tbuckley/cabot-search huggingface dataset:
Increased Oral Bioavailability of Topotecan in Combination With the Breast Cancer Resistance Protein and P-Glycoprotein Inhibitor GF120918
Authors: C. M.F. Kruijtzer, J. H. Beijnen, H. Rosing, W. W. ten Bokkel Huinink, M. Schot, R. C. Jewell, E. M. Paul, J. H.M. Schellens
Journal: Journal of Clinical Oncology (2002)

PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate–binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(−/−) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m 2 oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m 2 intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. RESULTS: After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 ± 9.6 μg·h/L without GF120918 to 78.7 ± 20.6 μg·h/L when GF120918 was coadministered (P = .008). The mean maximum plasma concentration of total topotecan increased from 4.1 ± 1.5 μg/L without GF120918 to 11.5 ± 2.4 μg/L with GF120918 (P = .008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P = .008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. CONCLUSION: Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.
Epiglycanin-Immunoreactive Glycoproteins in Mouse Fetal Tissues and Fetal Cells in Culture<xref ref-type="fn" rid="FN2">2</xref>
Authors: M Beppu, J F Codington, R D Lasky, R W Jeanloz
Journal: JNCI Journal of the National Cancer Institute (1987)

Fetal tissues from time-pregnant female A/J mice of 16- and 19-day pregnancies and from neonates 1 day after birth, as well as from fetal cells in culture, absorbed significant amounts of anti-epiglycanin antibody. Detergent-solubilized glycoproteins, with epiglycanin activity, from fetal tissues and cells were separated by polyacrylamide gel electrophoresis, and the protein bands electroblotted onto a nitrocellulose gel. After the antigens were labeled with rabbit anti-epiglycanin antiserum and [125I]epiglycanin, autoradiography revealed two major bands containing the antigenic determinant at Mr 90,000 and 82,000. Bands of similar molecular weights, but with no demonstrated immunologic crossreactivity, were observed by fluorography, if intact cells prior to solubilization were labeled by galactose oxidase followed by sodium borotritiide. Immunoreactive epiglycanin activity could be destroyed by Pronase, endo-N-acetyl-α-d-galactosaminidase (Diplococcus pneumoniae), or periodate oxidation. Activity was enhanced with neuraminidase. The spleen, liver, or erythrocytes from adult A/J mice did not possess the antigen, but incubation of adult spleen or liver with neuraminidase (Vibrio cholerae) exposed the epitope.
Therapeutic Targeting of Transcription in Acute Promyelocytic Leukemia by Use of an Inhibitor of Histone Deacetylase
Authors: R. P. Warrell, L.-Z. He, V. Richon, E. Calleja, P. P. Pandolfi
Journal: JNCI Journal of the National Cancer Institute (1998)

Acetylation of DNA-associated histones is linked to activation of gene transcription, whereas histone deacetylation is associated with transcriptional repression. Recent studies have shown that inhibitors of histone deacetylases can relieve transcriptional repression caused by the products of certain oncogenes. We tested whether these findings could be applied clinically to a patient with highly resistant acute promyelocytic leukemia.A patient who had experienced multiple relapses was treated with all-trans-retinoic acid alone and in combination with sodium phenylbutyrate, an inhibitor of histone deacetylases. Immunohistochemistry and western blot analysis were used to assay for histone hyperacetylation in mononuclear cells from the patient's blood and bone marrow. Marrow mononuclear cells and reverse transcription-polymerase chain reaction (RT-PCR) analysis of messenger RNA encoded by the PML/RAR-alpha oncogene were used to assess minimal residual disease.The patient proved clinically resistant to treatment with all-trans-retinoic acid alone. However, 23 days after sodium phenylbutyrate was added to the treatment regimen, visible leukemic cells had been eliminated from her bone marrow, and she achieved a complete clinical and cytogenetic remission shortly thereafter. With a second treatment course, analysis for minimal residual disease by RT-PCR proved negative. Immunofluorescence and western blot analysis showed that phenylbutyrate caused a time-dependent increase in histone acetylation in blood and bone marrow mononuclear cells.Clinical treatment with an inhibitor of histone deacetylase induces histone hyperacetylation in target cells and may restore sensitivity to the anti-leukemic effects of all-trans-retinoic acid in acute promyelocytic leukemia. Similar therapy may prove useful in other neoplastic diseases that are associated with oncogenic repression of gene transcription due to recruitment of histone deacetylases.
Detection of multiple viral DNA species in synovial tissue and fluid of patients with early arthritis
Authors: H.-D. Stahl
Journal: Annals of the Rheumatic Diseases (2000)

