tbuckley/cabot-search huggingface dataset:
Endothelial Cell Cortactin Phosphorylation by Src Contributes to Polymorphonuclear Leukocyte Transmigration In Vitro
Authors: Lin Yang, Jennifer R. Kowalski, Xi Zhan, Sheila M. Thomas, Francis W. Luscinskas
Journal: Circulation Research (2005)

The underlying mechanisms that regulate leukocyte transendothelial migration through the vascular endothelium remain unclear. Cortactin is a substrate of Src tyrosine kinases and a regulator of cytoskeletal dynamics. Previous studies demonstrated a role for Src phosphorylation of cortactin in clustering of E-selectin and intercellular cell adhesion molecule-1 around adherent leukocytes. In the current study, we used an in vitro flow model to investigate the role of Src-induced cortactin phosphorylation in endothelium during polymorphonuclear leukocyte (PMN) transmigration through human umbilical vein endothelium (HUVEC) monolayers preactivated with tumor necrosis factor-alpha. Inhibition of Src in HUVEC using Src kinase inhibitors PP2 and SU6656 reduced PMN transmigration by 45+/-8% and 36+/-6%, respectively. Live cell imaging of green fluorescent protein-tagged cortactin in HUVEC revealed redistribution of cortactin in the region surrounding transmigrating PMN. Knockdown of cortactin in HUVEC by small interfering RNA also impaired transmigration to a similar degree, and this phenotype was rescued by reexpression of wild-type cortactin. Analysis of the location of initial arrest and locomotion of PMN adherent to HUVEC demonstrated that inhibition of Src tyrosine kinases or pretreatment with cortactin small interfering RNA reduced PMN transmigration at endothelial cell-to-cell junctions and not adhesion. Tyrosine phosphorylation of cortactin was important for transmigration, because expression of a mutant, in which the tyrosine phosphorylation sites were mutated to phenylalanine (cortactin3F), failed to rescue PMN transmigration. Moreover, expression of cortactin3F alone partially blocked PMN transmigration. These data suggest a model whereby tyrosine phosphorylation of cortactin by Src family kinases regulates PMN transmigration.
Effect of beer drinking on risk of myocardial infarction: population based case-control study
Authors: M. Bobak
Journal: BMJ (2000)

costs and treatment effects observed within the trial period and do not require extrapolation of effects beyond the trial period.However, modelling indicated that these longer term benefits are likely to double the mean difference in event-free time.Our results suggest that intensive management of patients with type 2 diabetes is a feasible and economically supportable option.We thank the patients and staff at the study centres for their cooperation and Andrew Briggs, Philip Bassett, Valeria Frighi, and Ziyah Mehta for their contributions.Contributors: AG helped plan and design the health economics study, supervised and participated in the analysis, coordinated the writing of the paper, and is the guarantor.MR compiled, maintained, and analysed the economic data and participated in interpreting the results and writing the paper.AMcG helped plan and design the health economics study and participated in supervising analysis, interpreting results, and writing the paper.PF helped plan and design the health economics study and participated in supervision and interpretation of results and revising the paper.RS developed the simulation model and participated in interpreting the results and writing the paper.CC was responsible for maintenance of the database, prepared trial data for analysis, discussed statistical aspects of the analysis, and participated in revising the paper.IS participated in data preparation, interpretation, and revision of the paper.AA helped to develop the simulation model and participated in interpreting the results and revising the paper.RH was a principal clinical investigator in the UK prospective diabetes study and participated in data preparation, analysis, and interpretation and revising the paper.
Antitumor Activity of 3-Ingenyl Angelate
Authors: Steven M. Ogbourne, Andreas Suhrbier, Brad Jones, Sarah-Jane Cozzi, Glen M. Boyle, Melanie Morris, Devi McAlpine, Jenny Johns, Tania M. Scott, Kirsty P. Sutherland, Joy M. Gardner, Thuy T. T. Le, Aleksandra Lenarczyk, James H. Aylward, Peter G. Parsons
Journal: Cancer Research (2004)

