tbuckley/cabot-search huggingface dataset:
Pathogenesis of Hemolytic Anemia in Homozygous Hemoglobin C Disease*
Authors: Samuel Charache, C. Lockard Conley, David F. Waugh, Richard J. Ugoretz, J. Richard Spurrell
Journal: Journal of Clinical Investigation (1967)

Hemoglobin C is less soluble than hemoglobin A in red cells, in hemolysates, and in dilute phosphate buffer. Its relative insolubility may be explained by electrostatic interactions between positively charged beta6-lysyl groups and negatively charged groups on adjacent molecules. Red cells from patients with homozygous hemoglobin C (CC) disease exhibit aberrant physical properties which suggest that the cells are more rigid than normal erythrocytes. They pass through membrane filters less readily than normal red cells do, and their viscosity is higher than that of normal cells. Differences from normal cells are exaggerated if mean corpuscular hemoglobin concentration (MCHC) is increased, by suspension in hypertonic salt solution. Increased rigidity of CC cells, by accelerating their fragmentation, may be responsible for formation of microspherocytes. These small dense cells are exceptionally rigid, and probably are even more susceptible to fragmentation and sequestration. Rigidity of CC cells can be attributed to a "precrystalline" state of intracellular hemoglobin, in which crystallization does not occur, although the MCHC exceeds the solubility of hemoglobin in hemolysates.
Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial
Authors: Axel Le Cesne, Isabelle Ray-Coquard, Binh Nguyen Bui, Antoine Adenis, Maria Rios, François Bertucci, Florence Duffaud, Christine Chevreau, Didier Cupissol, Angela Cioffi, Jean-François Emile, Sylvie Chabaud, David Pérol, Jean-Yves Blay
Journal: The Lancet Oncology (2010)
Folic Acid Reverts Dysfunction of Endothelial Nitric Oxide Synthase
Authors: E. S. G. Stroes, E. E. van Faassen, M. Yo, P. Martasek, P. Boer, R. Govers, T. J. Rabelink
Journal: Circulation Research (2000)

Abstract —5-Methyltetrahydrofolate (MTHF), the active form of folic acid, has been reported to restore NO status in hypercholesterolemic patients. The mechanism of this effect remains to be established. We assessed the effects of L- and D-MTHF on tetrahydrobiopterin (BH 4 )–free and partially BH 4 -repleted endothelial NO synthase (eNOS). Superoxide production of eNOS and the rate constants for trapping of superoxide by MTHF were determined with electron paramagnetic resonance using 5-diethoxyphosphoryl-5-methyl-1-pyrroline- N -oxide (DEPMPO) as spin trap for superoxide. NO production was measured with [ 3 H]arginine–citrulline conversion or nitrite assay. The rate constants for scavenging of superoxide by L- and D-MTHF were similar, 1.4×10 4 ms –1 . In BH 4 -free eNOS, L- and D-MTHF have no effect on enzymatic activity. In contrast, in partially BH 4 -repleted eNOS, we observe a 2-fold effect of MTHF on the enzymatic activity. First, superoxide production is reduced. Second, NO production is enhanced. In cultured endothelial cells, a similar enhancement of NO production is induced by MTHF. In the present study, we show direct effects of MTHF on the enzymatic activity of NO synthase both in recombinant eNOS as well as in cultured endothelial cells, which provides a plausible explanation for the previously reported positive effects of MTHF on NO status in vivo.
Defining the directionality and quality of influenza virus–specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virus
Authors: Victoria Kasprowicz, Scott M. Ward, Alison Turner, Alexandros Grammatikos, Brian E. Nolan, Lia Lewis-Ximenez, Charles Sharp, Jenny Woodfruff, Vicki M. Fleming, Stuart Sims, Bruce D. Walker, Andrew K. Sewell, Georg M. Lauer, Paul Klenerman
Journal: Journal of Clinical Investigation (2008)

