tbuckley/cabot-search huggingface dataset:
Rudi Busse (1943–2007)
Authors: Ingrid Fleming, Ulrich Pohl
Journal: Circulation Research (2007)

in Bayreuth (home of Richard Wagner), in south East Germany, the youngest of four siblings.Rudi studied medicine and received his MD in 1971.After his internship, however, he realized that his true interests were in basic science, and not in clinical routine.Thus, in 1973 Rudi joined the Department of Physiology at Universität Erlangen-Nr ¨nberg, where the focus was on hemodynamics.The move was a real challenge for Rudi, as his basic education was "humanistic" and had focused on a thorough training in Latin and Greek, rather than complex mathematics.Encouraged and supported by his early mentor, Erik Wetterer, he began working on the mechanisms governing vascular mechanics and the related hemodynamics and pulse transmission characteristics of arteries.Only four years after joining the Department of Physiology, Rudi submitted his "habilitation" thesis entitled, "A new theoretical and experimental way of determining the propagation coefficient and visco-elastic behavior of arteries in situ".Although the topic sounded rather dry, if not dull, and the document itself was not easy reading, Rudi's anecdotes on how some of the measurements were made (particularly the first measurements of the human carotid pulse) were hairraising.Characteristic of the late 1970s, training in the basic sciences was considered part of a more universal education, and Erik Wetterer not only sparked Rudi's interests in hemodynamics, but also in antique Turkmenian carpets.Rudi remained an avid collector throughout his life.
Mechanisms of Gonadotropin-Releasing Hormone Agonist Action in the Human Male*
Authors: S. BHASIN, R. S. SWERDLOFF
Journal: Endocrine Reviews (1986)

AGONIST analogs of GnRH are being increasingly utilized to induce medical castration for treatment of a variety of hormonally responsive clinical disorders. However, the mechanism/s of their paradoxical antigonadal action in the human male remain poorly understood. Basal and integrated concentrations of immunoreactive LH after intermediate term (4–16 weeks) GnRH agonist treatment are only modestly decreased and cannot fully account for the far greater decline in serum testosterone (T) concentrations. Bioassayable LH concentrations, however, decrease markedly and parallel the fall in serum T suggesting secretion of qualitatively different LH species with diminished biological activity while the circulating concentrations of β-subunit parallel the measured bioassayable LH concentrations, free α-subunit secretion remains persistently and disproportionately elevated during chronic GnRH agonist treatment. Cross-reactivity of free α-subunits in the human LH RIA contributes to this disparity between the LH immuno and bioactivity. Chromatography of serum LH during GnRH agonist treatment suggests secretion of a qualitatively different LH species. Unlike the rat, in which the antifertility effects of the agonist are mediated predominantly by direct inhibition of testicular steroidogenesis, significant direct gonadal effects have not been demonstrated in man. Thus the bulk of evidence points to a predominant pituitary site of action in the human male. The molecular basis of the heterogeneity of LH during GnRH agonist, however, remains to be elucidated. The hypothesis that co- or posttranslational modification by the agonist may attenuate biologic activity of LH has not yet been directly tested.
Invariant Chain Controls H2-M Proteolysis in Mouse Splenocytes and Dendritic Cells
Authors: Philippe Pierre, Idit Shachar, Didi Matza, Evelina Gatti, Richard A. Flavell, Ira Mellman
Journal: The Journal of Experimental Medicine (2000)

The association of invariant (Ii) chain with major histocompatibility complex (MHC) class II dimers is required for proper antigen presentation to T cells by antigen-presenting cells. Mice lacking Ii chain have severe abnormalities in class II transport, T cell selection, and B cell maturation. We demonstrate here that H2-M, which is required for efficient class II antigenic peptide loading, is unexpectedly downregulated in splenocytes and mature dendritic cells (DCs) from Ii−/− mice. Downregulation reflects an increased rate of degradation in Ii−/− cells. Degradation apparently occurs within lysosomes, as it is prevented by cysteine protease inhibitors such as E64, but not by the proteasome inhibitor lactacystin. Thus, Ii chain may act as a lysosomal protease inhibitor in B cells and DCs, with its deletion contributing indirectly to the loss of H2-M.
MicroRNAs and the cancer phenotype: profiling, signatures and clinical implications
Authors: Carlos Stahlhut, Frank J Slack
Journal: Genome Medicine (2013)

