tbuckley/cabot-search huggingface dataset:
Fall in peak expiratory flow during haemodialysis in patients with chronic renal failure.
Authors: A Davenport, A J Williams
Journal: Thorax (1988)

Peak expiratory flow rate (PEF) was measured during haemodialysis in 30 unselected patients with chronic renal failure. The patients attended the hospital dialysis unit, where they received regular dialysis using a cuprophan dialyser with acetate buffered dialysate. Mean PEF had fallen by 60 l/min (13%) 30 minutes after the start of dialysis. In 10 of the 30 patients the fall in PEF was over 15%, the maximum fall being 32%. After the initial fall PEF increased throughout the next 2.5 hours of haemodialysis, but it fell again at five hours in the 14 patients who had been dialysed for four hours. During dialysis there was a reduction in blood white cell and platelet counts and in arterial oxygen tension at 30 and 60 minutes (p less than 0.05) and the white cell count and arterial oxygen tension were still reduced at three hours. The coincidence of the fall in PEF at 30 minutes and the fall in arterial oxygen tension suggests that bronchoconstriction might contribute to dialysis induced hypoxaemia by causing ventilation-perfusion disturbances. Appreciable airway dysfunction occurred in all the patients undergoing regular haemodialysis with new cuprophan dialysers and acetate buffered dialysate.
Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWS/FLI Modulator in Ewing Sarcoma
Authors: Kimberly Stegmaier, Jenny S Wong, Kenneth N Ross, Kwan T Chow, David Peck, Renee D Wright, Stephen L Lessnick, Andrew L Kung, Todd R Golub
Journal: PLoS Medicine (2007)

Background The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression–based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application. Methods and Findings A gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted. Conclusions We demonstrate that a gene expression–based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers.
Evolution of ribosomal RNA gene copy number on the sex chromosomes of Drosophila melanogaster.
Authors: E M Lyckegaard, A G Clark
Journal: Molecular Biology and Evolution (1991)

A diverse array of cellular and evolutionary forces--including unequal crossing-over, magnification, compensation, and natural selection--is at play modulating the number of copies of ribosomal RNA (rRNA) genes on the X and Y chromosomes of Drosophila. Accurate estimates of naturally occurring distributions of copy numbers on both the X and Y chromosomes are needed in order to explore the evolutionary end result of these forces. Estimates of relative copy numbers of the ribosomal DNA repeat, as well as of the type I and type II inserts, were obtained for a series of 96 X chromosomes and 144 Y chromosomes by using densitometric measurements of slot blots of genomic DNA from adult D. melanogaster bearing appropriate deficiencies that reveal chromosome-specific copy numbers. Estimates of copy number were put on an absolute scale with slot blots having serial dilutions both of the repeat and of genomic DNA from nonpolytene larval brain and imaginal discs. The distributions of rRNA copy number are decidedly skewed, with a long tail toward higher copy numbers. These distributions were fitted by a population genetic model that posits three different types of exchange events--sister-chromatid exchange, intrachromatid exchange, and interchromosomal crossing-over. In addition, the model incorporates natural selection, because experimental evidence shows that there is a minimum number of functional elements necessary for survival. Adequate fits of the model were found, indicating that either natural selection also eliminates chromosomes with high copy number or that the rate of intrachromatid exchange exceeds the rate of interchromosomal exchange.
Effects of the long‐term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study
Authors: Viviane M. Conraads, Marco Metra, Otto Kamp, Gilles W. De Keulenaer, Burkert Pieske, José Zamorano, Panos E. Vardas, Michael Böhm, Livio Dei Cas
Journal: European Journal of Heart Failure (2011)
A Phylogenomic Study of Endosymbiotic Bacteria
Authors: B. Canback
Journal: Molecular Biology and Evolution (2004)

