tbuckley/cabot-search huggingface dataset:
Translocation of Crohn's disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers
Authors: C. L. Roberts, A. V. Keita, S. H. Duncan, N. O'Kennedy, J. D. Soderholm, J. M. Rhodes, B. J. Campbell
Journal: Gut (2010)

<h3>Background</h3> Crohn9s disease is common in developed nations where the typical diet is low in fibre and high in processed food. Primary lesions overlie Peyer9s patches and colonic lymphoid follicles where bacterial invasion through M-cells occurs. We have assessed the effect of soluble non-starch polysaccharide (NSP) and food emulsifiers on translocation of <i>Escherichia coli</i> across M-cells. <h3>Methods</h3> To assess effects of soluble plant fibres and food emulsifiers on translocation of mucosa-associated <i>E coli</i> isolates from Crohn9s disease patients and from non-Crohn9s controls, we used M-cell monolayers, generated by co-culture of Caco2-cl1 and Raji B cells, and human Peyer9s patches mounted in Ussing chambers. <h3>Results</h3> <i>E coli</i> translocation increased across M-cells compared to parent Caco2-cl1 monocultures; 15.8-fold (IQR 6.2–32.0) for Crohn9s disease <i>E coli</i> (N=8) and 6.7-fold (IQR 3.7–21.0) for control isolates (N=5). Electron microscopy confirmed <i>E coli</i> within M-cells. Plantain and broccoli NSP markedly reduced <i>E coli</i> translocation across M-cells at 5 mg/ml (range 45.3–82.6% inhibition, p&lt;0.01); apple and leek NSP had no significant effect. Polysorbate-80, 0.01% vol/vol, increased <i>E coli</i> translocation through Caco2-cl1 monolayers 59-fold (p&lt;0.05) and, at higher concentrations, increased translocation across M-cells. Similarly, <i>E coli</i> translocation across human Peyer9s patches was reduced 45±7% by soluble plantain NSP (5 mg/ml) and increased 2-fold by polysorbate-80 (0.1% vol/vol). <h3>Conclusions</h3> Translocation of <i>E coli</i> across M-cells is reduced by soluble plant fibres, particularly plantain and broccoli, but increased by the emulsifier Polysorbate-80. These effects occur at relevant concentrations and may contribute to the impact of dietary factors on Crohn9s disease pathogenesis.
Induction of Cancer Metastasis by Cyclophosphamide Pretreatment of Host Mice: An Opposite Effect of Chemotherapy
Authors: Kensuke Yamauchi, Meng Yang, Katsuhiro Hayashi, Ping Jiang, Norio Yamamoto, Hiroyuki Tsuchiya, Katsuro Tomita, Abdool R. Moossa, Michael Bouvet, Robert M. Hoffman
Journal: Cancer Research (2008)

Abstract Although side effects of cancer chemotherapy are well known, “opposite effects” of chemotherapy that enhance the malignancy of the treated cancer are not well understood. In this report, we describe the induction of intravascular proliferation, extravasation, and colony formation by cancer cells, critical steps of metastasis, by pretreatment of host mice with the commonly used chemotherapy drug cyclophosphamide. In contrast, in the unpretreated mice, most cancer cells remained quiescent in vessels without extravasation. HT1080 human fibrosarcoma cells, labeled in the nucleus with green fluorescent protein and red fluorescent protein in the cytoplasm for imaging, were injected into the epigastric cranialis vein of nude mice. Twenty-four hours before cancer cell injection, cyclophosphamide was given i.p. Double-labeled cancer cells were imaged at the cellular level in live mice with the Olympus OV100 Small Animal Imaging System with variable magnification. Cyclophosphamide seems to interfere with a host process that inhibits intravascular proliferation, extravasation, and extravascular colony formation. Cyclophosphamide does not directly affect the cancer cells because cyclophosphamide has been cleared by the time the cancer cells were injected. This report shows an important unexpected “opposite effect” of chemotherapy that enhances critical steps in malignancy rather than inhibiting them, suggesting that certain current approaches to cancer chemotherapy should be modified. [Cancer Res 2008;68(2):516–20]
Why Aren't We Listening Yet? A Decade of Road Safety Begins Quietly
Authors: Tracey Pérez Koehlmoos
Journal: PLoS Medicine (2013)

