tbuckley/cabot-search huggingface dataset:
Effect of Imatinib Mesylate on Neuroblastoma Tumorigenesis and Vascular Endothelial Growth Factor Expression
Authors: K. Beppu, J. Jaboine, M. S. Merchant, C. L. Mackall, C. J. Thiele
Journal: JNCI Journal of the National Cancer Institute (2004)

Alternative treatment options are needed for advanced neuroblastoma patients because their prognosis remains poor after intensive chemotherapy. Neuroblastoma cells express platelet-derived growth factor (PDGF), stem cell factor (SCF), and vascular endothelial growth factor (VEGF) and their respective receptors, PDGFR, c-Kit, and Flk-1. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the tyrosine kinase activities of c-Kit and PDGFR, on the growth of neuroblastoma cells in vivo and in vitro.We tested seven human neuroblastoma cell lines for their sensitivity to imatinib. Cell viability was assessed by trypan blue dye exclusion. Apoptosis was evaluated by nuclear staining, flow cytometry, and western blotting. Protein assays included immunoprecipitation, western blotting, enzyme-linked immunosorbent assays, and immunohistochemistry. mRNA expression was assessed by northern blotting. We used a xenograft model in SCID mice (10 mice per group) to evaluate the effects of imatinib oral therapy (50 or 100 mg/kg every 12 hours for 14 days) on neuroblastoma tumor growth. All statistical tests were two-sided.All seven neuroblastoma cell lines treated with imatinib displayed concentration-dependent decreases in cell viability, which coincided with an induction of apoptosis, and with ligand-stimulated phosphorylation of c-Kit and PDGFR. The imatinib concentrations that caused 50% inhibition of growth and 50% inhibition of ligand-induced phosphorylation of these receptors were 9-13 micro M and 0.1-0.5 microM, respectively. Expression of VEGF, but not phosphorylation of Flk-1, its receptor, was reduced in neuroblastoma cells treated with imatinib at 10 microM or higher. Mice treated with imatinib at 50 mg/kg or 100 mg/kg had statistically significantly smaller tumors than control mice treated with vehicle (mean tumor volume in mice treated with imatinib at 50 mg/kg = 1546 mm3, in control mice = 2954 mm3; difference = 1408 mm3, 95% confidence interval [CI] = 657 to 2159 mm3; P<.001; mean tumor volume in mice treated with imatinib at 100 mg/kg = 463 mm3; difference = 2491 mm3, 95% CI = 1740 to 3242 mm3; P<.001).Imatinib inhibited the growth of neuroblastoma cells in vitro and in vivo. This inhibition was associated with suppression of PDGFR and c-Kit phosphorylation and inhibition of VEGF expression.
Rate Dependent Ventricular Ectopia Following Acute Coronary Occlusion
Authors: KUL D. CHADDA, VIDYA S. BANKA, RICHARD H. HELFANT
Journal: Circulation (1974)

Recent reports have indicated that tachycardia as well as bradycardia may be arrhythmogenic in acute myocardial infarction. The present experimental study was designed to systematically evaluate the arrhythmogenic and antiarrhythmic effect of heart rate over a wide spectrum using sinus node crush and atrial pacing. Serial recordings of the surface electrocardiograms and local electrograms for a maximum period of three hours were taken at rates of 60-200 beats/min before and after ligation of the left anterior descending coronary artery in 24 open chested dogs. Immediately following coronary occlusion, the incidence of ventricular ectopic complexes was 7.6 ± 1.6/min at a rate of 60, and gradually decreased to 2.5 ± 0.4/min at a rate of 90 ( P &lt; 0.01). At rates of 110-150 ⪕ 1 ventricular ectopic complex/min was noted. However, at rates of 180 and above, the incidence of ventricular ectopic complexes dramatically increased with frank ventricular tachycardia and/or fibrillation being provoked on seventeen occasions. Similarly, at rates of 60-90, ventricular tachycardia and/or fibrillation was exhibited on sixteen occasions, but never at rates between 110-150. Local electrograms exhibited marked ST segment elevation with higher heart rates compatible with increased local ischemia. It is concluded that ventricular ectopia is more common at rapid as well as slow heart rates after acute coronary occlusion. There appears to be an optimal intermediate rate for maximal antiarrhythmic effect.
Integrin-Induced Protein Kinase Cα and Cε Translocation to Focal Adhesions Mediates Vascular Smooth Muscle Cell Spreading
Authors: Hermann Haller, Carsten Lindschau, Christian Maasch, Heike Olthoff, Doris Kurscheid, Friedrich C. Luft
Journal: Circulation Research (1998)

