tbuckley/cabot-search huggingface dataset:
Interleukin (IL)‐31 induces pro‐inflammatory cytokines in human monocytes and macrophages following stimulation with staphylococcal exotoxins
Authors: S. Kasraie, M. Niebuhr, T. Werfel
Journal: Allergy (2009)

IL-31 is a cytokine expressed by T cells following activation with cytokines or staphylococcal exotoxins. A major function of IL-31 in atopic dermatitis (AD) is the induction of pruritus in the skin via the IL-31 receptor on sensory nerve cells. However, the regulation of the IL-31 receptor and pro-inflammatory functions of IL-31 in human monocytes and monocyte-derived cells are yet to be studied in detail.To investigate the regulation and function of IL-31 receptors in resting and activated human monocytes, macrophages and dendritic cells.Human monocytes, macrophages and dendritic cells were stimulated with staphylococcal exotoxins (SEB, alpha-toxin) or cytokines (IFN-gamma, IL-13). IL-31RA expression and regulation were then investigated at both the mRNA and the protein level. Subsequently, functional effects of IL-31 stimulation on cytokine secretion were measured at the protein level.Staphylococcal exotoxins significantly up-regulated IL-31RA expression on monocytes and macrophages but not on dendritic cells at both the mRNA and the protein level. IL-31 enhanced the secretion of IL-1beta, IL-6 and IL-18 and up-regulated CD86 expression. In patients with AD, functional IL-31RA was also detected following stimulation of PBMC with IFN-gamma. However, this was not observed in healthy individuals.IL-31 induces pro-inflammatory effects in activated human monocytes and macrophages. This may have implications for cutaneous inflammation in eczema where an over-expression of IL-31 has been described previously. Moreover, our findings provide a new link between staphylococcal colonization and the worsening of inflammation via IL-31. Further therapeutic considerations may include IL-31 as a target in AD.
Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia
Authors: Robert J. Arceci, Jane Sande, Beverly Lange, Kevin Shannon, Janet Franklin, Raymond Hutchinson, Terry A. Vik, David Flowers, Richard Aplenc, Mark S. Berger, Matthew L. Sherman, Franklin O. Smith, Irwin Bernstein, Eric L. Sievers
Journal: Blood (2005)
Comparison of the Efficacy, Toxicity, and Pharmacokinetics of a Uracil/Tegafur (UFT) Plus Oral Leucovorin (LV) Regimen Between Japanese and American Patients With Advanced Colorectal Cancer: Joint United States and Japan Study of UFT/LV
Authors: K. Shirao, P.M. Hoff, A. Ohtsu, P.J. Loehrer, I. Hyodo, S. Wadler, R.G. Wadleigh, P.J. O'Dwyer, K. Muro, Y. Yamada, N. Boku, F. Nagashima, J.L. Abbruzzese
Journal: Journal of Clinical Oncology (2004)

To compare the efficacy, toxicities, and pharmacokinetics of an oral regimen consisting of uracil/tegafur (UFT) and leucovorin (LV) between Japanese patients and patients in the United States with previously untreated metastatic colorectal cancer.Forty-four Japanese patients and 45 patients in the United States were enrolled in concurrent nonrandomized phase II trials. UFT 300 mg/m2/d and leucovorin 75 mg/d were administered orally for 28 days followed by a 7-day rest period. The total daily dose of each drug was divided into three equal doses. Treatment was repeated every 5 weeks until disease progression. Blood samples for the pharmacokinetic study were obtained after the initial dose on day 1 of the first course.The response rate for the Japanese patients and the patients in the United States was 36.4% (95% CI, 22.4% to 52.2%) and 34.1% (95% CI, 20.5% to 49.9%), respectively. The only major toxicity was diarrhea, and other toxicities were mild in both populations. The incidence of grade 3 or higher diarrhea in the Japanese and Americans was 9% and 22%, respectively. Although the area under the curve and maximum concentration of fluorouracil were found to be slightly higher in the Japanese patients than the patients in the United States, and area under the curve-adjusted body surface area appeared to be comparable between the two groups.The efficacy and pharmacokinetic parameters of UFT and LV are comparable in Japanese and American patients; however, a difference in toxicity profile, specifically diarrhea, was noted. This oral regimen of UFT and LV is considered to have similar activity against metastatic colorectal cancer and to have acceptable toxicity in patients in both countries.
Air Temperature and the Occurrence of Myocardial Infarction in Augsburg, Germany
Authors: Kathrin Wolf, Alexandra Schneider, Susanne Breitner, Stephanie von Klot, Christa Meisinger, Josef Cyrys, Heiko Hymer, H. -Erich Wichmann, Annette Peters
Journal: Circulation (2009)

