tbuckley/cabot-search huggingface dataset:
Peroxisome Proliferator–Activated Receptor α Induces NADPH Oxidase Activity in Macrophages, Leading to the Generation of LDL with PPAR-α Activation Properties
Authors: Elisabeth Teissier, Atsushi Nohara, Giulia Chinetti, Réjane Paumelle, Bertrand Cariou, Jean-Charles Fruchart, Ralf P. Brandes, Ajay Shah, Bart Staels
Journal: Circulation Research (2004)

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors controlling lipid and glucose metabolism as well as inflammation. PPARs are expressed in macrophages, cells that also generate reactive oxygen species (ROS). In this study, we investigated whether PPARs regulate ROS production in macrophages. Different PPAR-alpha, but not PPAR-gamma agonists, increased the production of ROS (H2O2 and ) in human and murine macrophages. PPAR-alpha activation did not induce cellular toxicity, but significantly decreased intracellular glutathione levels. The increase in ROS production was not attributable to inherent prooxidant effects of the PPAR-alpha agonists tested, but was mediated by PPAR-alpha, because the effects were lost in bone marrow-derived macrophages from PPAR-alpha-/- mice. The PPAR-alpha-induced increase in ROS was attributable to the induction of NADPH oxidase, because (1) preincubation with the NADPH oxidase inhibitor diphenyleneiodinium prevented the increase in ROS production; (2) PPAR-alpha agonists increased production measured by superoxide dismutase-inhibitable cytochrome c reduction; (3) PPAR-alpha agonists induced mRNA levels of the NADPH oxidase subunits p47(phox), p67phox, and gp91phox and membrane p47phox protein levels; and (4) induction of ROS production was abolished in p47phox-/- and gp91phox-/- macrophages. Finally, induction of NADPH oxidase by PPAR-alpha agonists resulted in the formation of oxidized LDL metabolites that exert PPAR-alpha-independent proinflammatory and PPAR-alpha-dependent decrease of lipopolysaccharide-induced inducible nitric oxide synthase expression in macrophages. These data identify a novel mechanism of autogeneration of endogenous PPAR-alpha ligands via stimulation of NADPH oxidase activity.
An Immortalization-Dependent Switch in Integrin Function Up-regulates MMP-9 to Enhance Tumor Cell Invasion
Authors: John M. Lamar, Kevin M. Pumiglia, C. Michael DiPersio
Journal: Cancer Research (2008)

Abstract Integrins, the major receptors for cell adhesion to the extracellular matrix, play important roles during tumor progression. However, it is still unclear whether genetic lesions that occur during carcinoma development can lead to altered integrin function, and how changes in integrin function contribute to subsequent carcinoma progression. Loss-of-function mutations in p53 and activating mutations in H-Ras, which immortalize and transform epithelial cells, respectively, are common causal events in squamous cell carcinoma (SCC). Phenotypes resulting from these two genetic lesions promote SCC progression and are, therefore, potential targets for anticancer therapies. We developed a model system of keratinocyte transformation that has allowed us to investigate the individual roles of p53 mutation and oncogenic Ras mutation in the acquisition of integrin α3β1-regulated phenotypes that promote SCC progression. Using this model, we show that keratinocyte immortalization by p53-null mutation causes a switch in α3β1 function that induces matrix metalloproteinase (MMP)-9 gene expression in tumorigenic cells. This acquired α3β1-dependent regulation of MMP-9 was maintained during subsequent transformation by oncogenic Ras, and it promoted invasion of tumorigenic keratinocytes. Our results show that loss of p53 function leads to changes in integrin-mediated gene regulation that occur during SCC progression and play a critical role in tumor cell invasion. [Cancer Res 2008;68(18):7371–9]
Acetylcholine leads to free radical production dependent on KATP channels, Gi proteins, phosphatidylinositol 3-kinase and tyrosine kinase
Authors: O Oldenburg
Journal: Cardiovascular Research (2002)

