tbuckley/cabot-search huggingface dataset:
Targeting the PI3K/AKT Pathway for the Treatment of Prostate Cancer
Authors: Debashis Sarker, Alison H.M. Reid, Timothy A. Yap, Johann S. de Bono
Journal: Clinical Cancer Research (2009)

Abstract Despite recent advances in our understanding of the biological basis of prostate cancer, the management of the disease, especially in the castration-resistant phase, remains a significant challenge. Deregulation of the phosphatidylinositol 3-kinase pathway is increasingly implicated in prostate carcinogenesis. In this review, we detail the role of this pathway in the pathogenesis of prostate cancer and the rapidly evolving therapeutic implications of targeting it. In particular, we highlight the importance of the appropriate selection of agents and combinations, and the critical role of predictive and pharmocodynamic biomarkers.
Accurate Prediction of <i>BRCA1</i> and <i>BRCA2</i> Heterozygous Genotype Using Expression Profiling after Induced DNA Damage
Authors: Zsofia Kote-Jarai, Lucy Matthews, Ana Osorio, Susan Shanley, Ian Giddings, Francois Moreews, Imogen Locke, D. Gareth Evans, Diana Eccles, Richard D. Williams, Mark Girolami, Colin Campbell, Ros Eeles
Journal: Clinical Cancer Research (2006)

Abstract Purpose: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. Experimental Design: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. Results: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. Conclusions: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.
Metabolic Syndrome, Brain Magnetic Resonance Imaging, and Cognition
Authors: Margherita Cavalieri, Stefan Ropele, Katja Petrovic, Aga Pluta-Fuerst, Nina Homayoon, Christian Enzinger, Anja Grazer, Petra Katschnig, Petra Schwingenschuh, Andrea Berghold, Reinhold Schmidt
Journal: Diabetes Care (2010)

We explored cognitive impairment in metabolic syndrome in relation to brain magnetic resonance imaging (MRI) findings.We studied 819 participants free of clinical stroke and dementia of the population-based Austrian Stroke Prevention Study who had undergone brain MRI, neuropsychological testing, and a risk factor assessment relevant to National Cholesterol Education Program Adult Treatment Panel III criteria-defined metabolic syndrome. High-sensitivity C-reactive protein (hs-CRP) was also determined.Of 819 subjects, 232 (28.3%) had metabolic syndrome. They performed worse than those without metabolic syndrome on cognitive tests assessing memory and executive functioning after adjustment for possible confounders. Stratification by sex demonstrated that metabolic syndrome was related to cognitive dysfunction in men but not in women. Only in men was an increasing number of metabolic syndrome components associated with worse cognitive performance. MRI showed no significant differences in focal ischemic lesions and brain volume between subjects with and without metabolic syndrome, and MRI abnormalities failed to explain impaired cognition. Cognitive performance was most affected in male subjects with metabolic syndrome who also had high hs-CRP levels.Metabolic syndrome exerts detrimental effects on memory and executive functioning in community-dwelling subjects who have not had a clinical stroke or do not have dementia. Men are more affected than women, particularly if they have high inflammatory markers. MRI-detected brain abnormalities do not play a crucial role in these relationships.
A slippery disease: a microbiologist's view
Authors: T H Pennington
Journal: BMJ (2006)

The brachial plexus has always been a mystery to me.As a medical student in 1957, I missed out that part of the course because I was in bed with Asian flu.Memories of its onset are still vivid because the symptoms came on so rapidly and with such strength.We had dipped out of the dissecting room at St Thomas's for a mid-morning break and strolled along the Embankment to Lambeth Bridge.Going there I felt fine.Coming back was terrible because of fever and aching limbs.But the full importance of influenza in 1957 had passed me by-how a new virus (H2N2) had appeared in February in China in Guizhou province, spread to Yunan in March, Singapore and Hong Kong in April, Japan in May, and the United Kingdom in June and July, with a first peak incidence of disease here in October and a second in January 1958.And I did not know then that I had been a victim of the second biggest influenza pandemic in the 20th century.
Activation of chloride current by purinergic stimulation in guinea pig heart cells.
Authors: H Matsuura, T Ehara
Journal: Circulation Research (1992)

