tbuckley/cabot-search huggingface dataset:
The Requirement for DNAM-1, NKG2D, and NKp46 in the Natural Killer Cell-Mediated Killing of Myeloma Cells
Authors: Yasser M. El-Sherbiny, Josephine L. Meade, Tim D. Holmes, Dennis McGonagle, Sarah L. Mackie, Ann W. Morgan, Gordon Cook, Sylvia Feyler, Stephen J. Richards, Faith E. Davies, Gareth J. Morgan, Graham P. Cook
Journal: Cancer Research (2007)

Abstract Recent evidence suggests a role for natural killer (NK) cells in the control of multiple myeloma. We show that expression of the NK cell receptor DNAM-1 (CD226) is reduced on CD56dim NK cells from myeloma patients with active disease compared with patients in remission and healthy controls. This suggested that this receptor might play a role in NK-myeloma interactions. The DNAM-1 ligands Nectin-2 (CD112) and the poliovirus receptor (PVR; CD155) were expressed by most patient myeloma samples analyzed. NK killing of patient-derived myelomas expressing PVR and/or Nectin-2 was DNAM-1 dependent, revealing a functional role for DNAM-1 in myeloma cell killing. In myeloma cell lines, cell surface expression of PVR was associated with low levels of NKG2D ligands, whereas cells expressing high levels of NKG2D ligands did not express PVR protein or mRNA. Furthermore, NK cell-mediated killing of myeloma cell lines was dependent on either DNAM-1 or NKG2D but not both molecules. In contrast, the natural cytotoxicity receptor NKp46 was required for the killing of all myeloma cell lines analyzed. Thus, DNAM-1 is important in the NK cell-mediated killing of myeloma cells expressing the cognate ligands. The importance of NKp46, NKG2D, and DNAM-1 in myeloma killing mirrors the differential expression of NK cell ligands by myeloma cells, reflecting immune selection during myeloma disease progression. [Cancer Res 2007;67(18):8444–9]
Mycophenolate mofetil, together with cyclosporin A, prevents anti-OKT3 antibody response in kidney transplant recipients.
Authors: N Broeders, K M Wissing, A Crusiaux, P Kinnaert, P Vereerstraeten, D Abramowicz
Journal: Journal of the American Society of Nephrology (1998)

OKT3 monoclonal antibody, a murine IgG2a monoclonal antibody targeting the T cell CD3 antigen, elicits a neutralizing humoral response in 20 to 50% of kidney transplant recipients when the concomitant immunosuppression consists of CsA-Sandimmun (SAND) and azathioprine (AZA). In the present study, we investigated the impact of the newer agents, CsA-Neoral (NEO) and mycophenolate mofetil (MMF) on OKT3 sensitization. Sixty-two consecutive kidney transplant recipients received prophylactic OKT3 (5 mg/d) from days 0 to 13, together with steroids. Concomitant immunosuppression consisted of either AZA + SAND (n=20), AZA + NEO (n=31), or MMF + NEO (n=11). The following doses were used: AZA, 2 mg/kg per d from days 0 to 13, then 1 mg/kg per d; MMF, 2 g/d starting on day 1; and CsA, either SAND or NEO, 6 mg/kg per d from day 6. At least two serum samples per month were available during the initial 3 mo for each patient. IgG anti-OKT3 antibodies were first evaluated by enzyme-linked immunosorbent assay. Patients were considered sensitized if their serum scored positive at a dilution > or = 1/1000. Peak titers of IgG anti-OKT3 antibodies and the incidence of patients harboring neutralizing anti-idiotypic antibodies were also determined. A first reduction in OKT3 sensitization was seen in patients receiving Neoral instead of Sandimmun (AZA + SAND: 10 of 20 [50%] patients sensitized versus 6 of 31 [19%] in the AZA + NEO group; P=0.03). This was probably related to the achievement of higher mean CsA trough blood levels in the NEO group during the first month (253+/-44 versus 186+/-49 ng/ml in SAND patients). Peak antibody titers and the proportion of patients with anti-idiotypic antibodies were similar in the AZA + SAND and AZA + NEO groups. A further reduction in the sensitization rate was observed with the replacement of AZA by MMF (MMF + NEO: 0% sensitized patients; P=0.0013). It is concluded that the combination of CsA-Neoral and MMF efficiently prevents sensitization against OKT3.
A second chain of human CD8 is expressed on peripheral blood lymphocytes.
Authors: L Shiue, S D Gorman, J R Parnes
Journal: The Journal of Experimental Medicine (1988)