Objective: Acetylcholine (ACh) mimics ischemic preconditioning (PC) and therefore protects the heart against lethal ischemia. Steps common to both ischemic and drug-induced PC are opening of mitochondrial KATP channels (mito KATP) and generation of reactive oxygen species (ROS). The aim of this study was to test whether ACh-induced ROS production could be seen in a vascular smooth muscle cell line, and, if so, to investigate the underlying signaling pathway. Methods: Mitochondrial ROS generation was quantified by measuring changes in fluorescence of ROS-sensitive intracellular markers in vascular smooth muscle cells (A7r5). Results: Fluorescence, and, therefore, ROS production, was increased to 197.5±8.5% of baseline after 45 min of exposure of cells to 2 mM ACh (P<0.001 vs. untreated controls). This effect was blocked by co-treatment with a muscarinic receptor antagonist (atropine 102.8±2.9%, 4-DAMP 92.6±7.4%) or by inhibition of Gi with pertussis toxin (PTX) (90.5±4.4%), implicating a receptor-mediated rather than non-specific effect of ACh. The increased fluorescence induced by ACh was also abrogated by the free radical scavenger N-(2-mercaptopropionyl) glycine (104.2±10.1%), documenting that ROS were indeed the cause of the enhanced fluorescence. Both diazoxide, a KATP channel opener, and valinomycin, a potassium ionophore, also significantly increased ROS production, and these effects were not blocked by PTX, while the KATP channel closer 5-hydroxydecanoate blocked ACh-induced ROS production (92.3±3.8%). These results suggest ROS production is directly influenced by KATP activity and K+ movements in the cell. The tyrosine kinase inhibitor genistein (102.8±6.6%) and the phosphatidylinositol 3 (PI3)-kinase inhibitor wortmannin (90.7±4.1%) also inhibited the ability of ACh to increase ROS production. Conclusion: The signaling pathway by which ACh leads to ROS generation in A7r5 cells involves a muscarinic surface receptor, a pertussis toxin-sensitive G protein, PI3-kinase, at least one tyrosine kinase, and a 5-hydroxydecanoate (5-HD)-dependent KATP (presumably that in mitochondria).
Blisters in the small intestinal mucosa of coeliac patients contain T cells positive for cyclooxygenase 2
Authors: H Kainulainen
Journal: Gut (2002)

Background and aims: Coeliac disease is characterised by atrophy of the villi and hyperplasia of the crypts in the mucosa of the small intestine. It is caused by an environmental trigger, cereal gluten, which induces infiltration of the mucosa by inflammatory cells. We hypothesised that these inflammatory cells express cyclooxygenase 2 (COX-2), an enzyme that contributes to the synthesis of pro and anti-inflammatory prostaglandins and is known to be expressed at sites of inflammation in the stomach and colon. We have investigated expression of COX-2 in the coeliac disease affected small intestinal mucosa where it may be an indicator of either disease induction or mucosal restoration processes. Patients and methods: Small intestinal biopsy samples from 15 coeliac patients and 15 non-coeliac individuals were stained immunohistochemically for COX-2. Samples from 10 of the patients were also stained after these patients had been on a gluten free diet for 6–24 months. Various cell type marker antigens were used for immunohistochemical identification of the type of cell that expressed COX-2. To further verify colocalisation of the cell type marker and COX-2, double immunoperoxidase and immunofluorescence methods were employed. Immunoelectron microscopy was used to investigate the subcellular location of COX-2. Results: In all samples taken from coeliac patients, clusters of cells with strong immunoreactivity for COX-2 were found in those areas of the lamina propria where the epithelium seemed to blister or was totally detached from the basement membrane. These clusters were reduced in number or totally absent in samples taken after a gluten free diet. No such clusters were seen in any control samples. The density of COX-2 positive cells lining the differentiated epithelium decreased significantly from 13.5 (5.1) cells/10<sup>5</sup> μm<sup>2</sup> (mean (SD)) in the untreated patient samples to 6.5 (2.0) cells/10<sup>5</sup> μm<sup>2</sup> after a gluten free diet (p&lt;0.001), and was 3.3 (1.9) cells/10<sup>5</sup> μm<sup>2</sup> in control samples (p&lt;0.001 compared with untreated or diet treated coeliac samples). Staining for COX-2 was localised to CD3+ T cells and CD68+ macrophages in the mucosal lesions but not all of these cells were positive for COX-2. Immunoelectron microscopy revealed that the ultrastructure of the COX-2 positive cells resembled that of lymphocytes, and the immunoreaction was localised to the rough endoplasmic reticulum and the nuclear envelope. Conclusions: Our results show that in coeliac disease, blistering of small intestinal epithelial cells is associated with accumulation of COX-2 positive T cells, and the number of these cells decreases after a gluten free diet. These observations suggest that COX-2 mediated prostanoid synthesis contributes to healing of the coeliac mucosa and may be involved in maintenance of intestinal integrity.
Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML
Authors: Jingrui Jiang, J. Guillermo Paez, Jeffrey C. Lee, Ronghai Bo, Richard M. Stone, Daniel J. DeAngelo, Ilene Galinsky, Brian M. Wolpin, Anna Jonasova, Paula Herman, Edward A. Fox, Titus J. Boggon, Michael J. Eck, Ellen Weisberg, James D. Griffin, D. Gary Gilliland, Matthew Meyerson, William R. Sellers
Journal: Blood (2004)
Local interstitial delivery of z-butylidenephthalide by polymer wafers against malignant human gliomas
Authors: H.-J. Harn, S.-Z. Lin, P.-C. Lin, C.-Y. Liu, P.-Y. Liu, L.-F. Chang, S.-Y. Yen, D.-K. Hsieh, F.-C. Liu, D.-F. Tai, T.-W. Chiou
Journal: Neuro-Oncology (2011)

