tbuckley/cabot-search huggingface dataset:
AB0207 Enhanced Formation and Impaired Degradation of Neutrophil Extracellular TRAPS in Dermatomyositis and Polymyositis: A Potential Contributor to Dm/Pm- Complicated Ild
Authors: S. Zhang, G. Wang, X. Lu
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Dermatomyositis (DM) and polymyosits (PM) are systemic autoimmune diseases with ambiguous pathogenesis. Neutrophil extracellular traps (NETs) is considered to play an important role in pathogenesis of autoimmune disease. <h3>Objectives</h3> The present study tested the hypothesis that NETs may be pathogenic in DM/PM. <h3>Methods</h3> Plasma samples from 97 DM/PM patients (72DM, 25PM) and 54 healthy controls were tested for formation and degradation of NETs. Plasma DNase I activity was tested to further analyze the reason for abnormal degradation of NETs. Results from thirty five DM patients and seven PM patients with ILD were compared with DM/PM patients without ILD. <h3>Results</h3> Compared with Control, DM/PM exhibited a significantly enhanced NETs formation (191.6±52.88 RFUs vs. 246±93.48 RFUs, P=0.002), which was supported by elevated level of plasma LL-37 and cfDNA in DM/PM. DM/PM also exhibited a significantly decreased ability to degrade NETs and DNase I activity. The percentage of NETs degraded by plasma significantly correlated with plasma DNase I activity in DM/PM. Moreover, DM/PM patients with ILD exhibited a significantly lower ability to degrade NETs and DNase I activity than patients without. DNase I activity in patients with anti-Jo-1 antibodies was significantly lower than that in patients with negative anti-Jo-1 antibodies. Glucocorticoids therapy seems to improve the activity of DNase I. <h3>Conclusions</h3> The collective evidence demonstrated that the excessively formed NETs cannot be completely degraded owing to impairment of DNase I activity in DM/PM, especially in DML/PML, suggesting that residual NETs may participate in pathogenesis of ILD and DNase I may be a potential target. <h3>References</h3> Lundberg IE. Pathogenesis, classification and treatment of inflammatory myopathies. Nat Rev Rheumatol 2011;7:297–306 Danoff SK, Casciola-Rosen L. The lung as a possible target for the immune reaction in myositis. Arthritis Research &amp; Therapy 2011;13:230. Cheng OZ, Palaniyar N. NET balancing: a problem in inflammatory lung diseases. Front Immunol 2013;4:1. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, et al. NETs Are a Source of Citrullinated Autoantigens and Stimulate Inflammatory Responses in Rheumatoid Arthritis. Sci Transl Med 2013 Mar 27;5(178):178ra40. Keshari RS, Jyoti A, Dubey M, Kothari N, Kohli M, Bogra J, Barthwal MK, Dikshit M. Cytokines Induced Neutrophil Extracellular Traps Formation: Implication for the Inflammatory Disease Condition. PLoS ONE 2012;7(10): e48111. <h3>Acknowledgements</h3> The authors thank all patients and volunteers who participated in this study. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2472
Effect of Dietary Enrichment with Eicosapentaenoic and Docosahexaenoic Acids on in Vitro Neutrophil and Monocyte Leukotriene Generation and Neutrophil Function
Authors: Tak H. Lee, Richard L. Hoover, John D. Williams, Richard I. Sperling, Joseph Ravalese, Bernd W. Spur, Dwight R. Robinson, E.J. Corey, Robert A. Lewis, K. Frank Austen
Journal: New England Journal of Medicine (1985)

