tbuckley/cabot-search huggingface dataset:
P78 Lung clearance index in children with acute exacerbation of asthma
Authors: H. S. Sheridan, S. Cunningham
Journal: Thorax (2011)

<h3>Introduction</h3> Lung clearance index (LCI) can detect small airways disease in asthma; however there is no published LCI data collected during acute exacerbation. We aimed to investigate LCI in asthmatic children requiring oral corticosteroids and admission to hospital. <h3>Methods</h3> Children were recruited from acute medical wards. We tested children once they did not require oxygen or &gt;2 hourly salbutamol. Admission details were extracted from medical notes. Multiple breath washout (MBW) was performed with sulphur hexafluoride and the Innocor photoacoustic gas analyser. Spirometry complied with ATS/ERS standards and was performed using the Easyone spirometer. MBW and spirometry were performed shortly before and 15 min after children9s clinically prescribed salbutamol. Paired t tests and Pearson correlation coefficients were used in the analysis. <h3>Results</h3> Nine children aged 6.4–13.6 years were recruited. Testing began on average 201 min after each child9s last salbutamol. LCI was calculated for eight children, the ninth was excluded due to variable FRC. Pre bronchodilator mean (SD) LCI was 8.6 (1.8), but was only abnormal (=7.4) in 5/8 children; following bronchodilator mean (SD) LCI was 8.1 (1.2). Mean (SD) FEV<sub>1</sub> z-score was −3.5 (1.6) and was abnormal (&lt;−1.96) in 6/8 children; post bronchodilator FEV<sub>1</sub> z-score was −2.9 (1.4). Mean LCI correlated with FEV<sub>1</sub> z-score before and after bronchodilator (r=−0.80, p=0.017 and r=−0.76, p=0.030). In patients with abnormal LCI there was a significant improvement after salbutamol; with a mean difference of −0.918, p=0.018. In this group FEV<sub>1</sub> z-score improved by a mean of 0.802, p=0.051. Although overall both measures improved, the degrees of improvement in LCI and FEV<sub>1</sub> did not correlate (r=−0.361, p=0.550). Two patients who both had abnormal pre bronchodilator LCI (mean 11.1) returned 8–10 weeks later, both had normal LCI (mean 6.9). <h3>Conclusions</h3> LCI is abnormal in children during exacerbation of asthma. Abnormal LCI improves following bronchodilator, but changes do not correlate with changes in FEV<sub>1</sub>. This suggests variable bronchodilator response throughout the airway. Recruitment for this study is ongoing.
NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22
Authors: Marianne R. Spalinger, Stephanie Kasper, Claudia Gottier, Silvia Lang, Kirstin Atrott, Stephan R. Vavricka, Sylvie Scharl, Petrus M. Gutte, Markus G. Grütter, Hans-Dietmar Beer, Emmanuel Contassot, Andrew C. Chan, Xuezhi Dai, David J. Rawlings, Florian Mair, Burkhard Becher, Werner Falk, Michael Fried, Gerhard Rogler, Michael Scharl
Journal: Journal of Clinical Investigation (2016)

Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.
Exciting Times in the Accounts Department
Authors: J. Aronson
Journal: BMJ (1995)

Paul Vaughan Sinclair-Stevenson, pounds sterling17.99, pp 237 ISBN 1 85619 526 0

Although received pronunciation—once de rigueur among serious broadcasters—has made way for regional accents (on the whole a welcome change), it is still to be heard. One of its best known exponents is Paul Vaughan, familiar as the voice-over on Horizon and as a presenter of Radio 4's Kaleidoscope and Radio 3's Record Review. It is therefore surprising that this volume of autobiography is more about medicine than broadcasting.