Viruses have a role in the pathogenesis of various forms of arthritis. This study aimed at determining whether viral DNA can be detected in joint samples in the early stages of idiopathic arthritides.Synovial fluid (SF) and synovial tissue (ST) samples were obtained from 73 patients, with undifferentiated arthritis (n=22), rheumatoid arthritis (n=13), spondyloarthropathy (n=17), crystal arthropathy (n=8), osteoarthritis (n=7), septic arthritis (n=5), and trauma (n=1). The presence of viral DNA was investigated by polymerase chain reaction analysis.Cytomegalovirus was present in 25 patients, parvovirus B19 in 15 patients, Epstein-Barr virus in 12 patients, and herpes simplex virus in 16 patients (in ST, SF, or both), respectively. The joint samples were negative for viral DNA from adenovirus and varicella-zoster virus. In ST, eight patients were double positive for parvovirus B19 and another viral DNA, with herpes simplex virus being the most prevalent. Seven patients were double positive for other viruses (cytomegalovirus, herpes simplex virus, Epstein-Barr virus). In SF, four patients were double or triple positive for viral DNA. Paired samples were available in 56 patients. In these, viral DNA was detected in 37 patients in ST, as compared with 19 in SF.These data show that one or more viruses can be detected in the synovial specimens of patients with early arthritis, irrespective of the clinical diagnosis. This observation might be explained by migration of inflammatory cells harbouring viral DNA into the inflamed joints.
Antineoplastons: The Controversy Continues-Reply
Authors: Saul Green
Journal: JAMA (1993)

<h3>In Reply.</h3> —The conclusions in my article were reached following a review and evaluation of the science in the material Dr Burzynski published. Rather than rebutting my conclusions, he resorts to charges of partiality because I served as scientific adviser in a litigation against him. Since my conclusions derived directly from his own statements, they would have been no different had I worked for Burzynski himself. I did not cite his other papers<sup>1</sup>because they were clinical reports, non-peer-reviewed speeches, or redundant reviews and as such were irrelevant for the evaluation of his science. Burzynski's curriculum vitae<sup>1</sup>does not list any paper as a PhD thesis. The Medical Academy of Lublin does not offer a PhD program (written communication, A. Gandara, International Education Research Foundation, Credentials Evaluation Service, Los Angeles, Calif, June 1991), a former professor recalls that his degree in 1968 was the DMSc,<sup>1</sup>his first
Pyridine nucleotide-dependent superoxide production by a cell-free system from human granulocytes.
Authors: B M Babior, J T Curnutte, B S Kipnes
Journal: Journal of Clinical Investigation (1975)

Using an assay that measured superoxide dismutase-inhibitable nitro blue tetrazolium reduction, we studied superoxide (O2-) production by a cell-free system from human granulocytes. At 40 muM NADPH and a protein concentration of 0.12 mg/ml, lysates prepared from human granulocytes formed O2- at a rate of 18. 4 +/- 4.6 SE nmol/ml reaction mixture per donor, but not with glucose-6-phosphate, 6-phosphogluconate, glyceraldehyde-3-phosphate, sodium lactate, glutathione, or ascorbic acid. The Km's for NADPH and NADH were 8.6 +/- 4.6 muM and 0.83 +/- 0.30 mM, respectively, suggesting that NADPH is the physiological electron donor in this system. O2- production was not inhibited by 1mM KCN. The rate of O2- production by the cell-free system was comparable to the rate of O2-production by an equivalent quantity of intact granulocytes incubated under similar conditions. O2- production by lysates from granulocytes preincubated with serum under conditions previously shown to stimulate O2- production in the intact cells was no different than its production by lysates from unstimulated cells. O2- production at 0.2 mM and 0.02 mM NADPH by lysates from the granulocytes of two patients with chronic granulomatous disease was similar to O2- production by control lysates. This finding was interpreted in terms of the possibility that the metabolic lesion in chronic granulomatous disease may lie outside the oxygen-metabolizing enzyme system of the granulocyte, or alternatively, that the granulocytes may contain two O2- - forming enzymes, one of which is inactive in chronic granulomatous disease.
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Authors: Tony S. Mok, Yi-Long Wu, Sumitra Thongprasert, Chih-Hsin Yang, Da-Tong Chu, Nagahiro Saijo, Patrapim Sunpaweravong, Baohui Han, Benjamin Margono, Yukito Ichinose, Yutaka Nishiwaki, Yuichiro Ohe, Jin-Ji Yang, Busyamas Chewaskulyong, Haiyi Jiang, Emma L. Duffield, Claire L. Watkins, Alison A. Armour, Masahiro Fukuoka
Journal: New England Journal of Medicine (2009)

Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non–small-cell lung cancer.
Prediction of in-hospital death from community-acquired pneumonia by varying CRB-age groups
Authors: Santiago Ewig, Torsten Bauer, Klaus Richter, Joachim Szenscenyi, Günther Heller, Richard Strauss, Tobias Welte
Journal: European Respiratory Journal (2012)

C(U)RB-65 (confusion, (urea >7 mol · L(-1),) respiratory frequency ≥ 30 breaths · min(-1), systolic blood pressure <90 mmHg or diastolic blood pressure ≤60 mmHg and age ≥ 65 years) is now the generally accepted severity score for patients with community-acquired pneumonia (CAP) in Europe. In an observational study based on the large database from the German nationwide performance measurement programme in healthcare quality, including data from all hospitalised patients with CAP during 2008-2010, different CRB-age groups (≥ 50 and ≥ 60 years) across the total CAP population and three entities of CAP (younger population aged <65 years, patients aged ≥ 65 years not residing in nursing homes and those with nursing home-acquired pneumonia (NHAP)) were validated for their potential to predict in-hospital death. 660 594 patients were investigated. Mortality was n=93 958 (14.0%). In the total population, CRB-80 had the optimal area under the curve (0.690, 95% CI 0.688-0.691). However, in the younger cohort, CRB-50 performed best (0.730, 95% CI 0.724-0.736), with good identification of low-risk patients (CRB-50 risk class 1: 1.28% deaths, negative predictive value 98.7%). In the elderly, CRB-80 as the optimal age group performed worse (0.663, 95% CI 0.660-0.655 in patients not residing in nursing homes; 0.608, 95% CI 0.605-0.611 in those with NHAP). In the latter group, all CRB-age groups failed to identify low-risk patients (CRB-80 risk class 1: 22.75% deaths, negative predictive value 81.8%). Patients with hospitalised CAP aged <65 years may be assessed by the CRB-50 score. In those aged ≥65 years (not NHAP) assessed by the CRB-65 score, low-risk patients are already are at an increased risk of death. In NHAP patients, even the use of CRB-80 does not identify low-risk patients and should be accompanied by the evaluation of functional status and comorbidity.
Ultrasound measurements of the spinal canal in spinal stenosis.
Authors: P Davies
Journal: BMJ (1982)

been in a surgical bed for a prolonged period is a "bed-blocker."On our evidence, most such patients are likely to be appropriately placed.Preservation and expansion of residential, geriatric, and psychogeriatric facilities are essential if some of the major needs of the aged population are to be met.It would be wrong, however, to expect such an expansion to solve the problem of prolonged surgical bed occupancy by the elderly.
Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk?
Authors: J Lagergren
Journal: Gut (2005)

The incidence of oesophageal adenocarcinoma is increasing and the prognosis is poor. There is a strong predominance of white males, and heredity plays a minor role. The established risk factors are Barrett's oesophagus, gastro-oesophageal reflux, and obesity. Infection with <i>Helicobacter pylori</i> and use of non-steroidal anti-inflammatory drugs might reduce the risk. Medications that relax the lower oesophageal sphincter might contribute to increasing the risk. Among dietary factors, low intake of fruit, vegetables, and cereal fibres seem to increase the risk of oesophageal adenocarcinoma. The role of tobacco smoking is probably limited and alcohol consumption is not a risk factor. It is uncertain which factors cause the increasing incidence. Increasing prevalences of reflux and obesity, and decreasing prevalence of <i>H pylori</i> infection may contribute to this development; however, the sex distributions of these factors do not match the incidence trends well. Endoscopic surveillance for oesophageal adenocarcinoma among persons with reflux and obesity is discussed, but presently there is no evidence that strongly supports such a strategy.
The U wave in the electrocardiogram: A solution for a 100-year-old riddle
Authors: H RITSEMAVANECK, J KORS, G VANHERPEN
Journal: Cardiovascular Research (2005)

