tbuckley/cabot-search huggingface dataset:
89Zr-trastuzumab and 89Zr-bevacizumab PET to Evaluate the Effect of the HSP90 Inhibitor NVP-AUY922 in Metastatic Breast Cancer Patients
Authors: Sietske B.M. Gaykema, Carolien P. Schröder, Joanna Vitfell-Rasmussen, Sue Chua, Thijs H. Oude Munnink, Adrienne H. Brouwers, Alfons H.H. Bongaerts, Mikhail Akimov, Cristina Fernandez-Ibarra, Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Charles Swanton, Udai Banerji
Journal: Clinical Cancer Research (2014)

Abstract Purpose: HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim of this clinical trial was to evaluate the feasibility of using 89Zr-trastuzumab PET (for HER2-positive breast cancer) or 89Zr-bevacizumab PET [for estrogen receptor (ER)–positive breast cancer] to determine in vivo degradation of client proteins caused by the novel HSP90 inhibitor NVP-AUY922. Experimental Design: Of note, 70 mg/m2 NVP-AUY922 was administered intravenously in a weekly schedule to patients with advanced HER2 or ER-positive breast cancer. Biomarker analysis consisted of serial PET imaging with 2[18F]fluoro-2-deoxy-D-glucose (FDG), 89Zr-trastuzumab, or 89Zr-bevacizumab. Response evaluation was performed according to RECIST1.0. FDG, 89Zr-trastuzumab, and 89Zr-bevacizumab distributions were scored visually and quantitatively by calculating the maximum standardized uptake values (SUVmax). In blood samples, serial HSP70 levels, extracellular form of HER2 (HER2-ECD), and pharmacokinetic and pharmacodynamic parameters were measured. Results: Sixteen patients (ten HER2-positive and six ER-positive tumors) were included. One partial response was observed; seven patients showed stable disease. SUVmax change in individual tumor lesions on baseline versus 3 weeks 89Zr-trastuzumab PET was heterogeneous and related to size change on CT after 8 weeks treatment (r2 = 0.69; P = 0.006). Tumor response on 89Zr-bevacizumab PET and FDG-PET was not correlated with CT response. Conclusions: NVP-AUY922 showed proof-of-concept clinical response in HER2-amplified metastatic breast cancer. Early change on 89Zr-trastuzumab PET was positively associated with change in size of individual lesions assessed by CT. Clin Cancer Res; 20(15); 3945–54. ©2014 AACR.
Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus
Authors: Uwe Raaz, Isabel N. Schellinger, Ekaterina Chernogubova, Christina Warnecke, Yosuke Kayama, Kiril Penov, Jan K. Hennigs, Florian Salomons, Suzanne Eken, Fabian C. Emrich, Wei H. Zheng, Matti Adam, Ann Jagger, Futoshi Nakagami, Ryuji Toh, Kensuke Toyama, Alicia Deng, Michael Buerke, Lars Maegdefessel, Gerd Hasenfuß, Joshua M. Spin, Philip S. Tsao
Journal: Circulation Research (2015)

Accelerated arterial stiffening is a major complication of diabetes mellitus with no specific therapy available to date.The present study investigates the role of the osteogenic transcription factor runt-related transcription factor 2 (Runx2) as a potential mediator and therapeutic target of aortic fibrosis and aortic stiffening in diabetes mellitus.Using a murine model of type 2 diabetes mellitus (db/db mice), we identify progressive structural aortic stiffening that precedes the onset of arterial hypertension. At the same time, Runx2 is aberrantly upregulated in the medial layer of db/db aortae, as well as in thoracic aortic samples from patients with type 2 diabetes mellitus. Vascular smooth muscle cell-specific overexpression of Runx2 in transgenic mice increases expression of its target genes, Col1a1 and Col1a2, leading to medial fibrosis and aortic stiffening. Interestingly, increased Runx2 expression per se is not sufficient to induce aortic calcification. Using in vivo and in vitro approaches, we further demonstrate that expression of Runx2 in diabetes mellitus is regulated via a redox-sensitive pathway that involves a direct interaction of NF-κB with the Runx2 promoter.In conclusion, this study highlights Runx2 as a previously unrecognized inducer of vascular fibrosis in the setting of diabetes mellitus, promoting arterial stiffness irrespective of calcification.
Botulinum Toxin A (Botox®) Intradetrusor Injections in Adults with Neurogenic Detrusor Overactivity/Neurogenic Overactive Bladder: A Systematic Literature Review
Authors: Gilles Karsenty, Pierre Denys, Gérard Amarenco, Marianne De Seze, Xavier Gamé, François Haab, Jacques Kerdraon, Brigitte Perrouin-Verbe, Alain Ruffion, Christian Saussine, Jean-Marc Soler, Brigitte Schurch, Emmanuel Chartier-Kastler
Journal: European Urology (2007)
Risk of New Vertebral Fracture in the Year Following a Fracture
Authors: Robert Lindsay
Journal: JAMA (2001)