We have shown that the natural compound z-butylidenephthalide (Bdph), isolated from the chloroform extract of Angelica sinensis, has antitumor effects. Because of the limitation of the blood-brain barrier, the Bdph dosage required for treatment of glioma is relatively high. To solve this problem, we developed a local-release system with Bdph incorporated into a biodegradable polyanhydride material, p(CPP-SA; Bdph-Wafer), and investigated its antitumor effects. On the basis of in vitro release kinetics, we demonstrated that the Bdph-Wafer released 50% of the available Bdph by the sixth day, and the release reached a plateau phase (90% of Bdph) by the 30th day. To investigate the in situ antitumor effects of the Bdph-Wafer on glioblastoma multiforme (GBM), we used 2 xenograft animal models—F344 rats (for rat GBM) and nude mice (for human GBM)—which were injected with RG2 and DBTRG-05MG cells, respectively, for tumor formation and subsequently treated subcutaneously with Bdph-Wafers. We observed a significant inhibitory effect on tumor growth, with no significant adverse effects on the rodents. Moreover, we demonstrated that the antitumor effect of Bdph on RG2 cells was via the PKC pathway, which upregulated Nurr77 and promoted its translocation from the nucleus to the cytoplasm. Finally, to study the effect of the interstitial administration of Bdph in cranial brain tumor, Bdph-Wafers were surgically placed in FGF-SV40 transgenic mice. Our Bdph-Wafer significantly reduced tumor size in a dose-dependent manner. In summary, our study showed that p(CPP-SA) containing Bdph delivered a sufficient concentration of Bdph to the tumor site and effectively inhibited the tumor growth in the glioma.
AN ORGANISM RESEMBLING BACILLUS ACTINOIDES ISOLATED FROM PNEUMONIC LUNGS OF WHITE RATS
Authors: F. S. Jones
Journal: The Journal of Experimental Medicine (1922)

An organism obtained from the pneumonic lungs of eleven white rats is described. It has been maintained in pure culture in a number of instances. In young cultures the organism appears as a long slender bacillus. In older cultures on coagulated serum media characteristic club-like capsular material is formed. On blood agar characteristic swellings appear at one or both ends of the rod. These become more refringent, and the body of the organism begins to shrink. Finally only rounded spore-like refringent bodies are found. The organism is Gram-negative.
Discovery and Expression Analysis of Alternative Splicing Events Conserved among Plant SR Proteins
Authors: Hypaitia B. Rauch, Tara L. Patrick, Katarina M. Klusman, Fabia U. Battistuzzi, Wenbin Mei, Volker P. Brendel, Shailesh K. Lal
Journal: Molecular Biology and Evolution (2013)

