tbuckley/cabot-search huggingface dataset:
Adverse Effects of Phenobarbital on Corticosteroid Metabolism in Patients with Bronchial Asthma
Authors: Stuart M. Brooks, Emile E. Werk, S. Jeffrey Ackerman, Irene Sullivan, Katherine Thrasher
Journal: New England Journal of Medicine (1972)

The effects of phenobarbital therapy on plasma kinetics of labeled dexamethasone were investigated in 11 asthmatic patients. Phenobarbital caused a mean decrease in half-life of 117 minutes (-44 per cent) and an increase in metabolic clearance rate of 272 liters per day (+88 per cent). Urinary radioactivity excretion rate rose, the greatest increase occurring in the unconjugated ethyl acetate fraction. Increased urinary 6-hydroxycortisol excretion supported the presence of hepatic enzyme induction. These effects were not noted in five placebo-treated patients. Three prednisone-dependent patients showed clinical worsening, deterioration of spirometric tests and increased eosinophil counts following phenobarbital. Phenobarbital withdrawal reversed these changes; reduction of prednisone dosage or discontinuation was then possible. Nonsteroid-dependent patients did not show similar changes after phenobarbital therapy. Dexamethasone and prednisone seem to be metabolized more rapidly during phenobarbital administration, resulting in lower blood levels and less physiologic activity. Thus, caution is necessary in prescribing barbiturates to asthmatic patients treated with these steroids.
Destruction endoscopique par radiofréquence des ectasies vasculaires antrales: résultats d'une étude rétrospective, multicentrique, internationale
Authors: X Dray, P Gonzalez Carro, C Fristrup, S Kantsevoy, D Wengrower, P Elbe, S Lecleire, F Perez Roldan, A Tomer, A Dlugosz, P Marteau
Journal: Endoscopy (2013)

Les ectasies vasculaires antrales (EVA) sont des lésions rares responsables de saignements digestifs chroniques, avec dépendance aux transfusions chez 2/3 des patients atteints. La destruction par coagulation plasma argon (CPA), traitement endoscopique de référence, est parfois en échec. Notre objectif était d'évaluer la faisabilité, l'efficacité et la tolérance de la destruction par radiofréquence (RF) des lésions d'EVA.
Abstract 1244: Differential requirements for the receptor tyrosine kinase c-Met in scirrhous gastric carcinoma cell lines
Authors: Nachi Yoshida, Hideki Yamaguchi, Emi Muroi, Miho Takanashi, Kiyoko Fukami, Ryuichi Sakai
Journal: Cancer Research (2012)

Abstract The prognosis of patients with scirrhous gastric carcinoma (SGC) has been very poor. SGC cells do not form obvious tumor mass, but cause diffuse infiltration and eventually rigid thickening of the gastric wall. Furthermore, SGC cells frequently infiltrate through gastric serosa and cause peritoneal dissemination. However, the mechanisms underlying the progression of SGC have not yet been fully elucidated. In the present study, we performed immunoblotting and proteomic analyses of tyrosine-phosphorylated proteins in differentiated non-SGC cell lines (MKN7, MKN1, and MKN74) and poorly differentiated or SGC cell lines (MKN45, NUGC-4, KATO III, HSC59, 58As9, HSC44-PE, and 44As3) to identify signaling pathways and molecules that are characteristics of SGC. We found that the tyrosine kinase receptor c-Met is overexpressed and highly phosphorylated in SGC cell lines. c-Met is a cell surface receptor for HGF and implicated in the growth, survival, invasion, and metastasis of various human cancers. Amplification of c-Met gene in SGC was also previously reported. We analyzed the downstream signaling pathways of c-Met in SGC cells by using two c-Met inhibitors PHA-665752 and JNJ-38877605. Treatment of 58As9 cells with the c-Met inhibitors markedly inhibited phosphorylation of Erk, Akt, and Stat3, but promoted phosphorylation of Src. In contrast, 44As3 cells treated with the c-Met inhibitors showed no significant changes in phosphorylation of these molecules, in spite of successful inhibition of c-Met phosphorylation. Reflecting these observations, c-Met inhibitors blocked cell proliferation and caused morphological alterations in 58As9 cells but not in 44As3 cells. Similar results were obtained when MKN45 and NUGC-4 cells were analyzed in the same manner: MKN45 cells but not NUGC-4 cells were sensitive to c-Met inhibition. These results suggest that SGC can be classified into two subtypes according to their dependencies on the c-Met signaling pathway. Further studies are now conducted to identify therapeutic targets in c-Met-independent SGC cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1244. doi:1538-7445.AM2012-1244
Abstract 3467: A novel interplay between Rap1, Epac and PKA regulates induction of angiogenesis
Authors: Jyotsana Menon, Robert C. Doebele, Marsha R. Rosner
Journal: Cancer Research (2011)