This Perspective discusses the following Essay published in PLOS Medicine: Redelmeier DA, McLellan BA (2013) Modern Medicine is Neglecting Road Traffic Crashes. PLoS Med 10(6): e10001463. doi:10.1371/journal.pmed.1001463 Tracey Perez Koehlmoos offers a personal view on road traffic crashes and the disappointing lack of visibility of the WHO-led Decade of Action for Road Safety. The dogs bark, the bell rings, I shuffle to the door in my pajamas to discover a Jakarta police officer who stammers, “Madam, hospital.” Fifteen minutes later, the drawer slides open. Yes, that is my husband on the morgue tray. I touch his face; he is still warm. ‘Get up,’ I think. I kiss his forehead. ‘Get up!’ I want to shout. Larger than life, a force of nature — how can a great man fit in such a small space? Every plan, every hope, and every dream for the rest of my life died with him in the instant our car crumpled like an accordion, and so I become a widow of the road.... We should be alarmed by Redelmeier and McLellan's article in this week's PLOS Medicine that argues modern medicine is neglecting road traffic crashes. The issue of road safety is enormous—so enormous that perhaps it is easily forgotten as each among us hops into our car to drive to work, crosses the street to go to the store, or presses on with our daily life, unaware of the risk. Only 28 countries, accounting for just 7% of the world's population, have comprehensive road safety laws on five key risk factors: drinking and driving; speeding; and failing to use motorcycle helmets, seat-belts, and child restraints. There is a cache of proven, cost-effective interventions, such as speed bumps and lowering speed limits, but the pervasive lack of evidence from developing countries hinders the implementation of these strategies where they are most needed..... Language: en
Relief of experimentally induced pruritus with a novel eutectic mixture of local anaesthetic agents
Authors: D. SHUTTLEWORTH, S. HILL, R. MARKS, D. M. CONNELLY
Journal: British Journal of Dermatology (1988)

Journal Article Relief of experimentally induced pruritus with a novel eutectic mixture of local anaesthetic agents Get access D. SHUTTLEWORTH, D. SHUTTLEWORTH Department of Medicine (Dermatology), University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, U.K. Search for other works by this author on: Oxford Academic Google Scholar S. HILL, S. HILL Department of Medicine (Dermatology), University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, U.K. Search for other works by this author on: Oxford Academic Google Scholar R. MARKS, R. MARKS Department of Medicine (Dermatology), University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, U.K. Professor R.Marks. Search for other works by this author on: Oxford Academic Google Scholar D. M. CONNELLY D. M. CONNELLY Medical Department, Astra Pharmaceuticals Ltd, Kings Langley, Herts WD4 8DH, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 119, Issue 4, 1 October 1988, Pages 535–540, https://doi.org/10.1111/j.1365-2133.1988.tb03259.x Published: 01 October 1988
Mast cell chymase in pulmonary hypertension
Authors: Y. Mitani, M. Ueda, K. Maruyama, H. Shimpo, A. Kojima, M. Matsumura, K. Aoki, M. Sakurai
Journal: Thorax (1999)

Mast cells are known to be involved in various types of tissue remodelling but their role in pulmonary hypertension is still poorly understood. Two subtypes of mast cells have recently been identified by demonstrating one protease, chymase. This enzyme might be implicated in vascular remodelling. The changes in mast cells in lung tissue from three patients with primary or secondary pulmonary hypertension were therefore investigated. Compared with tissue from four control subjects the number of mast cells in the three patients was markedly increased, which suggests that chymase containing mast cells are involved in tissue remodelling accompanied by fibrotic changes in primary and secondary pulmonary hypertension.
Predicting survival in pulmonary hypertension in the United Kingdom: Comparison of prognostic equations
Authors: Wai-Ting Nicola Lee, Yi Ling, Karen Sheares, Joanna Pepke-Zaba, Andrew Peacock, Martin Johnson
Journal: European Respiratory Journal (2011)