The high frequency of alternative splicing among the serine/arginine-rich (SR) family of proteins in plants has been linked to important roles in gene regulation during development and in response to environmental stress. In this article, we have searched and manually annotated all the SR proteins in the genomes of maize and sorghum. The experimental validation of gene structure by reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed, with few exceptions, that SR genes produced multiple isoforms of transcripts by alternative splicing. Despite sharing high structural similarity and conserved positions of the introns, the profile of alternative splicing diverged significantly between maize and sorghum for the vast majority of SR genes. These include many transcript isoforms discovered by RT-PCR and not represented in extant expressed sequence tag (EST) collection. However, we report the occurrence of various maize and sorghum SR mRNA isoforms that display evolutionary conservation of splicing events with their homologous SR genes in Arabidopsis and moss. Our data also indicate an important role of both 5′ and 3′ untranslated regions in the regulation of SR gene expression. These observations have potentially important implications for the processes of evolution and adaptation of plants to land.
An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation
Authors: Andres J. López-Contreras, Paula Gutierrez-Martinez, Julia Specks, Sara Rodrigo-Perez, Oscar Fernandez-Capetillo
Journal: The Journal of Experimental Medicine (2012)

Replicative stress (RS) is a type of endogenous DNA damage that cells suffer every time they duplicate their genomes, and which is further boosted by oncogenes. In mammals, the RS response (RSR) is coordinated by ATR and Chk1 kinases. We sought to develop a mammalian organism that is selectively protected from RS. To this end, mice carrying an extra copy of the Chk1 gene were generated. In vitro, Chk1 transgenic cells are protected from RS-inducing agents. Moreover, an extra Chk1 allele prolongs the survival of ATR-Seckel mice, which suffer from high levels of RS, but not that of ATM-deficient mice, which accumulate DNA breaks. Surprisingly, increased Chk1 levels favor transformation, which we show is associated with a reduction in the levels of RS induced by oncogenes. Our study provides the first example where supra-physiological levels of a tumor suppressor can promote malignant transformation, which is a result of the protection from the RS found in cancer cells.
T cell metabolism drives immunity
Authors: Michael D. Buck, David O’Sullivan, Erika L. Pearce
Journal: The Journal of Experimental Medicine (2015)

Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism.
Tumor Necrosis Factor-α Blocks Apoptosis in Melanoma Cells when BRAF Signaling Is Inhibited
Authors: Vanessa C. Gray-Schopfer, Maria Karasarides, Robert Hayward, Richard Marais
Journal: Cancer Research (2007)

The protein kinase BRAF, a component of the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, regulates cell fate in response to extracellular signals. Activating mutations in BRAF occur in approximately 70% of human melanomas. The active proteins stimulate constitutive pathway signaling, proliferation, and survival. Thus, inhibition of BRAF signaling in melanoma cells causes cell cycle arrest and induces cell death through apoptosis, validating BRAF as an important therapeutic target. Here, we show that the apoptosis induced by inhibition of BRAF signaling in melanoma cells can be prevented if the cells are treated with tumor necrosis factor (TNF)-alpha. This allows the cells to recover from the inhibition of BRAF signaling and reenter the cell cycle. This effect occurs due to a specific TNF-alpha and BRAF interaction because TNF-alpha does not prevent cell death in the presence of cisplatin, nitrogen mustard or thapsigargin. Furthermore, the cytokines Fas ligand, TNF-related apoptosis-inducing ligand, interleukin (IL)-1, and IL-6 do not prevent cell death when BRAF signaling is inhibited. The survival mechanism requires nuclear factor-kappaB (NF-kappaB) transcription factor activity, which is strongly induced by TNF-alpha in these cells. These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF-alpha and/or NF-kappaB signaling to provide exciting new therapeutic opportunities for the treatment of melanoma.
Criminal prosecution for medical manslaughter
Authors: Dieneke Hubbeling
Journal: Journal of the Royal Society of Medicine (2010)

Doctors like everybody else do make the occasional error. Sometimes these mistakes have disastrous consequences and somebody might even die. But when is an unintentional error so serious that a criminal offence has been committed?

Gross negligence is currently the legal threshold for medical manslaughter in English criminal law. Interpretation of ‘gross negligence’ is contentious and this does give rise to some uneasiness within the medical profession. However, it is not only the definition of ‘gross negligence’ which is problematic, the underlying intuitions about moral luck and personal control are controversial as well.