MicroRNAs (miRNAs) have emerged as key genetic regulators of a wide variety of biological processes, including growth, proliferation, and survival. Recent advances have led to the recognition that miRNAs can act as potent oncogenes and tumor suppressors, playing crucial roles in the initiation, maintenance, and progression of the oncogenic state in a variety of cancers. Determining how miRNA expression and function is altered in cancer is an important goal, and a necessary prerequisite to the development and adoption of miRNA-based therapeutics in the clinic. Highly promising clinical applications of miRNAs are the use of miRNA signatures as biomarkers for cancer (for example, for early detection or diagnosis), and therapeutic supplementation or inhibition of specific miRNAs to alter the cancer phenotype. In this review, we discuss the main methods used for miRNA profiling, and examine key miRNAs that are commonly altered in a variety of tumors. Current studies underscore the functional versatility and potency of miRNAs in various aspects of the cancer phenotype, pointing to their potential clinical applications. Consequently, we discuss the application of miRNAs as biomarkers, clinical agents, and therapeutic targets, highlighting both the enormous potential and major challenges in this field.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for the Pharmacological Response of PTK787/ZK 222584, an Inhibitor of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, in Patients With Advanced Colorectal Cancer and Liver Metastases: Results From Two Phase I Studies
Authors: Bruno Morgan, Anne L. Thomas, Joachim Drevs, Juergen Hennig, Martin Buchert, Asvina Jivan, Mark A. Horsfield, Klauss Mross, Howard A. Ball, Lucy Lee, William Mietlowski, Stefan Fuxius, Clemens Unger, Ken O’Byrne, Andrew Henry, Graham R. Cherryman, Dirk Laurent, Margaret Dugan, Dieter Marmé, William P. Steward
Journal: Journal of Clinical Oncology (2003)

PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies.Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points.A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P =.01 for oral dose; P =.0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P =.004%; and 51%, P =.006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status.These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitors, such as PTK/ZK, for further clinical development.
Serotonin-induced coronary spasm in a swine model. A minor role of defective endothelium-derived relaxing factor.
Authors: T Fukai, K Egashira, H Hata, K Numaguchi, Y Ohara, T Takahashi, H Tomoike, A Takeshita
Journal: Circulation (1993)

