tbuckley/cabot-search huggingface dataset:
Increased Production and Expression of Tissue Thromboplastin-Like Procoagulant Activity In Vitro by Allogeneically Stimulated Human Leukocytes
Authors: Henry Rothberger, Theodore S. Zimmerman, John H. Vaughan
Journal: Journal of Clinical Investigation (1978)

Intravascular coagulation, thrombosis, and fibrin deposition often produce tissue damage in allogeneic inflammatory reactions such as allograft rejection. The mechanisms which initiate blood clotting in these reactions are poorly understood. We find that allogeneic stimulation of human leukocytes in vitro increases production and expression of tissue thromboplastin-like activity. In our experiments mixed leukocyte cultures (MLC) of cells from allogeneic (unrelated) donors produced and expressed more procoagulant activity than control cultures of cells from each donor alone. After 7 days, allogeneic MLC had 5- to 50-fold more total procoagulant activity than controls, as shown by assaying lysed whole cultures. Additionally, allogeneic MLC had 8- to 240-fold more procoagulant activity expressed on leukocyte surfaces and in culture supernates than controls after 7 days, as shown by assaying intact whole cultures and cell-free supernates. These increases were largely accounted for by gains in the amounts of procoagulant activity produced and expressed per cell in MLC as compared to controls. Controls and MLC produced and expressed considerable amounts of procoagulant activity during the 1st day of culture, and there were no differential effects of allogeneic stimulation on day 1. However, after day 1, the total amount of procoagulant activity produced and the amount expressed declined steadily in controls, nearly reaching preculture levels by day 7. In contrast, the total amount of procoagulant activity in allogeneic MLC remained high, and the amount of activity expressed on cell surfaces and in supernates increased severalfold by day 7. MLC of syngeneic (identical twin) cells produced and expressed the same amount of activity as controls over a 7-day period, whereas MLC of cells from each twin and an allogeneic donor produced and expressed more activity than controls (at least 9- and 35-fold more, respectively). Thus, increases of procoagulant activity production and expression were found only in MLC of genetically dissimilar cells. Therefore, these increases must have resulted from allogeneic stimulation.
Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene (LTC4S) in asthma
Authors: I Sayers
Journal: Thorax (2003)

<b>Background:</b> LTC4 synthase is essential for the production of cysteinyl leukotrienes (Cys-LT), critical mediators in asthma. We have identified a novel promoter polymorphism at position −1072 (G/A) and a −444 (A/C) polymorphism has previously been reported. The role of these polymorphisms in the genetic susceptibility to asthma was examined. <b>Methods:</b> To test for genetic association with asthma phenotypes, 341 white families (two asthmatic siblings) and 184 non-asthmatic control subjects were genotyped. Genetic association was assessed using case control and transmission disequilibrium test (TDT) analyses. LTC4S promoter luciferase constructs and transiently transfected human HeLa and KU812F cells were generated to determine the functional role of these polymorphisms on basal transcription. <b>Results:</b> No associations were observed in case control analyses (–1072 A, q=0.09; −444 C, q=0.29); the TDT identified a borderline association between the −444 C allele and bronchial responsiveness to methacholine (p=0.065). Asthmatic children with the −444 C allele had a lower mean basal forced expiratory volume in 1 second (97.4 <i>v</i> 92.7% predicted, p=0.005). LTC4S promoter luciferase analyses provided no evidence for a functional role of either polymorphism in determining basal transcription. <b>Conclusion:</b> This study does not support a role for these polymorphisms in genetic susceptibility to asthma but provides evidence to suggest a role in determining lung function parameters.
Olive Phenol Hydroxytyrosol Prevents Passive Smoking–Induced Oxidative Stress
Authors: Francesco Visioli, Claudio Galli, Elena Plasmati, Serena Viappiani, Alicia Hernandez, Claudio Colombo, Angelo Sala
Journal: Circulation (2000)