Single atrial cells from guinea pig heart were voltage-clamped using the whole-cell configuration of the patch-clamp technique under conditions in which most of the ionic and exchange currents known in cardiac cells were minimized. Extracellular 5 or 50 microM ATP activated a Cl- current, in addition to a rapidly desensitizing cation-selective current. A nonhydrolyzable ATP analogue, adenosine-5'-O-(3-thiotriphosphate) (50 microM), also evoked these two currents, indicating involvement of purinoceptors rather than ecto-ATPase on the membrane. ADP, AMP, and adenosine were also effective in inducing the Cl- current, showing no clear order of potency for the purinoceptor subtypes involved. The purinoceptor-activated Cl- current, like the beta-catecholamine-cAMP-dependent cardiac Cl- current, showed outward rectification and time independence.
The role of kinin B<sub>1</sub>receptor and the effect of angiotensin I-converting enzyme inhibition on acute gout attacks in rodents
Authors: Cássia R Silva, Sara M Oliveira, Carin Hoffmeister, Vinícius Funck, Gustavo P Guerra, Gabriela Trevisan, Raquel Tonello, Mateus F Rossato, João B Pesquero, Michael Bader, Mauro S Oliveira, Jason J McDougall, Juliano Ferreira
Journal: Annals of the Rheumatic Diseases (2014)

Verify the role of the kinin B1 receptors (B1R) and the effect of ACE inhibitors (ACEi) on acute gout induced by monosodium urate (MSU) crystals in rodents.Painful (overt pain and allodynia) and inflammatory parameters (joint oedema, leukocyte trafficking, interleukin-1β levels) of acute gout attacks were assessed several hours after an intra-articular injection of MSU (1.25 or 0.5 mg/articulation) into the ankle of rats or mice, respectively. The role of B1R was investigated using pharmacological antagonism or gene deletion. Additionally, B1R immunoreactivity in ankle tissue and sensory neurons, kininase I activity and des-Arg(9)-bradykinin synovial levels were also measured. Similar tools were used to investigate the effects of ACEi on a low dose of MSU (0.0125 mg/articulation)-induced inflammation.Kinin B1R antagonism or gene deletion largely reduced all painful and inflammatory signs of gout. Furthermore, MSU increased B1R expression in articular tissues, the content of the B1 agonist des-Arg(9)-bradykinin and the activity of the B1 agonist-forming enzyme kininase I. A low dose of MSU crystals, which did not induce inflammation in control animals, caused signs of acute gout attacks in ACEi-treated animals that were B1R-dependent.Kinin B1R contributes to acute gouty attacks, including the ones facilitated by ACEi. Therefore, B1R is a potential therapeutic target for the treatment and prophylaxis of gout, especially in patients taking ACEi.
Management of Acute Bleeding from a Peptic Ulcer
Authors: Ian M. Gralnek, Alan N. Barkun, Marc Bardou
Journal: New England Journal of Medicine (2008)

The mortality associated with acute bleeding from a peptic ulcer remains high (5 to 10%), and the condition accounts for more than 400,000 hospital admissions per year in the United States. This review summarizes the approach to patient triage and risk stratification, the goals of early endoscopy, the options for medical therapy, and the role of surgery and interventional radiology.
Cardiovascular Risk Factors in CKD Associate with Both ESRD and Mortality
Authors: Paul Muntner, Suzanne E. Judd, Liyan Gao, Orlando M. Gutiérrez, Dana V. Rizk, William McClellan, Mary Cushman, David G. Warnock
Journal: Journal of the American Society of Nephrology (2013)

The American Heart Association's Life's Simple 7 initiative allows individuals to assess health factors (BP, cholesterol, and glucose) and health behaviors (cigarette smoking, physical activity, diet, and body mass index) to promote improved cardiovascular health. Because several cardiovascular risk factors also associate with progressive kidney disease, Life's Simple 7 may also inform an individual's risk for ESRD. Here, we investigated the association of Life's Simple 7 components with both ESRD incidence and all-cause mortality among 3093 participants with an estimated GFR (eGFR) <60 ml/min per 1.73 m2 from the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. During a median 4 years of follow-up, 160 participants developed ESRD, and 610 participants died. Compared with individuals who had zero or one of the Life's Simple 7 components in the ideal range, those individuals with two, three, and four ideal factors had progressively lower risks for ESRD; furthermore, no participant with five to seven ideal factors developed ESRD. The risk for all-cause mortality exhibited a similar trend. Adjusting for eGFR and albuminuria, however, completely attenuated the associations between the number of ideal factors and the risks for both ESRD and all-cause mortality. In conclusion, a favorable cardiovascular risk profile among individuals with CKD associates with a reduced risk for ESRD and mortality, but whether the severity of kidney disease confounds or mediates this association requires additional investigation.
Selective Down-Regulation of Glioma-Associated Oncogene 2 Inhibits the Proliferation of Hepatocellular Carcinoma Cells
Authors: Youngsoo Kim, Joon Won Yoon, Xiaokun Xiao, Nicholas M. Dean, Brett P. Monia, Eric G. Marcusson
Journal: Cancer Research (2007)