Abstract —The extracellular matrix influences the cellular spreading of vascular smooth muscle cells (VSMCs) via integrin receptors. However, the intracellular signaling mechanisms are still incompletely understood. We investigated the hypothesis that VSMCs binding to fibronectin activates the protein kinase C (PKC) pathway, causes differential intracellular PKC isoform translocation, and mediates cell spreading. VSMCs binding to poly- l -lysine or preincubated with Arg-Gly-Asp (RGD) peptides were used as controls. Diacylglycerol (DAG) and phospholipase D (PLD) activity were measured by thin-layer chromatography. Intracellular distribution of PKC isoforms was assessed by confocal microscopy. VSMCs binding to fibronectin induced focal adhesions and cell spreading within 30 minutes. Fibronectin induced a rapid increase in DAG content, peaking at 10 minutes with a sustained response for &lt;1 hour. In contrast, PLD activity was not influenced by specific binding to fibronectin. PKC isoforms α, δ, ε, and ζ were assessed by confocal microscopy. Fibronectin induced a PKC isoform translocation to the cell nucleus and to focal adhesions within minutes. The nuclear PKCα immunoreactivity was transiently increased. PKC isoforms α and ε were both translocated to focal adhesions. The intracellular distributions of other PKC isoforms were not influenced by fibronectin. The effects of fibronectin on DAG generation, the translocation of PKCα and PKCε, and cell spreading were all abolished by the incubation with RGD peptides. Downregulation of PKC isoforms α and ε with specific antisense oligodinucleotides resulted in a significant inhibition of cell spreading. Our results show that integrins induce intracellular signaling in VSMCs via DAG and PKC. PKC isoform α is translocated to the nucleus, whereas PKC isoforms α and ε are translocated to focal adhesions. Both isoforms seem to play a role in inside-out integrin signaling and cell spreading.
Validation of an Enhanced International Prognostic Index(Nccn-Ipi)For Risk Stratification of Dlbcl Patients
Authors: Yusuke Kanemasa, Tatsu Shimoyama, Akira Kojima, Eisaku Sasaki, Yasushi Omuro, Yoshiharu Maeda, Tsunekazu Hishima, Tsuneo Sasaki
Journal: Annals of Oncology (2014)
The Cost-Effectiveness of Personalized Genetic Medicine
Authors: Siri Atma W. Greeley, Priya M. John, Aaron N. Winn, Joseph Ornelas, Rebecca B. Lipton, Louis H. Philipson, Graeme I. Bell, Elbert S. Huang
Journal: Diabetes Care (2011)

Neonatal diabetes mellitus is a rare form of diabetes diagnosed in infancy. Nearly half of patients with permanent neonatal diabetes have mutations in the genes for the ATP-sensitive potassium channel (KCNJ11 and ABCC8) that allow switching from insulin to sulfonylurea therapy. Although treatment conversion has dramatic benefits, the cost-effectiveness of routine genetic testing is unknown.We conducted a societal cost-utility analysis comparing a policy of routine genetic testing to no testing among children with permanent neonatal diabetes. We used a simulation model of type 1 diabetic complications, with the outcome of interest being the incremental cost-effectiveness ratio (ICER, $/quality-adjusted life-year [QALY] gained) over 30 years of follow-up.In the base case, the testing policy dominated the no-testing policy. The testing policy was projected to bring about quality-of-life benefits that enlarged over time (0.32 QALYs at 10 years, 0.70 at 30 years) and produced savings in total costs that were present as early as 10 years ($12,528 at 10 years, $30,437 at 30 years). Sensitivity analyses indicated that the testing policy would remain cost-saving as long as the prevalence of the genetic defects remained >3% and would retain an ICER <$200,000/QALY at prevalences between 0.7 and 3%.Genetic testing in neonatal diabetes improves quality of life and lowers costs. This paradigmatic case study highlights the potential economic impact of applying the concepts of personalized genetic medicine to other disorders in the future.
The role of vascular myoglobin in nitrite-mediated blood vessel relaxation
Authors: J. O. M. Ormerod, H. Ashrafian, A. R. Maher, S. Arif, V. Steeples, G. V. R. Born, S. Egginton, M. Feelisch, H. Watkins, M. P. Frenneaux
Journal: Cardiovascular Research (2010)