Options for skin cancer treatment currently include surgery, radiotherapy, topical chemotherapy, cryosurgery, curettage, and electrodessication. Although effective, surgery is costly and unsuitable for certain patients. Radiotherapy can leave a poor cosmetic effect, and current chemotherapy is limited by low cure rates and extended treatment schedules. Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005), a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Three daily topical applications of 42 nmol (18 micro g) of PEP005 cured a series of s.c. mouse tumors (B16 melanoma, LK2 UV-induced squamous cell carcinoma, and Lewis lung carcinoma; n = >14 tumors/group) and human tumors (DO4 melanoma, HeLa cervical carcinoma, and PC3 and DU145 prostate carcinoma; n = >4 tumors/group) previously established (5-10 mm(3)) on C57BL/6 or Foxn1(nu) mice. The treatment produced a mild, short-term erythema and eschar formation but, ultimately, resulted in excellent skin cosmesis. The LD(90) for PEP005 for a panel of tumor cell lines was 180-220 micro M. Electron microscopy showed that treatment with PEP005 both in vitro (230 micro M) and in vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. (51)Cr release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 micro M) treatment of tumor cells in vitro resulted in a rapid plasma membrane perturbation and loss of mitochondrial membrane potential. PEP005 thus emerges as a new topical anti-skin cancer agent that has a novel mode of action involving plasma membrane and mitochondrial disruption and primary necrosis, ultimately resulting in an excellent cosmetic outcome.
Defective Development of γ/δ T Cells in Interleukin 7 Receptor–Deficient Mice Is Due to Impaired Expression of T Cell Receptor γ Genes
Authors: Joonsoo Kang, Mark Coles, David H. Raulet
Journal: The Journal of Experimental Medicine (1999)

Mice lacking the interleukin 7 receptor (IL-7R) generate α/β T cells at a detectable but greatly reduced rate, but γ/δ T cells are completely absent. The special role of IL-7R signaling in γ/δ T cell development has remained unclear. IL-7Rα−/− mice exhibit a paucity of γ gene rearrangements. This striking observation can be explained by a defect in T cell receptor (TCR)-γ gene rearrangement, a defect in TCR-γ gene transcription leading to death of γ/δ lineage cells, and/or a requirement for IL-7R in commitment of cells to the γ/δ lineage. To determine the role of IL-7R signaling in γ/δ T cell development, we examined transcription of a prerearranged TCR-γ transgene in IL-7Rα−/− mice, as well as the effects of IL-7 on transcription of endogenous, rearranged TCR-γ genes in α/β lineage cells. The results demonstrate that IL-7R–mediated signals are necessary for the normal expression of rearranged TCR-γ genes. Equally significant, the results show that the poor expression of TCR-γ genes in IL-7Rα−/− mice is responsible for the selective deficit in γ/δ cells in these mice, since a high copy TCR-γ transgene exhibited sufficient residual expression in IL-7Rα−/− mice to drive γ/δ cell development. The results indicate that the absence of γ/δ T cells in IL-7Rα−/− mice is due to insufficient TCR-γ gene expression.
Duration of Dual Antiplatelet Therapy after Implantation of Drug-Eluting Stents
Authors: Seung Jung Park, Duk Woo Park, Young Hak Kim, Soo Jin Kang, Seung Whan Lee, Cheol Whan Lee, Ki Hoon Han, Seong Wook Park, Sung Cheol Yun, Sang Gon Lee, Seung Woon Rha, In Whan Seong, Myung Ho Jeong, Seung Ho Hur, Nae Hee Lee, Junghan Yoon, Joo Young Yang, Bong Ki Lee, Young Jin Choi, Wook Sung Chung, Do Sun Lim, Sang Sig Cheong, Kee Sik Kim, Jei Keon Chae, Deuk Young Nah, Doo Soo Jeon, Ki Bae Seung, Jae Sik Jang, Hun Sik Park, Keun Lee
Journal: New England Journal of Medicine (2010)