Endosymbiotic bacteria of aphids, Buchnera aphidicola, and tsetse flies, Wigglesworthia glossinidia, are descendents of free-living γ-Proteobacteria. The acceleration of sequence evolution in the endosymbiont genomes is here estimated from a phylogenomic analysis of the γ-Proteobacteria. The tree topologies associated with the most highly conserved genes suggest that the endosymbionts form a sister group with Escherichia coli, Salmonella sp., and Yersinia pestis. Our results indicate that deviant tree topologies result from high substitution rates and biased nucleotide patterns, rather than from lateral gene transfer, as previously suggested. A reinvestigation of the relative rate increase in the endosymbiont genomes reveals variability among genes that correlate with host-associated metabolic dependencies. The conclusion is that host-level selection has retarded both the loss of genes and the acceleration of sequence evolution in endocellular symbionts.
Congenital peristernal dermal sinuses: a new entity?
Authors: T. Kubo, T. Takagi, Y. Yamaguchi, K. Yano, K. Hosokawa
Journal: British Journal of Dermatology (2008)

Conflicts of interest: none declared. Sir, Congenital dermal sinuses, including periauricular sinuses, spinal dermal sinuses and nasal dermoid sinuses, are sometimes encountered. Dermal sinuses have also been described in every region of the scalp, including the occipital region1, 2 and the frontotemporal region.3 However, congenital peristernal dermal sinuses are extremely rare. To the best of our knowledge they have not been reported in the English language literature. We present seven patients with congenital dermal sinuses in the peristernal region (Table 1, Fig. 1). All the lesions were detected at birth. Probing of all cases revealed a subcutaneous tract. In five of the seven cases, the lesions were extirpated and surgical exploration showed a blind‐ended tract ending at the fascial layer of the pectoralis major muscle. We describe a representative case. A 10‐year‐old Japanese girl (patient 4 in Table 1) with a punctum in her left anterior thoracic wall was referred to our department (Fig. 2a). Her parents noticed the punctum at birth. The punctum was located at the intersection of the left parasternal line and the left first intercostal space. She was clinically well and asymptomatic. Ultrasonography revealed a subcutaneous tract extending toward the pectoralis major muscle (Fig. 2b). Therefore, we diagnosed it as a sinus and excised it after staining with a blue dye. Surgical exploration disclosed a blind‐ended sinus ending at the fascia of the pectoralis major muscle (Fig. 2c,d). Histopathological examination showed that the lesion was lined by keratinized squamous epithelium. Numerous hair follicles, in varying stages of development, were observed in the sinus wall (Fig. 2e,f). The lesion was diagnosed histologically as a dermal sinus. The postoperative course was uneventful.
Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Authors: Anju Singh, Vikas Misra, Rajesh K Thimmulappa, Hannah Lee, Stephen Ames, Mohammad O Hoque, James G Herman, Stephen B Baylin, David Sidransky, Edward Gabrielson, Malcolm V Brock, Shyam Biswal
Journal: PLoS Medicine (2006)

Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs.Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.
THE ADJUSTMENT OF RESPONSE TO NERVE STIMULUS IN VOLUNTARY MUSCLES
Authors: G. M. Levick
Journal: BMJ (1919)

tlle outbreak of the revolution.At the railway station our gluard was deprived of his shipulder str4ps showing the number of his regimnent, and his cap badges were also removed.Trains flyinig the red-flag, crowded witlh troops without arms and badgeless, passed through the station.The red flag was flying over an aeroplane factory at Gotha, over the station and over various barracks.Aeroplanes flying low dropped leaflets over-all towns and villages requesting the troops to join in the movement.As a result of this change we were informed on arrival at our destination by a private soldier wearing a,red armlet 'that he was now hlead of the hospital, and that all requests imust be addressed to him.A new Chef-arzt of socialistic opinions was introduced to the hospital, but as he was qlosely supervised by the Soldatenrat, or soldiers' council, lie was more or less powerless, and we had few dealings with him beyond drawing lis attention to various matters in connexion with the sanitation of the hospital.We left this hospitql on Christmas Day by hospital train, taking all the British with us.Lying cases were conveyed to the station in pantechnicons, tlle floors of which were covered-with mattresses.The hospital train provided by the Germans was .good of its kind, and had enough bunks, with clean bed-linen, for the majority of the patients.A day and a half later we ran alongside the naval hospital ship Garth Ca8tle at Stettin, where we were warmly welcomed, and on her we travelled in all comfort.WNe returned from Germany with a higher opinion of ,British organization than ever before.
Repeated tuberculin testing does not induce false positive ELISPOT results
Authors: L Richeldi
Journal: Thorax (2006)