Background —Oxidative stress is involved in the onset of several degenerative disorders, and epidemiological studies indicate that a high intake of dietary antioxidants, as in the case of the Mediterranean basin, is protective. Olive mill waste waters (OMWWs) are a byproduct of olive oil production rich in phenolic antioxidants, such as hydroxytyrosol. We tested the effects of a low dose of an OMWW extract in a model of sidestream smoke–induced oxidative stress in rats by evaluating the urinary excretion of 8-iso-prostaglandin (PG) F 2α (iPF 2α -III). Methods and Results —An OMWW extract (5 mg/kg, providing 414 μg/kg of hydroxytyrosol) was administered to rats daily for 4 days, during which time the animals were exposed to sidestream smoke for 20 minutes once a day. Daily urines were collected, and the urinary excretion of 8-iso-PGF 2α was evaluated as an index of oxidative stress–induced in vivo lipid peroxidation. The exposure of rats to passive smoking increased the urinary excretion of 8-iso-PGF 2α by 44±4.2% at 48 hours and by 55±10% at 96 hours. Treatment with the OMWW extract was able to completely prevent the increase at 48 hours and resulted in lower increments (34±18% versus 55±10%) of 8-iso-PGF 2α excretion at 96 hours. Conclusions —A low dose of hydroxytyrosol, administered through OMWW, reduces the consequences of sidestream smoke–induced oxidative stress in rats.
Tie2 Signaling Regulates Osteoclastogenesis and Osteolytic Bone Invasion of Breast Cancer
Authors: Yongfen Min, Xiubao Ren, David B. Vaught, Jin Chen, Edwin Donnelly, Conor C. Lynch, P. Charles Lin
Journal: Cancer Research (2010)

Breast to bone metastasis is a common occurrence in the majority of patients with advanced breast cancer. The metastases are often incurable and are associated with bone destruction and high rates of morbidity. Understanding the underlying mechanisms of how metastatic tumor cells induce bone destruction is critically important. We previously reported that Tie2, a receptor tyrosine kinase, is significantly increased in human breast cancer tissues compared with normal and benign breast tumors and regulates tumor angiogenesis. In this study, we identify a new function of Tie2 in osteoclastogenesis and osteolytic bone invasion of breast cancer. Tie2 is present in hematopoietic stem/precursor cells. Genetic deletion of Tie2 or neutralization of Tie2 function using soluble Tie2 receptor impaired osteoclastogenesis in an embryonic stem cell differentiation assay. In contrast, deletion of Tie2 has no effect on osteoblastogenesis. As CD11b myeloid cells have the potential to become osteoclasts and Tie2 is present in a certain population of these cells, we isolated Tie2(+) and Tie2(-) myeloid cells. We observed a significant reduction of osteoclastogenesis in Tie2(-) compared with Tie2(+) CD11b cells. Consistently, neutralization of Tie2 activity in vivo significantly inhibited osteolytic bone invasion and tumor growth in a mammary tumor model, which correlated with a significant reduction of osteoclasts and tumor angiogenesis. Collectively, these data reveal a direct and novel role of Tie2 signaling in osteoclast differentiation. These findings identify Tie2 as a therapeutic target for controlling not only tumor angiogenesis but also osteolytic bone metastasis in breast cancer.
Exhalation flow and pressure-controlled reservoir collection of exhaled nitric oxide for remote and delayed analysis
Authors: P Paredi, S Loukides, S Ward, D Cramer, M Spicer, S A Kharitonov, P J Barnes
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Expiratory flow rate, soft palate closure, and dead space air may influence exhaled levels of nitric oxide (NO). These factors have not been evaluated in the reservoir collection of NO. <h3>METHODS</h3> Exhaled NO was collected into a reservoir during a single flow and pressure controlled exhalation. <h3>RESULTS</h3> NO collected in a reservoir containing silica gel was stable for 24 hours. Nasally delivered 4.8% argon measured by mass spectrometry did not contaminate exhaled argon levels (0.1 (0.02)%) in five volunteers during exhalation against a resistance (10 (0.5) cmH<sub>2</sub>O), hence proving an effective soft palate closure. Exhaled NO in the reservoir was 11 (0.2) ppb, 8.6 (0.1) ppb, 7.1 (0.6) ppb, and 6.6 (0.4) ppb in five normal subjects and 48.3 (18) ppb, 20.3 (12) ppb, 16.9 (0.3) ppb and 10.1 (0.4) ppb in 10 asthmatic subjects at four studied expiratory flows (5–6, 7–8, 10–11, and 12–13 l/min, respectively), with NO levels equal to direct measurement (7.3 (0.5) ppb and 17.4 (0.5) ppb for normal and asthmatic subjects respectively, p&lt;0.05) at the flow rate 10–11 l/min. Elimination of dead space proved necessary to provide NO levels comparable to the direct measurement. Exhaled NO collected into the reservoir without dead space during flow controlled exhalation against mild resistance provided close agreement (mean (SD) difference –0.21 (0.68), coefficient of variation 4.58%) with direct measurement in 74 patients (NO range 1–69 ppb). <h3>CONCLUSIONS</h3> Flow and pressure controlled collection of exhaled NO into a reservoir with silica gel provides values identical to the direct measurement and may be used to monitor asthma at home and where analysers are not on site.
Congenital oesophageal stenosis due to tracheobronchial remnants
Authors: A. K. Deiraniya
Journal: Thorax (1974)

