tbuckley/cabot-search huggingface dataset:
Monitoring of Serum Her-2/<b> <i>neu</i> </b> Predicts Response and Progression-Free Survival to Trastuzumab-Based Treatment in Patients with Metastatic Breast Cancer
Authors: Wolfgang J. Köstler, Barbara Schwab, Christian F. Singer, Rainer Neumann, Ernst Rücklinger, Thomas Brodowicz, Sandra Tomek, Monika Niedermayr, Michael Hejna, Günther G. Steger, Michael Krainer, Christoph Wiltschke, Christoph C. Zielinski
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The present pilot study was performed to elucidate whether early changes in serum Her-2/neu extracellular domain (ECD) levels during trastuzumab-based treatment would predict the clinical course of disease in patients with metastatic breast cancer. Experimental Design: Sera from 55 patients with Her-2/neu-overexpressing metastatic breast cancer obtained immediately before each weekly administration of trastuzumab were analyzed by a serum Her-2/neu ELISA. Results: Whereas response rates were significantly higher in patients with elevated (≥15 ng/ml) ECD levels before initiation of treatment (35% versus 7%, P = 0.045), progression-free and overall survival did not differ significantly between patients with normal and elevated ECD levels. In patients responding to treatment, ECD levels decreased significantly as early as from day 8 of treatment onwards (all P for weekly measurements versus baseline &amp;lt;0.001). In contrast, no significant change in ECD levels was observed in patients with progressive disease. Multiple logistic regression analyses identified kinetics of ECD levels as the only factor that allowed for the accurate prediction of response likelihood as early as from day 8 of trastuzumab-based treatment onwards (P = 0.020). In addition, determination of serial ECD levels allowed for the prediction of the risk for disease progression within the observed period as early as day 15 of treatment (P = 0.010). Conclusions: Serial monitoring of the ECD may represent a valuable tool for early prediction of the probability of response and progression-free survival to trastuzumab-based treatment and is thus likely to contribute to an optimization of treatment and resource allocation.
Regulation of blood flow in Paget's disease of bone.
Authors: D D Heistad, F M Abboud, P G Schmid, A L Mark, W R Wilson
Journal: Journal of Clinical Investigation (1975)

Previous studies have demonstrated an increase in blood flow to extremities involved by Paget's disease of bone. It has been assumed that the increase in blood flow is through bone, but warmth of skin overlying Pagetic bone suggests that cutaneous blood flow might be increased. In three patients with Paget's disease involving one extremity, we compared blood flow in "Pagetic" extremities with flow in the contralateral normal extremities. Resting blood flow (measured with water plethysmographs) was 14.2plus or minus2.9 (meanplus or minusSE) ml/min times 100 ml extremity in the Pagetic limbs. The contribution of cutaneous flow to the increase in extremity blood flow was evaluated with epinephrine iontophoresis, which suppresses flow to skin but not to underlying tissue. Epinephrine iontophoresis of the Pagetic extremities decreased blood flow from 14.2plus or minus2.9 to 3.6plus or minus1.5 ml/min. Local heating (which increases cutaneous flow only) failed to increase blood flow in the Pagetic extremities as much as it did in the normal extremities. This suggests that cutaneous vessels in the Pagetic extremities were already dilated. During heating, blood flow in the normal extremities was similar to resting flow in the Pagetic extremities; this indicates that increases in cutaneous flow could account for most of the increase in total blood flow in the Pagetic extremities. Adrenergic control of blood flow to the Pagetic extremities was compared with that of the normal extremities. Vasoconstrictor responses to reflex stimuli in the Pagetic extremities were reduced; when vasoconstriction occurred it was gradual and sustained after termination of the stimuli, which suggests an exaggerated humoral response but reduced neural response to the stimuli. Intravenous epinephrine produced vasoconstriction in the Pagetic extremities and vasodilatation in the normal extremities. In summary, responses to epinephrine iontophoresis and heating suggest that the increase in blood flow in Pagetic extremities is primarily the result of cutaneous vasodilatation.
Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy&lt;subtitle&gt;A Randomized Clinical Trial&lt;/subtitle&gt;
Authors: Alan E. Jones
Journal: JAMA (2010)