Coronary spasm may be caused by endothelial dysfunction, vascular smooth muscle hyperreactivity, or both. We aimed to determine the relative role of endothelial dysfunction and vascular smooth muscle hyperreactivity in the pathogenesis of coronary artery spasm in the swine model in vivo.In Göttingen miniature pigs given a high cholesterol diet, a segment of the left coronary artery was denuded and irradiated with x-ray (total, 30 Gy). Three months after endothelial denudation and irradiation, vasomotor responses of the denuded and control sites to agonists were assessed by quantitative arteriography. Serotonin (10 micrograms/kg) provoked coronary spasm at the denuded site (diameter reduction, 79 +/- 6%) associated with ST elevation but not at the nondenuded control site (21 +/- 6%). Intracoronary infusion of N omega-nitro-L-arginine methyl ester (LNNA, an inhibitor of endothelium-derived nitric oxide) of 1 and 3 mg/kg potentiated constriction evoked with serotonin (1, 3, 10 micrograms/kg) at the control site but did not alter it at the denuded site. However, serotonin-induced constriction after LNNA was still less at the control site (31 +/- 3%) than at the denuded site (80 +/- 5%). Endothelium-dependent vasodilation with substance P (0.1, 1, 10 ng/kg), which was inhibited by LNNA, was less (P < .01) at the denuded site than at the control site, whereas vasodilation with the nitrovasodilator SIN-1 (0.1, 1, 10 ng/kg) was comparable between the two sites. Histological study revealed regenerated endothelial cells and intimal thickening at the denuded site.The results suggest that the denuded segment of the coronary artery with regenerated endothelium was associated with defective endothelium-dependent vasodilation mediated by nitric oxide and vascular smooth muscle hyperreactivity to serotonin. However, provocation of coronary spasm with serotonin resulted primarily from vascular smooth muscle hyperreactivity but not by defective nitric oxide production in this swine model.
Effective Assessment of <i>egfr</i> Mutation Status in Bronchoalveolar Lavage and Pleural Fluids by Next-Generation Sequencing
Authors: Fiamma Buttitta, Lara Felicioni, Maela Del Grammastro, Giampaolo Filice, Alessia Di Lorito, Sara Malatesta, Patrizia Viola, Irene Centi, Tommaso D'Antuono, Roberta Zappacosta, Sandra Rosini, Franco Cuccurullo, Antonio Marchetti
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The therapeutic choice for patients with lung adenocarcinoma depends on the presence of EGF receptor (EGFR) mutations. In many cases, only cytologic samples are available for molecular diagnosis. Bronchoalveolar lavage (BAL) and pleural fluid, which represent a considerable proportion of cytologic specimens, cannot always be used for molecular testing because of low rate of tumor cells. Experimental Design: We tested the feasibility of EGFR mutation analysis on BAL and pleural fluid samples by next-generation sequencing (NGS), an innovative and extremely sensitive platform. The study was devised to extend the EGFR test to those patients who could not get it due to the paucity of biologic material. A series of 830 lung cytology specimens was used to select 48 samples (BAL and pleural fluid) from patients with EGFR mutations in resected tumors. These samples included 36 cases with 0.3% to 9% of neoplastic cells (series A) and 12 cases without evidence of tumor (series B). All samples were analyzed by Sanger sequencing and NGS on 454 Roche platform. A mean of 21,130 ± 2,370 sequences per sample were obtained by NGS. Results: In series A, EGFR mutations were detected in 16% of cases by Sanger sequencing and in 81% of cases by NGS. Seventy-seven percent of cases found to be negative by Sanger sequencing showed mutations by NGS. In series B, all samples were negative for EGFR mutation by Sanger sequencing whereas 42% of them were positive by NGS. Conclusions: The very sensitive EGFR-NGS assay may open up to the possibility of specific treatments for patients otherwise doomed to re-biopsies or nontargeted therapies. Clin Cancer Res; 19(3); 691–8. ©2012 AACR.
Net Clinical Benefit of Warfarin in Patients With Atrial Fibrillation
Authors: Leif Friberg, Mårten Rosenqvist, Gregory Y.H. Lip
Journal: Circulation (2012)

Known risk factors for bleeding during anticoagulant treatment are largely the same as those predicting thromboembolic events in patients with atrial fibrillation (AF). Our objective was to investigate how to maximize the likelihood of avoiding both stroke and bleeding.All 182 678 subjects with atrial fibrillation in the Swedish Hospital Discharge Register were studied for an average of 1.5 years (260 000 patient-years at risk). Patients were stratified according to risk scores with the use of historic International Classification of Disease diagnostic codes in the register. Information about medication was obtained from the Swedish Drug Registry. Our primary end point was net benefit defined as number of avoided ischemic strokes with anticoagulation minus the number of excess intracranial bleedings with a weight of 1.5 to compensate for the generally more severe outcome with intracranial bleedings. The adjusted net clinical benefit favored anticoagulation for almost all atrial fibrillation patients. The exceptions were patients at very low risk of ischemic stroke with a CHA(2)DS(2)-VASc score of 0 and moderately elevated bleeding risk (-1.7%/y). The results were broadly similar with CHADS(2), except for patients with very low embolic risk; the CHA(2)DS(2)-VASc was able to identify those patients (n=6205, 3.9% of all patients) who had no net clinical benefit or even some disadvantage from anticoagulant treatment.In almost all patients with atrial fibrillation, the risk of ischemic stroke without anticoagulant treatment is higher than the risk of intracranial bleeding with anticoagulant treatment. Analysis of the net benefit indicates that more patients may benefit from anticoagulant treatment.
Trefoil peptide TFF2 (spasmolytic polypeptide) potently accelerates healing and reduces inflammation in a rat model of colitis
Authors: C P Tran, G A Cook, N D Yeomans, L Thim, A S Giraud
Journal: Gut (1999)

