tbuckley/cabot-search huggingface dataset:
Effects of methotrexate in vitro on epidermal cell proliferation
Authors: J.RICHARD TAYLOR, KENNETH M. HALPRIN, VICTOR LEVINE, CLYDE WOODYARD
Journal: British Journal of Dermatology (1983)

Epidermal cell migration activity and epidermal cell proliferation are clearly dissociable in explant culture. Epidermal cell migration requires a non-dialysable, 65,000 mol. wt factor which is destroyed at 100 degrees C but is stable at 80 degrees C for at least 30 min. In the presence of dialysed serum or heated (80 degrees C for 30 min) or DNA synthesis inhibitors (methotrexate or hydroxyurea), cells will migrate from the explant but will not proliferate. At least two factors are required for normal proliferation under these restricted conditions--an adequate supply of DNA precursers, i.e. nucleosides, and a heat liable (80 degrees C) non-dialysable serum component. Methotrexate in concentrations of 1.0 microgram/ml or greater added to cultures in normal fetal calf serum significantly inhibited mitoses; however, when added to serum dialysed to remove thymidine, mitotic inhibition occurred at a concentration of 0.1 microgram/ml of methotrexate and when added to dialysed serum and kept in dialysed serum, inhibition occurred with 0.01 microgram/ml of methotrexate. Methotrexate did not inhibit outgrowth. Hydroxyurea also inhibited mitoses but did not effect outgrowth.
Three million US patients can now see their medical records online
Authors: K. Chinthapalli
Journal: BMJ (2014)

Online access to doctors’ clinic notes has been expanded to include over three million patients in the United States, a leading expert has said. 

Tom Delbanco, professor of primary care at Harvard Medical School and co-founder of the OpenNotes initiative for shared notes, announced the finding in a keynote speech at the International Forum on Quality & Safety in Healthcare in Paris on 10 April. “We have more than three million patients in the USA, and thousands of doctors, nurses, therapists, trainees, physician assistants, case managers, and other clinicians sharing notes,” he said.

The new figure comes …
Tumor necrosis factor identified in multiple sclerosis brain.
Authors: F M Hofman, D R Hinton, K Johnson, J E Merrill
Journal: The Journal of Experimental Medicine (1989)

Frozen brain specimens from patients with multiple sclerosis (MS) and other neurologic diseases were analyzed using immunocytochemical techniques for the presence of TNF. In brain lesions in MS, and subacute sclerosing panencephalitis, TNF+ cells were demonstrated. At the lesion site in MS, TNF+ staining is associated with both astrocytes and macrophages. These observations were not made in Alzheimer's disease or normal brain tissue. The presence of TNF in MS lesions suggests a significant role for cytokines and the immune response in disease progression.
Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells.
Authors: C Heufler, F Koch, G Schuler
Journal: The Journal of Experimental Medicine (1988)

Freshly isolated, murine epidermal Langerhans cells (LC) are weak accessory cells for primary T cell-dependent immune responses, but increase their stimulatory capacity at least 20-fold progressively over a 3-d culture with keratinocytes. We have studied the mediators of LC maturation. LC enriched from 12-h epidermal cultures by negative selection do not survive when cultured for 60 h in standard medium. LC survive and show increased stimulatory capacity for oxidative mitogenesis and the primary MLR when 30% keratinocyte-conditioned medium is included. Of the three cytokines that are known to be produced by keratinocytes, only granulocyte/macrophage CSF (GM-CSF) maintains viability and increases stimulatory capacity. IL-1 alone does not keep LC alive, but further enhances the stimulatory activity when combined with GM-CSF. IL-3 has no effect. The increase in LC stimulatory capacity is not due to increased Ia antigen expression, which does not change between 12 and 60 h. Function is not simply due to improved viability, as GM-CSF does not enhance the function of 12-h LC when added to the short-term oxidative mitogenesis assay. By generating LC with strong stimulating activity for resting T cells, GM-CSF and IL-1 may be critical in the sensitization phase of T cell-mediated immunity.
Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages
Authors: Stanley Ching-Cheng Huang, Bart Everts, Yulia Ivanova, David O'Sullivan, Marcia Nascimento, Amber M Smith, Wandy Beatty, Latisha Love-Gregory, Wing Y Lam, Christina M O'Neill, Cong Yan, Hong Du, Nada A Abumrad, Joseph F Urban, Maxim N Artyomov, Erika L Pearce, Edward J Pearce
Journal: Nature Immunology (2014)
Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome
Authors: F. Favero, N. McGranahan, M. Salm, N.J. Birkbak, J.Z. Sanborn, S.C. Benz, J. Becq, J.F. Peden, Z. Kingsbury, R.J. Grocok, S. Humphray, D. Bentley, B. Spencer-Dene, A. Gutteridge, M. Brada, S. Roger, P.-Y. Dietrich, T. Forshew, M. Gerlinger, A. Rowan, G. Stamp, A.C. Eklund, Z. Szallasi, C. Swanton
Journal: Annals of Oncology (2015)