In 1950, aged 25 (his earlier years have been described in a previous book, Something in …
The Hypothalamic–Pituitary–Adrenal Axis and Immune-Mediated Inflammation
Authors: George P. Chrousos
Journal: New England Journal of Medicine (1995)

Celsus described four of the five cardinal signs of inflammation 2000 years ago, and Eustachio discovered the adrenal glands almost 500 years ago, but not until 1936 did Selye note that in rats exposed to stressors, the adrenal glands were enlarged, and the thymus and lymph nodes shrunken.13 Cortisone, the active principle of the adrenal glands, was isolated by Kendall and Reichstein in the late 1940s and shown to suppress immune organs. These scientists, along with Hench, received the Nobel Prize in Physiology and Medicine, after Hench and colleagues showed that cortisone could ameliorate rheumatoid arthritis.4,5 In recent . . .
Intermittent Acute Porphyria — Demonstration of a Genetic Defect in Porphobilinogen Metabolism
Authors: Urs A. Meyer, L. James Strand, Manfred Doss, A. Clegg Rees, Harvey S. Marver
Journal: New England Journal of Medicine (1972)

Abstract In a family with intermittent acute porphyria (IAP) five affected members were found to have decreased erythrocyte uroporphyrinogen I (URO)-synthetase activity, when compared to unaffected...
Cumulative Meta-Analysis of Therapeutic Trials for Myocardial Infarction
Authors: Joseph Lau, Elliott M. Antman, Jeanette Jimenez-Silva, Bruce Kupelnick, Frederick Mosteller, Thomas C. Chalmers
Journal: New England Journal of Medicine (1992)

The large volume of published randomized, controlled trials has led to a need for meta-analyses to track therapeutic advances. Performing a new meta-analysis whenever the results of a new trial of a particular therapy are published permits the study of trends in efficacy and makes it possible to determine when a new treatment appears to be significantly effective or deleterious. We describe the use of such a procedure, cumulative meta-analysis, to assess therapeutic trials among patients with myocardial infarction.
Trabectedin and Pegylated Liposomal Doxorubicin (Pld) Versus Carboplatin and Pld in Partially Platinum-Sensitive Ovarian Cancer Patients: Inovatyon Study
Authors: N. Colombo, E. Biagioli, E. Copreni, I.C. Floriani, R. Fossati
Journal: Annals of Oncology (2014)
FIP1L1-PDGFRA +Ve Clonal Chronic Eosinophilic Leukemia; Low Burden Disease with Dramatic Response to Low Dose Imatinib
Authors: A. Kumar, K.C. Lakshmiah, A. Loknatha, T.M. Suresh, J. Linu, A. Govindbabu
Journal: Annals of Oncology (2013)
Abstract LB-198: Ryl hydrocarbon receptor agonist Aminoflavone disrupts mammosphere formation via alpha 6 integrin inhibition
Authors: Eileen J. Brantley, Michael Yee, Ashley Quitugua, Dain Zylstra, Ubaldo Soto
Journal: Cancer Research (2012)