The sonic hedgehog (Shh) pathway contributes to the initiation and progression of tumors with various origins when aberrantly activated. In this study, we investigated if the Shh pathway is important for the proliferation of hepatocellular carcinoma (HCC) cells and also began to identify which components of the pathway play a pivotal role in the biology of HCC. Expression levels of components in the pathway were measured, and glioma-associated oncogene (Gli) 2 levels were found to be considerably higher in human HCC lines compared with normal liver. Gli2 levels were also higher in tumor tissue from HCC patients compared with normal liver. Antisense oligonucleotides (ASO) were used to specifically down-regulate Gli2, and this led to decreased proliferation of various HCC cell lines. However, inhibition of Gli1 and Gli3 with ASOs did not decrease proliferation in most HCC cell lines and inhibitors targeting the upstream components of the pathway, including smoothened (Smo), displayed antiproliferative effects in only a subset of HCC cell lines. Moreover, in cancer cells harboring Smo mutations or unresponsive to the Smo inhibitor 3-keto-N-aminoethylaminoethylcaproyldihydrocinnamoyl cyclopamine, the Gli2 ASO was still able to inhibit proliferation. The importance of Gli2 in HCC proliferation was further confirmed by the changes in expression levels of genes, such as Bcl-2, c-Myc, and p27, following suppression of Gli2 expression. Taken together, these results suggest that, among the Gli transcription factors, Gli2 plays a predominant role in the proliferation of HCC cells and the suppression of Gli2 expression may provide a useful therapeutic option for the treatment of HCC.
CD34 expression is associated with poor clinical outcome in patients with acute promyelocytic leukemia
Authors: Je‐Jung Lee, Duck Cho, Ik‐Joo Chung, Sang‐Hee Cho, Kyeong‐Soo Park, Moo‐Rim Park, Dong‐Wook Ryang, Hyeoung‐Joon Kim
Journal: American Journal of Hematology (2003)

Abstract This study investigated the clinical characteristics and prognostic relevance of CD34 expression in 47 patients with acute promyelocytic leukemia (APL), showing t(15;17) or PML/RARα . Ten (21.3%) of the APL patients were CD34 + . CD34 expression was associated with hypogranular morphology ( P = 0.002) and hyperleukocytosis ( P = 0.015). However, there were no statistically significant differences in age, sex, hemoglobin level, platelet count, or percentage of blasts between the CD34 + and CD34 − APL groups. Multiplex RT‐PCR analysis showed that the L‐form ( BCR1 ) and S‐form ( BCR3 ) were correlated with CD34 − APL and CD34 + APL, respectively. Despite the lack of a difference in the complete remission rate, overall survival (OS) and disease‐free survival (DFS) were significantly lower in the CD34 + group than in the CD34 − group ( P = 0.012 and P = 0.0051, respectively). By multivariate analysis, the CD34 + group showed a significant independent variable in DFS compared with the CD34 − group, but this was not demonstrated for OS. In conclusion, CD34 expression in APL is a unique clinical feature associated with leukocytosis and atypical morphology with hypogranular pattern and is associated with a poor clinical outcome. Am. J. Hematol. 73:149–153, 2003. © 2003 Wiley‐Liss, Inc.
Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study
Authors: Jean-François Bosset, Gilles Calais, Laurent Mineur, Philippe Maingon, Suzana Stojanovic-Rundic, René-Jean Bensadoun, Etienne Bardet, Alexander Beny, Jean-Claude Ollier, Michel Bolla, Dominique Marchal, Jean-Luc Van Laethem, Vincent Klein, Jordi Giralt, Pierre Clavère, Christoph Glanzmann, Patrice Cellier, Laurence Collette
Journal: The Lancet Oncology (2014)
Postprandial antropyloroduodenal motility and gastric emptying in gastroparesis--effects of cisapride.
Authors: R J Fraser, M Horowitz, A F Maddox, J Dent
Journal: Gut (1994)

