tbuckley/cabot-search huggingface dataset:
Does platelet-derived growth factor-A chain stimulate proliferation of arterial mesenchymal cells in human atherosclerotic plaques?
Authors: M D Rekhter, D Gordon
Journal: Circulation Research (1994)

Previous studies have indicated the focal presence of growth factors and focal low levels of cell proliferation in human atherosclerotic plaques. Using human carotid plaques and an antibody to platelet-derived growth factor (PDGF)-A chain, we have begun to assess growth factor significance by spatially correlating growth factor gene expression with actual cell proliferation. Since PDGF is a mitogen for smooth muscle and related cells and since inflammatory cells (eg, macrophages) can also proliferate in these lesions, it was important to exclude inflammatory cell proliferation from this consideration. Therefore, we have used a triple immunolabeling approach, combining the above anti-PDGF-A chain antibody with an inflammatory cell cocktail (CD68+CD45 for monocyte/macrophages and lymphocytes) and adding an anti-proliferating cell nuclear antigen (PCNA) antibody to mark proliferating cells. In the carotid atherosclerotic plaques, PDGF immunostaining was distributed focally, preferentially in the fibrous cap and vascularized regions, and was present in two distinct patterns: cytoplasmic and diffuse extracellular staining. When we considered colocalization within the same cells, cytoplasmic PDGF-A staining did not appear to colocalize with inflammatory markers. PCNA nuclear staining combined with PDGF cytoplasmic staining of the same cell was detected extremely rarely. Considering colocalization within the same microscopic fields, PDGF-A staining was detected more frequently than noninflammatory PCNA positivity. Quantitative logistic regression analysis demonstrated that localization in vascularized regions and (independently) the presence of PDGF-A are good predictors of noninflammatory cell proliferation, within the same microscopic fields. Therefore, PDGF-A and other factors especially associated with vascularized regions may be involved in the regulation of mesenchymal cell proliferation in human atherosclerotic plaques.
High incidence of oesophageal and gastric cancer in Kashmir in a population with special personal and dietary habits.
Authors: M S Khuroo, S A Zargar, R Mahajan, M A Banday
Journal: Gut (1992)

Over a three year period (1 July 1986 to 30 June 1989) all newly diagnosed and histologically proved cases of oesophageal and gastric cancer were recorded prospectively. Some 1515 cases of oesophageal cancer (1050 men and 465 women) and 966 cases of gastric cancer (789 men and 177 women) were registered. Seven patients had simultaneous oesophageal and gastric cancer. Age standardised incidence rates for oesophageal cancer were: men 43.6/100,000 per year; women 27.9/100,000 per year. The rates for gastric cancer were: men 36.7/100,000 per year, women 9.9/100,000 per annum. These figures were three to six times higher than those recorded by cancer registries in Banglore, Madras, and Bombay. The incidence rates for oesophageal and gastric cancer in Islamabad (southern district of Kashmir) were 4.1 to 5.4 times higher in men and 1.5 to 2.0 times higher in women than those for Kupwara (northern district of Kashmir). The incidence rates for oesophageal and gastric cancer in Muslims, Hindus, and Sikhs were different. The epidemiology of oesophageal cancer in Kashmir was similar to that found in the 9Asian oesophageal cancer belt9. At the same time Kashmir also had an unprecedented high incidence of gastric cancer. Kashmiries have special personal and dietary habits. Further studies are needed to define the relation between these habits and the occurrence of oesophageal and gastric cancer.
Human CD4-major histocompatibility complex class II (DQw6) transgenic mice in an endogenous CD4/CD8-deficient background: reconstitution of phenotype and human-restricted function.
Authors: R S Yeung, J M Penninger, T M Kündig, Y Law, K Yamamoto, N Kamikawaji, L Burkly, T Sasazuki, R Flavell, P S Ohashi, T W Mak
Journal: The Journal of Experimental Medicine (1994)