In a glioblastoma tumour with multi-region sequencing before and after recurrence, we find an IDH1 mutation that is clonal in the primary but lost at recurrence. We also describe the evolution of a double-minute chromosome encoding regulators of the PI3K signalling axis that dominates at recurrence, emphasizing the challenges of an evolving and dynamic oncogenic landscape for precision medicine.BackgroundGlioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches.MethodsWe describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour.ResultsWe found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after.ConclusionThis case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success.
Identification of Fc epsilon RIneg mast cells in mouse bone marrow cell cultures. Use of a monoclonal anti-p161 antibody.
Authors: C A Kinzer, A D Keegan, W E Paul
Journal: The Journal of Experimental Medicine (1995)

A monoclonal hamster antibody (K-1) specific for a 161-kD mast cell surface glycoprotein was derived. p161 is expressed on normal and cultured mast cells and on some macrophages, but not on basophils or other hematopoietic cells. A population of Fc epsilon Rneg cells expressing p161 was found in short term cultures of bone marrow cells grown in interleukin (IL)-3. These cells were purified and propagated for extended periods in IL-3. They express c-kit and Fc gamma RII/III, contain alcian blue-positive granules and histamine, and secrete IL-3 in response to ionomycin treatment. Their morphology is consistent with that of mast cells. We propose that they represent Fc epsilon RIneg mast cells that can be detected and purified because of their p161 expression.
Therapeutic Roles of Selective COX-2 Inhibitors: Edited by J R Vane, R M Botting. William Harvey Press, 2001. ISBN-0 9534039-1-2
Authors: I Bjarnason
Journal: Gut (2003)

The review editor sent me a book to review for Gut with holidays looming. He left a week before me and is currently observing whales off the east cost of the USA where I hope he will encounter the albino whale. I, on the other hand, am in a more peaceful location surrounded by the truly magnificent lochs, standing stones, stone circles, chambered cains, duns, and crannogs on the Outer Hebridean island of North Uist.

The book Therapeutic Roles of Selective COX-2 Inhibitors is the latest in a series of similar books edited by Vane and Bolting, and I have found it in many ways as interesting and extraordinary as my surroundings. It exceeded all expectations, bringing …
P84 How was it for them? Experiences of parents of children undergoing surgical treatment for empyema thoracis
Authors: C Simmister, Rp Lee, Mf Thomas, Da Spencer
Journal: Thorax (2013)

<h3>Introduction</h3> Opinion is divided regarding the management of empyema thoracis in children. There is wide regional variation in treatment, which is only partially related to variations in the availability of skills and resources. There is currently no published evidence of parent experience of treatment of empyema thoracis in children. <h3>Objective</h3> To explore the experiences of parents of children who have undergone definitive surgical treatment for empyema thoracis. <h3>Methods</h3> Qualitative, face-to-face, semi-structured interviews with parents of children who had undergone definitive surgical treatment for empyema thoracis. Methodology: interpretative phenomenological analysis. Participants were recruited from a large UK teaching hospital between December 2012 and March 2013. They were interviewed in hospital just before discharge. Parents of 8 children aged 11 months to 6 years, 8 mothers and 2 fathers (2 sets of both parents). <h3>Results</h3> The overarching theme revealed in all of the parents’ accounts was trust. The parents’ perceptions of development or undermining of trust was influenced by several factors. They include: communication and interactions with staff; information provision and methods used to provide explanations including use of visual aids; staff competence demonstrated by knowledge and experience; evidence of team-work and non-verbal actions such as smiling, eye contact and perceived attitude. The establishment of trust also differed through the stages from GP referral, admittance to secondary and tertiary hospitals, peri- and post-operative phases. Additionally the accounts revealed that parents were relieved when surgery was undertaken. Most parents were pragmatic about the scars following surgery, but considered that <i>all</i> of the scars were significant, not just the thoracotomy scar. <h3>Conclusions</h3> Verbal and non-verbal communication used by staff when talking to families can have a significant impact on the development or undermining of trust. This can affect parental perception of competence and care provided by practitioners.
Mechanism of Vasopressin-induced Bradycardia in Dogs
Authors: SARLA VARMA, BHUWANESHWAR P. JAJU, KRISHNA P. BHARGAVA
Journal: Circulation Research (1969)

