tbuckley/cabot-search huggingface dataset:
Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Authors: Nancy U. Lin, Lisa A. Carey, Minetta C. Liu, Jerry Younger, Steven E. Come, Matthew Ewend, Gordon J. Harris, Elizabeth Bullitt, Annick D. Van den Abbeele, John W. Henson, Xiaochun Li, Rebecca Gelman, Harold J. Burstein, Elizabeth Kasparian, David G. Kirsch, Ann Crawford, Fred Hochberg, Eric P. Winer
Journal: Journal of Clinical Oncology (2008)

Purpose One third of women with advanced human epidermal growth factor receptor 2 (HER-2)–positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2–positive brain metastases. Patients and Methods Patients had HER-2–positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity. Results Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%). Conclusion The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2–positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.
Plasminogen Activator Inhibitor-1 Protects Endothelial Cells from FasL-Mediated Apoptosis
Authors: Khalid Bajou, Hongjun Peng, Walter E. Laug, Catherine Maillard, Agnes Noel, Jean M. Foidart, Joseph A. Martial, Yves A. DeClerck
Journal: Cancer Cell (2008)
Detection of Coronary Stenoses at Rest With Myocardial Contrast Echocardiography
Authors: Kevin Wei, Khim Leng Tong, Todd Belcik, Patrick Rafter, Michael Ragosta, Xin-Qun Wang, Sanjiv Kaul
Journal: Circulation (2005)

Background— We hypothesized that autoregulatory changes in arteriolar blood volume (aBV) that develop distal to a stenosis can be measured with myocardial contrast echocardiography, allowing coronary stenosis detection at rest without recourse to stress. Methods and Results— Patients with varying degrees of coronary artery stenosis on quantitative angiography underwent high-mechanical-index myocardial contrast echocardiography at 15 Hz to allow measurement of phasic changes in aBV in large intramyocardial vessels using either Definity (group 1; n=22) or Imagent (group 2; n=22). Progressive increases in the background-subtracted systolic/diastolic aBV signal ratio were noted between each level (none, mild [&lt;50%], moderate [50% to 75%], and severe [&gt;75%]) of stenosis severity for both group 1 (0.09±0.13, 0.13±0.08, 0.58±0.22, and 0.77±0.40; P &lt;0.001) and group 2 (0.10±0.05, 0.27±0.18, 0.39±0.28, and 0.74±0.37; P &lt;0.0001) patients. A systolic/diastolic aBV signal ratio of &gt;0.34 provided a sensitivity and specificity of 80% and 71%, respectively, for the detection of &gt;75% coronary stenosis in group 1 patients, whereas a ratio of &gt;0.43 provided a sensitivity and specificity of 89% and 74%, respectively, for the detection of &gt;75% stenosis in group 2 patients. Conclusions— Both the presence and severity of a physiologically significant coronary stenosis can be detected at rest by measuring the increase in aBV on myocardial contrast echocardiography that occurs distally to the stenosis without recourse to any form of stress.
A Critical Role for Interleukin 18 in Primary and Memory Effector Responses to <i>Listeria monocytogenes</i> That Extends Beyond Its Effects on Interferon γ Production
Authors: Margaret Neighbors, Xiuling Xu, Franck J. Barrat, Sigrid R. Ruuls, Tatyana Churakova, Reno Debets, J. Fernando Bazan, Robert A. Kastelein, John S. Abrams, Anne O'Garra
Journal: The Journal of Experimental Medicine (2001)