Background— Air temperature changes have been associated with cardiovascular mortality and morbidity. The objective of this study was to examine in detail the registry-based myocardial infarction (MI) rates and coronary deaths in relation to air temperature in the area of Augsburg, Germany. Methods and Results— Between 1995 and 2004, the Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA) registry recorded 9801 cases of MI and coronary deaths. Over the same period, meteorological parameters and air pollutant concentrations were measured in the study region. Poisson regression analyses adjusting for time trend, relative humidity, season, and calendar effects were used to estimate immediate, delayed, and cumulative temperature effects on the occurrence of MIs. The daily rates of total MI, nonfatal and fatal events, and incident and recurrent events were analyzed. For the total MI cases, a 10°C decrease in 5-day average temperature was associated with a relative risk of 1.10 (95% confidence interval, 1.04 to 1.15). The effect of temperature on the occurrence of nonfatal events showed a delayed pattern, whereas the association with fatal MI was more immediate. No association could be observed for recurrent events. The effects of temperature decreases on total MI cases were more pronounced in years with higher average temperatures and were visible in summer. Conclusions— We observed an inverse relationship between temperature and MI occurrence not only during winter but also during summer. Thus, our results suggest not a pure “cold effect” but an influence of unusual temperature decreases.
Role of endoscopy, cross-sectional imaging and biomarkers in Crohn's disease monitoring
Authors: Jose-Manuel Benitez, Marie-Alice Meuwis, Catherine Reenaers, Catherine Van Kemseke, Paul Meunier, Edouard Louis
Journal: Gut (2013)

Crohn9s disease is characterised by recurrent and/or chronic inflammation of the gastrointestinal tract leading to cumulative intestinal tissue damage. Treatment tailoring to try to prevent this tissue damage as well as achieve optimal benefit/risk ratio over the whole disease course is becoming an important aspect of Crohn9s disease management. For decades, clinical symptoms have been the main trigger for diagnostic procedures and treatment strategy adaptations. However, the correlation between symptoms and intestinal lesions is only weak. Furthermore, preliminary evidence suggests that a state of remission beyond the simple control of clinical symptoms, and including mucosal healing, may be associated with better disease outcome. Therefore monitoring the disease through the use of endoscopy and cross-sectional imaging is proposed. However, the degree of mucosal or bowel wall healing that needs to be reached to improve disease outcome has not been appropriately studied. Furthermore, owing to their invasive nature and cost, endoscopy and cross-sectional imaging are not optimal tools for the patients or the payers. The use of biomarkers as surrogate markers of intestinal and systemic inflammation might help. Two biomarkers have been most broadly assessed in Crohn9s disease: C-reactive protein and faecal calprotectin. These markers correlate significantly with endoscopic lesions, with the risk of relapse and with response to therapy. They could be used to help make decisions about diagnostic procedures and treatment. In particular, with the use of appropriate threshold values, they could determine the need for endoscopic or medical imaging procedures to confirm the disease activity state.
OSI-930: A Novel Selective Inhibitor of Kit and Kinase Insert Domain Receptor Tyrosine Kinases with Antitumor Activity in Mouse Xenograft Models
Authors: Andrew J. Garton, Andrew P.A. Crew, Maryland Franklin, Andrew R. Cooke, Graham M. Wynne, Linda Castaldo, Jennifer Kahler, Shannon L. Winski, April Franks, Eric N. Brown, Mark A. Bittner, John F. Keily, Paul Briner, Chris Hidden, Mary C. Srebernak, Carrie Pirrit, Matthew O'Connor, Anna Chan, Bojana Vulevic, Dwight Henninger, Karen Hart, Regina Sennello, An-Hu Li, Tao Zhang, Frank Richardson, David L. Emerson, Arlindo L. Castelhano, Lee D. Arnold, Neil W. Gibson
Journal: Cancer Research (2006)

