tbuckley/cabot-search huggingface dataset:
Kinome Profiling in Pediatric Brain Tumors as a New Approach for Target Discovery
Authors: Arend H. Sikkema, Sander H. Diks, Wilfred F.A. den Dunnen, Arja ter Elst, Frank J.G. Scherpen, Eelco W. Hoving, Rob Ruijtenbeek, Piet J. Boender, Rik de Wijn, Willem A. Kamps, Maikel P. Peppelenbosch, Eveline S.J.M. de Bont
Journal: Cancer Research (2009)

Progression in pediatric brain tumor growth is thought to be the net result of signaling through various protein kinase-mediated networks driving cell proliferation. Defining new targets for treatment of human malignancies, without a priori knowledge on aberrant cell signaling activity, remains exceedingly complicated. Here, we introduce kinome profiling using flow-through peptide microarrays as a new concept for target discovery. Comprehensive tyrosine kinase activity profiles were identified in 29 pediatric brain tumors using the PamChip kinome profiling system. Previously reported activity of epidermal growth factor receptor, c-Met, and vascular endothelial growth factor receptor in pediatric brain tumors could be appreciated in our array results. Peptides corresponding with phosphorylation consensus sequences for Src family kinases showed remarkably high levels of phosphorylation compared with normal tissue types. Src activity was confirmed applying Phos-Tag SDS-PAGE. Furthermore, the Src family kinase inhibitors PP1 and dasatinib induced substantial tumor cell death in nine pediatric brain tumor cell lines but not in control cell lines. Thus, this study describes a new high-throughput technique to generate clinically relevant tyrosine kinase activity profiles as has been shown here for pediatric brain tumors. In the era of a rapidly increasing number of small-molecule inhibitors, this approach will enable us to rapidly identify new potential targets in a broad range of human malignancies.
THALASSIC SUBMERSION A MEANS FOR DISPOSAL OF OUR DEAD.
Authors: D. LICHTY
Journal: JAMA (1898)

The question most intimately following a<i>useful</i>existence here is a<i>harmless</i>absence after we are through. It is evident that some suggestion for the disposal of our dead, other than earth-burial or cremation, is needed, from the unsanitary character of the former and the natural repulsiveness of the latter. To show that ocean burial is practical, sanitary, and will meet most of the requirements of sentiment and religion, and<i>all</i>those of sanitation, will be the endeavor of this argument. That the beautiful fealty of genealogy and consanguinity and the sacred associations of religion are factors to be considered in this as well as any other method for the disposal of the dead is recognized; but above and beyond these is the unpurchaseable boon of health and its attendant uses and beauty. Every expedient that human thought could devise has been resorted to in all times past to conceal
SOME CLIKICAL ASPECTS OF CHOLHSTERGIC URTICARIA
Authors: MIRIAM MOORE-ROBINSON, ROBERT P. WARIN
Journal: British Journal of Dermatology (1968)

SUMMARY.— Clinical observations are made on a series of 22 patients with cholinergic urticaria, representing 0·2% of total referrals to dermatological out-patients and 7% of patients with urticarial eruptions. The average age of onset was 16 and the average duration 7·5 years. The weals are widely scattered and although some coincide with follicles, others arise between them. The precipitating factors are discussed, particularly in relation to water contact; it is concluded that this acts only when heat or exercise are coincident. The fact that the same precipitating factors can play a part in other physical urticarias often leads to confusion in diagnosis. Treatment is briefly discussed and a double blind comparison of hydroxyzine with antihistamine therapy in 14 patients is described; hydroxyzine was preferred in 8 patients.
Pharmacologic Treatment of Depression During Pregnancy
Authors: Katherine L. Wisner, Alan J. Gelenberg, Henrietta Leonard, Deborah Zarin, Ellen Frank
Journal: JAMA (1999)

