tbuckley/cabot-search huggingface dataset:
Induction of myelodysplasia by myeloid-derived suppressor cells
Authors: Xianghong Chen, Erika A. Eksioglu, Junmin Zhou, Ling Zhang, Julie Djeu, Nicole Fortenbery, Pearlie Epling-Burnette, Sandra Van Bijnen, Harry Dolstra, John Cannon, Je-in Youn, Sarah S. Donatelli, Dahui Qin, Theo De Witte, Jianguo Tao, Huaquan Wang, Pingyan Cheng, Dmitry I. Gabrilovich, Alan List, Sheng Wei
Journal: Journal of Clinical Investigation (2013)

Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.
Attempted Suicide by Burning
Authors: D. A. C. Reid
Journal: BMJ (1953)

<h3>Objectives</h3> To determine if street triage is effective at reducing the total number of people with mental health needs detained under section 136, and is associated with cost savings compared to usual police response. <h3>Design</h3> Routine data from a 6-month period in the year before and after the implementation of a street triage scheme were used to explore detentions under section 136, and to populate a decision analytic model to explore the impact of street triage on the cost to the NHS and the criminal justice sector of supporting people with a mental health need. <h3>Setting</h3> A predefined area of Sussex, South East England, UK. <h3>Participants</h3> All people who were detained under section 136 within the predefined area or had contact with the street triage team. <h3>Interventions</h3> The street triage model used here was based on a psychiatric nurse attending incidents with a police constable. <h3>Primary and secondary outcome measures</h3> The primary outcome was change in the total number of detentions under section 136 between the before and after periods assessed. Secondary analysis focused on whether the additional costs of street triage were offset by cost savings as a result of changes in detentions under section 136. <h3>Results</h3> Detentions under section 136 in the street triage period were significantly lower than in the usual response period (118 vs 194 incidents, respectively; χ<sup>2</sup> (1df) 18.542, p&lt;0.001). Total NHS and criminal justice costs were estimated to be £1043 in the street triage period compared to £1077 in the usual response period. <h3>Conclusions</h3> Investment in street triage was offset by savings as a result of reduced detentions under section 136, particularly detentions in custody. Data available did not include assessment of patient outcomes, so a full economic evaluation was not possible.
Insulin Receptor, Insulin Receptor Substrate-1, Raf-1, and Mek-1 during Hormonal Hepatocarcinogenesis by Intrahepatic Pancreatic Islet Transplantation in Diabetic Rats
Authors: Matthias Evert, Jianping Sun, Sabine Pichler, Nadia Slavova, Regine Schneider-Stock, Frank Dombrowski
Journal: Cancer Research (2004)

Abstract Low-number transplantation of pancreatic islets into the livers of diabetic rats leads to transformation of the downstream liver acini into clear-cell foci of altered hepatocytes (FAHs). These FAHs correspond to the glycogen-storing (clear-cell) phenotype of hepatocellular preneoplasias and develop into hepatocellular adenomas (HCAs) and hepatocellular carcinomas (HCCs) within 6 to 24 months. In addition, they show metabolic alterations that resemble well-known insulin effects, most likely constituting the result of the local hyperinsulinemia. Thus, we investigated FAHs, HCAs, and HCCs for altered expression of insulin receptor, insulin receptor substrate-1 (IRS-1), Raf-1 and Mek-1. Light and electron microscopic immunohistochemistry revealed a translocation of insulin receptor from the plasma membrane (normal tissue) into the cytoplasm in clear-cell FAHs and an increase in insulin receptor expression in HCAs and HCCs. FAHs also showed an increase in IRS-1 gene expression, investigated by in situ hybridization and quantitative reverse transcription-PCR. IRS-1, Raf-1, and Mek-1 proteins were strongly overexpressed in FAHs and tumors, as compared with the unaltered liver tissue. These overexpressions were closely linked to the clear-cell phenotype of preneoplastic and neoplastic hepatocytes, because basophilic FAHs (later stages) and basophilic tumors showed no overexpressions. In this endocrine model of hepatocarcinogenesis, severe alterations of insulin signaling were induced by the pathological local action of islet hormones in the livers and may substantially contribute to the carcinogenic process.
Open-Phylo: a customizable crowd-computing platform for multiple sequence alignment
Authors: Daniel Kwak, Alfred Kam, David Becerra, Qikuan Zhou, Adam Hops, Eleyine Zarour, Arthur Kam, Luis Sarmenta, Mathieu Blanchette, Jérôme Waldispühl
Journal: Genome biology (2013)