The effects of dietary fish-oil fatty acids on the function of the 5-lipoxygenase pathway of peripheral-blood polymorphonuclear leukocytes and monocytes were determined in seven normal subjects who supplemented their usual diet for six weeks with daily doses of triglycerides containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid. The diet increased the eicosapentaenoic acid content in neutrophils and monocytes more than sevenfold, without changing the quantities of arachidonic acid and docosahexaenoic acid. When the neutrophils were activated, the release of [3H]arachidonic acid and its labeled metabolites was reduced by a mean of 37 per cent, and the maximum generation of three products of the 5-lipoxygenase pathway was reduced by more than 48 per cent. The ionophore-induced release of [3H]arachidonic acid and its labeled metabolites from monocytes in monolayers was reduced by a mean of 39 per cent, and the generation of leukotriene B4 by 58 per cent. The adherence of neutrophils to bovine endothelial-cell monolayers pretreated with leukotriene B4 was inhibited completely, and their average chemotactic response to leukotriene B4 was inhibited by 70 per cent, as compared with values determined before the diet was begun and six weeks after its discontinuation. We conclude that diets enriched with fish-oil–derived fatty acids may have antiinflammatory effects by inhibiting the 5-lipoxygenase pathway in neutrophils and monocytes and inhibiting the leukotriene B4–mediated functions of neutrophils. (N Engl J Med 1985; 312:1217–24.)
Abstract 1214: RET fusion gene: translation to the therapy of lung adenocarcinoma.
Authors: Takashi Kohno, Hitoshi Ichikawa, Koji Tsuta, Tatsuji Mizukami, Yoko Shimada, Mamoru Kato, Hiromi Sakamoto, Katsuya Tsuchihara, Shun-ichi Watanabe, Hiroshi Nokihara, Koichi Goto, Jun Yokota, Teruhiko Yoshida, Tatsuhiro Shibata
Journal: Cancer Research (2013)

Abstract A considerable proportion of lung adenocarcinomas, the most common histological type of lung cancer that comprises 40% of the total cases, develops through activation of oncogenes, for example, somatic mutations in EGFR or KRAS or fusion of ALK, in a mutually exclusive manner. Tyrosine kinase inhibitors targeting the EGFR and ALK proteins are effective in the treatment of lung adenocarcinomas that carry EGFR mutations and ALK fusions, respectively. We performed whole-transcriptome sequencing (RNA sequencing) of 30 lung adenocarcinoma specimens from Japanese individuals to identify new chimeric fusion transcripts that could be targets for therapy. Then, we identified KIF5B (kinesin family 5B)-RET fusion gene, as another druggable oncogene that is present in 2% (6/319) of lung adenocarcinomas (Kohno et al., Nat Med, 2012). The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation segregating from mutations or fusions in EGFR, KRAS, HER2 and ALK. The RET fusion has preferentially been detected in well or moderately differentiated tumors of never smokers. The RET fusion in lung adenocarcinoma was also identified by three other groups: Dr. Ju et al of Seoul National University, Dr. Takeuchi et al of Japanese Foundation for Cancer Research, and Dr. Lipson et al of Foundation Medicine, USA. A clinical trial to address the therapeutic efficacy of a RET tyrosine kinase inhibitor, vandetanib, will be started in 2013 by Dr. Koichi Gotoh (kgoto@east.ncc.go.jp) of National Cancer Center Hospital East, Japan. Citation Format: Takashi Kohno, Hitoshi Ichikawa, Koji Tsuta, Tatsuji Mizukami, Yoko Shimada, Mamoru Kato, Hiromi Sakamoto, Katsuya Tsuchihara, Shun-ichi Watanabe, Hiroshi Nokihara, Koichi Goto, Jun Yokota, Teruhiko Yoshida, Tatsuhiro Shibata. RET fusion gene: translation to the therapy of lung adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1214. doi:10.1158/1538-7445.AM2013-1214
Ontogenetic increase of the maximal rate of rise of the chick embryonic heart action potential. Relationship to voltage, time, and tetrodotoxin.
Authors: T Iijima, A J Pappano
Journal: Circulation Research (1979)

The maximal rate of rise (Vmax) of the embryonic chick ventricular action potential increased about 2-fold from 112 +/- 6 V/sec and 113 +/- 5 V/sec on the 4th and 6th incubation days, respectively, to 217 +/- 7 V/sec on the 12th incubation day. Neither the steady state inactivation (hinfinity) of Vmax, the temperature-dependent shift of hinfinity, nor the time constant for recovery (tauRec) of Vmax changed significantly when Vmax had doubled. Inhibition of Vmax by tetrodotoxin (TTX) was the same in hearts from the 4th, 6th, and 18th incubation days. The relation between Vmax and TTX concentration could be described by a one-to-one binding curve with an apparent dissociation constant of 2 X 10(-8) M. The increase of Vmax, a valid measure of the early inward Na+ current (iNa) during the rising phase of the cardiac action potential, can be attributed to an elevated maximal Na+ conductance (-gNa) during ontogenesis. These results indicate that the physicochemical properties of the gNa unit responsible for the rapid rising phase of the action potential and of the TTX binding site associated with it may remain constant during a period of embryonic development when -gNa increased significantly.
Von Willebrand Factor — A New Target for TTP Treatment?
Authors: Agnès Veyradier
Journal: New England Journal of Medicine (2016)