The potential benefits and risks of the use of dual antiplatelet therapy beyond a 12-month period in patients receiving drug-eluting stents have not been clearly established.In two trials, we randomly assigned a total of 2701 patients who had received drug-eluting stents and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of at least 12 months to receive clopidogrel plus aspirin or aspirin alone. The primary end point was a composite of myocardial infarction or death from cardiac causes. Data from the two trials were merged for analysis.The median duration of follow-up was 19.2 months. The cumulative risk of the primary outcome at 2 years was 1.8% with dual antiplatelet therapy, as compared with 1.2% with aspirin monotherapy (hazard ratio, 1.65; 95% confidence interval [CI], 0.80 to 3.36; P=0.17). The individual risks of myocardial infarction, stroke, stent thrombosis, need for repeat revascularization, major bleeding, and death from any cause did not differ significantly between the two groups. However, in the dual-therapy group as compared with the aspirin-alone group, there was a nonsignificant increase in the composite risk of myocardial infarction, stroke, or death from any cause (hazard ratio, 1.73; 95% CI, 0.99 to 3.00; P=0.051) and in the composite risk of myocardial infarction, stroke, or death from cardiac causes (hazard ratio, 1.84; 95% CI, 0.99 to 3.45; P=0.06).The use of dual antiplatelet therapy for a period longer than 12 months in patients who had received drug-eluting stents was not significantly more effective than aspirin monotherapy in reducing the rate of myocardial infarction or death from cardiac causes. These findings should be confirmed or refuted through larger, randomized clinical trials with longer-term follow-up. (ClinicalTrials.gov numbers, NCT00484926 and NCT00590174.)
Is There an Epidemic of HIV Infection in the US ESRD Program?
Authors: Paul W. Eggers, Paul L. Kimmel
Journal: Journal of the American Society of Nephrology (2004)

Surveys revealed increases in the prevalence of HIV-infected patients in the US end-stage renal disease (ESRD) program in the 1980s and early 1990s, with clustering in young black men 25 to 44 yr old. Since the availability of highly active antiretroviral therapy in 1996, the prognosis of HIV-infected patients has improved, and therapy has been shown to change the course of classic HIV-associated nephropathy. We used the United States Renal Data System database to determine if the incidence and prevalence of HIV-infected patients with renal disease has increased in the ESRD program, by means of principal diagnoses and comorbid AIDS-defining diagnoses. As the number of US patients living with AIDS increased 57% from 214,711 in 1995 to 337,017 in 2000, and the number of incident ESRD patients increased 29.9% from 72,827 to 94,602, the number of incident HIV-infected patients increased only by 3.5%, from 1133 to 1171. Over this time, the percentage of incident ESRD patients with HIV infection fell from 1.56% to 1.24%. Among black men 25 to 44 yr of age, HIV infection as a proportion of incident ESRD cases fell from 8.5% to 6.2% from 1995 to 2000. The incident rate per million of AIDS or HIV infection in black men aged 25 to 44 fell from 107 in 1995 to 78 per million in 2000. The incidence rate for HIV-infected women in the ESRD program rose 14% while it declined 7% in men. Almost 2000 HIV-infected women, or 28.8% of the population, have initiated therapy for ESRD with hemodialysis. The number of prevalent cases increased in absolute numbers 81.3% from 2687 to 4871 (0.90% to 1.16% of the ESRD program). One-year survival rates for HIV-infected incident ESRD patients increased from 53.1% to 67.1% from 1995 to 2000. Although these values may be underestimates because of underreporting due to confidentiality concerns and lack of biopsy confirmation, we conclude that although the prevalence of HIV infection is increasing in the US ESRD population, the increase as a proportion of the program is minimal and is due to better survival after development of renal failure. The incidence of HIV infection in the US ESRD program is stable. Highly active antiretroviral therapy may be responsible for the change in epidemiology of HIV infection in the US ESRD program.
Maternal cholestasis during pregnancy programs metabolic disease in offspring
Authors: Georgia Papacleovoulou, Shadi Abu-Hayyeh, Evanthia Nikolopoulou, Oscar Briz, Bryn M. Owen, Vanya Nikolova, Caroline Ovadia, Xiao Huang, Marja Vaarasmaki, Marc Baumann, Eugene Jansen, Christiane Albrecht, Marjo-Riitta Jarvelin, Jose J.G. Marin, A.S. Knisely, Catherine Williamson
Journal: Journal of Clinical Investigation (2013)

The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.
Functional comparison of long and short splice forms of RPTPβ: Implications for glioblastoma treatment
Authors: Gustavo Lorente, April Nelson, Sabine Mueller, Jane Kuo, Roman Urfer, Karoly Nikolich, Erik D. Foehr
Journal: Neuro-Oncology (2005)

