tbuckley/cabot-search huggingface dataset:
ZD6474, a Novel Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor, Inhibits Tumor Growth of Multiple Nervous System Tumors
Authors: Jeremy N. Rich, Sith Sathornsumetee, Stephen T. Keir, Mark W. Kieran, Andrea Laforme, Arja Kaipainen, Roger E. McLendon, Michael W. Graner, B.K. Ahmed Rasheed, Ling Wang, David A. Reardon, Anderson J. Ryan, Catherine Wheeler, Isaiah Dimery, Darell D. Bigner, Henry S. Friedman
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. Experimental Design: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. Results: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. Conclusions: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.
Emergence of Multidrug-Resistant, Community-Associated, Methicillin-Resistant <i>Staphylococcus aureus</i> Clone USA300 in Men Who Have Sex with Men
Authors: Binh An Diep, Henry F. Chambers, Christopher J. Graber, John D. Szumowski, Loren G. Miller, Linda L. Han, Jason H. Chen, Felice Lin, Jessica Lin, Tiffany HaiVan Phan, Heather A. Carleton, Linda K. McDougal, Fred C. Tenover, Daniel E. Cohen, Kenneth H. Mayer, George F. Sensabaugh, Françoise Perdreau-Remington
Journal: Annals of Internal Medicine (2008)

Background: Infection with multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus (MRSA) has been reported but seems to be isolated. Objective: To determine the incidence of a multidrug-resistant MRSA clone (USA300) in San Francisco, and to determine risk factors for the infection. Design: Population-based survey and cross-sectional study using chart review. Setting: 9 hospitals in San Francisco (population-based survey) and 2 outpatient clinics in San Francisco and Boston (cross-sectional study). Patients: Persons with culture-proven MRSA infections in 2004 to 2006. Measurements: Annual incidence, spatial clustering, and risk factors for multidrug-resistant USA300 infection. Pulsed-field gel electrophoresis, polymerase chain reaction assays, and DNA sequencing were used to characterize MRSA isolates. Results: The overall incidence of multidrug-resistant USA300 infection in San Francisco was 26 cases per 100 000 persons (95% CI, 16 to 36 cases per 100 000 persons); the incidence was higher in 8 contiguous ZIP codes with a higher proportion of male same-sex couples. Male–male sex was a risk factor for multidrug-resistant USA300 infection (relative risk, 13.2 [CI, 1.7 to 101.6]; P < 0.001) independent of past MRSA infection (relative risk, 2.1 [CI, 1.2 to 3.7]; P = 0.007) or clindamycin use (relative risk, 2.1 [1.2 to 3.6]; P = 0.007). The risk seemed to be independent of HIV infection. In San Francisco, multidrug-resistant USA300 manifested most often as infection of the buttocks, genitals, or perineum. In Boston, the infection was recovered exclusively from men who had sex with men. Limitations: The study was retrospective, and sexual risk behavior was not assessed. Conclusion: Infection with multidrug-resistant USA300 MRSA is common among men who have sex with men, and multidrug-resistant MRSA infection might be sexually transmitted in this population. Further research is needed to determine whether existing efforts to control epidemics of other sexually transmitted infections can control spread of community-associated, multidrug-resistant MRSA.
Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa
Authors: L M Jackson
Journal: Gut (2000)