To reconstitute the human immune system in mice, transgenic mice expressing human CD4 and human major histocompatibility complex (MHC) class II (DQw6) molecules in an endogenous CD4- and CD8-deficient background (mCD4/8-/-), after homologous recombination, have been generated. We report that expression of human CD4 molecule in mCD4/8-/- mice rescues thymocyte development and completely restores the T cell compartment in peripheral lymphoid organs. Upon vesicular stomatitis virus (VSV) challenge, the reconstituted mature T cell population effectively provide T help to B cells in immunoglobulin class switching from IgM to specific IgG-neutralizing antibodies. Human CD4+DQw6+ double transgenic mice are tolerant to DQw6 and the DQw6 molecule functions in antigen presentation, effectively generating a human MHC class II-restricted T cell response to streptococcal M6C2 peptide. These data show that both the hCD4 and DQw6 molecules are functional in mCD4/8-/- mice, fully and stably reconstituting this limb of the human immune system in mice. This animal model provides a powerful in vivo tool to dissect the human CD4-human class II MHC interaction, especially its role in human autoimmune diseases, superantigen-mediated diseases, and acquired immunodeficiency syndrome (AIDS).
Guidelines for evaluation and management of urticaria in adults and children
Authors: C.E.H. Grattan, F. Humphreys
Journal: British Journal of Dermatology (2007)

Appropriate management of urticaria depends on the correct evaluation of clinical patterns and causes where these can be identified. Guidance for treatment is presented, based on the strength of evidence available at the time of preparation. As many of the recommendations relate to the off-licence use of drugs, it is particularly important that clinicians should be familiar with dosing and side-effects of treatment in the context of managing urticaria.
First-line bevacizumab-containing therapy for breast cancer: results in patients aged ≥70 years treated in the ATHENA study
Authors: L. Biganzoli, E. Di Vincenzo, Z. Jiang, M. Lichinitser, Z. Shen, R. Delva, N. Bogdanova, G.L. Vivanco, Z. Chen, Y. Cheng, M. Just, M. Espié, J. Vinholes, C. Hamm, D. Crivellari, E. Chmielowska, V. Semiglazov, F. Dalenc, I. Smith
Journal: Annals of Oncology (2011)
Infliximab in combination with methotrexate in active ankylosing spondylitis: a clinical and imaging study
Authors: H Marzo-Ortega
Journal: Annals of the Rheumatic Diseases (2005)

<h3>Background</h3> Tablet splitting can provide dose flexibility and cost savings; however, pharmaceutical representatives typically discourage the practice. <h3>Aim</h3> To identify and summarise all published concerns related to tablet splitting and to present the experimental evidence that investigates those concerns. <h3>Design &amp; setting</h3> Systematic review and qualitative synthesis of tablet-splitting concerns and evidence. <h3>Method</h3> Medline and EMBASE databases were searched over all years of publication for articles in English discussing the splitting of tablets. Eligible articles included original research, narrative reviews, systematic reviews, and expert opinion. <h3>Results</h3> After removing duplicates, 1837 potentially relevant articles underwent dual review, whereupon 1612 articles were excluded based on title and abstract. After examination of 225 full texts, 138 articles were included (one systematic review, four narrative reviews, 101 original research articles, and 32 opinion articles). The described concerns included difficulty breaking tablets, loss of mass, weight variability, chemical instability, overly rapid dosing if sustained-release medications are split, non-compliance, and patient confusion resulting in medication errors. No substantive evidence was found to support concerns regarding loss of mass, weight variability, chemical instability, or non-compliance. Evidence does support some older adults struggling to split tablets without tablet splitters, and the inappropriateness of splitting sustained-release preparations, given the potential for alteration of the rate of drug release for some products. <h3>Conclusion</h3> With the exception of sustained-release tablets, which should not be split, and excepting those older people who may struggle to split tablets based on physical limitations, there is little evidence to support tablet-splitting concerns.
Iloprost Prevents Contrast-Induced Nephropathy in Patients With Renal Dysfunction Undergoing Coronary Angiography or Intervention
Authors: Konstantinos Spargias, Elias Adreanides, Eftihia Demerouti, Angeliki Gkouziouta, Athanassios Manginas, Gregory Pavlides, Vassilis Voudris, Dennis V. Cokkinos
Journal: Circulation (2009)