ContextVertebral fractures significantly increase lifetime risk of future fractures, but risk of further vertebral fractures in the period immediately following a vertebral fracture has not been evaluated.ObjectiveTo determine the incidence of further vertebral fracture in the year following a vertebral fracture.Design and SettingAnalysis of data from 4 large 3-year osteoporosis treatment trials conducted at 373 study centers in North America, Europe, Australia, and New Zealand from November 1993 to April 1998.SubjectsPostmenopausal women who had been randomized to a placebo group and for whom vertebral fracture status was known at entry (n = 2725).Main Outcome MeasureOccurrence of radiographically identified vertebral fracture during the year following an incident vertebral fracture.ResultsSubjects were a mean age of 74 years and had a mean of 28 years since menopause. The cumulative incidence of new vertebral fractures in the first year was 6.6%. Presence of 1 or more vertebral fractures at baseline increased risk of sustaining a vertebral fracture by 5-fold during the initial year of the study compared with the incidence in subjects without prevalent vertebral fractures at baseline (relative risk [RR], 5.1; 95% confidence interval [CI], 3.1-8.4; P&lt;.001). Among the 381 participants who developed an incident vertebral fracture, the incidence of a new vertebral fracture in the subsequent year was 19.2% (95% CI, 13.6%-24.8%). This risk was also increased in the presence of prevalent vertebral fractures (RR, 9.3; 95% CI, 1.2-71.6; P = .03).ConclusionOur data indicate that women who develop a vertebral fracture are at substantial risk for additional fracture within the next year.
Phenotype and Genotype of Advanced Premalignant Head and Neck Lesions After Chemopreventive Therapy
Authors: L. Mao, V. Papadimitrakopoulou, D. M. Shin, Y. Fan, X. Zhou, J. S. Lee, W. K. Hong, A. K. El-Naggar, H. C. Shin, G. Clayman, J. J. Lee, W. N. Hittelman, S. M. Lippman
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: The goal of chemoprevention is to reduce the risk of cancer development by reversing or blocking the tumorigenic process through the use of pharmacologic or natural agents. To determine the potential role of genetic alterations in assessing cancer risk and in evaluating the efficacy of chemopreventive agents, we studied 22 patients with advanced premalignant lesions of the head and neck who were part of a prospective cancer prevention trial that is investigating a regimen of 13-cis-retinoic acid, interferon alfa, and et-tocopherol administered for 12 months or until disease progression. Methods: We used polymerase chain reaction analysis of microsatellite DNA sequences in cells from precancerous lesions to determine the frequencies of genetic alterations—namely, loss of heterozygosity (LOH) and microsatellite instability—at chromosomal loci that are commonly deleted in head and neck cancer. Results : Prior to treatment, 17 (81%) of 21, eight (44%) of 18, and eight (42%) of 19 patients who were informative (i.e., heterozygous) at chromosomes 9p21, 3p14, and 17p13, respectively, exhibited LOH in at least one of their lesion biopsy specimens. Among nine patients who exhibited LOH at chromosome 9p21 in pretreatment biopsy specimens and who had completed at least 5 months of therapy, the genetic loss persisted in eight—including three of the four patients who exhibited complete histologic responses (i.e., no evidence of dysplasia in their biopsy specimens). Implication: Our data suggest that clinical and histologic assessments of the response to chemopreventive agents may be insufficient to determine their efficacy and that critical genetic alterations could be used as independent biomarkers to augment the ability to evaluate the efficacy of such agents. [J Nall Cancer Inst 1998;90:1545-51]
Cervical vertebral dislocation in a rugby player with congenital vertebral fusion.
Authors: A T Scher
Journal: British Journal of Sports Medicine (1990)