<b>Deiraniya, A. K. (1974).</b><i>Thorax</i>, <b>29</b>, 720-725. <b>Congenital oesophageal stenosis due to tracheobronchial remnants.</b> Two cases of distal oesophageal obstruction due to tracheobronchial remnant after the successful treatment of proximal oesophageal atresia with an associated tracheo-oesophageal fistula are reported. This association of congenital distal oesophageal stenosis due to tracheobronchial remnant with oesophageal atresia and tracheo-oesophageal fistula has not previously been reported in the literature. The diagnosis should be suspected in cases of distal oesophageal obstruction presenting in childhood or adult life with a history dating back to infancy or childhood. Radiologically a short stenotic non-relaxing segment is the hallmark. There is no hiatus hernia and no gastro-oesophageal reflux. Surgical excision is recommended and can be achieved easily through a thoracic approach. Dilatation is difficult, at times impossible and occasionally hazardous, and any benefit is transient. Excision of the stenotic segment with primary end-to-end anastomosis is the method of choice and almost always possible.
Superoxide production by polymorphonuclear leucocytes in rheumatoid arthritis and osteoarthritis: in vivo inhibition by the antirheumatic drug piroxicam due to interference with the activation of the NADPH-oxidase.
Authors: P Biemond, A J Swaak, J M Penders, C M Beindorff, J F Koster
Journal: Annals of the Rheumatic Diseases (1986)

The superoxide (O2-) production of stimulated polymorphonuclear leucocytes is increased in patients with rheumatoid arthritis and osteoarthritis compared with controls. Treatment of these different groups with pharmacological amounts of the non-steroidal anti-inflammatory drug piroxicam in vivo resulted in a decrease of about 25% in O2- secretion by isolated granulocytes. In vitro experiments showed that piroxicam inhibits O2- production of granulocytes by interference with the stimulation of the NADPH-oxidase. Piroxicam caused diminished O2- production of membrane fragments if it was present during the stimulation of the NADPH-oxidase of the intact cells. During the actual O2- production of the stimulated membrane fragments piroxicam had no effect. It is concluded that piroxicam is able to inhibit granulocyte O2- production by blocking the activation of NADPH-oxidase, which results in diminished tissue destruction by oxygen free radicals in inflammatory diseases.
Histopathologic Staging at Initial Diagnosis of Mycosis Fungoides and the Sézary Syndrome
Authors: Edward A. Sausville
Journal: Annals of Internal Medicine (1988)