The stimulation of interferon (IFN)-gamma by interleukin (IL)-12 has been shown to provide protection from intracellular pathogens such as Listeria monocytogenes. Tumor necrosis factor (TNF) is also a major player in the resolution of Listeria infections and is suggested to have more global effects than can be explained by the induction of IFN-gamma alone. Since IL-18 synergizes with IL-12 to induce IFN-gamma production by natural killer and T helper (Th)1 cells, we determined its role in responses to Listeria. IL-18 appeared to be even more potent than either IL-12 or IFN-gamma for protection against this pathogen and IL-18 enhanced bacterial clearance in the complete absence of IFN-gamma. Indeed IL-18 was comparable to TNF in its ability to resolve the infection and showed a lowered protective capacity in the absence of TNF. Moreover, IL-18 induced macrophages to secrete both TNF and nitric oxide after a Listeria infection. IL-18 was also essential for optimal IFN-gamma production by antigen-specific T cells. Therefore, IL-18 operates via its effects on both the innate immune response, including macrophages, as well as on Th1 cells, to protect against Listeria.
Monovalent fragments (Fab) of monoclonal antibodies to a sporozoite surface antigen (Pb44) protect mice against malarial infection.
Authors: P Potocnjak, N Yoshida, R S Nussenzweig, V Nussenzweig
Journal: The Journal of Experimental Medicine (1980)

Monoclonal antibodies (IG1, k) directed against a surface component of Plasmodium berghei sporozoites (Pb-44) confer complete protection to mice against a lethal inoculum of parasites. The degree of protection is a function of the number of parasites used in the challenge and of the antibody concentration in serum. Passive transfer of 10 micrograms of antibody per mouse abolished or profoundly diminished the infectivity of 10(3) sporozoites, but much higher amounts of antibody were required for complete protection against challenge with 10(4) parasites. Fab fragments of the monoclonal antibodies were as effective as the intact antibodies in mediating protection as determined by the neutralizing assay. This observation suggests that the antibodies interfere with a parasite function necessary for its infectivity, such as, for example, the ability to penetrate into the target cell or to multiply in the hepatocytes. When sporozoites are incubated with the intact monoclonal antibodies at 37 degrees C, a long filament appears at its posterior end (circumsporzoite precipitation [CSP] reaction). Fab fragments are ineffective at high concentrations. However, if after treatment with Fab, the sporozoites are incubated with rabbit antibodies to mouse k-chains, a strong CSP reaction is observed. We conclude that the CSP reaction can result from the cross-linking of Pb44 and that it has the characteristics of a capping reaction followed by the shedding of the immune complexes.
Bronchodilator responsiveness: interpret with caution
Authors: James Fingleton, Mark Weatherall, Richard Beasley
Journal: Thorax (2012)

Bronchodilator responsiveness (BDR) is widely considered to be a key diagnostic criterion for asthma, and is used to differentiate asthma from chronic obstructive pulmonary disease (COPD). Currently, the threshold of a 12% increase in FEV1 from baseline following inhaled salbutamol, with at least a 200 ml increase in absolute terms, is recommended as a response indicative of asthma,1 although recent British guidelines recognise the poor discriminatory function of this criterion.2 Thus, despite this criterion being commonly used in clinical practice, there is uncertainty regarding its clinical utility, in particular its ability to differentiate asthma from COPD, or indeed, normal subjects.

One approach to enable a better understanding of the clinical utility of BDR is to determine the worldwide distribution of BDR in health and disease, which has been undertaken by Tan and colleagues, and reported in Thorax.3 The authors report BDR in terms of change in FEV1 and FVC following 200 μg of salbutamol delivered by metered dose inhaler via a spacer, in around 10 000 adults aged 40 years and older from 14 countries in North America, Europe, Asia and Africa who participated in the Burden of Obstructive Lung Disease study. The Burden of Obstructive Lung Disease methodology is robust and has many strengths, …
<i>In situ</i> Expression of Tumor Antigens by Messenger RNA–Electroporated Dendritic Cells in Lymph Nodes of Melanoma Patients
Authors: Danita H. Schuurhuis, Pauline Verdijk, Gerty Schreibelt, Erik H.J.G. Aarntzen, Nicole Scharenborg, Annemiek de Boer, Mandy W.M.M. van de Rakt, Marieke Kerkhoff, Marie-Jeanne P. Gerritsen, Femke Eijckeler, Johannes J. Bonenkamp, Willeke Blokx, J. Han van Krieken, Otto C. Boerman, Wim J.G. Oyen, Cornelis J.A. Punt, Carl G. Figdor, Gosse J. Adema, I. Jolanda M. de Vries
Journal: Cancer Research (2009)