BACKGROUND The trefoil peptides are major secretory products of mucus cells of the gastrointestinal tract and show increased expression after inflammatory or ulcerative damage. Recombinant human TFF2 (spasmolytic polypeptide) has been shown to be cytoprotective, and enhances repair in models of gastric injury. AIMS To test the healing effects of recombinant human (h)TFF2 in a rat model of chronic colitis. METHODS Colitis was induced by intracolonic administration of dinitrobenzene sulphonic acid in ethanol. Mucosal repair was quantified macroscopically, microscopically by image analysis of tissue histology, and by measuring myeloperoxidase activity. RESULTS Initial validation studies showed that maximal injury and inflammation occurred at the end of the first week after colitis induction (active phase), and that spontaneous healing was complete by eight weeks. Once daily intrarectal application of hTFF2 (2.5 mg/kg; approximately 0.5 mg/rat) for five days after maximal damage had been sustained, reduced both microscopic and macroscopic injury by 80% and inflammatory index by 50% compared with vehicle controls. In addition, endogenous concentrations of rat TFF2 and TFF3 (intestinal trefoil factor) were increased in the active phase of colitis and were reduced to basal levels by hTFF2 treatment. CONCLUSIONS This study has shown that hTFF2 enhances the rate of colonic epithelial repair, and reduces local inflammation in a rat model of colitis, and suggests that luminal application of trefoil peptides may have therapeutic potential in the treatment of inflammatory bowel disease.
p53 status correlates with histopathological response in patients with soft tissue sarcomas treated using isolated limb perfusion with TNF-α and melphalan
Authors: J. Muret, M. Yacoub, P. Terrier, F. Drusch, A. Laplanche, C. Gaudin, C. Richon, C. Le Péchoux, A. Le Cesne, F.J. Lejeune, T. Tursz, P. Fouret, S. Bonvalot, S. Chouaib
Journal: Annals of Oncology (2007)
Oxidation-Specific Biomarkers, Prospective 15-Year Cardiovascular and Stroke Outcomes, and Net Reclassification of Cardiovascular Events
Authors: Sotirios Tsimikas, Peter Willeit, Johann Willeit, Peter Santer, Manuel Mayr, Qingbo Xu, Agnes Mayr, Joseph L. Witztum, Stefan Kiechl
Journal: Journal of the American College of Cardiology (2012)
The waiting period after allergen skin testing and immunotherapy
Authors: John A. Anderson, Maichael Kaliner, Allen P. Kaplan, Lawrence M. Lichtenstein, Phillip L. Lieberman, Richard F. Lockey, William E. Pierson, Guy A. Settipane, Albert L. Sheffer, Martin D. Valentine, John W. Yunginger, Burton Zweiman
Journal: Journal of Allergy and Clinical Immunology (1990)
Identification of hundreds of conserved and nonconserved human microRNAs
Authors: Isaac Bentwich, Amir Avniel, Yael Karov, Ranit Aharonov, Shlomit Gilad, Omer Barad, Adi Barzilai, Paz Einat, Uri Einav, Eti Meiri, Eilon Sharon, Yael Spector, Zvi Bentwich
Journal: Nature Genetics (2005)
IMMUNOLOGICAL REACTIONS OF THE COXSACKIE VIRUSES
Authors: Joseph L. Melnick, Nada Ledinko
Journal: The Journal of Experimental Medicine (1950)