Study Objective: To determine the optimal staging evaluation at the time of initial diagnosis of mycosis fungoides or the Sézary syndrome. Design: Retrospective review of a uniformly staged inception cohort. Setting: Single-institution tertiary care center. Patients: 152 consecutive patients who had mycosis fungoides with or without the Sézary syndrome within 6 months of the initial definitive diagnosis. Intervention: A detailed staging evaluation including physical examination, routine laboratory studies, chest roentgenogram, lymphangiogram, peripheral blood smear, lymph node biopsy, bone marrow aspirate or biopsy, and liver biopsy in selected patients. Measurements and Main Results: Univariate adverse prognostic features at initial diagnosis in patients with mycosis fungoides included (P < 0.01) one or more cutaneous tumors or generalized erythroderma, adenopathy, blood smear involvement with Sézary cells, lymph node effacement, eosinophilia, and visceral involvement. Important, independent prognostic factors in a multivariate analysis are the presence of visceral disease and type of skin involvement. Conclusions: A staging system based on histopathologic evaluation of skin, lymph nodes, blood, and visceral sites provides more comprehensive prognostic information than clinical evaluation of skin disease and adenopathy. Patients may be divided at initial presentation into three prognostic groups: good-risk patients, who have plaque-only skin disease without lymph node, blood, or visceral involvement (median survival, > 12 years); intermediate-risk patients, who have cutaneous tumors, erythroderma, or plaque disease with node or blood involvement but no visceral disease or node effacement (median survival, 5 years); and poor-risk patients, who have visceral involvement or node effacement (median survival, 2.5 years).
INTELLECTUAL AND AFFECTIVE FUNCTIONS IN CHRONIC BRUCELLOSIS
Authors: RALPH M. REITAN
Journal: American Journal of Psychiatry (1953)

The Rorschach test was administered to 3 diagnostic groups composed of patients with neurosis, organic brain damage, and brucellosis. The subjects were individually matched in the 3 groups on the basis of sex, age, formal education, and IQ. Intergroup statistical comparisons were made of the mean performances on each of the Rorschach variables. Secondly, the frequency with which scores in one group exceeded the matched scores in the other groups was tabulated and the frequency differences tested for statistical significance. The relative frequencies of Rorschach "signs" of organic cerebral damage in the 3 groups were also compared statistically. The results obtained indicate quite consistently that the scores of subjects with brucellosis fall between those of the other 2 groups. Generally, the brucellosis group is more similar to the neurosis group with respect to Rorschach variables having primarily intellectual significance, and more similar to the brain-damaged group with respect to reduction of emotional spontaneity and capacity for emotional responsiveness. The various Rorschach "signs" of brain damage occur much more frequently in brucellosis than neurosis (p..001). While these signs occur more frequently among brain-damaged patients than those with brucellosis, the statistical significance is not as great (p..05). An interpretative review of the protocols in the 3 groups indicates a considerable amount of neurotic symptomatology in each group, but confirms the earlier result of typical indications of organic brain involvement occurring among the patients with brucellosis as well as those with verified brain damage.
A Phase I Combination Study of Olaparib with Cisplatin and Gemcitabine in Adults with Solid Tumors
Authors: Arun Rajan, Corey A. Carter, Ronan J. Kelly, Martin Gutierrez, Shivaani Kummar, Eva Szabo, Mary Ann Yancey, Jiuping Ji, Baskar Mannargudi, Sukyung Woo, Shawn Spencer, William Douglas Figg, Giuseppe Giaccone
Journal: Clinical Cancer Research (2012)

To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination.We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m(2) on days 3 and 10, and cisplatin 60 mg/m(2) on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC).Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with ≤ 2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100 mg once daily on days 1 to 4 (DL-1). No DLTs were seen in six patients at DL-1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration.Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy.
Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells
Authors: Julio Gomez-Rodriguez, Elizabeth A. Wohlfert, Robin Handon, Françoise Meylan, Julie Z. Wu, Stacie M. Anderson, Martha R. Kirby, Yasmine Belkaid, Pamela L. Schwartzberg
Journal: The Journal of Experimental Medicine (2014)