Abstract Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) for cancer immunotherapy has been proved efficient and clinically safe. It obviates prior knowledge of CTL and Th epitopes in the antigen and leads to the presentation of multiple epitopes for several HLA alleles. Here we studied the migration capacity and the antigen expression of mRNA-electroporated DC (mRNA-DC) in lymph nodes after vaccination in melanoma patients. DC were electroporated with mRNA encoding gp100 or tyrosinase, labeled with indium-111 and superparamagnetic iron oxide particles, and injected intranodally in melanoma patients 24 to 48 hours before scheduled dissection of regional lymph nodes. Immunohistochemical analysis of the lymph nodes after surgery revealed that mRNA-DC migrated from the injection site into the T-cell areas of the same and subsequent lymph nodes, where they expressed the antigen encoded by the electroporated mRNA. Furthermore, vaccine-related CD8+ T-cell responses could be detected in 7 of 11 patients vaccinated with mRNA-DC. Together these data show that mature DC electroporated with mRNA encoding TAA migrate and express antigens in the lymph nodes and induce specific immune responses. [Cancer Res 2009;69(7):2927–34]
Prevention of leucocyte elastase-induced emphysema in mice by heparin fragments
Authors: C Lafuma, E Frisdal, A Harf, L Robert, W Hornebeck
Journal: European Respiratory Journal (1991)

Heparin and its derivatives inhibit human leucocyte proteinases i.e. elastase and cathepsin G, but do not inhibit porcine pancreatic elastase and Pseudomonas aeruginosa elastase. In vitro experiments, reported here, also indicate that elastin, one of the physiological substrates of human leucocyte elastase (HLE), could decrease by 30-fold the inhibitory potential of an hexadecasaccharide heparin fragment (dp 16) isolated from CY 222. Nevertheless, the inhibitory capacity of the heparin fragment still remains elevated with IC50 = 2.7 x 10(-7) M and still inhibits HLE in its free and adsorbed state to elastin. These overall data prompted us to evaluate the influence of CY 222 in HLE-induced emphysema. Emphysema was induced in mice eight weeks old, following a single instillation of 200 micrograms of HLE. CY 222 treated animals received 2.5 mg.kg-1 subcutaneously once daily, 6 days per week during 4 weeks prior to HLE instillation, and for eight weeks following HLE instillation. The heparin fragment treatment of the mice halved the mortality rate observed early following HLE instillation. After 8 weeks, surviving animals were examined for lung histological and morphometrical changes: mean linear intercept (MLI) and internal alveolar area (ISA). The CY 222 heparin fragments exerted a protective effect against HLE-induced emphysema by decreasing by 70% the MLI; these heparin fragments exerted no effect on emphysema induced by pancreatic elastase in hamsters or mice. Heparin derivatives represent a new class of physiological HLE low molecular weight inhibitors capable of preventing HLE-induced emphysema.
Pulmonary sarcoidosis: patterns of cytokine release in vitro
Authors: C Prior, RA Knight, M Herold, G Ott, MA Spiteri
Journal: European Respiratory Journal (1996)

