tbuckley/cabot-search huggingface dataset:
MLN120B, a Novel IκB Kinase β Inhibitor, Blocks Multiple Myeloma Cell Growth <i>In vitro</i> and <i>In vivo</i>
Authors: Teru Hideshima, Paola Neri, Pierfranchesco Tassone, Hiroshi Yasui, Kenji Ishitsuka, Noopur Raje, Dharminder Chauhan, Klaus Podar, Constantine Mitsiades, Lenny Dang, Nikhil Munshi, Paul Richardson, David Schenkein, Kenneth C. Anderson
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The purpose of this study is to delineate the biological significance of IκB kinase (IKK) β inhibition in multiple myeloma cells in the context of bone marrow stromal cells (BMSC) using a novel IKKβ inhibitor MLN120B. Experimental Design: Growth-inhibitory effect of MLN120B in multiple myeloma cells in the presence of cytokines [interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-1)], conventional agents (dexamethasone, melphalan, and doxorubicin), or BMSC was assessed in vitro. In vivo anti-multiple myeloma activity of MLN120B was evaluated in severe combined immunodeficient (SCID)–hu model. Results: MLN120B inhibits both baseline and tumor necrosis factor-α–induced nuclear factor-κB activation, associated with down-regulation of IκBα and p65 nuclear factor-κB phosphorylation. MLN120B triggers 25% to 90% growth inhibition in a dose-dependent fashion in multiple myeloma cell lines and significantly augments tumor necrosis factor-α–induced cytotoxicity in MM.1S cells. MLN120B augments growth inhibition triggered by doxorubicin and melphalan in both RPMI 8226 and IL-6-dependent INA6 cell lines. Neither IL-6 nor IGF-1 overcomes the growth-inhibitory effect of MLN120B. MLN120B inhibits constitutive IL-6 secretion by BMSCs by 70% to 80% without affecting viability. Importantly, MLN120B almost completely blocks stimulation of MM.1S, U266, and INA6 cell growth, as well as IL-6 secretion from BMSCs, induced by multiple myeloma cell adherence to BMSCs. MLN120B overcomes the protective effect of BMSCs against conventional (dexamethasone) therapy. Conclusions: Our data show that the novel IKKβ inhibitor MLN120B induces growth inhibition of multiple myeloma cells in SCID-hu mouse model. These studies provide the framework for clinical evaluation of MLN120B, alone and in combined therapies, trials of these novel agents to improve patient outcome in multiple myeloma.
The Molecular Mechanism of B Cell Activation by <i>toll</i>-like Receptor Protein RP-105
Authors: Vivien W.F. Chan, Ingrid Mecklenbräuker, I-hsin Su, Gemma Texido, Michael Leitges, Rita Carsetti, Clifford A. Lowell, Klaus Rajewsky, Kensuke Miyake, Alexander Tarakhovsky
Journal: The Journal of Experimental Medicine (1998)

The B cell–specific transmembrane protein RP-105 belongs to the family of Drosophila toll-like proteins which are likely to trigger innate immune responses in mice and man. Here we demonstrate that the Src-family protein tyrosine kinase Lyn, protein kinase C β I/II (PKCβI/II), and Erk2-specific mitogen-activated protein (MAP) kinase kinase (MEK) are essential and probably functionally connected elements of the RP-105–mediated signaling cascade in B cells. We also find that negative regulation of RP-105–mediated activation of MAP kinases by membrane immunoglobulin may account for the phenomenon of antigen receptor–mediated arrest of RP-105–mediated B cell proliferation.
EU doctors get caught in training trap
Authors: A. Perinti
Journal: BMJ (1998)

EDITOR—The specialist medical order is a national law implementing the European directive 93/16, which regulates postgraduate training; it came into effect on 16 January 1996. The Specialist Training Authority is now the government body designed by law to grant certificates of completion of specialist training.

Before the implementation of directive 93/16 the General Medical Council granted a certificate of specialist training to those applicants from the European Union …
Electrophysiological Delineation of the Specialized A-V Conduction System in Patients with Congenital Heart Disease
Authors: EHUD KRONGRAD, JAMES R. MALM, FREDERICK O. BOWMAN, BRIAN F. HOFFMAN, ALBERT L. WALDO
Journal: Circulation (1974)