ContextDespite the frequency of depression in women of childbearing age, information to guide patients and physicians through a consideration of treatment during pregnancy is limited.ObjectiveTo identify risk factors associated with treatment of major depression during pregnancy to help physicians develop treatment plans that optimize clinical care.Data SourcesReports of prospective controlled trials in English were identified from MEDLINE and Health STAR using the search terms antidepressant during pregnancy and depression during pregnancy, by manually searching bibliographies of review articles, and through discussions with investigators for 1989-1999.Study SelectionWe selected studies in which maternal and infant health outcomes associated with antidepressant exposure were compared with those of nonteratogen-exposed controls. Four studies published since 1993 were identified and included in the analysis.Data ExtractionWe abstracted information about identification of subjects, comparison groups, pregnancy, and birth outcomes. We organized the data along 5 domains of reproductive toxicity: intrauterine fetal death, morphologic teratogenicity, growth impairment, behavioral teratogenicity, and neonatal toxicity.Data SynthesisData were available for tricyclic antidepressants (collectively), fluoxetine, and newer selective serotonin reuptake inhibitors (collectively). Exposure to these agents did not increase risk for intrauterine death or major birth defects. Decreased birth weights of infants exposed to fluoxetine in the third trimester were identified in 1 study. The development of children whose mothers took tricyclics or fluoxetine during gestation did not differ from that of controls. Direct drug effects and withdrawal syndromes occurred in some neonates whose mothers were treated with antidepressants near term.ConclusionsAlthough few in number, new information from prospective studies provides a welcome change from decision making based on nonprospective data. Monitoring and interventions for patients with identified risks (eg, poor weight gain) are recommended.
NIH will partner drug industry to study Alzheimer's, diabetes, and autoimmune disorders
Authors: M. McCarthy
Journal: BMJ (2014)

The US National Institutes of Health (NIH) will partner 10 biopharmaceutical companies to identify promising drug targets and disease biomarkers, the agency announced on 4 February. Eight nonprofit organizations will also participate in the collaboration.

The initiative, called the Accelerating Medicines Partnership, will initially focus on biomarkers and drug targets for Alzheimer’s disease, type 2 diabetes, and the autoimmune disorders of rheumatoid arthritis and systemic erythematosus.

All data and analyses generated by the initiative will be made publicly available “to the broad biomedical community,” the NIH said.

In a …
Inhibition of hepatitis C virus replication using adeno-associated virus vector delivery of an exogenous anti-hepatitis C virus microrna cluster
Authors: Xiao Yang, Virginia Haurigot, Shangzhen Zhou, Guangxiang Luo, Linda B Couto
Journal: Hepatology (2010)

RNA interference (RNAi) is being evaluated as an alternative therapeutic strategy for hepatitis C virus (HCV) infection. The use of viral vectors encoding short hairpin RNAs (shRNAs) has been the most common strategy employed to provide sustained expression of RNAi effectors. However, overexpression and incomplete processing of shRNAs has led to saturation of the endogenous miRNA pathway, resulting in toxicity. The use of endogenous microRNAs (miRNAs) as scaffolds for short interfering (siRNAs) may avoid these problems, and miRNA clusters can be engineered to express multiple RNAi effectors, a feature that may prevent RNAi-resistant HCV mutant generation. We exploited the endogenous miRNA-17-92 cluster to generate a polycistronic primary miRNA that is processed into five mature miRNAs that target different regions of the HCV genome. All five anti-HCV miRNAs were active, achieving up to 97% inhibition of Renilla luciferase (RLuc) HCV reporter plasmids. Self-complementary recombinant adeno-associated virus (scAAV) vectors were chosen for therapeutic delivery of the miRNA cluster. Expression of the miRNAs from scAAV inhibited the replication of cell culture-propagated HCV (HCVcc) by 98%, and resulted in up to 93% gene silencing of RLuc-HCV reporter plasmids in mouse liver. No hepatocellular toxicity was observed at scAAV doses as high as 5 × 10(11) vector genomes per mouse, a dose that is approximately five-fold higher than doses of scAAV-shRNA vectors that others have shown previously to be toxic in mouse liver.We have demonstrated that exogenous anti-HCV miRNAs induce gene silencing, and when expressed from scAAV vectors inhibit the replication of HCVcc without inducing toxicity. The combination of an AAV vector delivery system and exploitation of the endogenous RNAi pathway is a potentially viable alternative to current HCV treatment regimens.
Angiotensin II AT1-receptor induces biglycan in neonatal cardiac fibroblasts via autocrine release of TGFβ in vitro
Authors: K Tiede
Journal: Cardiovascular Research (2003)