Abstract Advanced stage prostate cancer is associated with poor prognosis since therapeutic options are limited when the disease has progressed into a hormone refractory state. One therapeutic strategy is angiogenesis inhibition, which interferes with the blood supply of the tumor instead of targeting tumor cells directly. Here we focus on the role of three factors as regulators of angiogenesis: Rap1, a small GTPase homologous to Ras; Epac, a cAMP-activated guanine nucleotide factor for Rap1; and Protein kinase A (PKA), a cAMP-activated kinase. In previous studies, we showed that activation of Epac/Rap1 in human microvascular endothelial cells (HMVECs) inhibited VEGF-mediated chemotaxis and angiogenesis in a SCID mouse model of human angiogenesis. To test the efficacy of Epac/Rap1 activation in a prostate tumor xenograft model, we analyzed the effects of constitutive Rap1 or 8 CPT-2Me-cAMP (8CPT), a strong Epac agonist and weak PKA agonist, in PC-3 cells. PC3 cells rank high in expression levels of Rap1. Surprisingly, although 8CPT did not alter tumor growth in PC-3 cells, the drug significantly reduced tumor size in PC-3 cells expressing constitutively active Rap1. Tumor analysis showed an increase in VEGF and CD31 immunostaining in Rap1-expressing tumors, and a significant decrease in their levels upon treatment of the mice with 8CPT. To understand the mechanism of tumor inhibition, we cultured PC-3 cells under hypoxic conditions that mimic the tumor microenvironment. As observed in vivo, constitutive Rap-1 expression induced VEGF and Glut-1 mRNA levels as well as HIF-1α protein, and 8CPT reversed this effect. However, in contrast to HMVECs, 8CPT acts in PC-3 cells via PKA. A PKA activator mimicked 8CPT by inhibiting VEGF secretion in PC3-Rap1 cells under hypoxic conditions. Furthermore, the PKA inhibitor, H-89, reversed the inhibition of VEGF secretion in PC3-Rap1 cells in culture and inhibited growth in mouse xenografts. Thus, expression of Rap1 in PC-3 human prostate tumor cells promotes hypoxic induction of angiogenesis and increases the susceptibility of the cells to PKA inhibition. Taken together, our results suggest that a novel interplay between Rap1, Epac and PKA regulates tumor-microenvironment induction of angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3467. doi:10.1158/1538-7445.AM2011-3467
LOW BODY MASS INDEX &lt;20 ALONE IS NOT A PREDICTOR OF ADVERSE EVENTS IN PATIENTS UNDERGOING TRANSCATHETER AORTIC VALVE IMPLANTATION
Authors: Masanori Yamamoto, Kentaro Hayashida, Jean-Luc Dubois Rande, Thierry Lefevre, Marie Morice, Emmanuel Teiger
Journal: Journal of the American College of Cardiology (2015)
Abstract LB-49: The endoplasmic reticulum chaperone protein GRP94 is required for maintaining hematopoietic stem cell interactions with the adult bone marrow niche
Authors: Biquan Luo, Ben S. Lam, Sung Hyung Lee, Shiuan Wey, Hui Zhou, Miao Wang, Si-Yi Chen, Gregor B. Adams, Amy S. Lee
Journal: Cancer Research (2011)