Cross-reactivity of murine and recently human CD8(+) T cells between different viral peptides, i.e., heterologous immunity, has been well characterized. However, the directionality and quality of these cross-reactions is critical in determining their biological importance. Herein we analyzed the response of human CD8(+) T cells that recognize both a hepatitis C virus peptide (HCV-NS3) and a peptide derived from the influenza neuraminidase protein (Flu-NA). To detect the cross-reactive CD8(+) T cells, we used peptide-MHC class I complexes (pMHCs) containing a new mutant form of MHC class I able to bind CD8 more strongly than normal MHC class I complexes. T cell responses against HCV-NS3 and Flu-NA peptide were undetectable in normal donors. In contrast, some responses against the Flu-NA peptide were identified in HCV(+) donors who showed strong HCV-NS3-specific reactivity. The Flu-NA peptide was a weak agonist for CD8(+) T cells in HCV(+) individuals on the basis of novel pMHCs and functional assays. These data support the idea of cross-reactivity between the 2 peptides, but indicate that reactivity toward the Flu-NA peptide is highly CD8-dependent and occurs predominantly after priming during HCV infection. Our findings indicate the utility of the novel pMHCs in dissecting cross-reactivity and suggest that cross-reactivity between HCV and influenza is relatively weak. Further studies are needed to relate affinity and functionality of cross-reactive T cells.
Costal diaphragm and parasternal intercostal function during CO2 stimulation
Authors: Giovanni Tagliabue, Jenny Jagers, Paul Easton
Journal: European Respiratory Journal (2013)

INTRODUCTION: Classically, with increasing CO2 there is a linear increase in minute ventilation (VI) and diaphragm electromyogram (EMG). Although all respiratory muscles would be expected to increase in parallel with VI, given diverse mechanical advantage of individual muscles, there is no a priori reason that all muscles would have equivalent recruitment.

QUESTION: Are two primary muscles of inspiration, Costal Diaphragm (COS) and Parasternal Intercostal (PARA), recruited identically during CO2 stimulated ventilation?

METHODS: Sonomicrometry transducers and EMG electrodes were implanted in the left COS and PARA. After recovery, the animals were studied awake, breathing through a mask. Airflow, ETCO2, muscle length and Mavg EMG were recorded during room air and CO2 rebreathing. Output included breath-by-breath breathing pattern, muscle shortening and EMG, averaged at 3 levels of ETCO2.

![Figure][1] 



RESULTS: For N=7 (wgt 31.1 kg) studied 25 days after implant, VI and tidal volume increased significantly with CO2 stimulated breathing. Simultaneously, both SHORT and EMG of COS and PARA exhibited a linear increase. However, changes in action of the two muscles were significantly different, with greater SHORT and EMG of PARA compared to COS per mmHG CO2.

SUMMARY: With CO2 stimulation, both shortening and EMG of parasternal increased in lock-step with ventilation. Relative action of costal diaphragm was less than parasternal at equivalent CO2.

 [1]: pending:yes
Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis
Authors: Yun-Jiu Cheng, Zhi-Hao Liu, Feng-Juan Yao, Wu-Tao Zeng, Dong-Dan Zheng, Yu-Gang Dong, Su-Hua Wu
Journal: PLoS Medicine (2013)

In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism. Please see later in the article for the Editors' Summary
Perspective on the Pipeline of Drugs Being Developed with Modulation of DNA Damage as a Target
Authors: Ruth Plummer
Journal: Clinical Cancer Research (2010)

Inhibitors of various elements of the DNA repair pathways have entered clinical development or are in late preclinical stages of drug development. It was initially considered that agents targeting DNA repair would act to overcome tumor resistance to chemotherapy and radiotherapy. More recent data have shown that targeting DNA repair pathways can be effective in selected tumors via a synthetically lethal route, with single agent activity having been shown with poly-ADP ribose polymerase (PARP) inhibitors. An increased understanding of the biology and interaction of the DNA repair pathways also means that rational combination of DNA repair inhibitors may also give great benefit in the clinic.
Repetitive high-dose therapy with ifosfamide, thiotepa and paclitaxel with peripheral blood progenitor cell and filgrastim support for metastatic and locally advanced breast cancer: Results of a phase I study
Authors: H.M. Prince, M.J. Millward, D. Rischin, D. Blakey, P. Francis, P. Gates, P. Chappie, M. Quinn, S. Juneja, M. Wolf, E.H. Januszewicz, J.F. Seymour, M. Brettell, A. Strickland, J. Zalcberg, G. Richardson, J. Scarlett, P. Briggs, G.C. Toner
Journal: Annals of Oncology (1999)
FOCAL DESTRUCTION OF NERVOUS TISSUE BY FOCUSED ULTRASOUND: BIOPHYSICAL FACTORS INFLUENCING ITS APPLICATION
Authors: H. T. Ballantine, T. F. Hueter, W. J. H. Nauta, D. M. Sosa
Journal: The Journal of Experimental Medicine (1956)