The receptor protein tyrosine phosphatase beta (RPTPbeta/PTPzeta) is overexpressed in glioblastoma tumors and plays a functional role in tumor cell migration and adhesion. Glioblastomas express at least three splice variants of RPTPbeta, including long and short receptor forms and a secreted chondroitin sulfate proteoglycan called phosphacan. Here we explore the differences in the expression pattern and function of long RPTPbeta and short RPTPbeta. The short form of RPTPbeta lacks exon 12, which encodes 860 amino acids located in the extracellular domain. Until now, functional differences between long and short RPTPbeta have been difficult to elucidate. In this study, antibodies specific to the splice junction, unique to short RPTPbeta, allowed for the discrimination of the two receptors. A study of normal brain tissue and graded astrocytomas indicates that long and short RPTPbeta forms have an overlapping expression pattern. In order to study functional differences between long and short RPTPbeta, we created stable U87 glioblastoma cells that expressed these receptors. U87 stable cell lines overexpressing long or short RPTPbeta migrate faster and adhere more robustly than parental U87 cells. The two forms differ in that long-RPTPbeta-overexpressing cells migrate and adhere better than short-RPTPbeta-overexpressing cells. A study of the extracellular domain of short RPTPbeta indicates that it retains much of the functional capacity of phosphacan. Indeed, the action of recombinant, short-RPTPbeta extracellular domain protein is similar to that of phosphacan as a repulsive substrate for glioblastoma cells. Comparison of the signaling capacity of long RPTPbeta to that of short RPTPbeta reveals very similar abilities to activate transcription pathways. Moreover, transient transfection with either long or short RPTPbeta activates NF-kappaB reporter gene transcription. Because of their tumor-restricted and largely overlapping expression patterns in glioblastoma, both RPTPbeta splice forms are potential therapeutic targets. The involvement of long and short RPTPbeta in glioma tumor cell biology also contributes to the value of RPTPbeta as a cancer target.
Measurement of absolute lung volumes by imaging techniques
Authors: J Clausen
Journal: European Respiratory Journal (1997)

In this paper, the techniques available for estimating total lung capacities from standard chest radiographs in children and infants as well as adults are reviewed. These techniques include manual measurements using ellipsoid and planimetry techniques as well as computerized systems. Techniques are also available for making radiographic lung volume measurements from portable chest radiographs. There are inadequate data in the literature to support recommending one specific technique over another. Though measurements of lung volumes by radiographic, plethysmographic, gas dilution or washout techniques result in remarkably similar mean results when groups of normal subjects are tested, in patients with disease, the results of these different basic measurement techniques can differ significantly. Computed tomographic and magnetic resonance techniques can also be used to measure absolute lung volumes and offer the theoretical advantages that the results in individual subjects are less affected by variances of thoracic shape than are measurements made using conventional chest radiographs.
Epidermal Growth Factor Receptor Signaling Is Up-regulated in Human Colonic Aberrant Crypt Foci
Authors: Greg Cohen, Reba Mustafi, Anusara Chumsangsri, Nathaniel Little, Jeff Nathanson, Sonia Cerda, Sujatha Jagadeeswaran, Urszula Dougherty, Loren Joseph, John Hart, Lisa Yerian, Maria Tretiakova, Weihua Yuan, Piotr Obara, Sharad Khare, Frank A. Sinicrope, Alessandro Fichera, Gerry R. Boss, Robert Carroll, Marc Bissonnette
Journal: Cancer Research (2006)