The neutralization test is a reliable and useful procedure for following immunological reactions of the Coxsackie viruses (C virus). The standard procedure has been an incubation period of 1 hour at room temperature followed by subcutaneous inoculation into newborn mice. However, this time and temperature are not critical, for the virus in neutralized within 10 minutes of mixing with immune serum and remains neutralized for long periods. During the variable incubation periods used, the control virus remained active, even in dilute suspensions. The neutralization test is not affected by the presence or absence of complement. Neutralizing antibody is stable at 65 degrees C. for 30 minutes, and immune serum has to be heated to 80 degrees C. for 30 minutes before the antibody is no longer detectable. As the quantity of virus is increased, the quantity of serum required for neutralization likewise increases, but not in a regular or predictable fashion. Neutralized mixtures of the virus can be made infective again by simple dilution before inoculation. The neutralization test is a satisfactory means for typing Coxsackie viruses. At least seven antigenic types have been identified. Similar antigenic types have been found to be scattered over wide areas. Thus the Conn.-5 type was present in 1948 in Massachusetts, Connecticut, New York, and North Carolina. The Texas-1 type was present in 1943 in Connecticut and in 1948 in North Carolina and Texas. Further information on the specificity of the neutralizing antibody response has been obtained from a study of the occurrence and development of antibodies in 6 patients who contracted infections with one or another of the C viruses while working with them in the laboratory. From each patient a virus was isolated during the illness. No patient had detectable antibodies to his strain before his illness, but each soon thereafter developed antibodies to his own strain and to the prototype strain to which it was related. By means of the neutralization test, it has been shown that a family epidemic may include two different immunological types of virus. Neutralizing antibodies appear at the time of or soon after onset of illness, increase rapidly to titers of about 1:1000 which are maintained during the period of 1 to 3 months following infection, and are still present 2 years later, although at lower levels. Neutralizing antibodies are present in the normal population. In North Carolina, over 80 per cent of the children have antibodies at birth. The level falls rapidly to a minimum of 14 per cent at the age of 1, and then it quickly rises to reach the adult level at the age of 7. Gamma globulin collected in various parts of the United States between 1944 and 1949 and in Denmark in 1949 neutralizes at least four antigenically different Coxsackie viruses.
Low socioeconomic status and lung function
Authors: Philip H. Quanjer
Journal: European Respiratory Journal (2015)

The study by Taylor-Robinson et al . [1] is unique because of the large number of subjects with cystic fibrosis, the careful follow-up and detailed statistical analysis upon which the authors base their conclusions. This remarkable study was performed in a population with reduced life expectancy. Evaluating the impact of socioeconomic status (SES) on lung function over many decades is particularly daunting in subjects with respiratory disease. Ever since the pioneering work of Villermé [2, 3], the founding father of social epidemiology, numerous studies have documented an association of SES with growth as well as with mortality in adulthood. It is also generally accepted that adverse conditions during childhood lead to stunted growth. For example, in a study of Indian children [4], stature was 4% smaller in the group with the lowest, compared with the highest, SES, and associated with up to 16.7% differences in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC); adjusting for age and differences in height did not explain these differences. It is therefore attractive to conclude that the lower ("worse", "poorer" or "compromised") FEV1 and FVC represent damage associated with poor SES. Whereas this may well be the case, association is no proof of causality. The conclusion hinges entirely on the notion that stature is a good proxy for the dimensions of the chest cavity. However, poor SES or nutritional and health problems (lumped together as SES for short) during early childhood are associated with smaller leg length relative to the height of the upper body segment [5], which biases prediction equations of lung function based on height. There is no evidence that growth stunting due to poor SES is limited to height, so it is logical to assume that chest dimensions will also be affected. If poor SES leads to a 1%, 2% or 3% lower width, depth and height of the thoracic cage, this leads to a 3%, 6% and 9% lower volume of the chest cavity, respectively. Taking into account measurement error and individual variability, it will be difficult to assess such small differences, but they cannot be discarded and might (in part) explain the observed difference in growth of FEV1. Measurements of chest circumference in a large number of subjects might throw some light on the role of differences in body frame. It is bold to disregard the potential role of poor socioeconomic status in lung function over decades of adult life <http://ow.ly/DW6kn>
Responsibility of the Scientist
Authors: C. d. F. W. Goonaratna
Journal: BMJ (1971)

Uses of Allopuninol SIR,-With reference to your excellent leading article (23 October, p. 185), I would raise two points.Having followed up a series of gouty patients for 20 years, first on uricosurics and then on allopurinol, I have no doubt in stating that the urinary complications while using the uricosuric drugs make allopurinol the preferable method of treat- ment in any case where it is decided to start long-term treatment.Secondly, from a follow-up of 50 cases, now for over five years,' the dangers of long-term treatment seem to be minimal.Moreover, the return to statu quo on gradually ceasing treatment with allopurinol in the least severe cases is much less rapid than on discontinuing the uricosuric agents.-Iam, etc.,