Background:  Prognostic equations in pulmonary arterial hypertension (PAH) have been developed in the United States [1,2] and France [3]. It is not known if these would perform as well in the United Kingdom (UK) as a locally derived scoring scheme.   Aims:  To develop and validate a UK composite score (CS) to predict prognosis in pre-capillary pulmonary hypertension (PCPH).   Methods:  The CS was derived from 209 patients with PCPH (except congenital heart disease) treated in the Scottish Pulmonary Vascular Unit (2000-09) by including independent baseline prognostic variables identified in multivariate Cox analysis. Brier scores (BS) were used to compare its performance with other equations in 121 patients with PCPH treated at Papworth Hospital, UK. Superior performance was indicated by a lower BS.   Results:   The risk of death increased with CS in the Papworth cohort (HR 1.5, p 1  (0.096 vs 0.114) and French Registry 3  equations (0.096 vs 0.126) at 1 year, and French Registry equation 3  (0.153 vs 0.200) at 2 years.   Conclusions:  The CS predicts survival and appears to be superior to other equations in an independent UK cohort.   References:   1Benza et al. Circulation 2010.  2Thenappan et al. ERJ 2010.  3Humbert et al. ERJ 2010.
Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth
Authors: Carles Barceló, Noelia Paco, Mireia Morell, Blanca Alvarez-Moya, Neus Bota-Rabassedas, Montserrat Jaumot, Felip Vilardell, Gabriel Capella, Neus Agell
Journal: Cancer Research (2013)

Abstract KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors. Cancer Res; 74(4); 1190–9. ©2013 AACR.
Prevention of distal embolization and “no reflow” during saphenous vein graft and acute infarction coronary interventions: use of a novel occluder balloon-wash out procedure
Authors: A. Shaknovich, S. Forman, M. Parikh, T.A. Sanborn, T.A. McCaffrey, G. Bergman, D.D. Altmann, J. McCrossan, C. Undomir, N. Tarazona, E. Deutsch
Journal: Journal of the American College of Cardiology (1998)
<i>A20</i>, <i>ABIN-1/2</i>, and <i>CARD11</i> Mutations and Their Prognostic Value in Gastrointestinal Diffuse Large B-Cell Lymphoma
Authors: Gehong Dong, Estelle Chanudet, Naiyan Zeng, Alex Appert, Yun-Wen Chen, Wing-Yan Au, Rifat A. Hamoudi, A. James Watkins, Hongtao Ye, Hongxiang Liu, Zifen Gao, Shih-Sung Chuang, Gopesh Srivastava, Ming-Qing Du
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas with the activated B-cell–like subtype characterized by constitutive NF-κB activation. Activating mutations of CARD11 and inactivating mutations of A20 are frequent events in DLBCL. However, the full extent of genetic alterations in the NF-κB pathway regulators and their potential prognostic value in DLBCL remain to be investigated. We investigated the genetic abnormalities of CARD11, A20, and ABIN-1/2/3 (the A20 binding inhibitor of NF-κB) and their clinicopathologic correlation in gastrointestinal DLBCL. Experimental Design: The somatic mutation and copy number changes of CARD11, A20, and ABIN-1/2/3 were investigated in 71 gastrointestinal DLBCLs by PCR/sequencing, and interphase FISH/array comparative genomic hybridization, respectively. The mutations identified were functionally characterized by NF-κB reporter assays and immunoprecipitation experiments. Results: Recurrent somatic mutations were found in CARD11 (10%), A20 (17%), ABIN-1 (4%), and ABIN-2 (3%), but not in ABIN-3. In comparison with the wild-type, all CARD11 mutants were potent NF-κB activators in vitro. On the basis of the destructive nature of the observed mutations, and the findings by reporter assays and immunoprecipitation studies, most if not all of the somatic mutations that were seen in A20, ABIN-1, and ABIN-2 could impair their normal functions. Among these genetic abnormalities, A20 somatic mutation was significantly associated with both poor overall survival and event-free survival. Conclusions: We show further evidence of NF-κB pathway genetic abnormalities in DLBCL, which are potentially valuable in the prognosis and design of future therapeutic strategies. Clin Cancer Res; 17(6); 1440–51. ©2011 AACR.
Pleiotropic Locus for Emotion Recognition and Amygdala Volume Identified Using Univariate and Bivariate Linkage
Authors: Emma E.M. Knowles, D. Reese McKay, Jack W. Kent, Emma Sprooten, Melanie A. Carless, Joanne E. Curran, Marcio A.A. de Almeida, Thomas D. Dyer, Harald H.H. Göring, Rene L. Olvera, Ravi Duggirala, Peter T. Fox, Laura Almasy, John Blangero, David C. Glahn
Journal: American Journal of Psychiatry (2014)