Aberrant crypt foci (ACF) are collections of abnormal colonic crypts with heterogeneous molecular and pathologic characteristics. Large and dysplastic ACF are putative precursors of colon cancer with neoplastic risk related to increased proliferation. In this study, we examined the role of epidermal growth factor receptor (EGFR) signaling in regulating ACF proliferation. Using magnification chromoendoscopy, we collected large ACF with endoscopic features of dysplasia and separately biopsied adjacent mucosa. Transcript levels were measured by real-time PCR, proteins were assessed by Western blotting, and levels were expressed as fold changes of adjacent mucosa. K-ras and B-Raf mutations were assessed by PCR and Ras activation by the ratio Ras-GTP / (Ras-GTP + Ras-GDP). At the RNA level, 38% of ACF were hyperproliferative, with proliferating cell nuclear antigen (PCNA) mRNA >/=2-fold of adjacent mucosa. Hyperproliferative ACF had significantly increased mRNA levels of EGFR (6.0 +/- 1.7-fold), transforming growth factor-alpha (14.4 +/- 5.0-fold), heparin-binding EGF-like growth factor (4.5 +/- 1.4-fold), cyclin D1 (4.6 +/- 0.7-fold), and cyclooxygenase-2 (COX-2; 9.3 +/- 4.2-fold; P < 0.05). At the protein level, 46% of ACF were hyperproliferative (PCNA, 3.2 +/- 1.2-fold). In hyperproliferative ACF, 44% possessed significant increases in four EGFR signaling components: EGFR (9.5 +/- 1.3-fold), phosphoactive ErbB2 (2.6 +/- 0.4-fold), phosphoactive extracellular signal-regulated kinase (3.7 +/- 1.1-fold), and cyclin D1 (3.4 +/- 0.8-fold; P < 0.05). Ras was activated in 46% of ACF (3.2 +/- 0.4-fold; P < 0.05), but K-ras mutations were present in only 7% of ACF. In contrast to COX-2 mRNA, the protein was not increased in hyperproliferative ACF. In summary, we have shown that ACF with up-regulated PCNA possess increased EGFR signaling components that likely contribute to the enhanced proliferative state of dysplastic-appearing ACF.
Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress
Authors: Mirjana Jerkic, Mohammed G. Kabir, Adrienne Davies, Lisa X. Yu, Brendan A.S. McIntyre, Nasir W. Husain, Masahiro Enomoto, Valentin Sotov, Mansoor Husain, Mark Henkelman, Jaques Belik, Michelle Letarte
Journal: Cardiovascular Research (2011)

Mutations in the ALK1 gene, coding for an endothelial-specific receptor of the transforming growth factor-β superfamily, are the underlying cause of hereditary haemorrhagic telangiectasia type 2, but are also associated with familial pulmonary hypertension (PH). We assessed the lung vasculature of mice with a heterozygous deletion of Alk1 (Alk1+/−) for disease manifestations and levels of reactive O2 species (ROS) implicated in both disorders. Several signs of PH, including elevated right ventricular (RV) systolic pressure leading to RV hypertrophy, reduced vascular density, and increased thickness and outward remodelling of pulmonary arterioles, were observed in 8- to 18-week-old Alk1+/− mice relative to wild-type littermate controls. Higher ROS lung levels were also documented. At 3 weeks, Alk1+/− mice were indistinguishable from controls and were prevented from subsequently developing PH when treated with the anti-oxidant Tempol for 6 weeks, confirming a role for ROS in pathogenesis. Levels of NADPH oxidases and superoxide dismutases were higher in adults than newborns, but unchanged in Alk1+/− mice vs. controls. Prostaglandin metabolites were also normal in adult Alk1+/− lungs. In contrast, NO production was reduced, while endothelial NO synthase (eNOS)-dependent ROS production was increased in adult Alk1+/− mice. Pulmonary near resistance arteries from adult Alk1+/− mice showed less agonist-induced force and greater acetylcholine-induced relaxation; the later was normalized by catalase or Tempol treatment. The increased pulmonary vascular remodelling in Alk1+/− mice leads to signs of PH and is associated with eNOS-dependent ROS production, which is preventable by anti-oxidant treatment.
Sequence of Atrial Depolarization at Different Stages of Development of the Chick Embryo
Authors: GERSHON HAIT, RICHARD H. LICATA
Journal: Circulation Research (1967)

Simultaneous left and right atrial surface electrograms were obtained from the right and left atria of 30 chick embryos. These were divided into 3 equal groups that were studied at 15 to 16, 10 to 11, and 5 to 7 days of incubation. The embryos were removed from the shell with their circulation intact and temperature maintained constant. In an early stage of development (5 to 6 days), the left atrium and its appendage were larger than the right, and left preceded right atrial depolarization. At and after 7 days of incubation, the right atrium and its appendage were larger than the left, and right preceded left atrial depolarization. The intervals for interatrial conduction and for atrio-ventricular conduction were about the same at all stages of development. Since the length and width of the heart at 15 to 16 days of incubation were about 3 times those of a heart at 5 to 7 days of incubation, it is proposed that the higher the stage of development of the chick embryo the greater must be the conduction velocity between the two atria and from atrium to ventricle. This was assumed to be related to the degree of development of the specialized conduction pathways that are probably absent or underdeveloped in early stages of development.