In the electrocardiogram (ECG) the U wave follows the T, which is considered to reflect the repolarization of the cardiac ventricles. Despite the U wave's well-known clinical relevance, a satisfactory explanation of its origin is still outstanding. We have undertaken to explain the formation of the U wave by means of a simple digital model of the left ventricle.The model employs a multi-layered segment of the myocardium. To each layer an action potential (AP) is assigned with shape and duration according to published data. The potential differences between the APs produce time-varying electrical sources. Each source contributes to the potentials in an arbitrary point P of the body. The strength of this contribution is determined by a specific coefficient, the "lead vector", linking P to the source. The ECG recorded at P is calculated as the sum of all potential contributions.The repolarization waves constructed in this way reproduce the natural aspects of a T wave followed by a U wave. The creation of a U wave is conditional on small voltage differences between the tail ends of the APs. No fundamental demarcation exists between U wave and preceding T wave. The morphology of the T-U wave is dependent on the geometrical position of P with respect to the myocardium.T and U form a continuum. Together they are the resultant of one and the same process of repolarization of the ventricular myocardium. This has implications for the measurement of QT duration and for safety testing of drug-induced QT prolongation.
Planning cancer control in Latin America and the Caribbean
Authors: Paul E Goss, Brittany L Lee, Tanja Badovinac-Crnjevic, Kathrin Strasser-Weippl, Yanin Chavarri-Guerra, Jessica St Louis, Cynthia Villarreal-Garza, Karla Unger-Saldaña, Mayra Ferreyra, Márcio Debiasi, Pedro ER Liedke, Diego Touya, Gustavo Werutsky, Michaela Higgins, Lei Fan, Claudia Vasconcelos, Eduardo Cazap, Carlos Vallejos, Alejandro Mohar, Felicia Knaul, Hector Arreola, Rekha Batura, Silvana Luciani, Richard Sullivan, Dianne Finkelstein, Sergio Simon, Carlos Barrios, Rebecca Kightlinger, Andres Gelrud, Vladimir Bychkovsky, Gilberto Lopes, Stephen Stefani, Marcelo Blaya, Fabiano Hahn Souza, Franklin Santana Santos, Alberto Kaemmerer, Evandro de Azambuja, Andres Felipe Cardona Zorilla, Raul Murillo, Jose Jeronimo, Vivien Tsu, Andre Carvalho, Carlos Ferreira Gil, Cinthya Sternberg, Alfonso Dueñas-Gonzalez, Dennis Sgroi, Mauricio Cuello, Rodrigo Fresco, Rui Manuel Reis, Guiseppe Masera, Raúl Gabús, Raul Ribeiro, Renata Knust, Gustavo Ismael, Eduardo Rosenblatt, Berta Roth, Luisa Villa, Argelia Lara Solares, Marta Ximena Leon, Isabel Torres-Vigil, Alfredo Covarrubias-Gomez, Andrés Hernández, Mariela Bertolino, Gilberto Schwartsmann, Sergio Santillana, Francisco Esteva, Luis Fein, Max Mano, Henry Gomez, Marc Hurlbert, Alessandra Durstine, Gustavo Azenha
Journal: The Lancet Oncology (2013)
Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP
Authors: Renata Mazzucchelli, Julie A. Hixon, Rosanne Spolski, Xin Chen, Wen Qing Li, Veronica L. Hall, Jami Willette-Brown, Arthur A. Hurwitz, Warren J. Leonard, Scott K. Durum
Journal: Blood (2008)
DNA Repair and Cell Cycle Control Genes and the Risk of Young-Onset Lung Cancer
Authors: Stefano Landi, Federica Gemignani, Federico Canzian, Valérie Gaborieau, Roberto Barale, Debora Landi, Neonilia Szeszenia-Dabrowska, David Zaridze, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Lenka Foretova, Vladimir Janout, Vladimir Bencko, Lydie Gioia-Patricola, Janet Hall, Paolo Boffetta, Rayjean J. Hung, Paul Brennan
Journal: Cancer Research (2006)