<h3>Context</h3>Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department.<h3>Objective</h3>To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO<sub>2</sub>) as goals of early sepsis resuscitation.<h3>Design, Setting, and Patients</h3>Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.<h3>Interventions</h3>We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO<sub>2</sub> group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO<sub>2</sub> of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment.<h3>Main Outcome Measure</h3>The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Δ equal to −10%.<h3>Results</h3>Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO<sub>2</sub> group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined −10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, −3% to 15%). There were no differences in treatment-related adverse events between the groups.<h3>Conclusion</h3>Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO<sub>2</sub> did not result in significantly different in-hospital mortality.<h3>Trial Registration</h3>clinicaltrials.gov Identifier: NCT00372502
The Vaccine Controversy: The History, Use, and Safety of Vaccinations
Authors: Richard Roberts
Journal: BMJ (2005)

T he sleeve pictures an impassive young military recruit, an injecting gun pressed against each deltoid, other recruits waiting in line. For those interested in vaccine controversies this is a tempting title, but do the contents live up to the promise? Kurt Link Praeger, £19.99/$34.95, pp 208 ISBN 0 275 98472 9 http://www.praeger.com/ Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img>![Graphic][4]</img> The book contains some interesting historical detail, in particular about smallpox—which is not surprising given the recent US fiasco concerning mass vaccination against smallpox. It describes two accounts of early variolation before Jenner's work. In China in the 17th century children were deliberately … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif
Heparin regulates smooth muscle S phase entry in the injured rat carotid artery.
Authors: M W Majesky, S M Schwartz, M M Clowes, A W Clowes
Journal: Circulation Research (1987)

Smooth muscle cell (SMC) proliferation in injured arteries is inhibited by heparin, but the mechanism of inhibition is unknown. In particular, it is not clear whether heparin prevents exit of quiescent SMC from the resting state, inhibits progression through the prereplicative (G1) sequence, or acts during DNA synthesis itself. In this study, induction of ornithine decarboxylase (ODC) activity was used as a marker of SMC entry into the cell cycle in an attempt to localize the site of heparin action during the initial hours after rat carotid injury. Rapid and transient induction of ODC activity was observed that reached a maximum (twenty-three-fold) 6 hours after wounding. Heparin failed to prevent ODC induction but greatly reduced frequencies of [3H]thymidine-labelled SMC nuclei 33 hours after injury. Moreover, heparin infusion could be delayed for up to 18 hours after the injury event with no significant loss of antiproliferative effect. Further delays resulted in marked loss of growth inhibition. The results of these studies show that SMC rapidly and synchronously leave the resting state after injury and suggest that heparin acts late in the prereplicative (G1) sequence or early in S phase to inhibit SMC proliferation in damaged arteries.
Homologue Scanning Mutagenesis Reveals Cd66 Receptor Residues Required for Neisserial Opa Protein Binding
Authors: Martine P. Bos, Daniel Hogan, Robert J. Belland
Journal: The Journal of Experimental Medicine (1999)

The immunoglobulin-like family of CD66 antigens, present on human neutrophils and epithelial cells, are used as receptors for adhesins expressed by the pathogenic Neisseriae. N. gonorrhoeae strain MS11 can express 11 isoforms of these adhesins, called opacity-related (Opa) proteins. Each MS11 Opa protein recognizes a distinct spectrum of CD66 receptors. CD66–Opa binding is mediated by the NH2-terminal domain of the receptor and occurs through protein–protein interactions. In this report, we have investigated the molecular basis for the binding between the CD66 and Opa protein families by mapping amino acids in CD66 receptors that determine Opa protein binding. We performed homologue scanning mutagenesis between CD66e, which binds multiple Opa variants, and CD66b, which binds none, and tested both loss-of-function by CD66e and gain-of-function by CD66b in solution assays and in assays involving full-length receptors expressed by epithelial cells. We found that three residues in the CD66e N-domain are required for maximal Opa protein receptor activity. Opa proteins that recognize the same spectrum of native CD66 molecules showed differential binding of receptors with submaximal activity, indicating that the binding characteristics of these Opa proteins are actually slightly different. These data provide a first step toward resolving the structural requirements for Opa–CD66 interaction.
Insertion/deletion polymorphism in the angiotensin-converting enzyme gene and risk of restenosis after coronary angioplasty
Authors: N.J. Samani, M. Brack, J. Cullen, D.P. de Bono, A.H. Gershlick, D.S. Martin, D. Lodwick, J.D. Swales, A. Chauhan, A. Harley
Journal: The Lancet (1995)
APE-Type Non-LTR Retrotransposons of Multicellular Organisms Encode Virus-Like 2A Oligopeptide Sequences, Which Mediate Translational Recoding during Protein Synthesis
Authors: Valerie Odon, Garry A. Luke, Claire Roulston, Pablo de Felipe, Lin Ruan, Helena Escuin-Ordinas, Jeremy D. Brown, Martin D. Ryan, Andriy Sukhodub
Journal: Molecular Biology and Evolution (2013)