There is little information about the organisation of antroduodenal contractions or pyloric motility in patients with gastroparesis. The mechanisms responsible for the acceleration of gastric emptying by cisapride in patients with gastroparesis are also poorly understood. Simultaneous manometric and scintigraphic recordings were performed in 12 patients with gastroparesis and nine healthy volunteers before and after cisapride administration. Antropyloroduodenal pressures were recorded with a sleeve/side hole manometric assembly and gastric emptying with a scintigraphic method. Thirty minutes after the solid component of the test meal had begun to empty from the stomach all subjects received 5 mg cisapride intravenously over 10 minutes and recordings continued for a further 60 minutes. In the 30 minutes before cisapride there was no significant difference in the number of antral pressure waves (median 20 v 33, NS), basal pyloric pressure, or the number of isolated pyloric pressure waves between patients and volunteers, but the number of antral waves of extent &gt; or = 6 cm (median 1 v 5, p &lt; 0.05) was less in the patients, as was gastric emptying (8% v 20%, p &lt; 0.05). In the patients, there was no change in the number of antral waves after cisapride, but there was an increase in the number of antral waves &gt; or = 6 cm in extent (median 7 v 1, p &lt; 0.05) and in the rate of gastric emptying (26% v 8%, p &lt; 0.01). In the healthy subjects, cisapride increased gastric emptying (31% v 20%, p &lt; 0.05), but reduced the number of antral waves (10 v 33, p &lt; 0.05). Cisapride had no significant effect on the number of antral waves of extent more than or equal to 6 cm (11 v 5, NS). The number of isolated pyloric pressure waves decreased after cisapride (4 v 11, p &lt; 0.05). There was a relationship between gastric emptying and the number of antral pressure waves of extent more than or equal to 6 cm in both the patients (r=0.38, p&lt;0.05) and healthy subjects (r=0.05, p&lt;0.01). There was no significant relationship between gastric emptying and the number of antral waves. It is concluded that disturbance of the relationship between antral, pyloric, and duodenal pressure waves is a major abnormality of postprandial gastric motor function in patients with gastroparesis. The stimulation of antral pressure waves of extent more than or equal to 6 cm may contribute to the acceleration of gastric emptying produced by cisapride in patients with gastroparesis and in normal subjects.
Suppression of BRAF/MEK/MAP Kinase Pathway Restores Expression of Iodide-Metabolizing Genes in Thyroid Cells Expressing the V600E BRAF Mutant
Authors: Dingxie Liu, Shuiying Hu, Peng Hou, David Jiang, Stephen Condouris, Mingzhao Xing
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The V600E BRAF mutant plays an important role in the pathogenesis of papillary thyroid cancer (PTC) and is associated with loss of expression of thyroid iodide-metabolizing genes. This study was done to investigate the restorability of expression of these genes by suppressing the BRAF/extracellular signal-regulated kinase kinase (MEK)/mitogen-activated protein (MAP) kinase pathway in V600E BRAF–harboring thyroid cells and to explore the mechanisms involved. Experimental Design: We used inducible expression of V600E BRAF, small interfering RNA transfection, and MEK-specific inhibitor to alter the MAP kinase pathway activities and subsequently examined the changes in expression, promoter activities, and methylation status of thyroid genes. Results: MEK inhibitor U0126 or cessation of V600E BRAF expression in PCCL3 cells restored expression of thyroid genes silenced by induced expression of V600E BRAF. U0126 also restored the expression of these genes in V600E BRAF–harboring PTC-derived NPA cells. Knockdown of BRAF by specific small interfering RNA restored expression of some of these genes in NPA cells. Luciferase reporter assay using thyroid-stimulating hormone receptor gene as a model showed that the promoter activity was modulated by the MAP kinase pathway. Promoter methylation in association with DNA methyltransferase expression played a role in gene silencing by MAP kinase pathway in NPA cells. Conclusions: We showed the restorability of expression of thyroid iodide-metabolizing genes silenced by V600E BRAF, and linked this process to gene methylation in PTC cells. The results provide clinical implications that therapeutic targeting at the BRAF/MEK/MAP kinase pathway may be a good approach in restoring thyroid gene expression for effective radioiodine therapy for BRAF mutation-harboring PTC.
Depression of polymorphonuclear chemotaxis and T-lymphocyte proliferation following histamine inhalation in man
Authors: TB Bury, MF Radermecker
Journal: European Respiratory Journal (1989)

Histamine, in vitro, via H2-receptor activation, exerts an inhibitory effect on polymorphonuclear (PMN) chemotaxis and T-lymphocyte proliferation. The aim of this study was to verify these histamine inhibitory effects in man. Healthy and asymptomatic asthmatic volunteers inhaled a histamine (0.1%), methacholine (0.1%) or saline aerosol for 3 min. Asthmatics were selected on the basis of low bronchial sensitivity to pharmacological agents. Blood was taken before and at different times following aerosol challenge. PMN chemotaxis was studied in vitro by the Boyden assay. T-lymphocyte proliferation was measured by counting H3-thymidine incorporation in cultured mononuclear cells. Plasma histamine was measured by a specific and sensitive radioimmunoassay. Inhalation of histamine or methacholine caused a 22-43% decrease in forced expiratory volume in one second (FEV1) in asthmatics only. In both groups, there was a transient increase of plasma histamine immediately following histamine inhalation, and 2 and 4 h later, a significant decrease of PMN chemotaxis and T-lymphocyte proliferation. Inhalation of methacholine or saline had no effect on leukocytes. Oral administration of an H2-receptor antagonist, cimetidine, before histamine inhalation, prevented the decrease of PMN chemotaxis and T-lymphocyte proliferation, whereas astemizole, an H1-antagonist, had no effect. In conclusion, histamine, at a dose commonly used for bronchial provocation tests, causes, in man, 2 and 4 h after inhalation, a depression of PMN chemotaxis (tested in vitro) and T-lymphocyte proliferation through activation of H2-receptors.