In dogs anesthetized with intravenous chloralose, vasopressin was injected either intravenously or into the cerebral ventricles, and the cardiovascular effects were studied before and after stabilizing the arterial blood pressure, bilateral vagotomy, and transection of the cervical cord at the level of C 2 . Intravenous vasopressin caused a rise in arterial blood pressure and pronounced bradycardia. The bradycardia appeared to be partly due to a peripheral depressant action on the heart, probably resulting from coronary constriction and partly from reflex vagal stimulation resulting from the rise in arterial blood pressure. A direct stimulating action of vasopressin on the central cardioinhibitory neurons played only a minor role in the production of the bradycardia. Injections of vasopressin, into either a lateral or the fourth ventricle, produced an insignificant rise in arterial blood pressure but marked bradycardia. A peripheral effect of the vasopressin after its absorption into the blood stream could be excluded as the cause of the bradycardia, since an injection of vasopressin into the cerebral ventricles produced diuresis, not antidiuresis. The bradycardia was more pronounced and occurred earlier when the vasopressin was injected into the fourth rather than into a lateral ventricle. The bradycardia produced by the injection of vasopressin into the cerebral ventricles could be almost fully accounted for by a central stimulating action on the cardioinhibitory neurons in the region of the vagal nuclei, which are closer to the fourth ventricle than to the lateral ventricles.
Dm Determines the Cryptic and Immunodominant Fate of T Cell Epitopes
Authors: Navreet K. Nanda, Andrea J. Sant
Journal: The Journal of Experimental Medicine (2000)

The ability of the immune system to focus T cell responses against a select number of potential epitopes of a complex antigen is termed immunodominance. Epitopes that trigger potent T cell activation, after in vivo priming, are classified as immunodominant. By contrast, determinants that fail to elicit any response are called cryptic. DM, a major histocompatibility complex (MHC) heterodimer, plays a pivotal role in the presentation of MHC class II–restricted epitopes by catalyzing the exchange of class II–associated invariant chain peptide with the antigen-derived peptides within the MHC class II binding groove. Using L cells transfected with genes for MHC class II, invariant chain, and DM, we have studied the contribution of DM in the presentation of two cryptic (peptide 11–25 and peptide 20–35) and one dominant (peptide 106–116) epitope of hen egg white lysozyme (HEL). Cells lacking DM heterodimers efficiently display the determinants HEL 11–25 and HEL 20–35 to T cells. Strikingly, however, cells expressing DM are severely compromised in their ability to present the cryptic HEL 11–25/Ad and 20–35/Ad epitopes. DM-mediated antagonism of HEL 11–25/Ad and 20–35/Ad presentation could thus be central to 11–25/Ad and 20–35/Ad being cryptic epitopes in the HEL system. Interestingly, the display of the immunodominant epitope of HEL, 106–116/Ed, and of a dominant epitope of sperm whale myoglobin (SWM), 102–118/Ad, is entirely dependent on the expression of DM. Thus, cells lacking DM molecules are unable to efficiently express HEL 106–116/Ed and SWM 102–118/Ad determinants. We conclude that the DM heterodimers direct the immunodominant and cryptic fate of antigenic epitopes in vivo.
Mechanisms of platelet-activating factor-induced lipid body formation: requisite roles for 5-lipoxygenase and de novo protein synthesis in the compartmentalization of neutrophil lipids.
Authors: P T Bozza, J L Payne, J L Goulet, P F Weller
Journal: The Journal of Experimental Medicine (1996)