2A oligopeptide sequences ("2As") mediate a cotranslational recoding event termed "ribosome skipping." Previously we demonstrated the activity of 2As (and "2A-like sequences") within a wide range of animal RNA virus genomes and non-long terminal repeat retrotransposons (non-LTRs) in the genomes of the unicellular organisms Trypanosoma brucei (Ingi) and T. cruzi (L1Tc). Here, we report the presence of 2A-like sequences in the genomes of a wide range of multicellular organisms and, as in the trypanosome genomes, within non-LTR retrotransposons (non-LTRs)—clustering in the Rex1, Crack, L2, L2A, and CR1 clades, in addition to Ingi. These 2A-like sequences were tested for translational recoding activity, and highly active sequences were found within the Rex1, L2, CR1, and Ingi clades. The presence of 2A-like sequences within non-LTRs may not only represent a method of controlling protein biogenesis but also shows some correlation with such apurinic/apyrimidinic DNA endonuclease-type non-LTRs encoding one, rather than two, open reading frames (ORFs). Interestingly, such non-LTRs cluster with closely related elements lacking 2A-like recoding elements but retaining ORF1. Taken together, these observations suggest that acquisition of 2A-like translational recoding sequences may have played a role in the evolution of these elements.
Accuracy and quality of massively parallel DNA pyrosequencing
Authors: Susan M Huse, Julie A Huber, Hilary G Morrison, Mitchell L Sogin, David Mark Welch
Journal: Genome biology (2007)

Abstract Background Massively parallel pyrosequencing systems have increased the efficiency of DNA sequencing, although the published per-base accuracy of a Roche GS20 is only 96%. In genome projects, highly redundant consensus assemblies can compensate for sequencing errors. In contrast, studies of microbial diversity that catalogue differences between PCR amplicons of ribosomal RNA genes (rDNA) or other conserved gene families cannot take advantage of consensus assemblies to detect and minimize incorrect base calls. Results We performed an empirical study of the per-base error rate for the Roche GS20 system using sequences of the V6 hypervariable region from cloned microbial ribosomal DNA (tag sequencing). We calculated a 99.5% accuracy rate in unassembled sequences, and identified several factors that can be used to remove a small percentage of low-quality reads, improving the accuracy to 99.75% or better. Conclusion By using objective criteria to eliminate low quality data, the quality of individual GS20 sequence reads in molecular ecological applications can surpass the accuracy of traditional capillary methods.
Chemotactic factors regulate lectin adhesion molecule 1 (LECAM-1)-dependent neutrophil adhesion to cytokine-stimulated endothelial cells in vitro.
Authors: C W Smith, T K Kishimoto, O Abbassi, B Hughes, R Rothlein, L V McIntire, E Butcher, D C Anderson, O Abbass
Journal: Journal of Clinical Investigation (1991)