Abstract Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and selectively regulates early T and B lymphopoiesis. Interestingly, multipotent hematopoietic progenitors persisted and even increased in GRP94 deficient bone marrow chimeras, however, the mechanism is not well understood. Here we employed a conditional knockout strategy to acutely eliminate GRP94 in the hematopoietic system. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 knockout (KO) HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared with WT control, suggesting a cell autonomous effect. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-49. doi:10.1158/1538-7445.AM2011-LB-49
EVEROLIMUS–ELUTING VERSUS BARE METAL STENTS IN OCTOGENARIANS: RESULTS FROM THE RANDOMIZED XIMA (XIENCE OR VISION STENT – MANAGEMENT OF ANGINA IN THE ELDERLY) TRIAL
Authors: Jose M. de la Torre Hernandez, Adam De Belder, Ramon Lopez Palop, David Hildick–Smith, Felipe Hernandez, Peter O'Kane, Federico Gimeno, Martin Thomas, Jose F. Diaz, Nick Curzen, Pliar Carrillo, Julian Strange, Eduardo Pinar, James Cotton, Jose A. Baz, Dawn Adamson, Iñigo Lozano, Daniel Blackman, Carlos Cuellas, Nicola Skipper, Nina Cooter, Jose A. Diarte, David Smith, Josepa Mauri
Journal: Journal of the American College of Cardiology (2013)
Abstract 524: Stromal fibroblasts diminish the growth-inhibitory effect of the epidermal growth factor receptor antagonist cetuximab in head and neck squamous cell carcinoma cell cultures
Authors: Ann-Charlotte Johansson, Anna Ansell, Arne Östman, Karin Roberg
Journal: Cancer Research (2011)

Abstract There is a growing body of evidence that components of the tumor microenvironment, including stromal fibroblasts, may modulate the treatment sensitivity of tumor cells. Thus, we aimed to investigate the possible influence of stromal fibroblasts on the cetuximab sensitivity of head and neck squamous cell carcinoma (HNSCC) cells. Stromal fibroblasts isolated from 7 HNSCC patients were co-cultured with HNSCC cells in a transwell system. Mono- and co-cultures were exposed to the epidermal growth factor receptor (EGFR) antagonist cetuximab (30 nM) and cell proliferation was determined by crystal violet staining. The level of EGFR, Akt, Erk (p42/p44 MAPK), and Met activation was assessed by western blot analysis. Cetuximab elicited an anti-proliferative response in tumor cell monocultures while the growth rate of stromal fibroblasts remained unchanged. When tumor cells were co-cultured with fibroblasts or grown in media conditioned from fibroblast cultures the anti-proliferative effect of cetuximab was diminished. Furthermore, stromal fibroblasts desensitized tumor cells to treatment with gefitinib, an EGFR tyrosine kinase inhibitor, excluding the possibility that fibroblast-derived factors confer resistance by interfering with the EGFR-cetuximab interaction. Results from experiments using size-fractionated conditioned media suggest that at least two soluble factors, 50-100 kDa and greater than 100 kDa in size, confer treatment resistance. In cetuximab-treated cultures, phosphorylation of EGFR and Erk was reduced, while the level of Akt phosphorylation remained unchanged. The cetuximab resistance observed in co-cultures could not be explained by changes in either EGFR or Erk phosphorylation. However, there was a higher level of activation of the hepatocyte growth factor (HGF) receptor Met in co-cultures, and when recombinant HGF was added to tumor cell monocultures the response to cetuximab was reduced. These results identify a previously unrecognized fibroblast-dependent modulation of cetuximab sensitivity, and also suggest fibroblast-derived HGF as one of the mediators of this paracrine cross-talk. The results also suggest targeting of fibroblast-derived factors, possibly including HGF, as a novel strategy to improve the therapeutic effects of cetuximab. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 524. doi:10.1158/1538-7445.AM2011-524
EUS in the preoperative staging and restaging of advanced rectal cancer
Authors: P Marone, M de Bellis, GB Rossi, P Delrio, A Avallone, A Tempesta
Journal: Endoscopy (2006)