Human CD8 has been thought to consist of disulfide-linked homodimers and homomultimers of a single polypeptide chain homologous to mouse and rat CD8 alpha. In contrast, mouse and rat CD8 are composed of disulfide-linked heterodimers of alpha and beta chains. We have now isolated and sequenced cDNA clones encoding a human homologue of mouse and rat CD8 beta. One such clone was inserted into an expression vector and its encoded product was shown to be expressed on the cell surface after cotransfection into L cells with the human CD8 alpha gene. A second form of human CD8 beta cDNA encoding a protein with an altered cytoplasmic tail was similarly transfected, but its product could not be demonstrated on the cell surface. CD8 beta was further shown to be expressed on the surface of almost all CD8+ human peripheral blood T cells. These data provide the first evidence that human CD8 is a heterodimeric protein.
Female editorship is an important indicator of gender imbalance
Authors: Kay Dickersin, Lisa Fredman, Katherine M Flegal, Jane Scott, Barbara Crawley
Journal: Journal of the Royal Society of Medicine (2010)

Your article on female authorship as an indicator of gender imbalance in academic medicine in the UK is a welcome addition to the nucleus of data tracking women's progress. Change has been frustratingly slow. Although women's productivity and authorship have been a traditional means to track the status of women in these fields,1 women's roles as editors are crucial.2-6 Authors, reviewers and editors each have progressively more professional influence over the scientific community and ultimately scientific and health policy. Topics considered worthy of research and funding can be meaningfully influenced by journal editors’ emphasis and direction. Furthermore, a woman's career advancement and influence are likely to be affected by whether or not she has editorial appointments.

In response to low representation of women in editorial roles pertaining to clinical trials, one of us (KD) has compiled a list of 91 senior women physicians and scientists from around the world who would be excellent candidates. Dr Dickersin has circulated this list to publishers and key editors-in-chief and will send it out on request to those in a position to appoint women. We suggest that others should produce similar lists to assist those who may be having a difficult time thinking of senior women in the field.

The research conducted on this topic is frequently unfunded and, for this reason, many questions are left unanswered; information is sparse and not always up-to-date. We applaud recent funding efforts in the United States and encourage the scientific community to continue research to better understand the causes of gender imbalances in medicine and the sciences, and to rectify them. In this way we will achieve better science overall.
Expression of two alpha chains on the surface of T cells in T cell receptor transgenic mice.
Authors: W R Heath, J F Miller
Journal: The Journal of Experimental Medicine (1993)