The course of the distal His bundle and the right bundle branch was electrophysiologically delineated during open heart surgery in nine patients with tetralogy of Fallot and in six other patients with various forms of congenital heart disease. In patients with tetralogy of Fallot, right bundle branch electrograms were usually recorded up to 25 mm from the plane of the tricuspid valve annulus and only rarely beyond this site, indicating that the electrical activity in the right bundle branch was isolated from right ventricular myocardium to a site 25 mm away from the tricuspid annulus in the patients studied. In one patient with right bundle branch block pattern on the electrocardiogram induced by a ventriculotomy, the right bundle branch was traced to the Purkinje fiber-ventricular muscle junction, supporting the observation that a right bundle branch block pattern induced by ventriculotomy does not indicate that injury to the proximal part of the right bundle branch occurred. In five patients with various forms of congenital heart disease we did not record electrical activity from the distal His and right bundle branch. The anatomic and functional reasons for this failure are discussed. In one patient with a common ventricle, the identification of the specialized atrioventricular (A-V) conduction system allowed for total surgical correction of this anomaly without injury to the conduction system. The electrophysiological delineation of the specialized atrioventricular conduction system is suggested for all patients undergoing open heart surgery who have complicated congenital heart disease on which no data are available regarding the exact location of the specialized atrioventricular conduction system, for patients with unusual ventricular anatomy, and for patients in whom the hemodynamic and angiographic studies do not correlate well with the electrocardiogram.
Leptin Augments Inflammatory and Profibrogenic Responses in the Murine Liver Induced by Hepatotoxic Chemicals
Authors: Kenichi Ikejima, Hajime Honda, Mutsuko Yoshikawa, Miyoko Hirose, Tsuneo Kitamura, Yoshiyuki Takei, Nobuhiro Sato
Journal: Hepatology (2001)

Lines of evidence suggested a possible link between leptin and hepatic fibrosis; however, whether leptin modulates the fibrogenesis in the liver remains unclear. The purpose of this study, therefore, was to evaluate the effect of leptin on inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. Male C57Bl/6 mice were given carbon tetrachloride (CCl 4 ) (0.1 μL/g body wieght [BW], intraperitoneally [IP]) and/or recombinant murine leptin (1 μg/g BW, IP) simultaneously, and sacrificed up to 72 hours later. Further, some mice were given thioacetamide (TAA; 200 μg/g BW, IP) and leptin 3 times per week for 4 weeks to evaluate the effect of leptin on chronic fibrogenic responses. A simultaneous injection of leptin enhanced acute CCl 4 –induced necroinflammatory and subsequent fibrotic changes in the hepatic lobules. The steady–state messenger RNA (mRNA) levels of α1(I) procollagen and heat shock protein 47 (HSP47) in the liver were potentiated when leptin was injected together with CCl 4 . Expression of α smooth muscle actin (α–SMA) in the liver after CCl 4 treatment was also augmented markedly in combination with leptin. Further, leptin increased transforming growth factor β1 (TGF–β1) mRNA in the liver 24 hours after acute CCl 4 about 4–fold higher than CCl 4 alone. Moreover, leptin enhanced hepatic fibrosis and induction of α1(I) procollagen mRNA caused by chronic TAA administration. Collectively, these findings indicated that leptin augments both inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. It is postulated that the increase in systemic leptin levels enhances up–regulation of TGF–β1, leading to activation of stellate cells, thereby augmenting the fibrogenic response in the liver.
The molecular mechanism regulating 24-hour rhythm of<i>CYP2E1</i>expression in the mouse liver
Authors: Naoya Matsunaga, Misaki Ikeda, Takako Takiguchi, Satoru Koyanagi, Shigehiro Ohdo
Journal: Hepatology (2008)