After myocardial infarction, angiotensin II (AngII) promotes ventricular remodeling and deposition of extracellular matrix (ECM), e.g., collagen type 1 and 3. Whether AngII regulates the expression of small leucine-rich proteoglycans (SLRP) which are important modulators of collagen fibrillogenesis and are induced after experimental myocardial infarction in rats is not known. The aim of the present study was therefore to analyse in cultured cardiac fibroblasts the expression and secretion of the SLRP biglycan in response to AngII.Cardiac fibroblasts were isolated from neonatal Wistar Kyoto rats and used in the first passage. Expression of AT(1)- and AT(2)-receptors was verified by RT-PCR. Expression of protoeglycans was analyzed after metabolic labeling with [35S]-sulfate, by SDS-PAGE and Western analysis. In addition, mRNA expression was examined by means of RT-PCR and Northern analysis. The activity of the biglycan promoter was analyzed using three biglycan promoter-luciferase fusion constructs.Biglycan was found to be the predominant proteoglycan produced by neonatal cardiac fibroblasts in vitro. In response to AngII (10(-7) M), secretion of total [35S]-labeled proteoglycans and mRNA of biglycan were increased to 116+/-1.8% and 121+/-11% (n=5, mean+/-S.E.M.) of unstimulated controls, respectively. Biglycan induction in response to AngII was sensitive to Losartan (10(-5) M) and unaffected by PD123177 (10(-6) M), suggesting that the AT(1)-receptor mediates the induction of biglycan. Direct activation of the biglycan promoter downstream of the AT(1)-receptor was excluded by promoter activity assays. Instead, increased release of transforming growth factor beta 1 (TGFbeta1) was detected by ELISA in response to AT(1)-receptor stimulation. Furthermore, neutralising antibodies to TGFbeta1 inhibited biglycan induction in response to AngII.The results indicate that in cardiac fibroblasts AngII via the AT(1)-receptor causes autocrine release of TGFbeta1, which in turn induces biglycan expression and secretion.
A framework for community and ecosystem genetics: from genes to ecosystems
Authors: Thomas G. Whitham, Joseph K. Bailey, Jennifer A. Schweitzer, Stephen M. Shuster, Randy K. Bangert, Carri J. LeRoy, Eric V. Lonsdorf, Gery J. Allan, Stephen P. DiFazio, Brad M. Potts, Dylan G. Fischer, Catherine A. Gehring, Richard L. Lindroth, Jane C. Marks, Stephen C. Hart, Gina M. Wimp, Stuart C. Wooley
Journal: Nature Reviews Genetics (2006)
Echocardiographic Detection of Regional Myocardial Infarction
Authors: RICHARD E. KERBER, FRANCOIS M. ABBOUD
Journal: Circulation (1973)

Posterior wall velocities have been advanced as a useful technic for the assessment of left ventricular function. To evaluate the echocardiographic effects of regional myocardial infarction on posterior wall motion (PWM), measurements were obtained in 22 open-chest dogs. Coronary artery ligation produced infarction of the apex in 11 dogs (group I) and the posterior wall in 11 dogs (group II). Echoes were thus received from noninfarcted myocardium in group I and from infarcted myocardium in group II. Postinfarct recordings in group I showed no significant changes in posterior wall velocities or excursion. In contrast, group II showed striking changes in the contour of PWM with a large initial posterior displacement (aneurysmal bulging) during isometric contraction, followed by a slow anterior movement during ventricular ejection and then a rapid anterior recoil motion during isometric relaxation. Mean posterior wall velocity fell from 31 ± se 3 mm/sec preinfarct to 13 ± 4 postinfarct ( P &lt; 0.01); from 33 ± 4 to 21 ± 5 mm/sec during atrial pacing pre- and postinfarction ( P &lt; 0.05); from 30 ± 3 to 18 ± 3 mm/sec during volume loading with dextran 20 ml/kg ( P &lt; 0.01); and from 32 ± 4 to 5 ± 2 mm/sec during aortic constriction ( P &lt; 0.01). Corresponding reductions in posterior wall systolic excursion were observed. Simultaneous hemodynamic measurements revealed moderate depression of ventricular performance in group II, but there was no significant correlation between the changes in hemodynamic parameters and echocardiographic velocities following infarction. We conclude that the marked changes in PWM following posterior infarction were due to echocardiographic detection of dyskinesis in the infarcted area rather than to generalized changes in ventricular function. Posterior wall velocities are not a reliable index of left ventricular performance when localized dyskinesis, as indicated by abnormal PWM, is present.
Enhanced Expression of Hepatocyte Growth Factor/c-Met by Myocardial Ischemia and Reperfusion in a Rat Model
Authors: Koh Ono, Akira Matsumori, Tetsuo Shioi, Yutaka Furukawa, Shigetake Sasayama
Journal: Circulation (1997)