This work investigates the role of myoglobin in mediating the vascular relaxation induced by nitrite. Nitrite, previously considered an inert by-product of nitric oxide metabolism, is now believed to play an important role in several areas of pharmacology and physiology. Myoglobin can act as a nitrite reductase in the heart, where it is plentiful, but it is present at a far lower level in vascular smooth muscle—indeed, its existence in the vessel wall is controversial. Haem proteins have been postulated to be important in nitrite-induced vasodilation, but the specific role of myoglobin is unknown. The current study was designed to confirm the presence of myoglobin in murine aortic tissue and to test the hypothesis that vascular wall myoglobin is important for nitrite-induced vasodilation. Aortic rings from wild-type and myoglobin knockout mice were challenged with nitrite, before and after exposure to the haem-protein inhibitor carbon monoxide (CO). CO inhibited vasodilation in wild-type rings but not in myoglobin-deficient rings. Restitution of myoglobin using a genetically modified adenovirus both increased vasodilation to nitrite and reinstated the wild-type pattern of response to CO. Myoglobin is present in the murine vasculature and contributes significantly to nitrite-induced vasodilation.
EFFECT OF IMMUNOSUPPRESSION ON CHRONIC LCM VIRUS INFECTION OF MICE
Authors: Phillip E. Hoffsten, Frank J. Dixon
Journal: The Journal of Experimental Medicine (1973)

C3H mice chronically infected with LCM virus were found to be lethally affected by small doses of immunosuppression which caused bone marrow aplasia but had no effect on the amount of virus carried by the mouse. Humoral immune response of SWR/J mice to acute LCM infection was found to be totally suppressed by repeated single doses of 300 R/wk with no alteration in the level of virus carried by the mouse. In contrast, the established anti-LCM humoral immune response encountered in mice chronically infected with LCM virus was not suppressed by the same irradiation procedure. Over half of the chronic LCM carrier SWR/J mice treated with cyclophosphamide for 6 mo had total anti-LCM humoral immunosuppression, but showed no change in the level of virus carried. The glomerulonephritis which occurs in chronic LCM carrier mice was prevented by cyclophosphamide treatment in 90% of the mice. The humoral immune response which occurs in chronic LCM carrier mice appears to play no role in controlling the amount of virus carried by the mouse. Suppression of the LCM immune response by cyclophosphamide does prevent the development of glomerulonephritis in these mice.
An upper abdominal swelling causing nausea and vomiting
Authors: I Oliver
Journal: Gut (2005)

Background: Flexible sigmoidoscopy (FS) is a complex technical procedure performed in a variety of settings, by examiners with diverse professional backgrounds, training, and experience.Potential variation in technical quality may have a profound impact on the effectiveness of FS on the early detection and prevention of colorectal cancer.Aim: We propose a set of consensus and evidence based recommendations to assist the development of continuous quality improvement programmes around the delivery of FS for colorectal cancer screening.Recommendations: These recommendations address the intervals between FS examinations, documentation of results, training of endoscopists, decision making around referral for colonoscopy, policies for antibiotic prophylaxis and management of anticoagulation, insertion of the FS endoscope, bowel preparation, complications, the use of non-physicians as FS endoscopists, and FS endoscope reprocessing.For each of these areas, continuous quality improvement targets are recommended, and research questions are proposed.
Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial
Authors: Tone Enden, Ylva Haig, Nils-Einar Kløw, Carl-Erik Slagsvold, Leiv Sandvik, Waleed Ghanima, Geir Hafsahl, Pål Andre Holme, Lars Olaf Holmen, Anne Mette Njaastad, Gunnar Sandbæk, Per Morten Sandset
Journal: The Lancet (2011)
Human Immunodeficiency Virus (HIV) Associated Nephropathy
Authors: T K Sreepada Rao
Journal: Annual Review of Medicine (1991)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
The Predictive Power of Peritraumatic Dissociation and Acute Stress Symptoms for Posttraumatic Stress Symptoms: A Three-Month Prospective Study
Authors: Philippe Birmes, Alain Brunet, Didier Carreras, Jean-Louis Ducassé, Jean-Paul Charlet, Dominique Lauque, Henri Sztulman, Laurent Schmitt
Journal: American Journal of Psychiatry (2003)