The Enzyme Linked ImmunoSpot (ELISPOT) is a new rapid T cell based blood test (otherwise known as an interferon-γ assay) for the diagnosis of latent tuberculosis infection.1–3 The commercially available form of the assay, T-SPOT® TB (Oxford Immunotec, Abingdon, UK) has European regulatory approval as an in vitro diagnostic test and is increasingly being used in clinical practice. The test is based on the enumeration of interferon-γ producing T cells which are specific for two highly antigenic proteins, early secretory antigenic target-6 (ESAT-6) and culture filtrate protein 10 (CFP-10).1 These proteins are expressed by Mycobacterium tuberculosis but are absent from M bovis BCG vaccine. Hence, the test does not give false positive results in BCG vaccinated individuals.1–3

ESAT-6 and CFP-10 are, however, contained within tuberculin purified protein derivative (PPD). Since ELISPOT is a highly sensitive method for measuring even low numbers of antigen specific T cells,4 concerns have been raised as to whether repeated tuberculin skin tests might induce T cell responses to these specific antigens, resulting in false …
Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3
Authors: Maria Amann, Klaus Brischwein, Petra Lutterbuese, Larissa Parr, Laetitia Petersen, Grit Lorenczewski, Eva Krinner, Sandra Bruckmeier, Sandra Lippold, Roman Kischel, Ralf Lutterbuese, Peter Kufer, Patrick A. Baeuerle, Bernd Schlereth
Journal: Cancer Research (2008)

EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibody-based immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 microg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 microg/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant therapeutic window for an EpCAM-specific BiTE antibody in mice. MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development.
Shared idiotypic determinants on B and T lymphocytes reactive against the same antigenic determinants. III. Physical fractionation of specific immunocompetent T lymphocytes by affinity chromatography using anti-idiotypic antibodies.
Authors: H Binz, H Wigzell
Journal: The Journal of Experimental Medicine (1975)

Anti-idiotypic antibodies made against antigen-binding receptors on T lymphocytes with specificity for certain Ag-B locus antigens selectively react with T lymphocytes with potential immune reactivity against the very same Ag-B antigens. This was shown by affinity chromatography of normal Lewis T lymphocytes on anti-Ig columns after contact with the relevant anti-idiotypic antiserum. Here, it could be shown that incubation of the cells with an anti-(Lewis-anti-BN) antiserum caused subsequent selective retention of potential graft-vs.-host (GvH)-reactive cells against BN on the anti-Ig column, whereas Lewis T cells with reactivity against DA or August (Au) (carrying distinct Ag-B antigens in comparison to BN) passed through. The retained cells could be eluted and shown to display highly increased reactivity against BN with virtually no reactivity left against DA or Au antigens. Analogous results were obtained using an anti-(Lewis-anti-DA) antiserum. The anti-idiotypic antibodies can be used in fluorescent antibody tests to directly visualize the idiotype-positive cells. Using the separation design described above we analyzed selectively enriched or deleted T lymphocytes for presence of idiotypic cells as well as specific GvH reactivity. A highly significant positive correlation was found between percentage of a given idiotype in a population of T cells and the relevant GvH potential of the same T cells that can be visualized are indeed the very same T cells that express immune reactivity against the expected antigens. The present data would thus directly demonstrate the existence of a largely nonoverlapping population of immunocompetent T cells capable of reacting against the various Ag-B locus antigens in the rat. Highly purified, functionally intact immunocompetent T lymphocytes with restricted immune reactivity can thus be produced from normal lymphocyte populations for further analysis.
High Level of Glutathione-<b> <i>S</i> </b>-Transferase π Expression in Mantle Cell Lymphomas
Authors: Annelise Bennaceur-Griscelli, Jacques Bosq, Serge Koscielny, François Lefrère, Ali Turhan, Nicole Brousse, Olivier Hermine, Vincent Ribrag
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Prognosis of mantle cell lymphoma (MCL) remains poor. Patients who achieve a response to first line therapy usually relapse, and the probability of cure remains low. Glutathione-S-transferase π (GST-π) overexpression has been associated with alkylating agents and anthracycline resistance. GST-π gene is located in 11q13 and is coamplified along with CCND1 gene in some human solid tumors. Experimental Design: We performed immunohistochemical analysis of GST-π expression in 24 consecutive MCLs, 12 follicular lymphomas (FLs), and 69 diffuse large B-cell lymphomas (DLBCLs). Cases were classified in three groups: high GST-π expression (&amp;gt; 50% of cells were stained), moderate (5 to 50% cells were stained), or absent (&amp;lt; 5% cells were stained). GST-π and CCND1 mRNA levels were also assessed by real-time reverse transcription-PCR analysis. Results: All MCLs exhibit high GST-π protein expression, compared with 29% of the DLBCLs and none of the FLs. MCLs expressed high levels of GST-π and CCND1 mRNAs compared with DLBCLs and FLs. There was a strong relation between GST-π and CCND1 mRNAs transcript levels in MCLs but not in DLBCLs. In conclusion, protein and mRNA GST-π expression is high in MCL compared with FL and DLBCL. Conclusions: Overexpression of CCND1 in MCL is associated with a transcriptional up-regulation of the GST-π gene. Our results suggest that the glutathione system could play a role in drug resistance in MCL.
Evolution of the vertebrate H1 histone class: evidence for the functional differentiation of the subtypes
Authors: I. Ponte, J. M. Vidal-Taboada, P. Suau
Journal: Molecular Biology and Evolution (1998)