CD8+ T cells taken directly from mice expressing a Kb-specific T cell receptor (TCR) transgene expressed the transgenic TCR in a bimodal profile as detected by flow cytometric analysis using a clonotype-specific monoclonal antibody. Those cells expressing the lower density of the transgenic TCR expressed the transgenic beta chain and two different alpha chains on their surface. One alpha chain was the product of the alpha transgene, whereas the other was derived by endogenous rearrangement. This report provides the first demonstration that T cells isolated directly from mice may express two different TCR clonotypes on their surface. The potential consequences of this finding for studies using TCR transgenic mice and for the induction of autoimmunity are discussed.
Endoscopic Ultrasound, Positron Emission Tomography, and Computerized Tomography for Lung Cancer
Authors: Annette Fritscher-Ravens, Bruce L. Davidson, Hans-Peter Hauber, Karl H. Bohuslavizki, Christoph Bobrowski, Christian Lund, Wolfram Trudo Knöfel, Nib Soehendra, Lars Brandt, Margaret S. Pepe, Almuth Pforte
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Staging of patients with lung cancer to determine operability is intended to efficiently limit futile thoracotomies without denying possibly curative surgery. Currently available staging tests are imperfect alone and in combination. Imaged suspected metastases often require tissue confirmation before surgery can be denied. Endoscopic ultrasound (EUS) may help identify inoperable patients by providing tissue proof of inoperability in a single staging test, with similar sensitivity for identifying inoperable patients as other staging tests. Therefore, we compared computed tomography, positron emission tomography (PET), and EUS with fine-needle aspiration under conscious sedation, each test interpreted blinded with respect to the other tests, for identifying inoperable patients in a consecutive cohort of 79 potentially operable patients with suspected or proven lung cancer. An economic analysis was also performed. Thirty-nine patients were found inoperable (a 40th patient's inoperability was missed by all preoperative staging tests). The sensitivity of computerized tomography was 43%. PET and EUS each had similar sensitivities (68 and 63%, respectively) and similar negative predictive values (64 and 68%, respectively), but EUS's superior specificity (100 vs. 72% for PET) and considerably lower expense means it may be preferred to PET early in staging to identify inoperable patients.
The correlation of emphysema or airway obstruction with the risk of lung cancer: a matched case-controlled study
Authors: K. Kishi, J.W. Gurney, D.R. Schroeder, P.D. Scanlon, S.J. Swensen, J.R. Jett
Journal: European Respiratory Journal (2002)

A matched case-controlled study was conducted to determine if airway obstruction or emphysema were associated with an increased risk of lung cancer. Lung cancer cases (n=24) were identified through a low-dose spiral computed tomography (CT) screening trial from 1,520 participants. Four controls without lung cancer were selected for each case from the participants and matched by sex, age and smoking history. Emphysema was assessed by quantitative CT analysis. Conditional logistic regression was employed to assess results of spirometry and CT quantitative analysis as potential risk factors for lung cancer. The likelihood of lung cancer was found to be significantly increased for those with forced expiratory volume in one second (FEV 1 ) ≤40% of predicted. The results suggested that a lower percentage of predicted FEV 1 was indicative of lung cancer. No compelling evidence was found to suggest that the percentage of emphysema was associated with lung cancer. These results suggest an increased risk of lung cancer associated with airway obstruction. However, percentage of emphysema as determined by computed tomography was not associated with an increased risk of lung cancer.
GENETIC STUDY OF HUMAN CELLS IN VITRO
Authors: R. Shihman Chang
Journal: The Journal of Experimental Medicine (1960)

The isolation of carbohydrate variants from cultures of HeLa and conjunctival cells was described. Factors inherent in the cell culture system, such as parent populations and dialyzed serums, have been shown to influence the outcome of variant isolations. Established stable variants incorporated significantly more pentoses or lactate into various cell fractions than the parent cultures. Besides their abilities to propagate continuously in the selecting environments, the variants multiplied slower, were more susceptible to sub-zero preservation and the cytotoxic effect of D-2-deoxyglucose, showed lower cloning efficiencies and were less susceptible to the deleterious effect of glucose oxidase. The ribose variants also differed from the parent cultures in morphological appearance such as formation of multinucleated cells and ring-shaped colonies. They converted more ribose into other component sugars of mucopolysaccharides than the parent cultures. Preliminary analyses of the mucopolysaccharides extracted from the ribose variants and parent cultures showed large difference in their carbohydrate (Molisch-positive materials) and DNA ratios. Evidence suggests that a sequence of interrelated events from genetic selection to primitive morphogenesis has been established.
A Factor XIIa Inhibitory Antibody Provides Thromboprotection in Extracorporeal Circulation Without Increasing Bleeding Risk
Authors: Magnus Larsson, Veronika Rayzman, Marc W. Nolte, Katrin F. Nickel, Jenny Björkqvist, Anne Jämsä, Matthew P. Hardy, Marion Fries, Stefan Schmidbauer, Patricia Hedenqvist, Michael Broomé, Ingo Pragst, Gerhard Dickneite, Michael J. Wilson, Andrew D. Nash, Con Panousis, Thomas Renné
Journal: Science Translational Medicine (2014)