The authors prospectively examined the power of peritraumatic dissociation and acute stress symptoms in predicting posttraumatic stress disorder (PTSD) symptoms.Thirty-five assault victims were assessed with the Peritraumatic Dissociative Experiences Questionnaire within 24 hours of the assault. Participants were reassessed 2 weeks after the trauma with the Stanford Acute Stress Reaction Questionnaire and 3 months after the trauma with the Clinician-Administered PTSD Scale and the Impact of Event Scale. Correlational analyses and a hierarchical multiple regression were conducted.Peritraumatic dissociation and acute stress symptoms were correlated with later PTSD symptoms and diagnosis. Together, peritraumatic dissociation and acute stress symptoms accounted for 33% of the variance in PTSD symptoms.These results support earlier findings that peritraumatic dissociative experiences and acute stress are robust predictors of PTSD. Such symptoms may be of use for identifying at an early stage individuals at highest risk of remaining symptomatic. Future studies should investigate the predictive power of specific peritraumatic and acute stress disorder symptom clusters.
Bioreducible poly(amido amine)s with oligoamine side chains: Synthesis, characterization, and structural effects on gene delivery
Authors: Chao Lin, Cees-Jan Blaauboer, Miguel Mateos Timoneda, Martin C. Lok, Mies van Steenbergen, Wim E. Hennink, Zhiyuan Zhong, Jan Feijen, Johan F.J. Engbersen
Journal: Journal of Controlled Release (2007)
HA-ving lymphatics improves lung transplantation
Authors: Jonathan S. Maltzman, Hasina Outtz Reed, Mark L. Kahn
Journal: Journal of Clinical Investigation (2015)

Lung allografts are prone to rejection, even though recipients undergo aggressive immunosuppressive therapy. Lymphatic vessels serve as conduits for immune cell trafficking and have been implicated in the mediation of allograft rejection. In this issue of the JCI, Cui et al. provide compelling evidence that lymphatic vessel formation improves lung allograft survival in a murine transplant model. Moreover, their data suggest a potential mechanism for the beneficial effects of lymphatics that does not involve immune cell or antigen transport. Together, the results of this study provide new insight into the role of lymphatic vessels in transplant tolerance.
Effect of Moderate-Intensity Exercise Versus Activities of Daily Living on 24-Hour Blood Glucose Homeostasis in Male Patients With Type 2 Diabetes
Authors: Jan-Willem van Dijk, Maarten Venema, Willem van Mechelen, Coen D.A. Stehouwer, Fred Hartgens, Luc J.C. van Loon
Journal: Diabetes Care (2013)

To investigate the impact of activities of daily living (ADL) versus moderate-intensity endurance-type exercise on 24-h glycemic control in patients with type 2 diabetes.Twenty males with type 2 diabetes participated in a randomized crossover study consisting of three experimental periods of 3 days each. Subjects were studied under sedentary control conditions, and under conditions in which prolonged sedentary time was reduced either by three 15-min bouts of ADL (postmeal strolling, ∼3 METs) or by a single 45-min bout of moderate-intensity endurance-type exercise (∼6 METs). Blood glucose concentrations were assessed by continuous glucose monitoring, and plasma insulin concentrations were determined in frequently sampled venous blood samples.Hyperglycemia (glucose >10 mmol/L) was experienced for 6 h 51 min ±1 h 4 min per day during the sedentary control condition and was significantly reduced by exercise (4 h 47 min ± 1 h 2 min; P < 0.001), but not by ADL (6 h 2 min ± 1 h 16 min; P = 0.67). The cumulative glucose incremental areas under the curve (AUCs) of breakfast, lunch, and dinner were, respectively, 35 ± 5% (P < 0.001) and 17 ± 6% (P < 0.05) lower during the exercise and ADL conditions compared with the sedentary condition. The insulin incremental AUCs were, respectively, 33 ± 4% (P < 0.001) and 17 ± 5% (P < 0.05) lower during the exercise and ADL conditions compared with the sedentary condition.When matched for total duration, moderate-intensity endurance-type exercise represents a more effective strategy to improve daily blood glucose homeostasis than repeated bouts of ADL. Nevertheless, the introduction of repeated bouts of ADL during prolonged sedentary behavior forms a valuable strategy to improve postprandial glucose handling in patients with type 2 diabetes.
A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer
Authors: Theresa A. DiMeo, Kristen Anderson, Pushkar Phadke, Chang Feng, Charles M. Perou, Steven Naber, Charlotte Kuperwasser
Journal: Cancer Research (2009)