This study was designed to investigate the ability of bronchoalveolar and blood mononuclear cells to produce inflammatory mediators in vitro in pulmonary sarcoidosis. Seventeen patients with pulmonary sarcoidosis (stage I n = 8; stage II/III n = 9) and 10 normal controls were investigated. Bronchoalveolar and peripheral blood mononuclear cells were cultured in serum-free medium, without stimulant, for 24 h, and the supernatants analysed for concentrations of interleukin (IL)-1 beta (IL-1 beta), IL-2, IL-6, tumour necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma) and neopterin. Bronchoalveolar lavage cells (BALC) of sarcoid patients released significantly higher amounts of TNF-alpha, IL-6, IFN-gamma and neopterin in comparison to normal controls. When smokers were excluded, there was also an increased release of IL-1 beta and GM-CSF. In the sarcoid group, the levels of IL-1 beta, IL-6, TNF-alpha and GM-CSF showed highly significant correlations between each other, but not with IL-2, IFN-gamma or neopterin. Sarcoid patients whose BALC released more TNF-alpha or GM-CSF had higher percentage counts of alveolar macrophages but fewer lavage lymphocytes. In sarcoid patients, peripheral blood mononuclear cells (PBMNC) also released higher amounts of IL-1 beta, TNF-alpha, IL-6 and GM-CSF but less neopterin than normal controls. Patients whose PBMNC produced more IL-1 beta, IL-6 and GM-CSF had higher absolute and relative lavage neutrophil counts. No relationships were observed between cytokine release and radiographic or physiological markers of disease severity. We conclude from this study that sarcoid inflammation is associated with an increased and concerted release of monocyte/macrophage-derived cytokines not only in the lung but also in the peripheral blood. We speculate that the lymphokines, IFN-gamma and IL-2, are not the primary triggers.
Elevated D8/17 Expression on B Lymphocytes, a Marker of Rheumatic Fever, Measured With Flow Cytometry in Tic Disorder Patients
Authors: Pieter J. Hoekstra, Johan Bijzet, Pieter C. Limburg, Mark-Peter Steenhuis, Pieter W. Troost, Menno D. Oosterhoff, Jakob Korf, Cees G.M. Kallenberg, Ruud B. Minderaa
Journal: American Journal of Psychiatry (2001)

Elevated D8/17 expression on B lymphocytes is a known susceptibility marker of rheumatic fever. Previous studies have reported higher than usual D8/17 expression on B lymphocytes of patients with tic disorders. The purpose of this study was to assess D8/17 expression on B lymphocytes of tic disorder patients by using an objective method in which no operator variability was involved.D8/17 expression on B lymphocytes was assessed with flow cytometry by using an immunoglobulin M (IgM) monoclonal D8/17-specific antibody in an unselected group of Dutch patients with tic disorders (N=33) and healthy volunteers (N=20). Binding of this monoclonal antibody was compared with binding of an irrelevant IgM monoclonal antibody, and the shift in mean fluorescence intensity of the D8/17-specific antibody compared to that of the irrelevant IgM monoclonal antibody was used as a measure of D8/17 overexpression. For the patients, Yale Global Tic Severity Scale scores were used to assess disease severity.D8/17 overexpression in the patient group (mean=16.8 arbitrary units, SD=30.5) was significantly higher than in the comparison group (mean=3.2, SD=3.0). A significant minority of the patients (N=13, 39.4%), however, had levels of D8/17 overexpression within the range of that of the healthy comparison subjects. Flow cytometric analysis did not indicate a separate subpopulation of D8/17-positive B cells.These data confirm the utility of D8/17 B cell overexpression as a peripheral blood marker in patients with tic disorders and are compatible with a streptococcus-related pathogenesis for at least a subgroup of patients with tic disorders.
Effect of Conditioned Anxiety Upon the Behavior, Blood Lipid Level, and Atherosclerosis of Cholesterol-Fed Cockerels
Authors: CLAUDE R. JOYNER, DONALD H. BULLOCK, HOWARD M. RAWNSLEY, MANLY Y. BRUNT
Journal: Circulation Research (1961)

Cholesterol-fed cockerels were subjected five days of each week to repetitive unavoidable shocks preceded by warning signals. The birds rapidly developed the intended conditioned emotional reaction. Comparison of these chicks with nonstressed cholesterol-fed cockerels over several months gave no iadication that this type of stress influenced weight gain, blood lipid level, or the development of atherosclerosis.
Induction of Unresponsiveness Limits Tumor Protection by Adoptively Transferred MDM2-Specific Cytotoxic T Lymphocytes
Authors: Gavin M. Bendle, Angelika Holler, Luke-Kwok Pang, Stephen Hsu, Mauro Krampera, Elizabeth Simpson, Hans J. Stauss
Journal: Cancer Research (2004)