Cytochrome P450 2E1 (CYP2E1) is clinically and toxicologically important and exhibits 24-hour periodicity in its activity. In the present study, we investigated whether hepatic nuclear factor-1alpha (HNF-1alpha) and clock genes with a striking 24-hour rhythm in mouse liver contributed to the 24-hour regulation of CYP2E1 expression. The results demonstrated that the expression of CYP2E1 messenger RNA (mRNA) in the liver was affected by HNF-1alpha and the circadian organization of molecular clocks. The mRNA levels of CYP2E1 in the liver increased from the late light phase to the early dark phase. Luciferase reporter gene analysis revealed that HNF-1alpha activated CYP2E1 promoter activity, which was restricted by CRY1, a member of the circadian organization of molecular clocks. Repressor activity of CRY1 was observed on the HNF-1alpha binding site of the CYP2E1 promoter region with mutated E-box. Serum shock induced approximately 24-hour oscillation in CYP2E1 mRNA in HepG2. Transfection of HNF-1alpha and CRY1 small interfering RNA dampened the oscillation of CYP2E1 mRNA in HepG2. Chromatin immunoprecipitation assay in the CYP2E1 promoter indicated that HNF-1alpha binding to the CYP2E1 promoter increased from the late light phase to the early dark phase. Using the chromatin immunoprecipitation reimmunoprecipitation assay, time-dependent differences were demonstrated for CRY1 protein interaction with HNF-1alpha transcriptional complexes, including coactivator p300 on the HNF-1alpha binding site in the CYP2E1 promoter.Our results suggest that the transcription activator of HNF-1alpha acts periodically and the negative limbs of molecular clocks periodically inhibit CYP2E1 transcription, resulting in the 24-hour rhythm of its mRNA expression.
Corrigendum to “Enhancement of periodontal tissue regeneration by locally controlled delivery of insulin-like growth factor-I from dextran-co-gelatin microspheres” [J. Control. Release 114 (2006) 209–222]
Authors: Fa-ming Chen, Yi-min Zhao, Hong Wu, Zhi-hong Deng, Qin-tao Wang, Wei Zhou, Qing Liu, Guang-ying Dong, Kun Li, Zhi-fen Wu, Yan Jin
Journal: Journal of Controlled Release (2009)
Safety and efficacy of sirolimus-eluting stent (cypher) in acute myocardial infarction: A substudy of the Rapamycin-Eluting Stent Evaluation at Rotterdam Cardiology Hospital (RESEARCH) study
Authors: None Chi Hang Lee, Pedro A. Lemos, Ron T. van Domburg, George Sianos, Pieter C. Smits, Willem J. van der Giessen, Pim de Feyter, Patrick W. Serruys
Journal: Journal of the American College of Cardiology (2003)
Reprogramming T Lymphocytes for Melanoma Adoptive Immunotherapy by T-Cell Receptor Gene Transfer with Lentiviral Vectors
Authors: Sara Bobisse, Maria Rondina, Anna Merlo, Veronica Tisato, Susanna Mandruzzato, Mario Amendola, Luigi Naldini, Ralph A. Willemsen, Reno Debets, Paola Zanovello, Antonio Rosato
Journal: Cancer Research (2009)

T-cell receptor (TCR) gene transfer for cancer immunotherapy is limited by the availability of large numbers of tumor-specific T cells. TCR alpha and beta chains were isolated from a highly lytic HLA-A2-restricted cytotoxic T lymphocyte (CTL) clone recognizing the melanoma-associated Melan-A/MART-1 antigen and inserted into a lentiviral vector carrying a bidirectional promoter capable of robust and coordinated expression of the two transgenes. Lentiviral vector-based gene delivery systems have shown increased transfer efficiency and transgene expression compared with the widely used gamma-retroviral vectors. This vector performed more efficiently than a gamma-retrovirus-based vector containing the same expression cassette, resulting in a T-cell population with 60% to 80% of transgenic TCR expression with mainly CD8(+) intermediate effector phenotype. Transgenic T cells specifically produced cytokine in response to and killed antigen-expressing melanoma cells, retained an overlapping functional avidity in comparison with the TCR donor CTL clone, and exerted significant therapeutic effects in vivo upon adoptive transfer in melanoma-bearing severe combined immunodeficient mice. Optical imaging showed their accumulation in the tumor site. Overall, our results indicate that lentiviral vectors represent a valid tool for stable and high-intensity expression of transgenic TCR and support clinical exploitation of this approach for therapeutic application.
Lymphocyte deficiency limits Epstein-Barr virus latent membrane protein 1 induced chronic inflammation and carcinogenic pathology in vivo
Authors: Adele Hannigan, Asif M Qureshi, Colin Nixon, Penelope M Tsimbouri, Sarah Jones, Adrian W Philbey, Joanna B Wilson
Journal: Molecular Cancer (2011)