Background Hepatocyte growth factor (HGF) is a multifunctional factor implicated in tissue regeneration, wound healing, and angiogenesis. Circulating HGF is reportedly elevated during the early stage of myocardial infarction. However, its precise effect on the heart is unknown. To evaluate the regulation of HGF in ischemically damaged myocardium, the production of HGF and its high-affinity receptor, c-Met, was studied in a rat model of myocardial ischemia and reperfusion. Methods and Results The plasma concentration of HGF began to increase within 1 hour of reperfusion after 1 hour of ischemia. The peak level was reached at 3 hours after reperfusion. Northern blotting revealed that HGF mRNA expression in the heart was augmented threefold at 24 and 48 hours and remained elevated by twofold at 120 hours after the myocardium was reperfused. The signal for c- met , high-affinity HGF receptor mRNA, was also upregulated parallel to upregulation for HGF. In the kidney, liver, lung, and spleen, HGF mRNA was also maximally increased at 12 hours after reperfusion. However, c- met was not upregulated in these organs. Immunohistochemical studies disclosed that capillary endothelial and interstitial cells, including infiltrating macrophages, were intensely stained for HGF, whereas capillary endothelial cells in the reperfused myocardium were positive for c-Met. Conclusions This study is the first to show that myocardial ischemia and reperfusion induced HGF expression in various organs in vivo. These results indicate that HGF/c-Met plays a role in capillary endothelial cell regeneration in the ischemically injured heart.
The Local and Systemic Complications of Inflammatory Bowel Disease
Authors: Joseph B. Kirsner
Journal: JAMA (1979)

THE NONSPECIFIC inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn's disease, continue to present challenging problems.<sup>1-3</sup>The rising incidence of IBD, especially of Crohn's disease, in recent years has generated increased interest in these disorders and the variety of their local and systemic complications that influence the response to therapy and the course of the illness. The complications may assume primary importance in the health of the patient, while in other cases, they may be the initial overt clinical manifestations of an existing underlying IBD. Some complications, eg, iritis, probably reflect an underlying generalized tissue abnormality. Others, such as "intestinal" arthritis and pericholangitis, may reflect intestinal bacterial overgrowth in Crohn's disease. In yet other circumstances, complications such as skin rashes, bone marrow suppression, superinfections, and electrolyte imbalance are among the many iatrogenic complications associated with the treatment of IBD. The pathophysiology of IBD complications probably represents several pathogenetic mechanisms.
Elevated serum sCD23 and sCD30 up to two decades prior to diagnosis associated with increased risk of non-Hodgkin lymphoma
Authors: M P Purdue, Q Lan, T J Kemp, A Hildesheim, S J Weinstein, J N Hofmann, J Virtamo, D Albanes, L A Pinto, N Rothman
Journal: Leukemia (2014)
Controlled low protein diets in chronic renal insufficiency: meta-analysis.
Authors: D. Fouque, M. Laville, J. P. Boissel, R. Chifflet, M. Labeeuw, P. Y. Zech
Journal: BMJ (1992)

To determine whether low protein diets retard the development of end stage renal disease.Meta-analysis of 46 trials since 1975, from which six randomised controlled trials were selected.Five trials in Europe and one in Australia between 1982 and 1991.890 patients with mild to severe chronic renal failure who were followed up for at least one year. 450 patients received a low protein diet and 440 a control diet.Difference in protein intake between control and treated groups of at least 0.2 g protein/kg/day.Number of renal deaths (the necessity to start dialysis or death of patient during study).156 renal deaths were recorded, 61 in the low protein diet group and 95 in the control group, leading to an odds ratio of low protein to control of 0.54 with a 95% confidence interval of 0.37 to 0.79.This result, obtained on a large population of patients suffering from chronic renal insufficiency, strongly supports the effectiveness of low protein diets in delaying the onset of end stage renal disease.
Interaction of serotonin reuptake inhibitors with tamoxifen
Authors: F. Andersohn, S. N Willich
Journal: BMJ (2010)

Avoid coprescribing paroxetine and tamoxifen in women with breast cancer

Tamoxifen has an established role in the treatment of hormone receptor positive invasive breast cancer.1 Evidence has emerged in recent years that the main pharmacological effects of tamoxifen are not mediated by the parent drug itself but by an active metabolite called endoxifen (4-hydroxy- N -desmethyltamoxifen).2 The bioactivation of tamoxifen to endoxifen is mainly catalysed by the cytochrome P450 isoenzyme 2D6 (CYP2D6).2 Certain drugs inhibit the activity of CYP2D6, and this results in decreased plasma concentrations of endoxifen.2 3

In the linked observational study (doi:10.1136/bmj.c693), Kelly and colleagues show that the risk of breast cancer related death is higher in women taking tamoxifen plus the selective serotonin reuptake inhibitor (SSRI) paroxetine. The authors suggest that this is explained by inhibition of CYP2D6.4