Judges and juries often face a difficult, if not impossible, task in medical manslaughter cases when deciding whether a criminal offence has been committed. One way to solve these problems would be to use a clearly-defined objective norm for personal failure as threshold, but this will imply a higher threshold for criminal prosecution.
Factoring PAF in Anaphylaxis
Authors: A. Wesley Burks
Journal: New England Journal of Medicine (2008)

Anaphylaxis has been recognized for more than 100 years, but it remains a condition that is difficult to predict, diagnose, and treat. Generally defined as a serious allergic reaction that is rapid in onset and may cause death,1 anaphylaxis and its potential to occur can be of great concern for patients and clinicians. Compounding this concern in the United States and other industrialized societies is the increasing incidence of food allergies, which are the leading cause of cases of anaphylaxis reported in hospital emergency departments, where there are approximately 30,000 reactions and 200 deaths from anaphylaxis each year.2 The alarming . . .
Should doctors prescribe cannabinoids?
Authors: M. Farrell, R. Buchbinder, W. Hall
Journal: BMJ (2014)

The medical use of cannabis was advocated in the United States in the 1970s and 1980s when clinical trials of oral synthetic tetrahydrocannabinol (THC) and other oral synthetic cannabinoids reported efficacy in controlling nausea in patients with cancer who were undergoing chemotherapy.1 Dronabinol (an oral synthetic THC) was approved by the Food and Drug Administration in 1985 for this indication,1 but it was not widely used because patients were unable to titrate doses or disliked its psychoactive effects.1 It is still available in the US, United Kingdom, and the rest of Europe.

Box 1 outlines the different formulations of cannabinoids, the term we use for the sake of clarity and convenience to refer to synthetic cannabinoids and drugs derived from the cannabis plant, such as nabiximols. Box 2 lists indications for which cannabinoids have been approved for medical use.

#### Box 1: Forms of cannabis and cannabinoids

#### Box 2: Approved medical uses for tetrahydrocannabinol and nabiximols

In the …
Priorities for Research on Equity and Health: Towards an Equity-Focused Health Research Agenda
Authors: Piroska Östlin, Ted Schrecker, Ritu Sadana, Josiane Bonnefoy, Lucy Gilson, Clyde Hertzman, Michael P. Kelly, Tord Kjellstrom, Ronald Labonté, Olle Lundberg, Carles Muntaner, Jennie Popay, Gita Sen, Ziba Vaghri
Journal: PLoS Medicine (2011)

Piroska Ostlin and colleagues argue that a paradigm shift is needed to keep the focus on health equity within the social determinants of health research agenda.
NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity
Authors: Leszek Wojnowski, Bettina Kulle, Markus Schirmer, Gregor Schlüter, Albrecht Schmidt, Albert Rosenberger, Stefan Vonhof, Heike Bickeböller, Mohammad Reza Toliat, Eun-Kyung Suk, Mladen Tzvetkov, Anke Kruger, Silvia Seifert, Marita Kloess, Heidi Hahn, Markus Loeffler, Peter Nürnberg, Michael Pfreundschuh, Lorenz Trümper, Jürgen Brockmöller, Gerd Hasenfuss
Journal: Circulation (2005)

A significant number of patients treated with anthracyclines develop cardiotoxicity (anthracycline-induced cardiotoxicity [ACT]), mainly presenting as arrhythmias (acute ACT) or congestive heart failure (chronic ACT). There are no data on pharmacogenomic predictors of ACT.We genotyped participants of the German non-Hodgkin lymphoma study (NHL-B) who were followed up for the development of heart failure for a median of >3 years. Single-nucleotide polymorphisms (SNPs) were selected from 82 genes with conceivable relevance to ACT. Of 1697 patients, 55 developed acute and 54 developed chronic ACT (cumulative incidence of either form, 3.2%). We detected 5 significant associations with polymorphisms of the NAD(P)H oxidase and doxorubicin efflux transporters. Chronic ACT was associated with a variant of the NAD(P)H oxidase subunit NCF4 (rs1883112, -212A-->G; symbols with right-pointing arrows, as edited?' odds ratio [OR], 2.5; 95% CI, 1.3 to 5.0). Acute ACT was associated with the His72Tyr polymorphism in the p22phox subunit (rs4673; OR, 2.0; 95% CI, 1.0 to 3.9) and with the variant 7508T-->A (rs13058338; OR, 2.6; 95% CI, 1.3 to 5.1) of the RAC2 subunit of the same enzyme. In agreement with these results, mice deficient in NAD(P)H oxidase activity, unlike wild-type mice, were resistant to chronic doxorubicin treatment. In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Polymorphisms in adrenergic receptors previously demonstrated to be predictive of heart failure were not associated with ACT.Genetic variants in doxorubicin transport and free radical metabolism may modulate the individual risk to develop ACT.