Thrombotic thrombocytopenic purpura (TTP), a rare thrombotic microangiopathy, is defined by a mechanical hemolytic anemia, severe thrombocytopenia, and visceral ischemia due to systemic platelet-rich microthrombi. Specifically in TTP microthrombi, von Willebrand factor, not fibrinogen, is the protein that binds to platelets.1 Von Willebrand factor is a multimeric glycoprotein that is crucial for physiologic platelet adhesion and aggregation at high shear rates of blood flow, and the largest von Willebrand factor multimers are the most adhesive. The hemostatic power of von Willebrand factor is regulated by a specific cleaving metalloprotease named ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, . . .
State-wide application of breast and colon cancer quality measures (QMs) using linked claims and registry data.
Authors: S. B. Edge, K. Mallin, B. E. Palis, A. Stewart, L. N. Newcomer, D. E. Walczak, J. Singer, J. Barron, W. J. Blumenthal, B. L. Warther
Journal: Journal of Clinical Oncology (2010)

6004 Background: The National Quality Forum (NQF) endorsed QMs for breast and colorectal (CR) cancer in 2007. Application by cancer registries may yield inaccurately low measures of QM concordance because of incomplete data on systemic therapy and radiation. Linkage of registry data to insurance claims may provide a more robust measure of quality at the community level. This study examined concordance with NQF QMs using payer claims linked to the National Cancer Data Base and the Ohio Cancer Incidence Surveillance System (combined data = REG). Methods: Claims from United Healthcare and Anthem Blue Cross Blue Shield of Ohio were linked to REG for patients treated in Ohio during 2004-06 for breast and CR cancer. Cases with fewer than 270 days of claims were excluded. Concordance with NQF QM's was assessed by examining radiation, chemotherapy, and endocrine therapy defined from REG and claims as treatment actually administered. Results: The claims-registry linkage identified 2,447 women with stage 0–III breast cancer and 668 patients with stage 0–III CR cancer. The Table shows concordance with NQF QMs. Conclusions: Linkage of claims to registries allows more accurate community-wide assessment of quality of cancer care. Concordance with NQF QMs among insured patients in Ohio was very high. Efforts to expand claims-registry linkages are warranted for quality assessment. NQF measure N cases Concordance with NQF QMs by data source Registry only Claims only Claims + registry Stage I-III breast cancer; breast-conserving surgery; age < 70; radiation < 365 days of diagnosis (Dx) 932 84% 95% 96% T1cN0M0 and stage II-III breast cancer; hormone receptor negative; age < 70; chemotherapy < 120 days of Dx 267 77% 92% 94% T1cN0M0 and stage II-III breast cancer; hormone receptor positive; endocrine therapy < 365 days of Dx 613 61% 84% 92% Stage III colon cancer; age < 80 chemotherapy < 120 days of Dx 161 82% 91% 96% Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration UnitedHealthCare
Smoking: The Need for Further Medical Studies
Authors: K. I. GOURGOULIANIS
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Smoking: The Need for Further Medical Studies Get access K. I. GOURGOULIANIS K. I. GOURGOULIANIS Athens Hospital for Diseases of the Chest5 Keas St., 151 27 Melissia Athens, Greece Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 21, 1 November 1989, Page 1668, https://doi.org/10.1093/jnci/81.21.1668 Published: 01 November 1989
The Dick Test in Military Personnel
Authors: Lowell A. Rantz, Paul J. Boisvert, Wesley W. Spink
Journal: New England Journal of Medicine (1946)

THE Dick skin test has been widely used for the detection of human beings susceptible to scarlet fever and has proved to be useful for this purpose. It has been demonstrated that a skin rash rarely appears in any but Dick-positive patients during an infection by a scarlatinogenic strain of hemolytic streptococcus. There is no evidence that failure to react to the erythrogenic toxin confers protection against infection by hemolytic streptococci. In fact, recent investigation shows that cases of respiratory infection associated with skin rash caused by these organisms occur much less frequently than do those without a rash, because . . .
Donor Exposures in Recipients of Pooled Platelet Concentrates
Authors: Thomas Thiele, Nancy Heddle, Andreas Greinacher
Journal: New England Journal of Medicine (2013)

measured total immunoreactive insulin (proinsulin, its degradation products, and insulin), whereas with current highly specific insulin immunoassays, the diagnosis of an insulinoma may depend on an elevated proinsulin level. 4,5 Our case also shows the usefulness of proinsulin as an immunohistochemical marker to confirm neuroendocrine beta-cell tumor-mediated hypoglycemia.
Abstract 1958: Signals activating mutant p53 in vivo
Authors: Young-Ah Suh, Sean Post, Cathalina Elizondo, Adel K. El-Naggar, Shunbin Xiong, Guillermina Lozano
Journal: Cancer Research (2010)