SSRIs are prescribed for women with breast cancer who are taking tamoxifen for two main reasons. Firstly, to treat depression or anxiety, and, secondly, to reduce hot flushes, which are a common side effect of tamoxifen. Some SSRIs such as paroxetine are strong inhibitors of CYP2D6. It is reasonable to suggest that concomitant use of these drugs attenuates the clinical effectiveness of tamoxifen, but observational data supporting this hypothesis were lacking until …
210 (+)-EPISESAMIN BLOCKS TUMOR CELL INVASIVENESS VIA SUPPRESSED ACTIVATION OF NUCLEAR FACTOR-κB AND ACTIVATOR PROTEIN-1 ALONG WITH DECREASED IL-6 RELEASE AND ENZYMATIC INHIBITION OF MMP-9
Authors: C. Freise, U. Erben, U.P. Neumann, D. Seehofer, K.Y. Kim, W. Trowitzsch-Kienast, M. Zeitz, M. Ruehl, R. Somasundaram
Journal: Journal of Hepatology (2011)
Clinical and serological follow-up studies of endemic pemphigus foliaceus (fogo selvagem) in Western Parana, Brazil (2001-2002)
Authors: J.C. Empinotti, V. Aoki, A. Filgueira, S.A.P. Sampaio, E.A. Rivitti, J.A. Sanches, N. Li, J. Hilario-Vargas, L.A. Diaz
Journal: British Journal of Dermatology (2006)

Background Fogo selvagem (FS) has been described in several regions of Brazil, including the Western regions of the state of Parana. In 1990, Empinotti et al. reported case studies of 213 patients with FS that were collected from 1976 to 1988. The same author (J.C.E.) has observed that the frequency of cases in these regions of Parana has decreased. Objectives The purpose of this study was to clinically and serologically evaluate a small group of the patients originally reported in 1990 and compare data with a group of control individuals. These patients were treated at the onset of the disease with systemic steroids. Patients and methods Patients with FS, their unaffected relatives (n = 80) and genetically unrelated controls (n = 15) were identified during a field study from 1 May 2001 to 30 June 2002. Sera from nine patients with FS and six normal controls that were collected in the 1976–1988 evaluation were available for this study. The sera were tested by indirect immunofluorescence, enzyme‐linked immunosorbent assay (ELISA) and immunoprecipitation using recombinant human desmoglein 1 (Dsg1). Results Only 16 of the originally identified 213 patients with FS were found during the field studies. Thirteen of the 16 patients were in clinical and serological remission; 20% of normal controls (19 of 95) were positive in the Dsg1 ELISA. The majority of these subjects (17 of 19) were genetically related to FS patients. Six normal controls that were positive in the Dsg1 ELISA in the original survey were found to be negative or weakly positive in this evaluation. Conclusion The reduced frequency of positive serological markers of disease in patients and normal controls from Western Parana, as well as the absence of recurrent disease in previously identified patients, suggest that environmental antigenic stimulation of the population at risk may have decreased in recent years.
Myeloperoxidase-positive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxide-mediated reactions
Authors: C Wu
Journal: Hepatology (2003)

Previous studies have suggested that increased nitric oxide (NO)-mediated products are found in the livers of subjects with primary biliary cirrhosis (PBC), but the mechanisms involved remain enigmatic. We took advantage of immunohistochemistry and several unique monoclonal antibodies to study inflammatory cells responsible for the generation of NO, the enzymes responsible for NO production, the expression of 3-nitrotyrosine, and the presence of CD68(+) and/or myeloperoxidase (MPO)(+) cells. We examined a total of 113 liver specimens, including 64 with PBC, 19 with primary sclerosing cholangitis (PSC), 6 with non-A, non-B hepatitis, 6 with alcoholic liver disease, 4 with cryptogenic cirrhosis, 4 with biliary atresia, and 10 normal subjects. Twenty-two percent of PBC had elevated expression of 3-nitrotyrosine in their bile duct epithelial cells (BECs) (P =.0316). Furthermore, the BECs in PBC also demonstrated apoptotic changes. MPO-positive inflammatory cells were also noted adjacent to the basement membrane. In contrast, the liver of normal subjects showed few apoptotic changes in the bile ducts, with no evidence of MPO staining in the portal area. Furthermore, sections from livers of subjects with stage I or stage II PBC demonstrated significantly increased inflammatory cell infiltration (P =.0064) and elevated 3-nitrotyrosine expression in BECs (P =.0246) compared with stage III and IV. The presence of 3-nitrotyrosine was closely associated with infiltrating CD68- and/or MPO-positive cells. There was also a stage-associated difference in the presence of bile duct infiltrating cells and 3-nitrotyrosine in PBC with an increase dominant in early stage disease. In conclusion, NO and reactive oxygen species, collectively determined as 3-nitrotyrosine, are associated with bile duct destruction in PBC and are particularly prevalent in early stage disease.