Abstract Introduction: Emerging evidence has suggested that cancer stem cells (CSCs) play a prominent role in the initiation and dissemination of a myriad of malignancies including breast cancer. CSCs have the capacity to self-renew within heterogeneous tumor cells. Currently available therapeutic options for breast cancer are incapable of suppressing CSC growth. Alpha 6 integrin contributes to CSC growth while aryl hydrocarbon receptor (AhR) activation impedes CSC proliferation. AhR agonist Aminoflavone, a synthetic flavonoid, is currently undergoing clinical evaluation for the treatment of breast cancer. We hypothesize that Aminoflavone alters the integrity and formation of cell suspension clusters initiated by breast cancer stem cells (mammospheres) by modulating alpha 6 integrin expression in an AhR-dependent manner Experimental Procedures: Mammospheres derived from MCF-7 breast cancer cells were exposed to Aminoflavone at varying times. We also treated mammospheres with Tamoxifen an anticancer agent frequently used in the treatment of breast cancer. Following Aminoflavone treatment, cells were analyzed microscopically to evaluate alterations in mammosphere structure. In addition, the expression of molecular targets associated with CSC growth in addition to alpha 6 integrin were evaluated by Western blotting and quantitative RT-PCR analysis. Results: We observed that Aminoflavone, but not Tamoxifen, disaggregates MCF-7 mammospheres. In contrast, Aminoflavone did not affect mammospheres produced from AhR defective MCF-7 (AHR100) cells. Aminoflavone abrogated the ability of secondary mammospheres to form. In addition, alpha-6-integrin expression was abolished following Aminoflavone treatment in MCF-7 but not AHR100 cells. The expression of several genes whose products regulate alpha-6 integrin expression were also modulated following Aminoflavone treatment in MCF-7 cells. Conclusion: These data suggest that Aminoflavone disrupts mammosphere formation via AhR signaling activation that results in alpha 6 integrin inhibition. These findings support continued efforts to develop novel AhR ligands with efficacy against breast CSCs as a viable therapeutic strategy for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-198. doi:1538-7445.AM2012-LB-198
THU0464 Lsd1-Mediated Demethylation of Histone H3 Lysine 9 Contributes to Interleukin 1-Induced Microsomal Prostaglandin E Synthase-1 Expression
Authors: F.E. El Mansouri, S. Nebbaki, M. Kapoor, H. Afif, J. Martel-Pelletier, J.-P. Pelletier, M. Benderdour, H. Fahmi
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE<sub>2</sub>, a critical mediator in the pathophysiology of osteoarthritis (OA). Histone methylation plays an important role in epigenetic gene regulation <h3>Objectives</h3> In this study, we investigated the roles of histone H3 (H3K9) methylation in interleukin-1β (IL-1)-induced mPGES-1 expression in human chondrocytes. <h3>Methods</h3> Chondrocytes were stimulated with IL-1 and the expression of mPGES-1 mRNA was evaluated using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). H3K9 methylation and the recruitment of the histone demethylase LSD1 to the mPGES-1 promoter were evaluated using chromatin immunoprecipitation (ChIP) assays. The role of LSD1 was further evaluated using the pharmacological inhibitors, tranylcypromine and pargyline <h3>Results</h3> The induction of mPGES-1 expression by IL-1 correlated with decreased levels of mono- and dimethylated H3K9 at the mPGES-1 promoter. These changes were concomitant with the recruitment of the histone demethylase LSD1. Treatment with tranylcypromine and pargyline, potent inhibitors of LSD1, prevented IL-1-induced H3K9 demethylation at the mPGES-1 promoter and mPGES-1 expression, suggesting that LSD1 mediates IL-1-induced mPGES-1 expression via H3K9 demethylation. <h3>Conclusions</h3> These results indicate that H3K9 demethylation by LSD1 contributes to IL-1-induced mPGES-1 expression and suggest that this pathway could be a potential target for pharmacological intervention in the treatment of OA and possibly other arthritic conditions. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1199
Abstract 4281: Real-time imaging of the cell-cycle in vivo
Authors: Atsushi Suetsugu, Hisataka Moriwaki, Shigetoyo Saji, Emmett Pinney, Gail Naughton, Shuya Yano, Toshiyoshi Fujiwara, Robert M. Hoffman
Journal: Cancer Research (2011)

Abstract FUCCI (Fluorescent Ubiquitination-based Cell Cycle Indicator) cells are labeled orange in the G1 phase nuclei (monomeric Kusabira-Orange2: mKO2) and labeled green in the S/G2/M phases (monomeric Azami-Green1: mAG1) (Cell 132, 487-498, 2008). FUCCI-expressing MKN45 gastric cancer cells were used for imaging cell-cycle dynamics in vivo and in vitro. When a confluent monolayer of MKN45-FUCCI was scratched, the edge of the wound turned green within 24hr, indicating that healing of the wound required proliferation of MKN45 cells. FUCCI-expressing MKN45 cells were injected subcutaneously in the nude mice. The injected cells gradually grew and emitted both green and red fluorescence for 14 days, indicating cell cycle progression. In the chorioallantonic membrane (CAM) chick embryo model, green and red fluorescence FUCCI cells and blood vessels were observed for 5 days. FUCCI cells of the edge in the tumor migrated into the transparent egg membrane. Mouse and CAM FUCCI tumor models will be used to study the role of cell cycle dynamics in metastasis including dormancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4281. doi:10.1158/1538-7445.AM2011-4281
Abstract 4419: Effect of sphingosine kinase 1 inhibition in validated syngeneic mouse breast cancer metastasis model
Authors: Masayuki Nagahashi, Omar M. Rashid, Subramanian Ramachandran, Sheldon Milstien, Sarah Spiegel, Kazuaki Takabe
Journal: Cancer Research (2011)