<h3>BACKGROUND AND AIMS</h3> Constitutive cyclooxygenase (COX) 1 is believed to mediate prostaglandin dependent gastric protection. However, gastric mucosa contains cells capable of expressing inducible COX-2. We therefore investigated COX-1 and COX-2 expression, localisation, and activity in normal and abnormal human gastric mucosa. <h3>METHODS</h3> COX-1 and COX-2 distribution was investigated by light and electron microscopic immunohistochemistry and by western blot analysis, and their contribution to prostaglandin (PG)E<sub>2</sub> synthesis using selective enzyme inhibitors. <h3>RESULTS</h3> There was strong parietal cell COX-1 and COX-2 immunoreactivity in all sections and isolated cells, with macrophage and myofibroblast reactivity in some sections. Immunostaining was specifically abolished by antigen absorption. Western blot analysis confirmed COX-1 and 2 expression. COX-1 and COX-2 immunostaining was increased in<i>Helicobacter pylori </i>gastritis, particularly the mid glandular zone and lamina propria inflammatory cells. This was associated with increased ex vivo PGE<sub>2</sub> synthesis (62.4 (13.5) pg/mg <i>v</i> 36.3 (15.5) pg/mg in uninflamed mucosa; p=0.017) which was significantly inhibited by COX-1 but not COX-2 inhibition. Increased COX-2 immunostaining in macrophages, endothelial cells, and myofibroblasts (with reduced epithelial expression) was seen at the rim of ulcers. <h3>CONCLUSION</h3> COX-2, as well as COX-1, is expressed by normal human gastric mucosa and is increased at the rim of ulcers. Although both are increased with<i>H pylori</i>, COX-1 contributes more than COX-2 to gastric PGE<sub>2</sub> production.
Mathematical models of myosin heterodimer formation in the rat heart during thyroid hormone alterations.
Authors: H Rupp, K Dietz
Journal: Circulation Research (1991)

To characterize the mechanisms involved in the formation of the myosin heavy chain (MHC) heterodimer V2 (alpha beta-MHC) and the homodimers V3 (beta beta-MHC) and V1 (alpha alpha-MHC), 82 5-week-old normotensive rats with homogeneous V1 were made hypothyroid with propylthiouracil (0.8%, drinking water), and the proportion of V2, V3, and V1 was determined by pyrophosphate gel electrophoresis in multicellular specimens of the left and right ventricles. After the switch from alpha-MHC to beta-MHC, the beta-MHC occurred initially in the form of the heterodimer. After 4 and 6 days, V2 was greater (p less than 0.05) than V3. At day 8, V2 was smaller than V3, and at day 10, V2 was not statistically different from V3. From day 12 onward, V2 was smaller than V3. After 21 days, the propylthiouracil treatment was stopped, and the remaining 34 hypothyroid rats were injected with a daily dose of thyroxine (average, 0.1 mg/kg body wt), resulting in a switch from beta-MHC to alpha-MHC. After 1 day, V2 still was greater than V1; however, already from day 3 onward, V2 was smaller than V1. This characteristic but unexplained heterodimeric and homodimeric organization of the thick filament was analyzed by mathematical models involving probability calculations. Two principally different models were established that assume either the exchange of MHC dimers or of single MHC in the thick filament. The parameters of the models were estimated by minimization routines using the squared discrepancies between the experimental and predicted isoenzyme populations. Based on goodness of fit and crucial model parameters, we concluded that the characteristic organization of the thick filament can be accounted for by an exchange involving predominantly MHC dimers and not single MHC. The fact that V2 was lower than expected if formation of heterodimers and homodimers were random was attributed to the preferred homodimerization of 35% of the newly synthesized MHC.
Chronic hepatitis C in children: A clinical and immunohistochemical comparative study with adult patients
Authors: Carmelo García-Monzón, Paloma Jara, Miguel Fernández-Bermejo, Loreto Hierro, Esteban Frauca, Carmen Camarena, Carmen Díaz, Angela De la Vega, Javier Larrauri, Consuelo García-Iglesias, María J. Borque, Paloma Sanz, Luisa García-Buey, José A. Moreno-Monteagudo, Ricardo Moreno-Otero
Journal: Hepatology (1998)