Lipid bodies, lipid rich cytoplasmic inclusions, are characteristically abundant in vivo in leukocytes associated with inflammation. Because lipid bodies are potential reservoirs of esterified arachidonate and sites at which eicosanoid-forming enzymes may localize, we evaluated mechanisms of lipid body formation in neutrophils (PMN). Among receptor-mediated agonists, platelet activating factor (PAF), but not C5a, formyl-methyl-phenylalanine, interleukin 8, or leukotriene (LT) B4, induced the rapid formation of lipid bodies in PMN. This action of PAF was receptor mediated, as it was dose dependently inhibited by the PAF receptor antagonist WEB 2086 and blocked by pertussis toxin. Lipid body induction by PAF required 5-lipoxygenase (LO) activity and was inhibited by the 5-lipoxygenase-activating protein antagonist MK 886 and the 5-LO inhibitor zileuton, but not by cyclooxygenase inhibitors. Corroborating the dependency of PAF-induced lipid body formation on 5-LO, PMN and macrophages from wild-type mice, but not from 5-LO genetically deficient mice, formed lipid bodies on exposure to PAF both in vitro and in vivo within the pleural cavity. The 5-LO product inducing lipid body formation was not LTB4 but was 5(S)-hydroxyeicosatetraenoic acid [5(S)-HETE], which was active at 10-fold lower concentrations than PAF and was also inhibited by pertussis toxin but not by zileuton or WEB 2086. Furthermore, 5-HETE was equally effective in inducing lipid body formation in both wild-type and 5-LO genetically deficient mice. Both PAF- and 5(S)-HETE-induced lipid body formation were inhibited by protein kinase C (PKC) inhibitors staurosporine and chelerythrine, the phospholipase C (PLC) inhibitors D609 and U-73122, and by actinomycin D and cycloheximide. Prior stimulation of human PMN with PAF to form lipid bodies enhanced eicosanoid production in response to submaximal stimulation with the calcium ionophore A23187; and the levels of both prostaglandin (PG) E2 and LTB4 correlated with the number of lipid bodies. Furthermore, pretreatment of cells with actinomycin D or cycloheximide inhibited not only the induction of lipid body formation by PAF, but also the PAF-induced "priming" for enhanced PGE2 and LTB4 in PMN. Thus, the compartmentalization of lipids to form lipid bodies in PMN is dependent on specific cellular responses that can be PAF receptor mediated, involves signaling through 5-LO to form 5-HETE and then through PKC and PLC, and requires new protein synthesis. Since increases in lipid body numbers correlated with priming for enhanced PGE2 and LTB4 production in PMN, the induction of lipid bodies may have a role in the formation of eicosanoid mediators by leukocytes involved in inflammation.
Nonredundant Roles of Basophils in Immunity
Authors: Hajime Karasuyama, Kaori Mukai, Kazushige Obata, Yusuke Tsujimura, Takeshi Wada
Journal: Annual Review of Immunology (2011)

Basophils are the rarest granulocytes and represent less than 1% of peripheral blood leukocytes. They are evolutionarily conserved in many animal species, but their functional significance remained an enigma long after their discovery by Paul Ehrlich in 1879. Studies of basophils were hindered by their rarity, by difficulties in identifying them, and by the paucity of useful analytical tools. Because basophils display several characteristics shared by tissue-resident mast cells, they were often considered minor and possibly redundant relatives of mast cells or even blood-circulating precursors of mast cells. However, newly developed tools for their functional analysis, including basophil-depleting antibodies and genetically engineered mice deficient only in basophils, have fueled basophil research and defined previously unrecognized functions of basophils. We now appreciate that basophils play nonredundant roles in acquired immunity regulation, protective immunity to pathogens, and immunological disorders such as allergy and autoimmunity.
Hyperosmolarity enhances the lung capillary barrier
Authors: Zeenat Safdar, Ping Wang, Hideo Ichimura, Andrew C. Issekutz, Sadiqa Quadri, Jahar Bhattacharya
Journal: Journal of Clinical Investigation (2003)