Background: Endoscopic ultrasonography (EUS) is highly accurate for locoregional staging of rectal cancer (RC). Purpose: The aim of the study was to evaluate both accuracy and clinical impact of EUS in the staging and restaging [after neoadjuvant chemotherapy+radiotherapy (NAT)] of patients (pts) with RC at our Institution. Material And Methods: From 1994 to 2005, 189 pts with RC underwent EUS for locoregional staging at our Institution. There were 108 men, and 81 women, with a mean age of 60 years (40–80). The EUS was performed using an echo-colonoscope Olympus â CF UM 20. After EUS staging, the pts were divided in 2 groups. Group 1 included 118 pts who underwent surgery directly. In group 2 there were 71 pts who underwent NAT before surgery. In group 2, EUS was performed before and after NAT. In all cases, T and N stages at EUS were compared with the correspondent pTN stages. Results: In group 1 EUS showed an overall accuracy of 82% for T stage. When T stages were analyzed separately, EUS showed an accuracy of 74% for T1, 74% for T2, 91% for T3 and 66% for T4, respectively. Fourteen (12%) RC were overstaged (OS), while 7 (6%) RC were understaged (US). Moreover, EUS showed an overall accuracy of 70% for N stage, with a sensitivity of 73% and a specificity of 68%. In group 2, EUS restaging (EUS-R) after NAT had an overall accuracy for T of 63% (24% OS; 8% US, 4% not evaluable). Overall accuracy of EUS-R for N stage was 60% (7.0% OS; 3% US; 29% not evaluable), with a sensitivity of 63% and a specificity of 60%. Conclusions: Our data shows that EUS is useful in order to select those pts who undergo directly surgery and those who need NAT before surgery. In the latter subset, EUS-R changed the therapeutic strategy in 11 pts (15%), who underwent anterior resection instead of a Miles operation. After NAT, R-EUS restaging was less satisfactory
Abstract 221: <i>TP53</i> mutations in serous tubal intraepithelial carcinoma, the putative precursor lesion of ovarian high-grade serous carcinoma
Authors: Elisabetta Kuhn, Robert J. Kurman, Robert A. Soslow, Guangming Han, Tian-Li Wang, Ie-Ming Shih
Journal: Cancer Research (2011)

Abstract Somatic mutation of TP53 is the most common molecular genetic alteration in high grade serous carcinoma (HGSC) of the ovary, occurring in more than 95% of cases. As serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of HGSC, we undertook a study to determine whether STICs harbor TP53 mutations as well. Mutations of TP53 have been reported in STICs and associated HGSC but that study was limited to 5 cases. We therefore performed TP53 mutational analysis in a larger series of STICs and concurrent HGSCs and correlated the mutational status with p53 immunoreactivity. Formalin-fixed paraffin-embedded tissue specimens were obtained from 18 HGSCs with concurrent STICs; 8 of them contained two discrete STICs. Approximately 1,000 cells from STIC and normal-appearing fallopian tubal epithelium were laser-capture microdissected, while HGSCs were manually microdissected. Genomic DNA was extracted, PCR amplified and sequenced. TP53 mutations were analyzed from exons 4 to 8. Immunohistochemistry (IHC) for p53 was performed in all the cases. TP53 mutations were detected in 15 (83.3%) of 18 HGSCs. Importantly, TP53 mutations were not detected in the corresponding FTE samples from the same patients, confirming they are somatic mutations in HGSCs. STIC and associated HGSC shared identical TP53 mutations in 15 (93.8%) of 16 patients including 7 who had two STICs. The discordant case showed TP53 mutation in the HGSC but not in two separate concurrent STICs. By IHC, all the cases demonstrated the same pattern of p53 immunoreactivity (either all positive or completely negative) except the case with wild-type TP53 in the STIC and mutant TP53 in the HGSC. By IHC the STIC was p53 negative and the HGSC p53 positive. The three TP53 wild-type HGSCs and their associated STICs exhibited undetectable nuclear p53 by IHC. In contrast, four p53-negative HGSCs contained mutant TP53 with either a deletion or an insertion mutation. Our findings provide cogent evidence that TP53 mutations occur in most STICs, and that both STIC and concurrent HGSC share the identical TP53 mutations in the majority of cases. Future molecular genetic studies are necessary to delineate the clonal relationship and tumor progression from STIC to HGSC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 221. doi:10.1158/1538-7445.AM2011-221
A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy
Authors: C. R. Garrett, L. L. Siu, G. Giaccone, A. El-Khoueiry, J. Marshall, P. LoRusso, L. Velasquez, G. Kollia, P. He, D. Feltquate
Journal: Journal of Clinical Oncology (2007)