Histone H1 subtypes are involved in chromatin higher-order structure. The representation of the subtypes varies greatly depending on the cellular and developmental context. We have estimated the rates of nucleotide substitution for several H1 subtypes, including mammalian and amphibian H1 degree, avian H5, and mammalian H1a-e and H1t, with the aim of finding evidence for their functional differentiation. The rates of nonsynonymous substitution differ among the subtypes by almost one order of magnitude. Such a wide variation in the degree of tolerance of amino acid substitutions is consistent with the functional differentiation of the subtypes. H1 has a characteristic three-domain structure. The rate ratios among the domains of the molecule are not systematically maintained in the different subtypes. This suggests the assumption of differentiated functions by the individual domains in chromatin structure. We have estimated the average time of divergence of H1a-e and H1t paralogs as 406 +/- 80 Myr. The lack of evidence for concerted evolution of H1a-e and H1t since long before the mammalian radiation further supports the functional differentiation of the subtypes.
Evidence for Involvement of Mast Cells in Tumor Suppression in Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: H Tanooka, Y Kitamura, T Sado, K Tanaka, M Nagase, S Kondo
Journal: JNCI Journal of the National Cancer Institute (1982)

Mast cell-deficient W/Wv mice had an increased tumor incidence after subcutaneous treatment with 3-methylcholanthrene, compared with that in normal congenic mice treated in the same way. This increased tumor incidence was suppressed to the normal level when the carcinogen was given after the mast cell deficiency had been overcome by transplantation of bone marrow cells from normal congenic mice. The W/Wv mice, however, were not defective in natural killer and T-cell-mediated cytotoxic activities. These results support the hypothesis that mast cells are involved in tumor suppression.
Cephalexin Levels in Human Bile in Presence of Biliary Tract Disease
Authors: J. E. L. Sales, M. Sutcliffe, F. O'Grady
Journal: BMJ (1972)

Cephalexin was given to 24 patients before and after operation on the bile ducts and gall bladder. Two patients had obstructive jaundice. Samples of the bile were taken either directly from the gall bladder at operation or via the T-tube. Cephalexin was excreted in the bile, peak levels being obtained after two to three hours. These levels could be raised if probenecid was given concurrently. Higher levels were found in patients with functioning gall-bladders. A trial of cephalexin seems justified for the treatment of typhoid carriers.