Abstract Exposure to tobacco smoke and to mutagenic xenobiotics can cause various types of DNA damage in lung cells, which, if not corrected by DNA repair systems, may lead to deregulation of the cell cycle and, ultimately, to cancer. Genetic variation could thus be an important factor in determining susceptibility to tobacco-induced lung cancer with genetic susceptibility playing a larger role in young-onset cases compared with that in the general population. We have therefore studied 102 single-nucleotide polymorphisms (SNP) in 34 key DNA repair and cell cycle control genes in 299 lung cancer cases diagnosed before the age of 50 years and 317 controls from six countries of Central and Eastern Europe. We have found no association of lung cancer risk with polymorphisms in genes related to cell cycle control, single-strand/double-strand break repair, or base excision repair. Significant associations (P &amp;lt; 0.05) were found with polymorphisms in genes involved in DNA damage sensing (ATM) and, interestingly, in four genes encoding proteins involved in mismatch repair (LIG1, LIG3, MLH1, and MSH6). The strongest associations were observed with heterozygote carriers of LIG1 −7C&amp;gt;T [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.13-2.64] and homozygote carriers of LIG3 rs1052536 (OR, 2.05; 95% CI, 1.25-3.38). Consideration of the relatively large number of markers assessed diminishes the significance of these findings; thus, these SNPs should be considered promising candidates for further investigation in other independent populations. (Cancer Res 2006; 66(22): 11062-9)
Temporal relation between depression and cognitive impairment in old age: prospective population based study
Authors: David J Vinkers, Jacobijn Gussekloo, Max L Stek, Rudi G J Westendorp, Roos C van der Mast
Journal: BMJ (2004)

Abstract Objective To examine the temporal relation between depression and cognitive impairment in old age. Design Prospective, population based study with four years of follow up. Setting City of Leiden, the Netherlands. Participants 500 people aged 85 years at recruitment. Main outcome measures Annual assessments of depressive symptoms (15 item geriatric depression scale), global cognitive function (mini-mental state examination), attention (Stroop test), processing speed (letter digit coding test), and immediate and delayed recall (12 word learning test). Results At 85 years old, participants' depressive symptoms and cognitive impairment were highly significantly correlated (P &lt; 0.001). During follow up, an accelerated annual increase of depressive symptoms was associated with impaired attention (0.08 points (95% confidence interval 0.01 to 0.16)), immediate recall (0.17 points (0.09 to 0.25)), and delayed recall (0.10 points (0.02 to 0.18)) at baseline. In contrast, depressive symptoms at baseline were not related to an accelerated cognitive decline during follow up (P &gt; 0.05). Conclusion Caregivers should be aware of the development of depressive symptoms when cognitive impairment is present. However, the presence of depression only does not increase the risk of cognitive decline.
Peers reject high profile bid to halt NHS competition rules
Authors: A. O'Dowd
Journal: BMJ (2013)

Peers have rejected a motion that would have forced a change to the rules governing competition when GPs are commissioning health services.

In a vote in the House of Lords on 24 April 254 peers rejected the motion put forward by Labour’s health spokesman, Philip Hunt, to annul the regulations, while 146 voted to support him.

During a two and a half hour debate peers put forward arguments about the extent to which the section 75 regulations in the Health and Social Care Act would open up all NHS services to market competition and result in possible legal challenges to clinical commissioning groups (CCG) from the private sector.

There has been significant opposition to the regulations from the BMA,1 the Royal College of General Practitioners, and other bodies, which claim that they will force almost every part of the NHS to be opened up to compulsory competition.

Last month the health minister Norman Lamb said that the regulations would be rewritten to make clear that “no CCG will be forced into competitive tendering,” and new regulations were published on 11 March.2

However, critics have said that they showed no significant improvement on the previous version; and on the day of the debate the Daily Telegraph published …