The prevention of contrast-induced nephropathy, which accounts for considerable morbidity and mortality, remains a vexing problem. Contrast-induced renal vasoconstriction is believed to play a pivotal role in the pathogenesis of contrast-induced nephropathy. The aim of this study was to examine the efficacy of the prostacyclin analog iloprost in preventing contrast-induced nephropathy in patients with renal dysfunction undergoing a coronary procedure.We conducted a randomized, double-blind, placebo-controlled trial of iloprost in 208 patients with a serum creatinine concentration >or=1.4 mg/dL who underwent coronary angiography and/or intervention. Iloprost 1 ng kg(-1) min(-1) or placebo was administered intravenously beginning 30 to 90 minutes before and ending 4 hours after the procedure. Contrast-induced nephropathy was defined by an absolute increase in serum creatinine >or=0.5 mg/dL or a relative increase >or=25% measured 2 to 5 days after the procedure. Contrast-induced nephropathy occurred in 23 of the 105 patients (22%) in the control group and in 8 of the 103 patients (8%) in the iloprost group (odds ratio, 0.29; 95% confidence interval, 0.12 to 0.69; P=0.005). In the control group, the estimated glomerular filtration rate declined from 49.7+/-15.5 to 46.6+/-16.6 mL min(-1) 1.73 m(-2) (P=0.01). In the iloprost group, the estimated glomerular filtration rate increased marginally from 47.5+/-14.5 to 48.6+/-16.1 mL min(-1) 1.73 m(-2) (P=0.26). The mean absolute estimated glomerular filtration rate decline in the control group was greater than its change in the iloprost group (difference, 4.2 mL min(-1) 1.73 m(-2); 95% confidence interval, 1.1 to 7.3; P=0.008).Prophylactic administration of iloprost may protect against contrast-induced nephropathy in high-risk patients undergoing a coronary procedure.
Reply to "Survival analysis for apparent diffusion coefficient measures in children with embryonal brain tumors," by Grech-Sollars et al.
Authors: K. Koral, D. C. Bowers, R. Timmerman
Journal: Neuro-Oncology (2012)

ELUCIDATING THE MECHANISM OF RECEPTOR TYROSINE KINASE INHIBITION BY SOLUBLE LRIG1 IN GLIOBLASTOMA
Release of endogenous C3b inactivator from lymphocytes in response to triggering membrane receptors for beta 1H globulin.
Authors: J D Lambris, N J Dobson, G D Ross
Journal: The Journal of Experimental Medicine (1980)

Human bone marrow-derived lymphocytes and cells from B lymphoblastoid lines were shown to have specific membrane receptors for beta 1H globin. Lymphocytes responded to the presence of beta 1H by releasing endogenously-synthesized C3b-inactivator. Very little spontaneous release of C3b-inactivator occurred in the absence of beta 1H. beta 1H-treated lymphocytes that either lacked complement receptor type one (CR1, the C4b-C3b receptor) or had their CR1 blocked with Fab'-anti-CR1 formed rosettes with C3b-coated sheep erythrocytes (EC3b) by adherence to complement receptor type two (CR2, the C3d-C3bi receptor). The mechanism of the beta 1H-induced EC3b rosette formation was shown to involve the release of lymphocyte C3b-inactivator that cleaved bound C3b into C3bi forming EC3bi. This lymphocytes-generated EC3bi then bound to CR2, forming rosettes. beta 1H-induced EC3b rosettes were completely inhibited by the presence of either anti-C3b-inactivator, F(ab')2-anti-CR2, Fab-anti-C3c, or Fab-anti-C3d, but were unaffected by the presence of fluid-phase concentrations of beta 1H up to 5.5 mg/ml or Fab'-anti-CR1. Analysis by sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography demonstrated that cell-free supernates of beta 1H-treated lymphocytes cleaved 3H-labeled C3b on EC3b into C3bi. Inhibition studies with chelating agents and sodium azide suggested that the release of C3b inactivator might involve a calcium and energy-dependent transport of this enzyme across the membranes of beta 1H-triggered cells. Because plasma beta 1H and C3b-inactivator are known to have important functions in the distinction of alternative pathway-activating substances from normal tissue, it is possible that this beta 1H receptor-C3b-inactivatory releasing system in lymphocytes may have an analogous function.
Simultaneous Inhibition of PDK1/AKT and Fms-Like Tyrosine Kinase 3 Signaling by a Small-Molecule KP372-1 Induces Mitochondrial Dysfunction and Apoptosis in Acute Myelogenous Leukemia
Authors: Zhihong Zeng, Ismael J. Samudio, Weiguo Zhang, Zeev Estrov, Hélène Pelicano, David Harris, Olga Frolova, Numsen Hail, Wenjing Chen, Steven M. Kornblau, Peng Huang, Yiling Lu, Gordon B. Mills, Michael Andreeff, Marina Konopleva
Journal: Cancer Research (2006)