Congenital cervical vertebral fusion is an anomaly which decreases the normal range of spinal movement and predisposes to trauma. The case history of a rugby player with a congenital fusion who sustained permanent quadriplegia after dislocation of the lower cervical spine is presented. The mechanism of injury is discussed. A plea is made for routine radiographic examination of the cervical spines of all rugby players in order to detect the presence of vertebral fusion and other conditions which may predispose to spinal trauma.
Pulmonary Hypertension and Computed Tomography Measurement of Small Pulmonary Vessels in Severe Emphysema
Authors: Shin Matsuoka, George R. Washko, Tsuneo Yamashiro, Raul San Jose Estepar, Alejandro Diaz, Edwin K. Silverman, Eric Hoffman, Henry E. Fessler, Gerard J. Criner, Nathaniel Marchetti, Steven M. Scharf, Fernando J. Martinez, John J. Reilly, Hiroto Hatabu
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Vascular alteration of small pulmonary vessels is one of the characteristic features of pulmonary hypertension in chronic obstructive pulmonary disease. The in vivo relationship between pulmonary hypertension and morphological alteration of the small pulmonary vessels has not been assessed in patients with severe emphysema.We evaluated the correlation of total cross-sectional area of small pulmonary vessels (CSA) assessed on computed tomography (CT) scans with the degree of pulmonary hypertension estimated by right heart catheterization.In 79 patients with severe emphysema enrolled in the National Emphysema Treatment Trial (NETT), we measured CSA less than 5 mm(2) (CSA(<5)) and 5 to 10 mm(2) (CSA(5-10)), and calculated the percentage of total CSA for the lung area (%CSA(<5) and %CSA(5-10), respectively). The correlations of %CSA(<5) and %CSA(5-10) with pulmonary arterial mean pressure (Ppa) obtained by right heart catheterization were evaluated. Multiple linear regression analysis using Ppa as the dependent outcome was also performed.The %CSA(<5) had a significant negative correlation with Ppa (r = -0.512, P < 0.0001), whereas the correlation between %CSA(5-10) and Ppa did not reach statistical significance (r = -0.196, P = 0.083). Multiple linear regression analysis showed that %CSA(<5) and diffusing capacity of carbon monoxide (DL(CO)) % predicted were independent predictors of Ppa (r(2) = 0.541): %CSA (<5) (P < 0.0001), and DL(CO) % predicted (P = 0.022).The %CSA(<5) measured on CT images is significantly correlated to Ppa in severe emphysema and can estimate the degree of pulmonary hypertension.
Feasibility of measuring lung function in preschool children
Authors: W Nystad
Journal: Thorax (2002)

<b>Background:</b> There have been difficulties in applying spirometric tests to children of preschool age. <b>Methods:</b> The feasibility of measuring lung function was examined in 652 children aged 3–6 years using dynamic spirometry with an animation programme and the guidelines approved by the European Respiratory Society. <b>Results:</b> Data from 603 (92%) children with at least two acceptable forced expiratory manoeuvres were analysed; 408 (68%) achieved at least three acceptable manoeuvres. Children with only two acceptable manoeuvres were younger, shorter, and weighed less (p&lt;0.001). The lower levels of lung function in this group were partly explained by body size. 63% of those with three acceptable manoeuvres had a difference of ≤5% between the highest and second highest forced expiratory volume in 1 second (FEV<sub>1</sub>); when a difference of ≤10% was applied, 91% of the children were included. A similar trend was seen for forced vital capacity (FVC). The acceptability and reproducibility increased with increasing age, and levels of lung function increased linearly with age. The linear regression model showed that standing height was a satisfactory predictor of lung function; the explained fraction of variance (<i>R</i><sup>2</sup>) was 59% for FEV<sub>1</sub>. Most FVC manoeuvres in children older than 3 years were acceptable and reproducible. <b>Conclusions:</b> Spirometric testing is feasible in preschool children and may be useful for both clinical practice and research. This study may fill the deficiency in reference values for European preschool children.
Using standardised patients to measure physicians' practice: validation study using audio recordings
Authors: J. Luck
Journal: BMJ (2002)

To assess the validity of standardised patients to measure the quality of physicians' practice.Validation study of standardised patients' assessments. Physicians saw unannounced standardised patients presenting with common outpatient conditions. The standardised patients covertly tape recorded their visit and completed a checklist of quality criteria immediately afterwards. Their assessments were compared against independent assessments of the recordings by a trained medical records abstractor.Four general internal medicine primary care clinics in California.144 randomly selected consenting physicians.Rates of agreement between the patients' assessments and independent assessment.40 visits, one per standardised patient, were recorded. The overall rate of agreement between the standardised patients' checklists and the independent assessment of the audio transcripts was 91% (kappa=0.81). Disaggregating the data by medical condition, site, level of physicians' training, and domain (stage of the consultation) gave similar rates of agreement. Sensitivity of the standardised patients' assessments was 95%, and specificity was 85%. The area under the receiver operator characteristic curve was 90%.Standardised patients' assessments seem to be a valid measure of the quality of physicians' care for a variety of common medical conditions in actual outpatient settings. Properly trained standardised patients compare well with independent assessment of recordings of the consultations and may justify their use as a "gold standard" in comparing the quality of care across sites or evaluating data obtained from other sources, such as medical records and clinical vignettes.
Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy
Authors: Peter E. Huber, Marc Bischof, Jürgen Jenne, Sabine Heiland, Peter Peschke, Rainer Saffrich, Hermann-Josef Gröne, Jürgen Debus, Kenneth E. Lipson, Amir Abdollahi
Journal: Cancer Research (2005)