Blocking the enzyme that initiates the intrinsic coagulation pathway protects against thrombosis in bypass systems and does not cause excess bleeding in vivo.
Clinical and virological characteristics associated with severe acute hepatitis B
Authors: N. Coppola, C. Sagnelli, M. Pisaturo, C. Minichini, V. Messina, L. Alessio, M. Starace, G. Signoriello, I. Gentile, P. Filippini, E. Sagnelli
Journal: Clinical Microbiology and Infection (2014)
Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis
Authors: Alessio Nencioni, Fei Hua, Christopher P. Dillon, Rayka Yokoo, Christoph Scheiermann, Mike H. Cardone, Eleonora Barbieri, Ilaria Rocco, Anna Garuti, Sebastian Wesselborg, Claus Belka, Peter Brossart, Franco Patrone, Alberto Ballestrero
Journal: Blood (2004)
A Phase I Pharmacokinetic and Pharmacodynamic Study of CHR-3996, an Oral Class I Selective Histone Deacetylase Inhibitor in Refractory Solid Tumors
Authors: Udai Banerji, Leni van Doorn, Dionysis Papadatos-Pastos, Rebecca Kristeleit, Phillip Debnam, Matthew Tall, Adam Stewart, Florence Raynaud, Michelle Dawn Garrett, Martin Toal, Leon Hooftman, Johann Sebastian De Bono, Jaap Verweij, Ferry ALM Eskens
Journal: Clinical Cancer Research (2012)

This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography-tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells.Thirty-nine patients were treated at dose levels of 5 mg (n = 3), 10 mg (n = 4), 20 mg (n = 3), 40 mg (n = 10), 80 mg (n = 10), 120 mg (n = 4), and 160 mg (n = 5) administered orally once daily. The dose-limiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma.Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials.
Differential sensitivity of canine cardiac sarcolemmal and microsomal enzymes to inhibition by free radical-induced lipid peroxidation.
Authors: J H Kramer, I T Mak, W B Weglicki
Journal: Circulation Research (1984)

Sarcolemmal and microsomal membranes prepared from adult canine cardiac myocytes (sarcolemmal Na+, K+-ATPase = 71.8 mumol/mg per hr and microsomal rotenone-insensitive NADH cytochrome c reductase = 114 mumol/mg per hr) were each preincubated at 37 degrees C in the presence of a free radical generating system consisting of dihydroxyfumarate and Fe -ADP; loss of the Na+, K+-ATPase and reductase activities, as well as the associated increases in lipid peroxidation, measured by malondialdehyde formation, were temporally correlated in both systems. The ATPase was inhibited 70% when the malondialdehyde was 71 nmol/mg protein at 20 minutes and 90% when malondialdehyde was 138 nmol/mg protein at 90 minutes. Inhibition of reductase activity occurred more gradually, displaying a 27% loss of activity when malondialdehyde reached 34 nmol/mg protein at 20 minutes and 60% with a malondialdehyde value of 67 nmol/mg protein at 90 minutes. The greater susceptibility of the sarcolemma to free radical-induced membrane damage may be due to the higher content of unsaturated fatty acids in this membrane, compared to microsomes.
Atrial Fibrillation Increases Production of Superoxide by the Left Atrium and Left Atrial Appendage
Authors: Samuel C. Dudley, Nyssa E. Hoch, Louise A. McCann, Clegg Honeycutt, Laura Diamandopoulos, Tohru Fukai, David G. Harrison, Sergey I. Dikalov, Jonathan Langberg
Journal: Circulation (2005)

Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO*) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO* levels observed in AF may be associated with increased superoxide (O2*-) production.After a week of AF induced by rapid atrial pacing in pigs, O2*- production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase-inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O2*- production was increased 2.7-fold (P<0.01) and 3.0-fold (P<0.02) in the LA and LAA, respectively. A similar 3.0-fold (P<0.01) increase in LAA O2*- production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O2*-, implying that NADPH and xanthine oxidases both contributed to increased O2*- production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase (P=0.04) and xanthine oxidase (P=0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase.AF increased O2*- production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O2*- production. This increase in O2*- and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.
Kinetics of Steady-state Differentiation and Mapping of Intrathymic-signaling Environments by Stem Cell Transplantation in Nonirradiated Mice
Authors: Helen E. Porritt, Kristie Gordon, Howard T. Petrie
Journal: The Journal of Experimental Medicine (2003)