Abstract Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser473 and Thr308; abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34+ cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC50 &amp;lt; 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells. (Cancer Res 2006; 66(7): 3737-46)
Overcoming barriers and thresholds – signaling of oligomeric Aβ through the prion protein to Fyn
Authors: Hansen Wang, Carl He Ren, C Geeth Gunawardana, Gerold Schmitt-Ulms
Journal: Molecular Neurodegeneration (2013)

Abstract Evidence has been mounting for an involvement of the prion protein (PrP) in a molecular pathway assumed to play a critical role in the etiology of Alzheimer disease. A currently popular model sees oligomeric amyloid β (oAβ) peptides bind directly to PrP to emanate a signal that causes activation of the cytoplasmic tyrosine kinase Fyn, an essential player in a cascade of events that ultimately leads to NMDA receptor-mediated excitotoxicity and hyper-phosphorylation of tau. The model does not reveal, however, how extracellular binding of oAβ to PrP is communicated across the plasma membrane barrier to affect activation of Fyn. A scenario whereby PrP may adapt a transmembrane topology to affect Fyn activation in the absence of additional partners is currently not supported by evidence. A survey of known candidate PrP interactors leads to a small number of molecules that are known to acquire a transmembrane topology and understood to contribute to Fyn activation. Because multiple signaling pathways converge onto Fyn, a realistic model needs to take into account a reality of Fyn acting as a hub that integrates signals from multiple inhibitory and activating effectors. To clarify the role of PrP in oAβ-dependent excitotoxicity, future studies may need to incorporate experimental designs that can probe the contributions of Fyn modulator pathways and rely on analogous readouts, rather than threshold effects, known to underlie excitotoxic signaling.
Bepridil as an antisickling agent: Membrane internalization and cell rigidity
Authors: Robert M. Johnson, Clemenceau Acquaye, Claude Féo, Sharada Sarnaik
Journal: American Journal of Hematology (1994)

Abstract The calcium channel antagonist, bepridil, β‐(2‐methylpropoxy)methyl‐N‐phenyl‐N‐(phenylemethyl)‐1‐pyrrolidineethanamine monocholoride monohydrate, inhibits the sickling of deoxygenated sickle (SS) erythrocytes, as determined by light microscopy. The antisickling effect was seen only in dilute suspensions of red cells. In concentrated erythrocyte suspensions, sickling was not inhibited and measurements of hematocrit and cell density were unchanged by bepridil. The determination of cell volume in dilute suspensions was complicated by bepridil's tendency to aggregate, but rapid measurements by electronic sizing also indicated no increase in cell volume, up to a bepridil concentration of 200 μM. Ektacytometry of dilute sickle cell suspensions suggested an explanation for the anti‐sickling action of bepridil. Osmotic scan ektacytometry disclosed that bepridil initially increased the surface area of the red cell, as shown by a shift in the low osmolality minimum. This change was complete in 10 sec, the shortest time that could be measured. Subsequently, at concentrations that were observed to inhibit the sickling of deoxygenated sickle cells (100 μM or greater), red cells underwent a loss in surface area that was complete in 1 min. There was a concomitant loss of cell deformability. Light and scanning electron microscopy has previously shown that bepridil is a stomatocytic agent. Using transmission electron microscopy, we verified that the loss of surface area was a consequence of endocytosis, presumably as the end stage of the stomatocytic transformation induced by bepridil. Bepridil did not inhibit intracellular hemoglobin S polymerization even at 200 μM, as shown by oxygen scan ektacytometry. Bepridil thus appears to inhibit the sickling of deoxygenated SS cells by inducing endocytosis and lowering cell deformability. This mechanism may explain the anti‐sickling effect of other basic amphiphiles, such as chlorpromazine. © 1994 Wiley‐Liss, Inc.
Protection from photodamage by topical application of caffeine after ultraviolet irradiation
Authors: S-W. Koo, S. Hirakawa, S. Fujii, M. Kawasumi, P. Nghiem
Journal: British Journal of Dermatology (2007)