Abstract Citizen science games such as Galaxy Zoo, Foldit, and Phylo aim to harness the intelligence and processing power generated by crowds of online gamers to solve scientific problems. However, the selection of the data to be analyzed through these games is under the exclusive control of the game designers, and so are the results produced by gamers. Here, we introduce Open-Phylo, a freely accessible crowd-computing platform that enables any scientist to enter our system and use crowds of gamers to assist computer programs in solving one of the most fundamental problems in genomics: the multiple sequence alignment problem.
Decreasing incidence of gastric MALT lymphomas in the era of anti-Helicobacter pylori interventions: results from a population-based study on extranodal marginal zone lymphomas
Authors: S. Luminari, M. Cesaretti, L. Marcheselli, I. Rashid, S. Madrigali, A. Maiorana, M. Federico
Journal: Annals of Oncology (2009)
Low pressure headaches caused by spontaneous intracranial hypotension
Authors: S. Scott, R. Davenport
Journal: BMJ (2014)

<h3>Abstract</h3> Mutations that enhance LRRK2 protein kinase activity cause inherited Parkinson’s disease. LRRK2 phosphorylates a group of Rab GTPase proteins, including Rab10, within the effector-binding switch-II motif. Previous work has indicated that the PARK16 locus, which harbors the gene encoding for Rab29, is mutated in Parkinson’s, and that Rab29 operates in a common pathway with LRRK2. Co-expression of Rab29 and LRRK2 stimulates LRRK2 activity by recruiting LRRK2 to the surface of the trans-Golgi network. Pathogenic mutations including LRRK2[R1441C] promote GTP-binding are more readily activated by Rab29. As previous work was based on overexpression approaches, we were curious to define the importance of endogenous Rab29 in regulating basal LRRK2 activity. We report that knock-out of Rab29 does not influence endogenous LRRK2 activity, based on assessment of Rab10 phosphorylation, in wildtype LRRK2, LRRK2[R1441C] as well as in VPS35[D620N] knock-in mouse tissues and embryonic fibroblasts. We also generated a transgenic mouse model that moderately overexpresses Rab29, and found that this was not sufficient to stimulate basal LRRK2 activity. Our data suggest that the bulk of the basal LRRK2 activity measured in whole cell and tissue extracts is not controlled by Rab29. LRRK2 is not associated with the Golgi unless Rab29 is highly overexpressed, which could account for the lack of effect that Rab29 knock-out or moderate overexpression has on basal LRRK2 activity. Further work is required to establish how basal LRRK2 activity is regulated, and whether other Rab proteins control basal LRRK2 by targeting it to diverse membranes.
On the Causative Relations of Phthisis
Authors: R. D. Powell
Journal: BMJ (1884)

turbid by fine granules.The impurity was removed by solution and recrystallisation.A simple test of the purity of picric acid for chemical purposes is to boil a mixture of one volume of the saturated solu- tioni with half its volume of liquor potassie.The resulting liquid should be quite pellucid, and of a pale lemon yellow colour, with no red tinge.
Conformation-Specific Blockade of the Integrin GPIIb/IIIa
Authors: Meike Schwarz, Gerardene Meade, Patrick Stoll, Jari Ylanne, Nicole Bassler, Yung Chih Chen, Christoph E. Hagemeyer, Ingo Ahrens, Niamh Moran, Dermot Kenny, Desmond Fitzgerald, Christoph Bode, Karlheinz Peter
Journal: Circulation Research (2006)

Platelet activation causes conformational changes of integrin GPIIb/IIIa (α IIb β 3 ), resulting in the exposure of its ligand-binding pocket. This provides the unique possibility to design agents that specifically block activated platelets only. We used phage display of single-chain antibody (scFv) libraries in combination with several rounds of depletion/selection to obtain human scFvs that bind specifically to the activated conformation of GPIIb/IIIa. Functional evaluation of these scFv clones revealed that fibrinogen binding to human platelets and platelet aggregation can be effectively inhibited by activation-specific scFvs. In contrast to clinically used GPIIb/IIIa blockers, which are all conformation unspecific, activation-specific GPIIb/IIIa blockers do not induce conformational changes in GPIIb/IIIa or outside-in signaling, as evaluated by ligand-induced binding-site (LIBS) exposure in flow cytometry or P-selectin expression in immunofluorescence microscopy, respectively. In contrast to the conformation-unspecific blocker abciximab, activation-specific scFvs permit cell adhesion and spreading on immobilized fibrinogen, which is mediated by nonactivated GPIIb/IIIa. Mutagenesis studies and computer modeling indicate that exclusive binding of activation-specific scFv is mediated by RXD motifs in the heavy-chain complementary-determining region (CDR) 3 of the antibodies, which in comparison with other antibodies forms an exceptionally extended loop. In vivo experiments in a ferric-chloride thrombosis model of the mouse carotid artery demonstrate similar antithrombotic potency of activation-specific scFv, when compared with the conformation-unspecific blockers tirofiban and eptifibatide. However, in contrast to tirofiban and eptifibatide, bleeding times are not prolonged with the activation-specific scFvs, suggesting lower bleeding risks. In conclusion, activation-specific GPIIb/IIIa blockade via human single-chain antibodies represents a promising novel strategy for antiplatelet therapy.
GLOMERULONEPHRITIS INDUCED IN SHEEP BY INJECTIONS OF HETEROLOGOUS GLOMERULAR BASEMENT MEMBRANE AND FREUND'S COMPLETE ADJUVANT
Authors: Raymond William Steblay
Journal: The Journal of Experimental Medicine (1962)