Limited information is available regarding the characteristics of the hepatitis C virus (HCV) infection in children. We compared the epidemiological background along with the virological and histological features as well as the intrahepatic immunologic phenotype of both children and adults with chronic hepatitis C (CHC). Serum samples of 24 pediatric and 32 adult patients were drawn for alanine transaminase (ALT) levels, HCV–typing, and viral load. The histological diagnosis and a semiquantitative immunohistochemical assessment were performed in all patients. The majority of children (62%) had been transfused and the mean duration of viral infection in these cases was 11 ± 4 years, being similar in adults (11 ± 9 years, not significant). Although genotype distribution was similar, viral load was lower in children than in adults. The mildest histological forms of chronic hepatitis along with a weak intrahepatic immunological phenotype were significantly more frequent among children than adult patients. In conclusion, in children with CHC, perinatal blood transfusion was the most frequent source of viral infection and the liver disease was characterized by both low ALT level and viral load, as well as the mildest histological and immunohistochemical forms of chronic hepatitis.
Oral (E)-5-(2-bromovinyl)-2'-deoxyuridine in severe herpes zoster.
Authors: E de Clercq, H Degreef, J Wildiers, G de Jonge, A Drochmans, J Descamps, P de Somer
Journal: BMJ (1980)

Oral (E)-5-(2-bromovinyl)-2'deoxyuridine in severe herpes zoster (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) is a nucleoside analogue that inhibits the replication of herpes simplex virus type 1 (HSV-1) in cell culture (primary rabbit kidney) at a concentration of 0 01 mg/l, but does not affect normal cell metabolism at concentrations up to 100 mg/I.' BVDU has also been found effective in the local and systemic treatment of HSV-1 skin lesions, and its associated mortality,
Evolution of Antigen Variation in the Tick-Borne Pathogen Anaplasma phagocytophilum
Authors: D. Rejmanek, P. Foley, A. Barbet, J. Foley
Journal: Molecular Biology and Evolution (2011)

Anaplasma phagocytophilum is an obligately intracellular tick-transmitted bacterial pathogen of humans and other animals. During the course of infection, A. phagocytophilum utilizes gene conversion to shuffle ∼100 functional pseudogenes into a single expression cassette of the msp2(p44) gene, which codes for the major surface antigen and major surface protein 2 (MSP2). The role and extent of msp2(p44) recombination, particularly in hosts that only experience acute infections, is not clear. In the present study, we explored patterns of recombination and expression of the msp2(p44) gene of A. phagocytophilum in a serially infected mouse model. Even though the bacterium was passed rapidly among mice, minimizing the opportunities for the host to develop adaptive immunity, we detected the emergence of 34 unique msp2(p44) expression cassette variants. The expression of msp2(p44) pseudogenes did not follow a consistent pattern among different groups of mice, although some pseudogenes were expressed more frequently than others. In addition, among 263 expressed pseudogenes, 3 mosaic sequences each consisting of 2 different pseudogenes were identified. Population genetic analysis showed that genetic diversity and subpopulation differentiation tended to increase over time until stationarity was reached but that the variance that was observed in allele (expressed pseudogene) frequency could occur by drift alone only if a high variance in bacterial reproduction could be assumed. These findings suggest that evolutionary forces influencing antigen variation in A. phagocytophilum may comprise random genetic drift as well as some innate but apparently nonpurifying selection prior to the strong frequency-dependent selection that occurs cyclically after hosts develop strong adaptive immunity.
Decreased hydrodynamic resistance in the two-phase flow of blood through small vertical tubes at low flow rates.
Authors: G R Cokelet, H L Goldsmith
Journal: Circulation Research (1991)