Abstract INTRODUCTION: Sphingosine kinase 1 (SphK1) is one of the two enzymes that generate sphingosine-1-phosphate (S1P), which promotes cancer growth, migration and angiogenesis. S1P is also known to have important roles in immune responses. Therefore, we utilized syngeneic models which better recapitulate the involvement of the host immune response to examine the role of SphK1 in breast cancer progression in vivo. The aims of this study are i) to critically evaluate syngeneic models to determine which is most appropriate for metastatic breast cancer drug development, and ii) to investigate the effect of inhibition of SphK1 on cancer progression using that model. METHODS: One of the major challenges in preclinical cancer research is the identification of animal models that adequately mimic the human disease. Three commonly used syngeneic (implantation of 4T1-luc2 luciferase-tagged murine breast cancer cells into immune-competent mice) models were compared: cells implanted subcutaneously (Sq); cells implanted Orthotopically under direct vision with Surgery (OS); cells implanted Orthotopically with Percutaneous injection blindly into the area under a nipple (OP). Bioluminescence was used for macroscopic analysis, together with pathological analysis, and genome-wide microarrays for gene expression profiling, with confirmation by qPCR. An isozyme-specific inhibitor of SphK1 (SK1-I) was administered intraperitoneally. Tumor burden were quantified using an in vivo imaging system (IVIS 200). RESULTS: Orthotopic implantation under direct vision with Surgery produced significantly more consistent tumors with less variability, more rapid cancer progression and metastasis, faster mortality, and more relevant clinical endpoints than OP or Sq models. There were significant differences between the genetic profiles of the tumors from OS compared to Sq tumors. Three fourth of the differentially expressed genes between OS and Sq are relevant to cancer biology. Using this OS model, we found that SK1-I treatment decreased tumor burden significantly. CONCLUSIONS: Use of the OS model, in place of more commonly used Sq model, may improve the efficiency of cancer drug development. Our results support the notion that SphK1 play a critical role in breast cancer progression and suggest that SK1-I is a promising candidate for breast cancer targeted therapy. This work was supported by Sumitomo Life Social Welfare Services Foundation grant to MN, NIH (K12HD055881) and Susan G. Komen for the Cure (KG090510) to KT, and NCI (R01CA61774) to SS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4419. doi:10.1158/1538-7445.AM2011-4419
Abstract 2844: Association of genetic variants in TNFRSF10B and breast cancer
Authors: Ryan P. Abo, Marina Parry, Sushila H. Rigas, Angela Cox, Nicola J. Camp
Journal: Cancer Research (2010)