Abstract The p53 protein is activated in response to stress signals and leads to cell cycle arrest and apoptosis. As thus, missense mutations in the p53 tumor suppressor are common alterations in tumors. p53 activity is tightly regulated by murine double minute 2 (Mdm2), an E3 ubiquitin ligase that targets wild type p53 for degradation. The Arf tumor suppressor also regulates p53 activity by binding Mdm2. Arf is activated by oncogenes, and the retinoblastoma (Rb) signaling pathway, connecting the p53 and Rb tumor suppressor pathways. Mice inheriting p53 missense mutations that mimic common hot spots in human cancers present with a gain-of-function metastatic phenotype. An analysis of tumors from these mice indicated that some but not all had stable mutant p53 implying that other alterations besides mutation in p53 are responsible for stabilization and the gain-of-function nature of the mutant protein. Additionally, mutant p53 in normal tissues and in some tumors of homozygous mutant mice is unstable. However mutant p53 was detected in normal tissues in mutant mice lacking Mdm2 showing an increased tumor incidence and decreased survival as compared to p53 mutant mice. Importantly, stabilization of p53 correlated with a metastatic phenotype. Disruption of the Rb pathway via p16INK4a deletion, a common event in human tumors, also stabilized mutant p53 in vivo. These observations indicate that mutant protein is also regulated in the same way as wild-type p53. Here, we examined the effects of DNA damage and oncogene activation on mutant p53 stability. Mice with Ras or c-Myc activation have stable mutant p53 and show a decreased survival in vivo. Surprisingly, stable mutant protein is also detected in mice treated with sub-dose of chemotherapeutic agent or low-dose of radiation implying that the factors affecting wild-type p53 are also responsible for mutant protein stability. Treated mice also showed decreased survival as compared to p53 mutant mice. Characterization of the mechanism by which the mutant p53 protein is stabilized in tumors is important to our understanding of the gain-of-function phenotype in these mice. 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 1958.
Results from a phase II randomized, placebo-controlled, double-blind trial suggest improved PFS with the addition of pertuzumab to gemcitabine in patients with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer
Authors: S. Makhija, D. Glenn, F. Ueland, M. Gold, D. Dizon, V. Paton, M. Birkner, C. Lin, M. Derynck, U. Matulonis
Journal: Journal of Clinical Oncology (2007)

5507 Background: Pertuzumab (P) is a humanized monoclonal antibody that blocks the ability of HER2 to heterodimerize with other HER/ErbB receptors. As a single agent, P has demonstrated clinical activity in relapsed/refractory epithelial ovarian cancer (EOC). Since platinum-resistant (CDDP-R) EOC remains a difficult disease to treat, this phase II study was conducted to determine if addition of P to gemcitabine (G) would improve results. Methods: Patients with CDDP-R EOC (including ovarian, fallopian tube, or primary peritoneal cancer) who had received up to one prior treatment for CDDP-R disease were randomized to Gem 800 mg/m 2 on D1, 8 of a 21-day cycle ± P or placebo (pl). P was given as an 840 mg initial dose followed by 420mg IV every 3 weeks. Tumor response was assessed by RECIST every 6 weeks using GOG criteria. The primary endpoint was progression free survival (PFS). Results: One hundred thirty patients (n = 65 each treatment cohort) were treated. Clinical characteristics were balanced between the treatment groups. Pts received a median of 2 prior regimens (range 1–6) for EOC. Based on 83 events, the adjusted hazard ratio for PFS was 0.67 (95% CI: 0.43–1.02), p =0.06 in favor of P+Gem. The median PFS was 3.0 months (0–8.7 months) vs. 2.6 months (0–9+ months), and the PFS rate at 4 months was 49% vs. 34% in the P+Gem and Gem/pl arms, respectively. The most common AEs increased in the P-treated pts were fatigue, nausea, diarrhea, back pain, Gr 3–4 neutropenia, rash, headache, stomatitis, epistaxis, and rhinorrhea. Clinically significant CHF was reported in one patient in the pertuzumab cohort. There was no imbalance in the LVEF results between treatment arms. One patient who received pertuzumab + gemcitabine experienced an adverse event that resulted in death (hemolytic-uremic syndrome). Conclusions: These data suggest that pertuzumab may add activity to gemcitabine as reflected by improvements in PFS in patients with CDDP-R ovarian, primary peritoneal, or fallopian tube cancer. Survival data will be presented at ASCO. No significant financial relationships to disclose.
Abstract 1526: Epithelial mesenchymal transition (EMT) is associated with non-transporter resistance to taxanes in human ovarian cancer cell
Authors: Cindy Y. Wang, George E. Duran, E. Brian Francisco, Dejan Juric, Daniela Witten, Rob Tibshrani, Branimir I. Sikic
Journal: Cancer Research (2010)