Sheep injected every 2 weeks with heterologous GBM and Freund's adjuvant by any one or combination of the following routes: intramuscular, subcutaneous, or intradermal, develop uniformly a fulminating, extracapillary glomerulonephritis, invariably fatal within 27 to 90 days after the first injection. The chief histologic feature is marked fibroepithelial proliferation of Bowman's capsule with crescent formation. The appearance of the lesions resembles the acute, subacute, and chronic stages of human glomerulonephritis, and depends on when the animal was sacrificed. Freund's adjuvant or heterologous GBM alone does not produce such a nephritis. The combination of placental tissue and Freund's adjuvant under the present experimental conditions was also unable to produce a nephritis. The clinical course, increase in nitrogen retention, evolution of renal lesions, and death, all describe a fulminating disease. The disease most characteristically resembles fatal, fulminating human subacute glomerulonephritis. The changes in serum proteins, decrease in serum albumin, and increase in serum globulin, occurred approximately the same in both the GBM-treated and the control adjuvant group. Similar changes have been reported from hyperimmunization alone, and so it is not clear how much these changes are due to immunization and how much is due to the nephritic process. The changes in serum cholesterol were not considered statistically significant. Circulating serum antibodies which localized (by fluorescent antibody technique in vitro) on basement membrane structures of the heterologous donor kidney antigen or which produced nephritis in the heterologous donor species (rat and dog) were found in serum of sheep sick or dying of nephritis. The passive transfer of nephritis by serum antibodies marks the first successful instance of transfer of nephritis by serum antibody to a heterologous species from an animal which had developed nephritis itself. The serum antibodies involved in the transfer of disease to the donor species appear to be unrelated to the mediators of nephritis in the sheep and may represent only the previously known heteronephrotoxic antibodies. By various biologic criteria the sheep nephritis presumably occurs by an autoimmune mechanism. However, it is not known whether the sheep nephritis is mediated by sensitized cells and/or antibodies. The latent period was estimated to end about 16 to 71 days after the first injection. Azotemia was estimated to begin about 17 to 78 days after the first injection. Proteinuria and azotemia began approximately 23 and 13 days before death. The rapid progression to a fatal termination defined the fulminating character of this disease.
ABO blood group and other genetic variants associated with pancreatic cancer
Authors: Anne Lennon, Alison P Klein, Michael Goggins
Journal: Genome Medicine (2010)

Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States. Recent reports, including genome-wide association studies and self-reported blood serotype studies, have shown that individuals of European ancestry who carry non-O blood group are at an increased risk of developing pancreatic cancer. Two recent genome-wide association studies of pancreatic cancer have identified associations between pancreatic cancer risk and genetic variants in the ABO blood group gene, the locus containing the telomerase reverse transcriptase (hTERT) gene, the nuclear receptor family gene NR5A2 and a non-genic region on chromosome 13q22.1.
Effects from application of antioxidant enzymes on the preservation of tracheal epithelium after burn injury
Authors: V. Novoselov, A. Volkova, M. Sharapov, F. Temnov, E. Karaduleva, A. Gordeeva, S. Soodaeva, I. Klimanov
Journal: European Respiratory Journal (2014)

Chemical burn of upper respiratory tract caused by hydrochloric acid vapors was used as a model of tracheal epithelium damage. To evaluate the possibility of neutralization of the oxidative stress, we applied exogenous antioxidant enzymes directly into the rat trachea upon burn. Since superoxide radicals and inorganic and organic hydroperoxides are the major ROS types, in our experiments we used Mn-superoxide dismutase (Mn-SOD), peroxiredoxin 6 (Prx6), chimeric enzyme PSH, combining superoxide dismutase and peroxidase activities.  The application of 1 mg/ml of Mn-SOD in a burnt trachea following 30 min after the burn injury resulted in a fast and complete destruction of tracheal epithelium associated with heavy bleeding from the rat larynx and subsequent death of the animal. When using reduced Mn-SOD concentration (0.1 mg/ml) the animals did not die, but their tracheal epithelium was significantly damaged. Completely different results were obtained upon the application of Prx6 and the chimeric PSH into the burnt trachea. The morphological analysis of the tracheal epithelium structure following one day after the burn and the application of both proteins demonstrated considerable preservation of the tracheal epithelium with a significant survival rate of ciliated cells, which were not present in the controls. Morphological analysis of the tracheal epithelium conducted in three days after the injury testified a similar pattern with even more pronounced preservation of the epithelium, witnessing intensive regenerative processes in the trachea upon the application of these proteins.
Antibiotic prescribing for self limiting respiratory tract infections in primary care: summary of NICE guidance
Authors: T. Tan, P. Little, T. Stokes
Journal: BMJ (2008)