Upon thymus entry, thymic-homing progenitors undergo distinct phases of differentiation as they migrate through the cortex to the capsule, suggesting that the signals that induce these differentiation steps may be stratified in corresponding cortical regions. To better define these regions, we transplanted purified stem cells into nonirradiated congenic recipients and followed their differentiation with respect to both tissue location and time. The earliest progenitors (DN1) remained confined to a very narrow region of the cortex for about the first 10 d of intrathymic residence; this region virtually overlaps the sites of thymic entry, suggesting that DN1 cells move very little during this lengthy period of proliferation and lineage commitment. Movement out of this region into the deeper cortex is asynchronous, and corresponds to the appearance of DN2 cells. Differentiation to the DN3 stage correlates with movement across the midpoint of the cortex, indicating that stromal signals that induce functions such as TCR gene rearrangement reside mainly in the outer half of the cortex. The minimum time to reach the capsule, and thus transit to the DP stage, is ∼13 d, with the average time a few days longer. These findings reveal for the first time the kinetics of steady-state progenitor differentiation in the thymus, as well as defining the boundaries of cortical regions that support different phases of the differentiation process. We also show that the first lineage-positive progeny of transplanted stem cells to appear in the thymus are dendritic cells in the medulla, suggesting that each new wave of new T cell production is preceded by a wave of regulatory cells that home to the medulla and ensure efficient tolerance and selection.
Expression of pro-inflammatory cytokines by flow-sorted alveolar macrophages in severe pneumonia
Authors: U Maus, S Rosseau, U Knies, W Seeger, J Lohmeyer
Journal: European Respiratory Journal (1998)

The aim of the present study was to further characterize the role of alveolar macrophages (AM) in acute human lung inflammation by evaluating their capacity to produce pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8. Patients with severe community-acquired pneumonia (CAP; n=12) and healthy volunteers (n=10) underwent bronchoalveolar lavage (BAL). AM were separated to high purity (>96%) using fluorescence-activated cell sorting. We determined the TNF-alpha, IL-6 and IL-8 cytokine gene expression in AM ex vivo using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). Moreover, we measured in vitro unstimulated, lipopolysaccharide (LPS)- and LPS/interferon-gamma inducible TNF-alpha, IL-6 and IL-8 cytokine release and evaluated samples of BAL fluids for the same pro-inflammatory cytokines using an enzyme-linked immunosorbent assay (ELISA). We found increased TNF-alpha, IL-6 and IL-8 messenger ribonucleic acid (mRNA) levels in AM from CAP patients that were significantly elevated only for IL-8. When challenged with endotoxin in vitro, AM obtained from CAP patients showed a strongly reduced potential to release TNF-alpha and IL-6 compared to healthy controls, whereas IL-8 secretion did not differ significantly between groups. Moreover, stimulation of AM from CAP patients with LPS plus IFN-gamma augmented TNF-alpha and IL-6 cytokine release to near normal levels. Interestingly, no TNF-alpha protein was measured in BAL samples from CAP patients, whereas IL-6 and IL-8 protein levels were found to be significantly increased. Together, highly purified alveolar macrophages from community-acquired pneumonia patients show relatively low ex vivo tumour necrosis factor-alpha and interleukin-6 but not interleukin-8 messenger ribonucleic acid levels that are associated with a decreased pro-inflammatory cytokine release in vitro which, however, can be restored by concurrent interferon-gamma stimulation.
An attempt to identify the nature of immunoglobulin-complement deposits in the skin in lupus erythematosus
Authors: TH. JOOST
Journal: British Journal of Dermatology (1973)

An attempt was made to verify whether DNA is located in the Ig deposits present in LE skin. No DNA could be detected in the deposits after incubation of lesional skin sections of five patients with LE (two SLE and three DLE) with antisera directed against DNA and UV-DNA, after preliminary ultraviolet irradiation of the sections. Duplicated skin sections previously subjected to an acid elution also gave negative results.