Abstract Susceptibility to non-Mendelian forms of breast cancer likely involves many low penetrance variants from multiple genes. Recent associations between genetic variants in CASP8 and breast cancer suggest that CASP8 is one such gene contributing to breast cancer risk (Cox et al. 2007; Shephard et al. 2009). Here we investigate TNFRSF10B for associations with breast cancer. TNFRSF10B is a death receptor gene whose protein signals via caspase-8 in the extrinsic apoptosis pathway. We selected 11 tagging-SNPs (tSNPs) to represent the majority of the common genetic variation in the TNFTRSF10B gene. These tSNPs were genotyped on 1,992 independent cases and controls from Sheffield, UK. We performed 11 single marker association analyses and a haplotype-mining analysis using hapConstructor (Abo et al. 2008). HapConstructor implements a stepwise forward-backward procedure to search for haplotypes associated with disease. The algorithm allows for automatic consideration of non-contiguous SNP sets and the construction of numerous different genetic models that consider haplotypes, composite genotypes, and both monotype (chromosome-based) and diplotype (individual-based) tests. Briefly, all single locus tests are performed, then loci that surpass predefined significance thresholds are considered in all two-locus combinations, and so on. For the single marker association testing, dominant, recessive, and trend tests were performed. For the hapConstructor analysis, monotype haplotype tests and diplotype dominant and recessive tests were considered. HapConstructor is implemented within a Monte Carlo testing framework, with all p-values estimated empirically from 100,000 simulations under the null. Seven SNPs reached nominal significance in at least one of the association tests performed in the single SNP tests. Five of these were based on a recessive model (most significant single SNP yielded p = 0.002). Using hapConstructor, the most significant finding was a 4-SNP haplotype that was associated with an increase of risk (p=0.0006; OR=1.75). Four haplotypes were also identified that were associated with a decrease in risk and each obtained the same level of significance and risk (p=0.00096; OR=0.35). These results for reduced risk were obtained using the diplotype recessive model, similar to the single SNP findings. These results provide initial evidence that further common genetic variants in genes in the extrinsic apoptosis pathway, beyond CASP8, are involved in breast cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2844.
SAT0165 Low-dose IL-2 therapy selectively expands regulatory T cells and suppresses murine lupus
Authors: J.Y. Humrich, L. Kloke, A. Rose, C. von Spee, A. Klaus, R. Undeutsch, G. Riemekasten
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Our previous studies in the (NZBxNZW) F1 model provide strong rationales for an IL-2 based immunotherapy of lupus in order to restore regulatory T cell (Treg) mediated tolerance that is impaired due to an acquired IL-2 deficiency (Humrich et al. 2010). However, although Treg appear to be the major target of IL-2 <i>in vivo</i>, because they constitutively express the high-affinity IL-2 receptor,other cells that potentially trigger autoimmunitycan also be activated by IL-2 in a dose dependent fashion. <h3>Objectives</h3> To determine an optimal dose and regimen for a therapy with IL-2 that induces a sufficient expansion of CD4+Foxp3+ Treg <i>in vivo</i> while only marginally affecting other cells, and that most efficiently influences active disease in the (NZBxNZW) F1 model for lupus. In addition, the underlying cellular mechanisms and side effects were studied. <h3>Methods</h3> Recombinant mouse IL-2 at different single doses (1, 5, 25, 50 ng/g body weight) was injected subcutaneously either into young or diseased (NZBxNZW) F1 mice every day for the duration of five days as induction therapy. After the induction phase, IL-2 injections were continued every 4 days until the end of the experiment. Control animals received an equal amount of PBS (carrier). Cells from lymphoid organs and peripheral blood were analyzed by flow cytometry at days 5, 7, 14 and 21. In addition survival and clinical parameters (weight, proteinuria, leukozyturia, autoantibodies) were analysed during IL-2 therapy of diseased mice for regimens with the single dosages of 5 and 25 ng/g body weight. <h3>Results</h3> We found that the low-dose IL-2 regimen with a single dose of 5ng/g body weight sufficiently promoted the expansion of CD4+Foxp3+Treg, while not or only marginally affecting CD4+ effector T cells and other cells. Although higher doses of IL-2 resulted in a more pronounced proliferation and expansion of Treg, this was accompanied by a considerable increase in CD44hi memory/effector CD4+ T cells and NK cells. Clinically, regimens with both 5ng/g and 25 ng/g were nearly equally sufficient to influence nephritis and to decrease mortality. In addition, we did not observe any signs of intolerability or other clinical side effects in the treated animals, even at higher dosages of 50ng/g body weight. <h3>Conclusions</h3> These studies provide the first evidence that low-dose IL-2 therapy selectively targets Treg and is clinically effective and also safe in murine lupus. This knowledge is very important for the future design of a clinical study with IL-2 in SLE. <h3>References</h3> Humrich, JY et al. (2010). Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc Natl Acad Sci USA 107, 204-9 <h3>Disclosure of Interest</h3> None Declared