Ultrasound at frequencies of 1.0 mcps and 2.5 mcps can be focused by a suitable lens system to produce a small region of high vibrational intensity. The concentrated energy within and around the focal region can be used to destroy structures of the central nervous system. The extent of destruction depends upon: (a) the size of the focal region, which varies inversely with the frequency, (b) the ultrasonic intensity, (c) the duration of exposure, and (d) the physical and physiologic characteristics of the tissue under irradiation. With proper choice of ultrasonic dosage, mice were rendered monoplegic by destruction of one-half of the spinal cord without demonstrable injury to the skin or subcutaneous tissues through which the converging ultrasonic beam had been transmitted. In similar fashion, focal lesions were produced in the basal ganglia of living cats by stereotaxic transdural application of a focused ultrasonic beam delivered through the superior aspect of the cerebral hemispheres. Histologic studies of mouse spinal cords and cat brains offered evidence that the fiber tracts of the central nervous system are more vulnerable to ultrasonic irradiation than aggregates of cell nuclei or vascular structures. The destructive action of the ultrasound is apparently a result of mechanical strain combined with a rise in temperature at the focus of the beam. The heating factor was found to assume greater importance under conditions of high intensity and continuous (rather than pulsed) irradiation. Trypan blue staining and radioautography using P(32) have been employed to identify the lesions 1 hour after irradiation. This has been a valuable adjunct in our attempts to determine the accuracy of placement of the lesions and their size. Perhaps more important, however, is the indication from these studies that ultrasonically produced lesions may offer a useful method for investigation of the nature of the blood-brain barrier. "Target studies" were undertaken to determine the precision with which lesions of predetermined size could be placed at predetermined sites in the basal ganglia of the cat. Results to date have been promising, but it is our opinion that further technical improvement will be necessary before ultrasound can be used as an accurate method for placing discrete lesions within the human brain.
Use of monoclonal antibodies for the characterization of novel DNA-binding proteins recognized by human autoimmune sera.
Authors: W H Reeves
Journal: The Journal of Experimental Medicine (1985)

Autoantibodies to a DNA-binding heterodimer consisting of 70,000 and 80,000 dalton subunits were identified in 30-50% of human autoimmune sera from patients with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and scleroderma. Three murine monoclonal antibodies (mAb) against the heterodimer were produced in BALB/c mice by immunizing with isolated human B cell nuclei. By immunofluorescence, the mAb and autoimmune sera demonstrated both speckled nucleoplasmic staining and diffuse nucleolar staining in all human cell types examined. The nucleoplasmic staining was sensitive to DNase but not RNase pretreatment, while the nucleolar staining was sensitive to RNase but not DNase pretreatment. Biochemical characterization of the 70,000 and 80,000 dalton proteins using the mAb indicated that two forms of the antigen, with different mobilities on sucrose gradients, are present in human B cells. A 10 S form consists of the physically associated 70,000 and 80,000 dalton proteins, while a larger, 10-20 S form probably represents the same two proteins bound to DNA. Binding of the proteins to nucleolar RNA could not be confirmed in biochemical studies. These studies indicate that non-histone, DNA-binding proteins may be more frequently recognized by autoantibodies in SLE, MCTD, and scleroderma than has been previously recognized. Along with previous studies on RNA-binding proteins such as Sm, RNP, Ro, and La, the present findings suggest that nucleic acid-binding proteins, as a class, may be particularly frequent targets of autoimmunity in SLE and related disorders.
Myocyte-fibroblast electrical coupling: the basis of a stable relationship?
Authors: E. L. Ongstad, R. G. Gourdie
Journal: Cardiovascular Research (2011)

This editorial refers to ‘Arrhythmogenic consequences of myofibroblast–myocyte coupling’ by T.P. Nguyen et al. , pp. 242–251, this issue. 

Fibroblasts are the most common cell type in the adult human heart, making up around 60% of total cell numbers. While fibroblasts are numerically in the majority, about 75% of the volume of the working muscle of the heart is composed of myocytes.1 Myocytes are highly coupled with other myocytes by gap junctions (GJs), and GJs in turn are thought to be necessary for propagation of the cardiac action potential.2 Interstitial fibroblasts can be found interspersed within the network of GJ-coupled myocytes,3 where their role is assumed largely to be in the synthesis of extracellular matrix, response to mechanical and electrical stimuli, and secretion of growth factors and hormones involved in cardiac homeostasis.