Although capillary barrier deterioration underlies major inflammatory lung pathology, barrier-enhancing strategies are not available. To consider hyperosmolar therapy as a possible strategy, we gave 15-minute infusions of hyperosmolar sucrose in lung venular capillaries imaged in real time. Surprisingly, this treatment enhanced the capillary barrier, as indicated by quantification of the capillary hydraulic conductivity. The barrier enhancement was sufficient to block the injurious effects of thrombin, TNF-α, and H2O2 in single capillaries, and of intratracheal acid instillation in the whole lung. Capillary immunofluorescence indicated that the hyperosmolar infusion markedly augmented actin filament formation and E-cadherin expression at the endothelial cell periphery. The actin-depolymerizing agent latrunculin B abrogated the hyperosmolar barrier enhancement as well as the actin filament formation, suggesting a role for actin in the barrier response. Furthermore, hyperosmolar infusion blocked TNF-α–induced P-selectin expression in an actin-dependent manner. Our results provide the first evidence to our knowledge that in lung capillaries, hyperosmolarity remodels the endothelial barrier and the actin cytoskeleton to enhance barrier properties and block proinflammatory secretory processes. Hyperosmolar therapy may be beneficial in lung inflammatory disease.
Role of Nrf2 in the Regulation of CD36 and Stress Protein Expression in Murine Macrophages
Authors: Tetsuro Ishii, Ken Itoh, Emilio Ruiz, David S. Leake, Hiroyuki Unoki, Masayuki Yamamoto, Giovanni E. Mann
Journal: Circulation Research (2004)

CD36 is an important scavenger receptor mediating uptake of oxidized low-density lipoproteins (oxLDLs) and plays a key role in foam cell formation and the pathogenesis of atherosclerosis. We report the first evidence that the transcription factor Nrf2 is expressed in vascular smooth muscle cells, and demonstrate that oxLDLs cause nuclear accumulation of Nrf2 in murine macrophages, resulting in the activation of genes encoding CD36 and the stress proteins A170, heme oxygenase-1 (HO-1), and peroxiredoxin I (Prx I). 4-Hydroxy-2-nonenal (HNE), derived from lipid peroxidation, was one of the most effective activators of Nrf2. Using Nrf2-deficient macrophages, we established that Nrf2 partially regulates CD36 expression in response to oxLDLs, HNE, or the electrophilic agent diethylmaleate. In murine aortic smooth muscle cells, expressing negligible levels of CD36, both moderately and highly oxidized LDL caused only limited Nrf2 translocation and negligible increases in A170, HO-1, and Prx I expression. However, treatment of smooth muscle cells with HNE significantly enhanced nuclear accumulation of Nrf2 and increased A170, HO-1, and Prx I protein levels. Because PPAR-gamma can be activated by oxLDLs and controls expression of CD36 in macrophages, our results implicate Nrf2 as a second important transcription factor involved in the induction of the scavenger receptor CD36 and antioxidant stress genes in atherosclerosis.
TCT-27 Comparison of Novel Zotarolimus-Eluting Cobalt-Chromium Stents and Everolimus-Eluting Platinum-Chromium Stents in Patients of the Randomized DUTCH PEERS Trial Presenting with Acute Myocardial Infarction
Authors: Clemens von Birgelen, Marije M. Löwik, Ming Kai Lam, Hanim Sen, Peter W. Danse, Gillian A. Jessurun, Melvyn Tjon Joe Gin, Rutger Anthonio, Frits H. de Man, Raymond Hautvast, Gerard C. Linssen, Liefke van der Heijden, Kenneth Tandjung, Carine J. Doggen, Gert van Houwelingen
Journal: Journal of the American College of Cardiology (2014)
Ovarian Cancer Biomarkers in Urine
Authors: Ann F. Chambers, Barbara C. Vanderhyden
Journal: Clinical Cancer Research (2006)

In this issue of Clinical Cancer Research , Ye et al. ([1][1]) have taken steps to address the pressing need for the identification of biomarkers for use in detecting ovarian cancer.

For the past 30 years, the statistics have remained the same. The majority of women who develop ovarian cancer will