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.
Detection of Overexpressed and Phosphorylated Wild-Type Kit Receptor in Surgical Specimens of Small Cell Lung Cancer
Authors: Elena Tamborini, Lorena Bonadiman, Tiziana Negri, Angela Greco, Samantha Staurengo, Paolo Bidoli, Ugo Pastorino, Marco A. Pierotti, Silvana Pilotti
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The combinations of various chemotherapeutic drugs currently used to treat advanced small cell lung cancer (SCLC) led to similarly poor survival outcomes, which is why new molecular biology approaches are needed to design and select targeted therapies. Experimental Design: Thirteen stage I SCLC surgical specimens were screened for c-Kit gene mutations by sequencing whole cDNA and for KIT receptor expression/activation by immunoprecipitation and Western blotting. Both the paraffin-embedded and frozen materials were analyzed by immunocytochemistry, and the stem cell factor cognate ligand was assessed by retrotranscription PCR. Results: In all cases, we showed the presence of wild-type KIT receptors by analyzing the entire coding sequence, which together with the detection of the cognate ligand stem cell factor, supports the establishment of an autocrine loop. In addition, the KIT receptor was activated/phosphorylated. The immunoprecipitation/Western blotting data fit the observed immunophenotype. Interestingly, comparison of the level of KIT expression was at least 10 times higher in the tumoral specimens than the normal reference lungs. Conclusions: The KIT molecular profile derived from the analysis of SCLC surgical specimens shows that wild-type KIT is overexpressed and phosphorylated in the presence of stem cell factor. This finding, which is consistent with pathological KIT activation driven by an autocrine loop, is particularly interesting in the light of the recent development of new tyrosine kinase inhibitory drugs, which are highly effective in blocking wild-type KIT receptors.
318 INCREASED LEVELS OF NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) IN THE PLASMA OF CHOLANGIOCARCINOMA PATIENTS
Authors: C.A. Wadsworth, V.M. Horneffer-van der Sluis, A. Zabron, K.M. Boberg, S.P. Pereira, S.D. Taylor-Robinson, R.J. Edwards, S.A. Khan
Journal: Journal of Hepatology (2012)
The comparative measurement of splenic blood flow using 133xenon and an electromagnetic flowmeter
Authors: L. M. Blendis, V. C. Roberts, M. Spiro, R. Williams
Journal: Cardiovascular Research (1970)

Measurements of the splenic blood flow in five greyhound dogs and one adult human undergoing splenectomy were performed using a 133Xenon clearance method and an electromagnetic flowmeter simultaneously. A highly significant correlation (r = 0·89 P < 0·001) between these two methods was found, indicating that the technique of measuring organ blood flow by monitoring the clearance of 133Xenon can be applied to the spleen.
Serum nitrite sensitively reflects endothelial NO formation in human forearm vasculature: evidence for biochemical assessment of the endothelial ?-arginine–NO pathway
Authors: M Kelm
Journal: Cardiovascular Research (1999)

Objective: A reduced bioactivity of endothelial nitric oxide (NO) has been implicated in the pathogenesis of atherosclerosis. In humans, the endothelial l-arginine–NO pathway has been indirectly assessed via the flow response to endothelium-dependent vasodilators locally administered into the coronary, pulmonary or forearm circulation. However, biochemical quantification of endothelial NO formation in these organ circulations has been hampered so far because of the rapid metabolism of NO. Therefore, we aimed to work out a reliable biochemical index to assess endothelial NO formation in human circulation. Methods: In 33 healthy volunteers, forearm blood flow (FBF) was measured by standard techniques of venous occlusion plethysmography at rest, after local application of the endothelium-dependent vasodilator acetylcholine (ACH), the endothelium-independent vasodilator papaverine (PAP), the stereospecific inhibitor of endothelial NO synthase (eNOS) L-NMMA, and l-arginine (ARG), the natural substrate of eNOS. In parallel, nitrite and nitrate concentrations in blood samples taken from the antecubital vein were measured by HPLC using anion-exchange chromatography in combination with electrochemical and ultraviolet detection following a specific sample preparation method. Results: ACH dose-dependently increased resting FBF (from 3.0±0.3 to 10.4±0.9 ml/min per 100 ml tissue) and serum nitrite concentration (from 402±59 to 977±82 nmol/l, both p<0.05, n=12). A significant correlation was observed between the changes in FBF and the serum nitrite concentration (r=0.61, p<0.0001). L-NMMA reduced resting FBF and endothelium-dependent vasodilation by 30% and this was paralleled by a significant reduction in serum nitrite concentration at the highest dose of ACH (n=9, p<0.001). PAP increased FBF more than fourfold, but did not affect serum nitrite concentration (n=11), whereas ARG significantly increased both FBF and nitrite. Basal serum nitrate amounted to 25±4 μmol/l and remained constant during the application of ACH, PAP and L-NMMA. Conclusions: The concentration of serum nitrite sensitively reflects changes in endothelial NO formation in human forearm circulation. This biochemical measure may help to characterize the l-arginine–NO pathway in disease states associated with endothelial dysfunction and to further elucidate its pathophysiological significance for the development of atherosclerosis in humans.
STUDIES ON HUMAN LEUKOCYTE MOTILITY
Authors: Richard E. Bryant, Roger M. DesPrez, Margery H. VanWay, David E. Rogers
Journal: The Journal of Experimental Medicine (1966)