There is evidence showing that high avidity CTLs can be more effective than low avidity CTLs for adoptive tumor immunotherapy. Because many T cell-recognized tumor antigens are nonmutated self-proteins, tolerance mechanisms are likely to render high avidity T cells unresponsive or cause T cell elimination by clonal deletion. We recently used the allo-restricted strategy to circumvent immunologic tolerance to a ubiquitously expressed tumor-associated protein, MDM2, and raised high avidity CTLs in humans and in mice. In this study, we investigated whether high avidity MDM2-specific CTLs can mediate tumor protection without causing damage to normal tissues in mice. Although the CTLs prolonged survival of tumor-bearing mice without causing damage to normal tissues, tumor protection was incomplete. We show that tumor growth occurred despite the continued presence of MDM2-specific CTLs and the continued susceptibility of tumor cells to CTL killing. However, analysis of the CTLs revealed that they had been rendered unresponsive in vivo because they did not produce interferon gamma in response to antigen-specific stimulation. These experiments suggest that induction of unresponsiveness may be an important mechanism limiting the efficacy of adoptive CTL therapy.
Massive aortic incompetence associated with the Bjork-Shiley prosthesis
Authors: G. H. Smith, K. Chandra
Journal: Thorax (1973)

<b>Smith, G. H., and Chandra, K. (1973)</b>. <i>Thorax</i>, <b>28</b>, 627-630. <b>Massive aortic incompetence associated with the Björk-Shiley prosthesis</b>. Three patients are described. In each, a diseased aortic valve was replaced by a Björk-Shiley valve prosthesis. For different reasons, ventricular fibrillation occurred when the patient was still on cardiopulmonary bypass. In these circumstances, a massive leak occurred through the valve and caused overdistension of the left ventricle. Subsequent examination of the valves in the laboratory showed that, under the conditions described above, there was a leakage equal in volume to half the forward flow.
Novel Oncogene–Induced Metastatic Prostate Cancer Cell Lines Define Human Prostate Cancer Progression Signatures
Authors: Xiaoming Ju, Adam Ertel, Mathew C. Casimiro, Zuoren Yu, Hui Meng, Peter A. McCue, Rhonda Walters, Paolo Fortina, Michael P. Lisanti, Richard G. Pestell
Journal: Cancer Research (2012)

Abstract Herein, murine prostate cancer cell lines, generated via selective transduction with a single oncogene (c-Myc, Ha-Ras, and v-Src), showed oncogene-specific prostate cancer molecular signatures that were recapitulated in human prostate cancer and developed lung metastasis in immune-competent mice. Interrogation of two independent retrospective cohorts of patient samples using the oncogene signature showed an ability to distinguish tumor from normal prostate with a predictive value for prostate cancer of 98% to 99%. In a blinded study, the signature algorithm showed independent substratification of reduced recurrence-free survival by Kaplan–Meier analysis. The generation of new oncogene-specific prostate cancer cell lines that recapitulate human prostate cancer gene expression, which metastasize in immune-competent mice, are a valuable new resource for testing targeted therapy, whereas the molecular signatures identified herein provides further value over current gene signature markers of prediction and outcome. Cancer Res; 73(2); 978–89. ©2012 AACR.
Functional Inhibition of Ras by <b> <i>S</i> </b> - <b> <i>trans</i> </b> , <b> <i>trans</i> </b> -Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice
Authors: Jacob George, Arnon Afek, Pnina Keren, Itzhak Herz, Iris Goldberg, Roni Haklai, Yoel Kloog, Gad Keren
Journal: Circulation (2002)

Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis.We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E-deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-kappaB expression were considerably reduced compared with controls.FTS suppressed atherosclerotic plaques in apolipoprotein E-deficient mice, providing a useful tool for research in atherosclerosis.