14018 Background: Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Prior studies have validated both VEGF and EGF signaling pathways as targets in AGM. The MTD of single-agent brivanib is 800 mg qd (ASCO #3051, 2006). Methods: An open-label Phase I dose-escalation study of brivanib in combination with cetuximab was conducted in pts with AGM who failed prior therapy. Brivanib was given po Day 1 and qd from Day 8, starting at 320 mg. Cetuximab was given IV Day 8 (400 mg/m 2 ) then weekly (250 mg/m 2 ). Dose escalation of brivanib continued to 800 mg qd, when an expansion cohort for pts with colorectal cancer (CRC) was opened for additional safety and efficacy. Fresh tissue and blood sampling for biomarker and pharmacokinetic (PK) analysis was performed. FDG-PET was obtained at Baseline X 2, Days 15 and 56. Tumor response (modified WHO) was evaluated q 8 weeks. Results: 18 pts (15 CRC, 2 esophageal, 1 other) were treated with 320, 600 or 800 mg qd of brivanib in combination with cetuximab for a median of 8 weeks (range 1 - 20+). A single DLT, bilateral pulmonary emboli, occurred at 320 mg qd. Few treatment-related AEs occurred across the 3 cohorts (Table). PK/biomarker data is pending. Available FDG-PET results from measurements in 8 pts with 2–3 target lesions showed good baseline reproducibility in SUVpeak, SUVmean and SUVmax, with intra-subject CV of 3.6%, 7.2% and 9.3%, respectively. Conclusions: Brivanib in combination with full-dose cetuximab was well tolerated at ≤800 mg qd and did not result in enhancement of cetuximab associated AEs. Pre-treatment FDG-PET is a highly reproducible imaging modality. [Table: see text] [Table: see text]
P1-07-17: Multiplex Plasma Biomarkers Associated with Bone Metastasis from Breast Cancer.
Authors: K Leitzel, S Ali, A Bisen, A Lomakin, V Simonyan, A Lipton
Journal: Cancer Research (2011)

Abstract Background: Over two-thirds of breast cancer patients who relapse will develop bone metastasis, and there are currently no effective biomarkers to predict for this event. Multiplex immunoassay technology for 60 bone metastasis-associated biomarkers was conducted on pretreatment plasma from 40 patients enrolled in a 2nd-line phase III hormone therapy trial of metastatic breast cancer, to discover effective circulating biomarkers predictive of bone metastasis. Methods: Pretreatment EDTA plasma from 20 patients with bone metastasis, and 20 patients with non-bone metastasis from the letrozole-megace 2nd-line phase III hormone therapy trial of metastatic breast cancer was evaluated using Searchlight multiplex immunoassay technology (Aushon Biosciences, Billerica, MA) on 60 biomarkers custom-selected for known association with bone metastasis. Multiplex data analysis for maximal discrimination of bone metastasis vs. no bone metastasis cohorts was performed by two independent statisticians: one evaluated the predictive capacity of individual biomarkers as well as two-marker combinations constructed by Monte Carlo optimization using Metropolis algorithm (MMC), and the other used a machine learning technique called hybrid bootstrapped RLDA +PCA (regularized linear discriminant analysis with principal component analysis, with dimensionality reduction used in the bootstrapping procedure). Results: One of the 60 analytes (IL-17) was undetectable at the 1.6 pg/ml lower limit of detection, and was not included in the multiplex statistical analyses. Of the remaining 59 analytes, MMC multiplex analysis yielded 9 biomarkers that predicted for bone metastasis, whereas RLDA + PCA multiplex analysis yielded 20 predictive biomarkers. Common to both analyses, which were limited in this small 40 patient study, were 5 biomarkers, with varying functions including growth factors, cytokines, inflammatory factors, protease inhibitors, and cell adhesion molecules. Conclusions: Multiplex analysis of 60 biomarkers custom-selected for known association with breast cancer metastasis to bone yielded 5 pretreatment plasma biomarkers classified as predictive of bone metastasis by 2 different multiplex statistical analysis methods. Evaluation of these biomarkers is now warranted in a larger validation cohort of breast cancer patients with and without bone metastasis. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-17.
ENTEROSCOPIA DE DOBLE BALON URGENTE COMBINADA CON CAPSULA ENDOSCOPICA VISUALIZADA EN TIEMPO REAL. ¿UNA OPCION FACTIBLE EN LA HEMORRAGIA DE ORIGEN OSCURO MANIFIESTA?
Authors: E Perez-Cuadrado, P Bebia, LE Zamora, B Martinez, P Esteban, JL Rodrigo, A López, E Torrella, S Chacón, J Shanabo, E Pérez-Cuadrado Martinez
Journal: Endoscopy (2014)

Introduccion: La enteroscopia de doble balón (EDB) y la capsula endoscópica (CE) están ampliamente aceptadas en el manejo de la hemorragia digestiva de origen oscuro (HDOO). Sin embargo, hay pocos estudios que analicen su utilidad en la HDOO urgente.