Characterization of mechanisms that can reverse residual damage from prior skin exposure to ultraviolet (UV) would be of considerable biological and therapeutic interest. Topical caffeine application to mouse skin that had previously been treated with UV has been shown to inhibit the subsequent development of squamous cell carcinomas.We used an established mouse photodamage model to investigate other possible effects of topical caffeine application after UV.SKH-1 hairless mice were treated with ultraviolet B (UVB) followed immediately by topical application of caffeine or vehicle three times weekly for 11 weeks.Caffeine applied topically after UV treatment resulted in a significant decrease in UV-induced skin roughness/transverse rhytides as assessed by treatment-blinded examiners. Histologically, topical caffeine application after a single dose of UVB more than doubled the number of apoptotic keratinocytes as evaluated by sunburn cell formation, caspase 3 cleavage and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) staining. A trend towards decreased solar elastosis was noted in the caffeine-treated group although this was not statistically significant. Other histological parameters including epidermal hyperplasia, solar elastosis and angiogenesis were increased in mice treated with UV but topical application of caffeine did not alter these particular UV effects.These findings support the concept that topical application of caffeine to mouse skin after UV irradiation promotes the deletion of DNA-damaged keratinocytes and may partially diminish photodamage as well as photocarcinogenesis.
Impact of gender on outcomes in ankylosing spondylitis
Authors: Ernst Feldtkeller, Gudrun Lind-Albrecht
Journal: Annals of the Rheumatic Diseases (2013)

We read with interest the article on the impact of gender on outcomes in ankylosing spondylitis (AS).1 In their analysis of four controlled clinical trials, the authors found a higher burden of AS in female patients and less improvement in outcome measures compared with men, ‘despite women having a later disease onset and shorter disease duration’. They conclude that the mechanism behind this observation is …
Mechanism of High Glucose–Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells
Authors: Eduard N. Lavrentyev, Anne M. Estes, Kafait U. Malik
Journal: Circulation Research (2007)

Angiotensin II (Ang II), a circulating hormone that can be synthesized locally in the vasculature, has been implicated in diabetes-associated vascular complications. This study was conducted to determine whether high glucose (HG) (≈23.1 mmol/L), a diabetic-like condition, stimulates Ang II generation and the underlying mechanism of its production in rat vascular smooth muscle cells. The contribution of various enzymes involved in Ang II generation was investigated by silencing their expression with small interfering RNA in cells exposed to normal glucose (≈4.1 mmol/L) and HG. Angiotensin I (Ang I) was generated from angiotensinogen by cathepsin D in the presence of normal glucose or HG. Although HG did not affect the rate of angiotensinogen conversion, it decreased expression of angiotensin-converting enzyme (ACE), downregulated ACE-dependent Ang II generation, and upregulated rat vascular chymase–dependent Ang II generation. The ACE inhibitor captopril reduced Ang II levels in the media by 90% in the presence of normal glucose and 19% in HG, whereas rat vascular chymase silencing reduced Ang II production in cells exposed to HG but not normal glucose. The glucose transporter inhibitor cytochalasin B, the aldose reductase inhibitor alrestatin, and the advanced glycation end product formation inhibitor aminoguanidine attenuated HG-induced Ang II generation. HG caused a transient increase in extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and ERK1/2 inhibitors reduced Ang II accumulation by HG. These data suggest that polyol pathway metabolites and AGE can stimulate rat vascular chymase activity via ERK1/2 activation and increase Ang II production. In addition, decreased Ang II degradation, which, in part, could be attributable to a decrease in angiotensin-converting enzyme 2 expression observed in HG, contributes to increased accumulation of Ang II in vascular smooth muscle cells by HG.