Monoclonal antibodies recognizing CD18, CD11a, CD11b, and neutrophil lectin adhesion molecule 1 (LECAM-1), i.e., the human homologue of the murine MEL-14 antigen, were used to assess the relative contribution of these glycoproteins to neutrophil-endothelial adhesion. Under static conditions, the adhesion of neutrophils to IL-1-stimulated human umbilical vein endothelial cell (HUVEC) monolayers was inhibited by antibodies to CD18, CD11a, and the neutrophil LECAM-1, and the effect of combining anti-LECAM-1 and anti-CD11a was almost additive. Under flow at a wall shear stress 1.85 dyn/cm2, a condition where CD18-dependent adhesion is minimal, anti-LECAM-1 inhibited adhesion by greater than 50%. Chemotactic stimulation of neutrophils induced a rapid loss of LECAM-1 from the neutrophil surface, and the level of neutrophil surface LECAM-1 was closely correlated with adhesion under flow. Neutrophils contacting the activated endothelial cells for 30 min lost much of their surface LECAM-1, a phenomenon induced by a soluble factor or factors released into the medium by the stimulated monolayers, and a high percentage migrated through the HUVEC monolayer. This migration was almost completely inhibited by anti-CD18, but was unaffected by antibodies to neutrophil LECAM-1. These results support the concept that LECAM-1 is a neutrophil adhesion molecule that participates in the adherence of unstimulated neutrophils to cytokine-stimulated endothelial cells under conditions of flow, and is then lost from the neutrophil surface coincident with the engagement of CD18-dependent mechanisms leading to transendothelial migration.
Heparin attenuates TNF-alpha induced inflammatory response through a CD11b dependent mechanism
Authors: A Salas, M Sans, A Soriano, J C Reverter, D C Anderson, J M Piqué, J Panés
Journal: Gut (2000)

<h3>BACKGROUND</h3> In addition to its anticoagulant properties, heparin has anti-inflammatory effects, the molecular and mechanistic bases of which are incompletely defined. <h3>AIMS</h3> The current studies were designed to test the hypothesis that heparin abrogates the expression or function of leucocyte-endothelial adherence molecules which are fundamental to the acute inflammatory response. <h3>METHODS</h3> The effects of heparin on tumour necrosis factor alpha (TNF-α) induced leucocyte rolling, adhesion, and migration as well as vascular permeability were assessed in rat mesenteric venules using intravital microscopy. Expression of adhesion molecules was quantitated using a double radiolabelled monoclonal antibody (mAb) binding technique in vivo (P-selectin, intercellular cell adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1)) or flow cytometry (CD11a, CD11b, and L-selectin). Ex vivo binding of heparin to neutrophils was assessed by flow cytometry. <h3>RESULTS</h3> TNF-α induced a significant increase in leucocyte rolling, adhesion, and migration, and vascular permeability, coincident with a significant increase in expression of P-selectin, ICAM-1, and VCAM-1. Ex vivo assessment of blood neutrophils showed significant upregulation of CD11a and CD11b and significant downregulation of L-selectin within five hours of TNF-α administration. Heparin pretreatment significantly attenuated leucocyte rolling, adhesion, and migration but did not affect expression of cell adhesion molecules or vascular permeability elicited by TNF-α administration. Binding of heparin was significantly increased on blood neutrophils obtained five hours after TNF-α administration. Preincubation with an anti-CD11b mAb but not with an anti-CD11a or anti-L-selectin antibody significantly diminished heparin binding ex vivo. <h3>CONCLUSIONS</h3> Our results support the concept that the anti-inflammatory effects of heparin involve attenuation of a CD11b dependent adherent mechanism.
SURFIN is a polymorphic antigen expressed on <i>Plasmodium falciparum</i> merozoites and infected erythrocytes
Authors: Gerhard Winter, Satoru Kawai, Malin Haeggström, Osamu Kaneko, Anne von Euler, Shin-ichiro Kawazu, Daniel Palm, Victor Fernandez, Mats Wahlgren
Journal: The Journal of Experimental Medicine (2005)