In response to injury, fibroblasts proliferate, undergo differentiation into myofibroblasts, and synthesize excess extracellular matrix, which can interrupt normal myocyte–myocyte coupling by physically separating cells.4 In the infarct border zone after myocardial infarction (MI), fibroblasts undergo this characteristic response, causing localized changes to tissue architecture that may contribute to non-uniform conduction and reentrant arrhythmias. Although GJs between myocytes are known to be essential for normal heart function, there has been debate as to whether myocytes and fibroblasts form electrical contacts via GJs under normal or diseased conditions5 (reviewed in Kohl and Camelliti6) and whether this coupling results in adverse electrophysiological consequences.

In co-culture, the lower negative resting potential of fibroblast cell membranes can contribute to depolarization of myocytes via GJs,7,8 raising the prospect that such electrotonic coupling may contribute to arrhythmias. Nguyen et al. 9 have used an ingenious biological-computational approach to study the potential implications …
Time Course of Stent Endothelialization After Intravascular Radiation Therapy in Rabbit Iliac Arteries
Authors: Edouard Cheneau, Michael C. John, Jana Fournadjiev, Rosanna C. Chan, Han-Soo Kim, Laurent Leborgne, Rajbabu Pakala, Hamid Yazdi, Andrew E. Ajani, Renu Virmani, Ron Waksman
Journal: Circulation (2003)

Late total occlusion after vascular brachytherapy (VBT) continues to be a serious complication. Delayed reendothelialization was suggested as a pivotal cause, but the time course for complete healing is unknown.Seventy-two rabbit iliac arteries underwent stent implantation and were treated with gamma-radiation using 192Ir. The prescribed doses were 0 Gy (controls, n=24 arteries), 15 Gy (n=24), or 30 Gy (n=24) at 2 mm. Animals were killed at 1 month (n=24), 3 months (n=24), or 6 months (n=24) and were analyzed for histomorphometry or scanning electron microscopy. Intimal area was reduced after VBT at 3 months with 15 and 30 Gy (0.66+/-0.07 and 0.66+/-0.04 mm2, respectively) compared with controls (1.01+/-0.11 mm2, P<0.05) and at 6 months with 30 Gy (0.75+/-0.09 versus 1.28+/-0.26 mm2 in controls, P<0.01). Intimal area was similar at 6 months between 15 Gy and controls. At 1 month, 92+/-4% of the control stented segment was covered with endothelial cells, whereas only 37+/-4% and 37+/-8% was covered in the 15- and 30-Gy arteries, respectively. Similarly, at 3 and 6 months, there was a difference in the extent of reendothelialized areas (at 3 months, 95+/-2%, 32+/-12%, and 29+/-13%; and at 6 months, 98+/-2%, 40+/-8%, and 35+/-12% in control, 15-Gy, and 30-Gy arteries, respectively). Excess platelets and leukocytes were seen in irradiated arteries without complete coverage of endothelium.Reendothelialization after VBT is not completed at 6 months after VBT. Special care with prolonged antiplatelet therapy should be considered beyond that time point.
Angiopoietin-1, angiopoietin-2 and Tie-2 receptor expression in human dermal wound repair and scarring
Authors: C.A. Staton, M. Valluru, L. Hoh, M.W.R. Reed, N.J. Brown
Journal: British Journal of Dermatology (2010)

Journal Article Angiopoietin‐1, angiopoietin‐2 and Tie‐2 receptor expression in human dermal wound repair and scarring Get access C.A. Staton, C.A. Staton Microcirculation Research Group, Academic Unit of Surgical Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, U.K. Correspondence: Carolyn A. Staton. E‐mail: c.a.staton@shef.ac.uk Search for other works by this author on: Oxford Academic Google Scholar M. Valluru, M. Valluru Microcirculation Research Group, Academic Unit of Surgical Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, U.K. Search for other works by this author on: Oxford Academic Google Scholar L. Hoh, L. Hoh Microcirculation Research Group, Academic Unit of Surgical Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, U.K. Search for other works by this author on: Oxford Academic Google Scholar M.W.R. Reed, M.W.R. Reed Microcirculation Research Group, Academic Unit of Surgical Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, U.K. Search for other works by this author on: Oxford Academic Google Scholar N.J. Brown N.J. Brown Microcirculation Research Group, Academic Unit of Surgical Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield S10 2RX, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 163, Issue 5, 1 November 2010, Pages 920–927, https://doi.org/10.1111/j.1365-2133.2010.09940.x Published: 01 November 2010
The Effect of Class II Major Histocompatibility Complex Expression on Adherence of <i>Helicobacter pylori</i> and Induction of Apoptosis in Gastric Epithelial Cells: A Mechanism for T Helper Cell Type 1–mediated Damage
Authors: Xuejun Fan, Sheila E. Crowe, Simon Behar, Harshani Gunasena, Gang Ye, Helene Haeberle, Nancy Van Houten, William K. Gourley, Peter B. Ernst, Victor E. Reyes
Journal: The Journal of Experimental Medicine (1998)