Leukocyte migration was studied in a microhematocrit system which permitted evaluation of the separate effects of leukocyte adhesiveness, intrinsic cell motility, and leukocyte clumping. Leukocyte adhesion to glass required the presence of magnesium ion, was totally independent of calcium ion, and was partially dependent on heat-labile plasma factors. Leukocyte migration was unimpaired by marked acidosis or by wide variations in sodium, potassium, or calcium concentrations. Marked impairment of individual leukocyte motility and increased leukocyte aggregation were observed after phagocytosis of particulate matter, suggesting a mechanism facilitating recruitment and retention of leukocytes at areas of microbial invasion.
The concentration and expression of L-selectin in normoglycemic obstructive sleep apnea patients
Authors: Szczepan Cofta, Ewa Wysocka, Slawomir Michalak, Hanna Piotrowska, Tomasz Piorunek, Halina Batura-Gabryel, Lech Torlinski
Journal: European Respiratory Journal (2013)

Researches of atherosclerosis try to explain cardiovascular context of obstructive sleep apnea (OSA), including the role of adhesion molecules.The aim of the study was to analyze leukocyte expression and plasma concentration of L-selectin in different stage-OSA patients.

OSA-suspected males with no acute or severe chronic disease were enrolled.Non-smoking Caucasians aged 34-64, BMI 25,0-35,0 kg/m2, submitted clinical, biochemical and polysomnographic examinations.EMBLA system was used to establish the apnea/hypopnea index (AHI).Oral glucose tolerance test was used to select normoglycemic persons, who were divided into groups: OSA-0 (AHI <5), OSA-1(AHI 5-15), OSA-2(AHI 16-30), OSA-3(AHI≥31), each consisting of 18 males. Complete blood count, high sensitivity C-reactive protein, fasting plasma lipids (T-C,HDL-C,TG,LDL-C) and insulin were determined as well as plasma concentration of L-selectin (L-sel) by ELISA method (R&D Systems) and leukocyte expression of gene for L-selectin (exL-sel) by real-time quantitative PCR analysis (Roche Diagnostics).Statistical analysis using Statistica 10.0 was made.

1. The study groups did not differ in their characteristics, except LDL-C increased in OSA-3.

2. Increasing L-sel was observed from OSA-0 to OSA-3 (1137±255,1784±390, 2342±576,2979±1006 ng/mL;p=0,0000) along with exL-sel (p=0,0000).

3. The whole study population (n=72) presented the correlations: L-sel&AHI (R=0,75), exL-sel&AHI (R=0,71) and L-sel&exL-sel (R=0,52). Different correlations concerning L-selectin and metabolic parameters were observed in particular stages of OSA.