The aggregation of red blood cells in blood flowing through small tubes at very low shear rates leads to the two-phase flow of an inner core of rouleaux surrounded by a cell-depleted peripheral layer. The formation of this layer is known to be accompanied by a decrease in hydrodynamic resistance to flow. To quantitate this effect, we measured the pressure gradient, flow rate, and the radius of the red blood cell core in suspensions flowing through tubes of 172-microns radius at mean linear flow rates (U) from 50 to 0.15 tube diameters.sec-1. Washed red blood cells were suspended in 1.5% buffered dextran 110 at hematocrits of 34-52%. Using syringe pumps, blood flowed from a stirred reservoir through a vertical 12-cm length of tube in either the upward or downward direction. The pressure drop was measured with transducers. Mean values in distributions in the core radius were obtained by analyzing cine films of flow taken through a microscope with flow in the upward direction, measuring the core radius at five equally spaced axial positions of the tube in each of 100 frames. At 34% and 46% hematocrit, the hydrodynamic resistance increased as U decreased from 50 sec-1, reaching a maximum at U-2 sec-1. It then decreased to a minimum at U less than 0.5 sec-1 as the red blood cell core formed in the tube, and the mean core radius/tube radius ratio decreased from 0.98 to 0.74 with marked axial fluctuations at the lower U. At higher hematocrits, both the increase and decrease in hydrodynamic resistance were greater. In a red blood cell albumin-saline suspension, where there is no aggregation of red blood cells and no two-phase flow, hydrodynamic resistance increases linearly with decreasing U. The experimental results were compared with the predictions of a two-phase steady-flow model, assuming axisymmetric flow of a core surrounded by cell-free suspending medium. Two models were considered, one in which the core is solid, the other in which the rheological properties of the suspension in the core are given by the Quemada equation. The effects of sedimentation of the core resulting in a zero net flow pressure gradient were taken into account. Provided that an experimentally extrapolated value for the zero pressure gradient was used, the Quemada-fluid model gave good agreement with the experimentally observed core radius as a function of U and hematocrit.
Long-term quality of life and neuropsychologic functioning for patients with CNS germ-cell tumors: From the First International CNS Germ-Cell Tumor Study
Authors: S A Sands, S J Kellie, A L Davidow, B Diez, J Villablanca, H L Weiner, M C Pietanza, C Balmaceda, J L Finlay
Journal: Neuro-Oncology (2001)

This study evaluated the quality of life and neuropsychologic functioning among patients enrolled between 1989 and 1993 in the First International CNS Germ-Cell Tumor Study. Quality-of-life questionnaires (Short Form-36 or Child Health Questionnaire) were completed on 43 patients at median follow-up of 6.1 years after diagnosis (range, 4.5-8.8 years), and intellectual and academic testing was performed on 22 patients. Psychosocial and physical functioning of patients aged 19 years and older at follow-up was within the average range, whereas the same functioning for patients aged 18 years and younger, as reported by their parents at follow-up, was low average and borderline, respectively. Overall psychosocial and physical health summary scores were positively correlated with age at diagnosis for both groups combined. Those who received CNS radiation therapy (n = 29) reported significantly worse physical health, but similar psychosocial health, compared with those treated without radiation. Neuropsychologic testing indicated full-scale and verbal IQ, reading, spelling, and math skills in the average range, and performance IQ in the low average range. Intelligence and math skills were positively correlated with age at diagnosis. Those with germinomas significantly outperformed those with nongerminomatous/ mixed tumors on all neuropsychological measures administered. Younger patients diagnosed with CNS germ-cell tumors are at increased risk for psychosocial and physical problems as well as neuropsychologic deficits. Exposure to irradiation adversely affects overall physical functioning, whereas tumor pathology appears to be a salient neurocognitive risk factor. Collaborative and randomized studies are required to further elucidate the late effects arising from factors such as age at diagnosis, tumor histology, level of irradiation therapy, and chemotherapy toxicity among these young and potentially curable patients.
Measurement of cat allergen levels in the home by use of an amplified ELISA
Authors: Mary Elizabeth Bollinger, Robert A. Wood, Peihua Chen, Peyton A. Eggleston
Journal: Journal of Allergy and Clinical Immunology (1998)