Objective: The role of the amygdala in emotion recognition is well established, and amygdala volume and emotion recognition performance have each been shown separately to be highly heritable traits, but the potential role of common genetic influences on both traits has not been explored. The authors investigated the pleiotropic influences of amygdala volume and emotion recognition performance. Method: In a sample of randomly selected extended pedigrees (N=858), the authors used a combination of univariate and bivariate linkage to investigate pleiotropy between amygdala volume and emotion recognition performance and followed up with association analysis. Results: The authors found a pleiotropic region for amygdala volume and emotion recognition performance on chromosome 4q26 (LOD score=4.40). Association analysis conducted in the region underlying the bivariate linkage peak revealed a variant meeting the corrected significance level (Bonferroni-corrected p=5.01×10−5) within an intron of PDE5A (rs2622497, p=4.4×10−5) as being jointly influential on both traits. PDE5A has been implicated previously in recognition-memory deficits and is expressed in subcortical structures that are thought to underlie memory ability, including the amygdala. Conclusions: This study extends our understanding of the shared etiology between the amygdala and emotion recognition by showing that the overlap between amygdala volume and emotion recognition performance is due at least in part to common genetic influences. Moreover, this study identifies a pleiotropic locus for the two traits and an associated variant, which localizes the genetic signal even more precisely. These results, when taken in the context of previous research, highlight the potential utility of PDE5 inhibitors for ameliorating emotion recognition deficits in individuals suffering from mental or neurodegenerative illness.
Amiodarone Interaction With β-Blockers
Authors: Florent Boutitie, Jean-Pierre Boissel, Stuart J. Connolly, A. John Camm, John A. Cairns, Desmond G. Julian, Michael Gent, Michiel J. Janse, Paul Dorian, Gerald Frangin
Journal: Circulation (1999)

Investigations with in vitro and animal models suggest an interaction between amiodarone and beta-blockers. The objective of this work was to explore if an interaction with beta-blocker treatment plays a role in the decrease of cardiac arrhythmic deaths with amiodarone in patients recovered from an acute myocardial infarction. A pooled database from 2 similar randomized clinical trials, the European Amiodarone Myocardial Infarction Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was used. Four groups of post-myocardial infarction patients were defined: beta-blockers and amiodarone used, beta-blockers used alone, amiodarone used alone, and neither used. All analyses were done on an intention-to-treat basis. Unadjusted and adjusted relative risks for all-cause mortality, cardiac death, arrhythmic cardiac death, nonarrhythmic cardiac death, arrhythmic death, or resuscitated cardiac arrest were lower for patients receiving beta-blockers and amiodarone than for those without beta-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest (P=0.05 and 0.03, respectively). Findings were consistent across subgroups. These findings are based on a post hoc analysis. However, they confirm prior results from in vitro and animal experiments suggesting an interaction between beta-blockers and amiodarone. In practice, not only is the adjunct of amiodarone to beta-blockers not hazardous, but beta-blocker therapy should be continued if possible in patients in whom amiodarone is indicated.
Observations on glutaraldehyde-treated heterologous cardiac valves.
Authors: E Bodnar, E G Olsen, D N Ross
Journal: Thorax (1979)

Recent publications on commercial porcine bioprosthetic cardiac valves have stated that the endothelium disappears during the glutaraldehyde processing and that in many cases histological evidence of early tissue deterioration was found. Our experiences have shown that porcine aortic valves can be processed in glutaraldehyde without loss of the integrity of the endothelium and with the development of optimum collagen fibre structure. The valve mounted in a Dacron tube is not restricted in diameter and performs well under biological conditions up to a period of six months.
VEGF165b, an Inhibitory Vascular Endothelial Growth Factor Splice Variant
Authors: Jeanette Woolard, Wen-Ying Wang, Heather S. Bevan, Yan Qiu, Lucia Morbidelli, Rowan O. Pritchard-Jones, Tai-Gen Cui, Marto Sugiono, Elizabeth Waine, Rachel Perrin, Rebecca Foster, Jonathon Digby-Bell, Jacqueline D. Shields, Cheryl E. Whittles, Rosey E. Mushens, David A. Gillatt, Marina Ziche, Steven J. Harper, David O. Bates
Journal: Cancer Research (2004)