Helicobacter pylori infection is associated with gastric epithelial damage, including apoptosis, ulceration, and cancer. Although bacterial factors and the host response are believed to contribute to gastric disease, no receptor has been identified that explains how the bacteria attach and signal the host cell to undergo apoptosis. Using H. pylori as “bait” to capture receptor proteins in solubilized membranes of gastric epithelial cells, class II major histocompatibility complex (MHC) molecules were identified as a possible receptor. Signaling through class II MHC molecules leading to the induction of apoptosis was confirmed using cross-linking IgM antibodies to surface class II MHC molecules. Moreover, binding of H. pylori and the induction of apoptosis were inhibited by antibodies recognizing class II MHC. Since type 1 T helper cells are present during infection and produce interferon (IFN)-γ, which increases class II MHC expression, gastric epithelial cell lines were exposed to H. pylori in the presence or absence of IFN-γ. IFN-γ increased the attachment of the bacteria as well as the induction of apoptosis in gastric epithelial cells. In contrast to MHC II–negative cell lines, H. pylori induced apoptosis in cells expressing class II MHC molecules constitutively or after gene transfection. These data describe a novel receptor for H. pylori and provide a mechanism by which bacteria and the host response interact in the pathogenesis of gastric epithelial cell damage.
Interleukin 15 Skews Monocyte Differentiation into Dendritic Cells with Features of Langerhans Cells
Authors: Mansour Mohamadzadeh, Frederic Berard, Gregory Essert, Cecile Chalouni, Bali Pulendran, Jean Davoust, George Bridges, A. Karolina Palucka, Jacques Banchereau
Journal: The Journal of Experimental Medicine (2001)

Langerhans cells (LCs) represent a subset of immature dendritic cells (DCs) specifically localized in the epidermis and other mucosal epithelia. As surrounding keratinocytes can produce interleukin (IL)-15, a cytokine that utilizes IL-2Rγ chain, we analyzed whether IL-15 could skew monocyte differentiation into LCs. Monocytes cultured for 6 d with granulocyte/macrophage colony-stimulating factor (GM-CSF) and IL-15 differentiate into CD1a+HLA-DR+CD14−DCs (IL15-DCs). Agents such as lipopolysaccharide (LPS), tumor necrosis factor (TNF)α, and CD40L induce maturation of IL15-DCs to CD83+, DC-LAMP+ cells. IL15-DCs are potent antigen-presenting cells able to induce the primary (mixed lymphocyte reaction [MLR]) and secondary (recall responses to flu-matrix peptide) immune responses. As opposed to cultures made with GM-CSF/IL-4 (IL4-DCs), a proportion of IL15-DCs expresses LC markers: E-Cadherin, Langerin, and CC chemokine receptor (CCR)6. Accordingly, IL15-DCs, but not IL4-DCs, migrate in response to macrophage inflammatory protein (MIP)-3α/CCL20. However, IL15-DCs cannot be qualified as “genuine” Langerhans cells because, despite the presence of the 43-kD Langerin, they do not express bona fide Birbeck granules. Thus, our results demonstrate a novel pathway in monocyte differentiation into dendritic cells.
An ATS/ERS report: 100 key questions and needs in occupational asthma
Authors: S. M. Tarlo, J-L. Malo
Journal: European Respiratory Journal (2006)

The second Jack Pepys Workshop on Occupational Asthma was held in Toronto, Canada, in May 2004. The present report summarises key questions and research needs as identified by the international participants. The audiotapes from the workshop discussions were summarised by the organising chairs of the Symposium and the resulting document was circulated for input from all invited workshop participants. In total, 100 key questions and research needs were identified. Identified needs included: provision of different definitions depending on the use of data; explanations for differences in frequency studies; and better characterisation of genetic and environmental determinants of occupational asthma. The role of irritants and the pathogenesis of various forms of work-related asthma need further research, and there are also questions and research needs for diagnosis, prevention and understanding of persistence and airway remodelling. In conclusion, although advances have been made in the understanding of occupational asthma and other work-related asthma, further key issues remain that need addressing.