Antibiotics probably provide little benefit for a large proportion of respiratory tract infections that present in primary care. Respiratory tract infections are largely self limiting, and complications are likely to be rare if antibiotics are withheld. However, respiratory tract infections account for 60% of all antibiotic prescribing in primary care,1 and the prescribing patterns for antibiotics vary widely among general practices, without evidence of significant benefit among higher prescribers. Three different management strategies for antibiotics can be used for patients with respiratory tract infection who present in primary care: no antibiotic prescribing; delayed (or deferred) prescribing, in which a prescription is written for use at a later date if symptoms worsen or do not start to settle in the expected timescale; and immediate prescribing. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on antibiotic prescribing for self limiting respiratory tract infections in primary care.2 NICE recommendations are based on systematic reviews of best available evidence. When minimal evidence is available, recommendations are based on the Guideline Development Group's opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Management strategies for antibiotics #### Adults and children (3 months or older) with acute otitis media; acute sore throat, acute pharyngitis, or acute tonsillitis; common cold; acute rhinosinusitis; acute cough or acute bronchitis
Ascorbic acid and tetrahydrobiopterin potentiate the EDHF phenomenon by generating hydrogen peroxide
Authors: Ambroise Garry, David H. Edwards, Ian F. Fallis, Robert L. Jenkins, Tudor M. Griffith
Journal: Cardiovascular Research (2009)

Our objective was to investigate whether pro-oxidant properties of ascorbic acid (AA) and tetrahydrobiopterin (BH(4)) modulate endothelium-dependent, electrotonically mediated arterial relaxation.In studies with rabbit iliac artery (RIA) rings, NO-independent, endothelium-derived hyperpolarizing factor (EDHF)-type relaxations evoked by the sarcoplasmic endoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid and the G protein-coupled agonist acetylcholine (ACh) were enhanced by AA (1 mM) and BH(4) (200 microM), which generated buffer concentrations of H(2)O(2) in the range of 40-80 microM. Exogenous H(2)O(2) potentiated cyclopiazonic acid (CPA)- and ACh-evoked relaxations with a threshold of 10-30 microM, and potentiation by AA and BH(4) was abolished by catalase, which destroyed H(2)O(2) generated by oxidation of these agents in the organ chamber. Adventitial application of H(2)O(2) also enhanced EDHF-type dilator responses evoked by CPA and ACh in RIA segments perfused intraluminally with H(2)O(2)-free buffer, albeit with reduced efficacy. In RIA rings, both control relaxations and their potentiation by H(2)O(2) were overcome by blockade of gap junctions by connexin-mimetic peptides (YDKSFPISHVR and SRPTEK) targeted to the first and second extracellular loops of the dominant vascular connexins expressed in the RIA. Superoxide dismutase attenuated the potentiation of EDHF-type relaxations by BH(4), but not AA, consistent with findings demonstrating a differential role for superoxide anions in the generation of H(2)O(2) by the two agents.Pro-oxidant effects of AA and BH(4) can enhance the EDHF phenomenon by generating H(2)O(2), which has previously been shown to amplify electrotonic hyperpolarization-mediated relaxation by facilitating Ca(2+) release from endothelial stores.
Co-Clinical Trials Demonstrate Superiority of Crizotinib to Chemotherapy in <i>ALK</i>-Rearranged Non–Small Cell Lung Cancer and Predict Strategies to Overcome Resistance
Authors: Zhao Chen, Esra Akbay, Oliver Mikse, Tanya Tupper, Katherine Cheng, Yuchuan Wang, Xiaohong Tan, Abigail Altabef, Sue-Ann Woo, Liang Chen, Jacob B. Reibel, Pasi A. Janne, Norman E. Sharpless, Jeffrey A. Engelman, Geoffrey I. Shapiro, Andrew L. Kung, Kwok-Kin Wong
Journal: Clinical Cancer Research (2013)

Abstract Purpose: To extend the results of a phase III trial in patients with non–small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion. Experimental Design: We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed. Results: Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared with chemotherapy-treated mice. Pemetrexed produced superior overall survival compared with docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. In addition, in the EML4-ALK–driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L. Conclusions: Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor–naïve disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance. Clin Cancer Res; 20(5); 1204–11. ©2013 AACR.