription could proceed.

The final transformation of the nucleosome into a truly exciting and colorful character has come through studies on the effects and properties of other enzymes that act on chromatin. It has been known for many years that the histone N-terminal tails are exposed on the surface of the nucleosome and that selected amino acid residues are subject to a variety of enzyme-catalyzed, posttranslational modifications. These include acetylation of lysines, phosphorylation of serines, and methylation of lysines and arginines. The locations of the histone N-terminal tails in the nucleosome and the residues that can be modified are shown in Figure ​Figure1.1. The function of these modifications, and indeed of the tails themselves, is the focus of much current attention, centered largely on the possibility that the nucleosome, with its modified tail domains, is not just a humble packer of DNA, but a carrier of epigenetic information that determines both how genes are expressed and how their expression patterns are maintained from one cell generation to the next.



Figure 1

A nucleosome core particle, showing the core histone N-terminal tail domains and sites of posttranslational modification. Residue numbers for modified residues are shown. Note that H3 lysine 9 (star) can be either acetylated or methylated. The C-terminal ...
The Self-reporting of Cocaine Use-Reply
Authors: Sally E. McNagny
Journal: JAMA (1992)

<h3>In Reply.</h3> —Drs Gleason and Barnum's references indicate that gas chromatography/mass spectrometry identifies cocaine use in patients who have negative EMIT cocaine metabolite assays, the assay used by us as our criterion standard. Using these data and the figures from our article, they have calculated the prevalence of cocaine use in our population to be an astonishingly high 51%. We agree that our prevalence rate was only a minimum estimate of recent cocaine use and appreciate his point that actual prevalence may be even higher. Dr Holland suggests a creative design to ensure informed consent and to address the question of how foreknowledge of urine testing would affect questionnaire responses. However, urine screening information based on those subjects who consent to urine testing is not easily extrapolated to those subjects who refuse consent for urine testing. Moreover, as Holland points out, analysis based on missing data can only approximate true
Prognostic Implications of Aberrations in p16&amp;sol;pRb Pathway in Urothelial Bladder Carcinomas: A Multivariate Analysis Including p53 Expression and Proliferation Markers
Authors: Penelope Korkolopoulou, Panayota Christodoulou, Andreas Lazaris, Euphemia Thomas-Tsagli, Panayotis Kapralos, Athanassios Papanikolaou, Ioanna Kalliteraki, Panayotis Davaris
Journal: European Urology (2001)