The surfaces of the infected erythrocyte (IE) and the merozoite, two developmental stages of malaria parasites, expose antigenic determinants to the host immune system. We report on surface-associated interspersed genes (surf genes), which encode a novel polymorphic protein family, SURFINs, present on both IEs and merozoites. A SURFIN expressed in 3D7 parasites, SURFIN4.2, was identified by mass spectrometric analysis of peptides cleaved off the surface of live IEs with trypsin. SURFINs are encoded by a family of 10 surf genes, including three predicted pseudogenes, located within or close to the subtelomeres of five of the chromosomes. SURFINs show structural and sequence similarities with exported surface-exposed proteins (PvSTP1, PkSICAvar, PvVIR, Pf332, and PfEMP1) of several Plasmodium species. SURFIN4.2 of a parasite other than 3D7 (FCR3S1.2) showed polymorphisms in the extracellular domain, suggesting sequence variability between genotypes. SURFIN4.2 not only was found cotransported with PfEMP1 and RIFIN to the IE surface, but also accumulated in the parasitophorous vacuole. In released merozoites, SURFIN4.2 was present in an amorphous cap at the parasite apex, where it may be involved in the invasion of erythrocytes. By exposing shared polymorphic antigens on IEs and merozoites, the parasite may coordinate the antigenic composition of these attachment surfaces during growth in the bloodstream.
Ulcerative colitis and Crohn's disease: a comparison of the colorectal cancer risk in extensive colitis.
Authors: C D Gillen, R S Walmsley, P Prior, H A Andrews, R N Allan
Journal: Gut (1994)

The risk of developing colorectal cancer has been compared in two identically selected cohorts of patients with extensive Crohn9s colitis (n = 125) and extensive ulcerative colitis (n = 486). In both groups the effects of selection bias have been reduced wherever possible. There was an 18-fold increase in the risk of developing colorectal cancer in extensive Crohn9s colitis and a 19-fold increase in risk in extensive ulcerative colitis when compared with the general population, matched for age, sex, and years at risk. The absolute cumulative frequency of risk for developing colorectal cancer in extensive colitis was 8% at 22 years from onset of symptoms in the Crohn9s disease group and 7% at 20 years from onset in the ulcerative colitis group. The relative risk of colorectal cancer was increased in both ulcerative colitis and Crohn9s disease among those patients whose colitis started before the age of 25 years. Whether the absolute risk is greater in the younger age group or merely reflects that the expected number of carcinomas increases with age is uncertain. While there is an increased risk of developing colorectal cancer in extensive colitis the number of patients with Crohn9s disease who actually develop colorectal cancer is small because many patients with extensive Crohn9s colitis undergo colectomy early in the course of their disease to relieve persistent symptoms unresponsive to medical treatment.
Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial
Authors: Jonathan Ledermann, Philipp Harter, Charlie Gourley, Michael Friedlander, Ignace Vergote, Gordon Rustin, Clare L Scott, Werner Meier, Ronnie Shapira-Frommer, Tamar Safra, Daniela Matei, Anitra Fielding, Stuart Spencer, Brian Dougherty, Maria Orr, Darren Hodgson, J Carl Barrett, Ursula Matulonis
Journal: The Lancet Oncology (2014)
Ventilation inhomogeneities assessed by the multibreath washout (MBW) technique
Authors: P. Latzin, C. Thamrin, R. Kraemer
Journal: Thorax (2007)

Intrapulmonary gas distribution and mixing is an important functional property of the lungs and can be characterised by the multibreath washout (MBW) technique. By computing indices from the entire washout curve, ventilation inhomogeneities can be characterised.1–5 Developed in the late 1980s for use in children,6–8 MBW measurements are taken during tidal breathing and have been used in infants9–12 as well as preschool children.7 12 13 This technique is especially advantageous in the latter as only a few tests exist for measuring pulmonary function without active subject cooperation.

The MBW allows us to measure functional residual capacity (FRCMBW), which can be used in combination with the plethysmographic intrathoracic gas volume (FRCpleth) to determine the amount of trapped gas in the lungs (VTG).14–17 In addition, using the washout curve, different measures of ventilation inhomogeneity can be obtained. The lung clearance index (LCI) is defined as the number of lung volume turnovers (cumulative expired volume divided by FRC).2 3 5 Other more sophisticated indices include the moment ratios (m1:m, m2:m),4–8 10 18 19 mixing ratio (ratio between the actual and ideal breaths needed to lower the tracer gas to a defined end-tidal concentration in relation to the starting concentration)13 20 and the alveolar-based gas dilation number.19 21

At present, LCI is the most commonly used of these indices, partly because it is arguably the most intuitive and easiest to be communicated to patients. Of note, these indices of intrapulmonary gas mixing are independent of age. Moreover, LCI has been shown in patients with cystic fibrosis (CF) to be more sensitive than spirometry for detecting changes in small airways,13 to be the …