Abstract Background The importance of the malignant cell environment to its growth and survival is becoming increasingly apparent, with dynamic cross talk between the neoplastic cell, the leukocyte infiltrate and the stroma. Most cancers are accompanied by leukocyte infiltration which, contrary to an anticipated immuno-protective role, could be contributing to tumour development and cancer progression. Epstein-Barr virus (EBV) associated cancers, including nasopharyngeal carcinoma and Hodgkin's Disease, show a considerable leukocyte infiltration which surrounds the neoplastic cells, raising the questions as to what role these cells play in either restricting or supporting the tumour and what draws the cells into the tumour. In order to begin to address this we have studied a transgenic model of multistage carcinogenesis with epithelial expression of the EBV primary oncoprotein, latent membrane protein 1 (LMP1). LMP1 is expressed particularly in the skin, which develops a hyperplastic pathology soon after birth. Results The pathology advances with time leading to erosive dermatitis which is inflamed with a mixed infiltrate involving activated CD8+ T-cells, CD4+ T-cells including CD4+/CD25+/FoxP3+ Treg cells, mast cells and neutrophils. Also significant dermal deposition of immunoglobulin-G (IgG) is observed as the pathology advances. Along with NF-kappaB activation, STAT3, a central factor in inflammation regulation, is activated in the transgenic tissue. Several inflammatory factors are subsequently upregulated, notably CD30 and its ligand CD153, also leukocyte trafficking factors including CXCL10, CXCL13, L-selectin and TGFβ1, and inflammatory cytokines including IL-1β, IL-3 and the murine IL-8 analogues CXCL1, CXCL2 and CXCL5-6, amongst others. The crucial role of mature T- and/or B-lymphocytes in the advancing pathology is demonstrated by their elimination, which precludes mast cell infiltration and limits the pathology to an early, benign stage. Conclusions LMP1 can lead to the activation of several key factors mediating proliferation, angiogenesis and inflammation in vivo . With the initiation of an inflammatory programme, leukocyte recruitment follows which then itself contributes to the progressing pathology in these transgenic mice, with a pivotal role for B-and/or T-cells in the process. The model suggests a basis for the leukocyte infiltrate observed in EBV-associated cancer and its supporting role, as well as potential points for therapeutic intervention.
Orbital Decompression for Graves' Ophthalmopathy by Inferomedial, by Inferomedial Plus Lateral, and by Coronal Approach
Authors: Maarten Ph. Mourits, Leo Koornneef, Wilmar M. Wiersinga, Mark F. Prummel, Arie Berghout, Ruth van der Gaag
Journal: Ophthalmology (1990)
A week of physical inactivity has similar health costs to smoking a packet of cigarettes
Authors: K. M. Khan, J. C. Davis
Journal: British Journal of Sports Medicine (2010)

Google knows everything, so we tried ‘What is the health cost of a week of physical inactivity compared with the health cost of cigarette smoking?’ 915 000 results provided no clear answer. PubMed, on the other hand, was concise. Two results but no help. What is your guess? Does a day of physical inactivity affect your health like just a couple of smokes (no big deal), or like a packet of 20? How much physical inactivity damages health as much as a carton of cigarettes?

Given Google's lack of help, we reused some backs of envelopes. It is really not hard. The US population in 1999 was 272 million. The percentage inactive ranged from 29% to 48%, depending on your source. You could use both of these numbers for a sensitivity analysis, but let's be optimistic: 29%=79 million inactive …
On his blindness
Authors: R. Gregson
Journal: BMJ (1991)

interest in one's former work must be subject to accepting that expertise in it declines at an accelerating rate. That means withdrawal from expressions of authority, even though one can still be an historical source for others. There are always other interests and physical activities to bepursued. The University of the Third Age in Cambridge?the oldest member of which is 98?provides many opportunities for learning in classes of anything from half a dozen to over a hundred. That may be too narrow a social group, but there are others. Golf may be a minimal intellectual load, but it is an example of low grade physical activity that continues. The recital of the activities open to those in an easy economic situation must bring them back to the fact that too many contemporaries do not have that good fortune. That is our society's problem; mere survival is not success, there must be involvement.
219 LIVER STIFFNESS MEASUREMENT: AN APPROPRIATE SCREENING METHOD TO DETECT LIVER FIBROSIS IN THE GENERAL POPULATION
Authors: D. Roulot, J.-F. Buyck, N. Gambier, U. Warzocha, S. Czernichow, J.-L. Costes, H. Le Clesiau, M. Beaugrand
Journal: Journal of Hepatology (2009)
The occupational physician's point of view: the model of man-made vitreous fibers.
Authors: P Brochard, J C Pairon, J Bignon
Journal: Environmental Health Perspectives (1994)

This article gives a detailed description of the procedure the occupational physician uses in interpreting the available scientific data to provide useful information for prevention of pulmonary diseases related to man-made mineral fibers, particularly lung cancer and mesothelioma. As it is difficult to reach definite conclusions from human data on the toxicity of specific fibers, an experimental approach is needed. Concerning animal data, we emphasize that adequate inhalation studies are the
CAPACITY OF PLEUROPNEUMONIA-LIKE MICROORGANISMS TO GROW ON CHORIOALLANTOIC MEMBRANES
Authors: Homer F. Swift
Journal: The Journal of Experimental Medicine (1941)