Abstract The establishment of metastasis depends on the ability of cancer cells to acquire a migratory phenotype combined with their capacity to recreate a secondary tumor in a distant tissue. In epithelial cancers, such as those of the breast, the epithelial-mesenchymal transition (EMT) is associated with basal-like breast cancers, generates cells with stem-like properties, and enables cancer cell dissemination and metastasis. However, the molecular mechanism(s) that connects stem cell–like characteristics with EMT has yet to be defined. Using an orthotopic model of human breast cancer metastasis to lung, we identified a poor prognosis gene signature, in which several components of the wnt signaling pathway were overexpressed in early lung metastases. The wnt genes identified in this signature were strongly associated with human basal-like breast cancers. We found that inhibiting wnt signaling through LRP6 reduced the capacity of cancer cells to self-renew and seed tumors in vivo. Furthermore, inhibition of wnt signaling resulted in the reexpression of breast epithelial differentiation markers and repression of EMT transcription factors SLUG and TWIST. Collectively, these results provide a molecular link between self-renewal, EMT, and metastasis in basal-like breast cancers. [Cancer Res 2009;69(13):5364–73]
Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components
Authors: Martha R. Neagu, Patrick Ziegler, Thomas Pertel, Caterina Strambio-De-Castillia, Christian Grütter, Gladys Martinetti, Luca Mazzucchelli, Markus Grütter, Markus G. Manz, Jeremy Luban
Journal: Journal of Clinical Investigation (2009)

New World monkeys of the genus Aotus synthesize a fusion protein (AoT5Cyp) containing tripartite motif-containing 5 (TRIM5) and cyclophilin A (CypA) that potently blocks HIV-1 infection. We attempted to generate a human HIV-1 inhibitor modeled after AoT5Cyp, by fusing human CypA to human TRIM5 (hT5Cyp). Of 13 constructs, 3 showed substantial HIV-1-inhibitory activity when expressed in human cell lines. This activity required capsid binding by CypA and correlated with CypA linkage to the TRIM5a capsid-specificity determinant and the ability to form cytoplasmic bodies. CXCR4- and CCR5-tropic HIV-1 clones and primary isolates were inhibited from infecting multiple human macrophage and T cell lines and primary cells by hT5Cyp, as were HIV-2ROD, SIVAGMtan, FIVPET, and a circulating HIV-1 isolate previously reported to be AoT5Cyp resistant. The anti-HIV-1 activity of hT5Cyp was surprisingly more effective than that of the well-characterized rhesus TRIM5alpha, especially in T cells. hT5Cyp also blocked HIV-1 infection of primary CD4+ T cells and macrophages and conferred a survival advantage to these cells without disrupting their function. Extensive attempts to elicit HIV-1 resistance to hT5Cyp were unsuccessful. Finally, Rag2-/-gammac-/- mice were engrafted with human CD4+ T cells that had been transduced by optimized lentiviral vectors bearing hT5Cyp. Upon challenge with HIV-1, these mice showed decreased viremia and productive infection in lymphoid organs and preserved numbers of human CD4+ T cells. We conclude that hT5Cyp is an extraordinarily robust inhibitor of HIV-1 replication and a promising anti-HIV-1 gene therapy candidate.