Abstract It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 ± 2.6 to 4.2 ± 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.
Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release.
Authors: K Inaba, R M Steinman
Journal: The Journal of Experimental Medicine (1984)

Previous studies have shown that unprimed or resting T lymphocytes will grow and release lymphokines when stimulated by dendritic cells (DC). We now have examined the stimulatory requirements for antigen-primed or blast-transformed T cells. The latter were derived from dendritic/T cell clusters that developed during the primary mixed leukocyte reaction (MLR). The specificity of the blasts was established by a binding assay in which most T cells aggregated small B lymphocytes of the appropriate haplotype within 2 h at 4 or 37 degrees C. Since unprimed T cells did not aggregate allogeneic B cells, we suggest that DC induce T lymphocytes to express additional functioning receptors for antigen. Lyt-2-T blasts did not grow or release interleukin 2 or B cell helper factors unless rechallenged with specific alloantigen, whereupon growth (generation time of 14-18 h) and lymphokine release rapidly resumed. The blasts could be stimulated by allogeneic macrophages, B cells, and B lymphoblasts, whereas the primary MLR was initiated primarily by DC. responsiveness appeared restricted to the I region of the major histocompatibility complex, and varied directly with the level of Ia antigens on the stimulator cells. The interaction of B cells and T blasts was bidirectional. The T blasts would grow and form B cell helper factors, while the B cells grew and secreted antibody. However, the efficacy of T cell-mediated antibody formation was enhanced some 10-fold by the addition of specific antigen. Therefore, responses of resting helper T cells, then, are initiated by antigen plus DC. Once sensitized, T blasts interact independently with antigen presented by other leukocytes.
First evidence of Anaplasma infection in Crete, Greece. Report of six human cases
Authors: D. Chochlakis, A. Psaroulaki, S. Kokkini, S. Kostanatis, E. Arkalati, E. Karagrannaki, K. Tsiatis, Y. Tselentis, A. Gikas
Journal: Clinical Microbiology and Infection (2008)
Proteomic Identification of Allergen-protein Interactions at the Human Skin Immune Barrier - a Prerequisite for Adaptive T cell Responses in Allergic Contact Dermatitis
Authors: H.J. Thierse, L. Dietz, S. Ohnesorge, B. Franke, I. Goette, M. Schnoelzer
Journal: Journal of Allergy and Clinical Immunology (2010)
Plasminogen-stimulated inflammatory cytokine production by airway smooth muscle cells is regulated by annexin A2
Authors: Michael Schuliga, Shenna Langnenbach, Yuxiu Xia, Trudi Harris, Alastair Stewart
Journal: European Respiratory Journal (2013)

Plasminogen has a potential role in airway inflammation and disease. Airway smooth muscle (ASM) cells cleave plasminogen into plasmin (Schuliga  et al  2011, Am J Respir Cell Mol Biol  44 ), a protease with pro-inflammatory activity. In this study, the effect of plasminogen on cytokine production by human ASM cells was investigated  in vitro . Levels of IL-6 and IL-8 in the medium of ASM cells were increased by incubation with plasminogen (5-50μg/mL) for 24h (P MAPK  or PI3K/Akt signalling by PD98059 (10μM), SB203580 (10μM) or LY294002 (10μM) respectively, modulated plasmin-stimulated cytokine production (P 005, n=5-14). In conclusion, plasmin(ogen) stimulates ASM cytokine production in a manner regulated by annexin A2. Modulation of plasmin-evoked signalling could provide a novel therapeutic approach to the treatment of chronic airway inflammation in diseases such as asthma.
Understanding and sharing intentions: The origins of cultural cognition
Authors: Michael Tomasello, Malinda Carpenter, Josep Call, Tanya Behne, Henrike Moll
Journal: Behavioral and Brain Sciences (2005)

We propose that the crucial difference between human cognition and that of other species is the ability to participate with others in collaborative activities with shared goals and intentions: shared intentionality. Participation in such activities requires not only especially powerful forms of intention reading and cultural learning, but also a unique motivation to share psychological states with others and unique forms of cognitive representation for doing so. The result of participating in these activities is species-unique forms of cultural cognition and evolution, enabling everything from the creation and use of linguistic symbols to the construction of social norms and individual beliefs to the establishment of social institutions. In support of this proposal we argue and present evidence that great apes (and some children with autism) understand the basics of intentional action, but they still do not participate in activities involving joint intentions and attention (shared intentionality). Human children's skills of shared intentionality develop gradually during the first 14 months of life as two ontogenetic pathways intertwine: (1) the general ape line of understanding others as animate, goal-directed, and intentional agents; and (2) a species-unique motivation to share emotions, experience, and activities with other persons. The developmental outcome is children's ability to construct dialogic cognitive representations, which enable them to participate in earnest in the collectivity that is human cognition.