Abstract Taxanes are important drugs in the treatment of ovarian cancers, but their efficacy is limited by intrinsic and acquired drug resistance. Over-expression of the MDR1 gene and its product, P-glycoprotein, is a well-characterized resistance mechanism to taxanes, but non-MDR1 taxane resistance mechanisms are not well elucidated. To study the mechanisms of non-MDR1 multidrug resistance related to taxanes, we established multiple MDR1-negative and MDR1-positive taxane resistant variants from four ovarian cancer cell lines (A2780/1A9, ES-2, MES-OV and OVCAR-3) by continuous exposure of the cells to either paclitaxel or docetaxel with or without the P-glycoprotein inhibitor PSC-833 (Valspodar). We profiled gene expression and gene copy number alterations in these cell lines using cDNA microarrays, and identified a transcriptomic signature that predicts in vitro non-MDR1 resistance, a portion of which was imprinted by gene dosage changes. Functional network analyses for genes associated with the taxane resistance signature revealed two highly significant networks built around FN1 and CDKN1A which are associated with cell adhesion, cell-to-cell signaling and cell cycle regulation. We also identified epithelial-mesenchymal transition (EMT) marker genes which are significantly associated with non-MDR1 resistance. Migration potential in wound-scratch-assay was markedly enhanced in non-MDR1 resistant variants compared to parental cells. Our results suggest that ECM-interacting genes, EMT-like changes and cell cycle regulatory elements may play important roles in resistance to taxanes. 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 1526.
Staff pay freezes may cease to be method of efficiency saving, says NHS head
Authors: A. O'Dowd
Journal: BMJ (2014)

Pay freezes for NHS staff are unlikely to continue as a means of achieving mandatory efficiency savings in the NHS, MPs have been told by the head of the NHS in England.

Simon Stevens, chief executive of NHS England, has voiced his scepticism concerning the ability to maintain significant pay restraint in the NHS if it is to remain a competitive employer. Stevens, appearing before the parliamentary health committee on 28 October as part of its inquiry into public expenditure on health and social care, also disclosed that the NHS was on target to end the current financial year with a small surplus.

MPs focused on the recent Five Year Forward …
Evaluation du rendement des coloscopies du programme national de dépistage du cancer colorectal par Hemoccult®: validation multicentrique de nouveaux indicateurs et de leurs seuils
Authors: B Denis, EA Sauleau, P Delasalle, J Faivre, Y Foll, JF Bretagne, P Bureau du Colombier, D Constantini, I Gendre, P Perrin
Journal: Endoscopy (2012)

Tout programme d'amélioration de la qualité de la coloscopie doit intégrer l'évaluation du rendement de l'endoscopiste. En France, seul le programme national de dépistage organisé (DO) du cancer colorectal (CCR) par Hemoccult offre la population homogène permettant une telle évaluation. Nous avons montré que le décompte des polypes pouvait remplacer celui des adénomes pour évaluer le rendement des coloscopies et avons proposé d'utiliser le nombre moyen de polypes (NMP) par coloscopie pour définir les endoscopistes «forts détecteurs» avec un seuil à 0,8 (1). Le but du travail présent était 1) de confirmer à grande échelle la bonne corrélation entre indicateurs dénombrant polypes et adénomes et 2) de proposer un standard pour une utilisation en routine dans le DO du CCR.