We previously reported that Fel d 1 was measurable in 10 of 40 air samples and 38 of 40 dust samples obtained from homes without cats.1 We have reanalyzed the samples from 39 of these homes using a recently described amplified ELISA for Fel d 1.2 This modification uses a signal amplification by catalyzed reporter deposition originally described by Bobrow et al.3 Because assay sensitivity is greatly increased, we reexamined the relationship of settled dust and airborne levels in samples that we had collected previously.
Nfatc1 Coordinates Valve Endocardial Cell Lineage Development Required for Heart Valve Formation
Authors: Bingruo Wu, Yidong Wang, Wendy Lui, Melissa Langworthy, Kevin L. Tompkins, Antonis K. Hatzopoulos, H. Scott Baldwin, Bin Zhou
Journal: Circulation Research (2011)

Formation of heart valves requires early endocardial to mesenchymal transformation (EMT) to generate valve mesenchyme and subsequent endocardial cell proliferation to elongate valve leaflets. Nfatc1 (nuclear factor of activated T cells, cytoplasmic 1) is highly expressed in valve endocardial cells and is required for normal valve formation, but its role in the fate of valve endocardial cells during valve development is unknown.Our aim was to investigate the function of Nfatc1 in cell-fate decision making by valve endocardial cells during EMT and early valve elongation.Nfatc1 transcription enhancer was used to generate a novel valve endocardial cell-specific Cre mouse line for fate-mapping analyses of valve endocardial cells. The results demonstrate that a subpopulation of valve endocardial cells marked by the Nfatc1 enhancer do not undergo EMT. Instead, these cells remain within the endocardium as a proliferative population to support valve leaflet extension. In contrast, loss of Nfatc1 function leads to enhanced EMT and decreased proliferation of valve endocardium and mesenchyme. The results of blastocyst complementation assays show that Nfatc1 inhibits EMT in a cell-autonomous manner. We further reveal by gene expression studies that Nfatc1 suppresses transcription of Snail1 and Snail2, the key transcriptional factors for initiation of EMT.These results show that Nfatc1 regulates the cell-fate decision making of valve endocardial cells during valve development and coordinates EMT and valve elongation by allocating endocardial cells to the 2 morphological events essential for valve development.
CCBE1 Is Essential for Mammalian Lymphatic Vascular Development and Enhances the Lymphangiogenic Effect of Vascular Endothelial Growth Factor-C In Vivo
Authors: Frank L. Bos, Maresa Caunt, Josi Peterson-Maduro, Lara Planas-Paz, Joe Kowalski, Terhi Karpanen, Andreas van Impel, Raymond Tong, James A. Ernst, Jeroen Korving, Johan H. van Es, Eckhard Lammert, Henricus J. Duckers, Stefan Schulte-Merker
Journal: Circulation Research (2011)

Rationale: Collagen- and calcium-binding EGF domains 1 (CCBE1) has been associated with Hennekam syndrome, in which patients have lymphedema, lymphangiectasias, and other cardiovascular anomalies. Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist. Objective: CCBE1 deficient mice were generated to understand the function of CCBE1 in cardiovascular development, and CCBE1 recombinant protein was used in both in vivo and in vitro settings to gain insight into the molecular function of CCBE1. Methods and Results: Phenotypic analysis of murine Ccbe1 mutant embryos showed a complete lack of definitive lymphatic structures, even though Prox1 + lymphatic endothelial cells get specified within the cardinal vein. Mutant mice die prenatally. Proximity ligation assays indicate that vascular endothelial growth factor receptor 3 activation appears unaltered in mutants. Human CCBE1 protein binds to components of the extracellular matrix in vitro, and CCBE1 protein strongly enhances vascular endothelial growth factor-C–mediated lymphangiogenesis in a corneal micropocket assay. Conclusions: Our data identify CCBE1 as a factor critically required for budding and migration of Prox-1 + lymphatic endothelial cells from the cardinal vein. CCBE1 probably exerts these effects through binding to components of the extracellular matrix. CCBE1 has little lymphangiogenic effect on its own but dramatically enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Thus, our data suggest CCBE1 to be essential but not sufficient for lymphangiogenesis.