A proper balance between Th17 and T regulatory cells (Treg cells) is critical for generating protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk (IL2-inducible T cell kinase), a component of T cell receptor (TCR) signaling pathways, influences this balance by regulating cross talk between TCR and cytokine signaling. Under both Th17 and Treg cell differentiation conditions, Itk(-/-) CD4(+) T cells develop higher percentages of functional FoxP3(+) cells, associated with increased sensitivity to IL-2. Itk(-/-) CD4(+) T cells also preferentially develop into Treg cells in vivo. We find that Itk-deficient T cells exhibit reduced TCR-induced phosphorylation of mammalian target of rapamycin (mTOR) targets, accompanied by downstream metabolic alterations. Surprisingly, Itk(-/-) cells also exhibit reduced IL-2-induced mTOR activation, despite increased STAT5 phosphorylation. We demonstrate that in wild-type CD4(+) T cells, TCR stimulation leads to a dose-dependent repression of Pten. However, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and phosphoinositide-3-kinase (PI3K) pathways. Moreover, Itk-deficient CD4(+) T cells show impaired TCR-mediated induction of Myc and miR-19b, known repressors of Pten. Our results demonstrate that Itk helps orchestrate positive feedback loops integrating multiple T cell signaling pathways, suggesting Itk as a potential target for altering the balance between Th17 and Treg cells.
CHIR-258 Is Efficacious in A Newly Developed Fibroblast Growth Factor Receptor 3–Expressing Orthotopic Multiple Myeloma Model in Mice
Authors: Xiaohua Xin, Tinya J. Abrams, Paul W. Hollenbach, Katherine G. Rendahl, Yan Tang, Yoko A. Oei, Millicent G. Embry, Debbie E. Swinarski, Evelyn N. Garrett, Nancy K. Pryer, Suzanne Trudel, Bahija Jallal, Dirk B. Mendel, Carla C. Heise
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in ∼15% of multiple myeloma (MM) patients and confers a particularly poor prognosis. This study assesses the antimyeloma activity of CHIR-258, a small-molecule inhibitor of multiple receptor tyrosine kinases that is currently in phase I trials, in a newly developed FGFR3-driven preclinical MM animal model. Experimental Design: We developed an orthotopic MM model in mice using a luciferase-expressing human KMS-11-luc line that expresses mutant FGFR3 (Y373C). The antimyeloma activity of CHIR-258 was evaluated at doses that inhibited FGFR3 signaling in vivo in this FGFR3-driven animal model. Results: Noninvasive bioluminescence imaging detected MM lesions in nearly all mice injected with KMS-11-luc cells, which were mainly localized in the spine, skull, and pelvis, resulting in frequent development of paralysis. Daily oral administration of CHIR-258 at doses that inhibited FGFR3 signaling in KMS-11-luc tumors in vivo resulted in a significant inhibition of KMS-11-luc tumor growth, which translated into a significant improvement in animal survival. Conclusions: Our data provide a relevant preclinical basis for clinical trials of CHIR-258 in FGFR3-positive MM patients.
Effect of Galantamine Hydrobromide in Chronic Fatigue Syndrome
Authors: C. V. Russell Blacker, David T. Greenwood, Keith A. Wesnes, Rosamund Wilson, Carol Woodward, Ian Howe, Tauhid Ali
Journal: JAMA (2004)

There is no established pharmacological treatment for the core symptoms of chronic fatigue syndrome (CFS). Galantamine hydrobromide, an acetyl cholesterone inhibitor, has pharmacological properties that might benefit patients with CFS.To compare the efficacy and tolerability of galantamine hydrobromide in patients with CFS.Randomized, double-blind trial conducted June 1997 through July 1999 at 35 outpatient centers in the United Kingdom (n = 17), United States (n = 14), the Netherlands (n = 2), Sweden (n = 1), and Belgium (n = 1) involving 434 patients with a clinical diagnosis of CFS (modified US Centers for Disease Control and Prevention criteria).A total of 89 patients were randomly assigned to receive 2.5 mg of galantamine hydrobromide; 86 patients, 5.0 mg; 91 patients, 7.5 mg; and 86 patients, 10 mg (these patients received medicine in the tablet form 3 times per day); a total of 82 patients received matching placebo tablets 3 times per day.The primary efficacy variable was the global change on the Clinician Global Impression Scale after 4, 8, 12, and 16 weeks of treatment. Secondary outcomes were changes in core symptoms of CFS on the Chalder Fatigue Rating Scale, the Fibromyalgia Impact Questionnaire, and the Pittsburgh Sleep Quality Index; changes in quality of life on the Nottingham Health Profile; and assessment of plasma-free cortisol levels and cognitive performance on a computer-based battery of tests.After 16 weeks, there were no statistically significant differences between any of the galantamine or placebo groups in clinical condition on the Clinician Global Impression Scale, or for any of the secondary end points. Exploratory regression analysis failed to detect any consistent prognostic factor that might have influenced the primary or any secondary outcome measures.This trial did not demonstrate any benefit of galantamine over placebo in the treatment of patients with CFS.