Abstract Growth of new blood vessels (angiogenesis), required for all tumor growth, is stimulated by the expression of vascular endothelial growth factor (VEGF). VEGF is up-regulated in all known solid tumors but also in atherosclerosis, diabetic retinopathy, arthritis, and many other conditions. Conventional VEGF isoforms have been universally described as proangiogenic cytokines. Here, we show that an endogenous splice variant, VEGF165b, is expressed as protein in normal cells and tissues and is circulating in human plasma. We also present evidence for a sister family of presumably inhibitory splice variants. Moreover, these isoforms are down-regulated in prostate cancer. We also show that VEGF165b binds VEGF receptor 2 with the same affinity as VEGF165 but does not activate it or stimulate downstream signaling pathways. Moreover, it prevents VEGF165-mediated VEGF receptor 2 phosphorylation and signaling in cultured cells. Furthermore, we show, with two different in vivo angiogenesis models, that VEGF165b is not angiogenic and that it inhibits VEGF165-mediated angiogenesis in rabbit cornea and rat mesentery. Finally, we show that VEGF165b expressing tumors grow significantly more slowly than VEGF165-expressing tumors, indicating that a switch in splicing from VEGF165 to VEGF165b can inhibit tumor growth. These results suggest that regulation of VEGF splicing may be a critical switch from an antiangiogenic to a proangiogenic phenotype.
Association between Physical Performance and All-Cause Mortality in CKD
Authors: Baback Roshanravan, Cassianne Robinson-Cohen, Kushang V. Patel, Ernest Ayers, Alyson J. Littman, Ian H. de Boer, T. Alp Ikizler, Jonathan Himmelfarb, Leslie I. Katzel, Bryan Kestenbaum, Stephen Seliger
Journal: Journal of the American Society of Nephrology (2013)

In older adults, measurements of physical performance assess physical function and associate with mortality and disability. Muscle wasting and diminished physical performance often accompany CKD, resembling physiologic aging, but whether physical performance associates with clinical outcome in CKD is unknown. We evaluated 385 ambulatory, stroke-free participants with stage 2-4 CKD enrolled in clinic-based cohorts at the University of Washington and University of Maryland and Veterans Affairs Maryland Healthcare systems. We compared handgrip strength, usual gait speed, timed up and go (TUAG), and 6-minute walking distance with normative values and constructed Cox proportional hazards models and receiver operating characteristic curves to test associations with all-cause mortality. Mean age was 61 years and the mean estimated GFR was 41 ml/min per 1.73 m(2). Measures of lower extremity performance were at least 30% lower than predicted, but handgrip strength was relatively preserved. Fifty deaths occurred during the median 3-year follow-up period. After adjustment, each 0.1-m/s decrement in gait speed associated with a 26% higher risk for death, and each 1-second longer TUAG associated with an 8% higher risk for death. On the basis of the receiver operating characteristic analysis, gait speed and TUAG more strongly predicted 3-year mortality than kidney function or commonly measured serum biomarkers. Adding gait speed to a model that included estimated GFR significantly improved the prediction of 3-year mortality. In summary, impaired physical performance of the lower extremities is common in CKD and strongly associates with all-cause mortality.
CANNABINOID RECEPTORS AS THERAPEUTIC TARGETS
Authors: Ken Mackie
Journal: The Annual Review of Pharmacology and Toxicology (2005)

▪ Abstract CB1 and CB2 cannabinoid receptors are the primary targets of endogenous cannabinoids (endocannabinoids). These G protein–coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. In the past several years, it has become apparent from preclinical studies that therapies either directly or indirectly influencing cannabinoid receptors might be clinically useful. This review considers the components of the endocannabinoid system and discusses some of the most promising endocannabinoid-based therapies.