In normoglycemic excessive body mass persons, OSA pathology increases expression and concentration of L-selectin in blood.
Comparison of cell lines deficient in antigen presentation reveals a functional role for TAP-1 alone in antigen processing.
Authors: R Gabathuler, G Reid, G Kolaitis, J Driscoll, W A Jefferies
Journal: The Journal of Experimental Medicine (1994)

Cytotoxic T lymphocytes (CTL) recognize antigenic peptides bound to major histocompatibility complex class I antigens on the cell surface of virus-infected cells. It is believed that the majority of peptides originate from cytoplasmic degradation of proteins assumed to be mediated by the "20S" proteasome. Cytosolic peptides are then translocated, presumably by transporters associated with antigen processing (TAP-1 and -2), into the lumen of the endoplasmic reticulum (ER) where binding and formation of the ternary complex between heavy chain, beta2-microglobulin (beta 2m) and peptide occurs. In this study, we have analyzed and compared the phenotype of two mutant cell lines, the thymoma cell line RMA-S and a small lung carcinoma cell line CMT.64, in order to address the mechanism that underlies the antigen processing deficiency of CMT.64 cells. Unlike RMA-S cells, vesicular stomatitis virus (VSV)-infected CMT.64 cells are not recognized by specific CTL. Interferon gamma (IFN-gamma) treatment of CMT.64 cells restores the ability of these cells to process and present VSV in the context of Kb. We show that although CMT.64 cells express a low level of beta 2m, the recognition of VSV-specific CTL is not restored by increasing the amount of beta 2m synthesized in CMT.64 cells. In addition, we find that CMT.64 cells express moderate levels of Kb heavy chain molecules, but most of it is unstable and rapidly degraded in the absence of IFN-gamma treatment. We infer that the antigen processing deficiency does not lie at the level of beta 2m or Kb production. We find also that the mRNAs for both TAP-1 and -2 are present in RMA and RMA-S cells but are absent in uninduced CMT.64 cells. Upon IFN-gamma induction, both mRNAs are highly expressed in CMT-64 cells. In addition, we find that the low molecular mass polypeptides 2 and 7, and additional components of the proteasome are induced by IFN-gamma in CMT-64 cells. Finally, introduction of the rat TAP-1 gene in CMT.64 cells restores CTL recognition of VSV-infected cells. These results indicate that a TAP-1 homodimer may translocate peptides in the ER and explain partially the CMT.64 defect and the RMA-S phenotype. These findings link a dysfunction in the transport and/or generation of antigenic peptides to the capacity of tumor cells to evade immunosurveillance and provide a unique model system to dissect this phenomenon.
Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp<sup>−−</sup>/rag2<sup>−−</sup>mice
Authors: Florian Gebauer, Daniel Wicklein, Katrin Stübke, Nina Nehmann, Anna Schmidt, Johannes Salamon, Kersten Peldschus, Michael Fabian Nentwich, Gerhard Adam, Genrich Tolstonog, Maximilian Bockhorn, Jakob R Izbicki, Christoph Wagener, Udo Schumacher
Journal: Gut (2012)

<h3>Background and objective</h3> E- and P-selectins expressed on the luminal surface of mesodermally derived endothelial cells play a crucial role in the formation of haematogenous metastases in a number of malignancies. As peritoneal mesothelial cells are also derived form the mesoderm, it was hypothesised that selectins are also of importance in peritoneal tumour spread. <h3>Methods</h3> Immunohistochemistry was used to identify selectin expression on normal human peritoneum and isolated mesothelial cells. E- and P-selectin interactions with human pancreatic adenocarcinoma cells were investigated in dynamic flow assays and flow cytometry; the latter was also used to determine the main selectin ligands on pancreatic adenocarcinoma cell lines PaCa 5061, BxPC-3 and PaCa 5072, and selectin expression on human mesothelial cells. All cell lines were xenografted into the peritoneum of E- and P-selectin-deficient pfp/rag2 mice and selectin wild-type controls. Peritoneal carcinomatosis was quantified using MRI or a scoring system. <h3>Results</h3> E- and P-selectin were constitutively expressed on human mesothelial and endothelial cells in the peritoneum. PaCa 5061 and BxPC-3 cells interacted with E- and P-selectins in dynamic flow assays and flow cytometry, with CA19-9 (Sialyl Lewis a) being the main E-selectin ligand. For xenografted PaCa 5061 and BxPC-3 cells, peritoneal metastasis was significantly reduced in E- and P-selectin double knockout mice compared with wild-type pfp/rag2 animals. In contrast, PaCa 5072 cells were almost devoid of selectin binding sites and no intraperitoneal tumour growth was observed. <h3>Conclusion</h3> Interactions of tumour cells with peritoneal selectins play an important role in the peritoneal spread of pancreatic adenocarcinoma.