1. Among eight strains or variants, included in four different immunological types of pleuropneumonia-like microorganisms, all grew on chorioallantoic membranes; those belonging to Klieneberger's Type L(5) (Sabin Type A) grew very poorly; and those included in three other types grew with varying degrees of vigor. 2. In all instances, strains of pleuropneumonia-like microorganisms tested grew better on dead sterile chorioallantoic membranes than on living membranes. 3. None of the strains tested was in itself lethal for chick embryos. 4. No constant macroscopic lesion developed as a result of inoculating chorioallantoic membranes with pleuropneumonia-like microorganisms.
The Problem of Adjusting the Wilson Central Terminal to a Zero of Potential in the Living Human Subject
Authors: ROBERT H. BAYLEY, ARTHUR E. SCHMIDT
Journal: Circulation Research (1955)

Evaluation of the potential of the Wilson terminal in 33 normal young adults indicates that its potential is zero about once in every twelve. Weighting of the terminal brought its potential to zero in ⅔ of the subjects and left a very small residual (technical) error in the remainder. The vertical component of the cardiac vector is primarily responsible for the error on the Wilson terminal. A weighted terminal in which the arm resistances are 2.6 times the left leg resistance has a zero potential in 50 percent of a small group of subjects. The residual error on the weighted terminal is at most one-half of that on the Wilson terminal. The eccentric origin of the cardiac vector varies only with respiration. Ordinarily, the zero-potential plane of the antero-posterior component of the cardiac vector passes simultaneously through or just dorsal to the limb electrodes and contributes little to the negative error on the Wilson terminal.
THE FOCAL PULMONARY TUBERCULOSIS OF CHILDREN AND ADULTS
Authors: Eugene L. Opie
Journal: The Journal of Experimental Medicine (1917)

Evidence of tuberculous infection has been found in the lungs of all of fifty adults who have been examined. Approximately one-half of all adults have encapsulated lesions of the lungs or bronchial lymphatic nodes, whereas in one-third pulmonary and lymphatic lesions are firmly calcified and completely healed. Tuberculous pulmonary lesions of adults who have died of diseases other than tuberculosis are of two types: (1) apical tuberculosis similar to the usual type of fatal phthisis and unaccompanied by caseation, of the regional lymphatic nodes; (2) focal tuberculosis not more commonly situated in the apices of the lungs than elsewhere and accompanied by caseation (or calcification) of the adjacent lymphatic nodes. Focal pulmonary tuberculosis of adults is identical with the tuberculosis of childhood. It occurs in at least 92 per cent of all adults. It may be acquired between the ages of 2 and 10 years but in more than half of all individuals (in this city) makes its appearance between the ages of 10 and 18 years. Tuberculosis of children does not select the apices of the lungs, is accompanied by massive tuberculosis of regional lymphatic nodes, and exhibits the characters of tuberculosis in a freshly infected animal, whereas tuberculosis which occurs in the pulmonary apices of adults has the characters of a second infection. Almost all human beings are spontaneously "vaccinated" with tuberculosis before they reach adult life.
Normalization of Low-Density Lipoprotein Receptor Expression in Receptor Defective Homozygous Familial Hypercholesterolemia by Inhibition of PCSK9 With Alirocumab
Authors: Gilles Lambert, Mathias Chatelais, Francine Petrides, Maxime Passard, Aurélie Thedrez, Kerry-Anne Rye, Uwe Schwahn, Viktoria Gusarova, Dirk J. Blom, William Sasiela, A. David Marais
Journal: Journal of the American College of Cardiology (2014)
High Survival Rates of Kidney Transplants from Spousal and Living Unrelated Donors
Authors: Paul I. Terasaki, J. Michael Cecka, David W. Gjertson, Steven Takemoto
Journal: New England Journal of Medicine (1995)

In the United States, increasing numbers of persons are donating kidneys to their spouses. Despite greater histoincompatibility, the survival rates of these kidneys are higher than those of cadaveric kidneys. We examined the factors influencing the high survival rates of spousal-donor kidneys.
Bronchogenic Carcinoma Stages III and IV
Authors: Philip Rubin
Journal: JAMA (1966)

The appalling results of treatment in lung cancer must be translated into the suffering of 43,568 individuals each year who will be dying due to the ravages of locally uncontrolled or extensively disseminated lung cancer. Approximately 80% of these patients will suffer and die within the first year and the average survival will be six to nine months following the date of diagnosis. Palliation is a major problem and the management of advanced lung cancer patients has caused much debate among practitioners. The attitude ranges from aggressive treatment by some surgeons and radiotherapists to therapeutic nihilism and a policy of judicious neglect. This may depend on whether the clinician's definition of palliation is limited to relieving distressful symptoms and increasing comfort, as opposed to the hope of adding to survival and avoiding impending complications. To answer this difficult question, one needs experience, judgment, compassion, and an intimate knowledge of the