tbuckley/cabot-search huggingface dataset:
Cortistatin Inhibits Migration and Proliferation of Human Vascular Smooth Muscle Cells and Decreases Neointimal Formation on Carotid Artery Ligation
Authors: Mario Duran-Prado, Maria Morell, Virginia Delgado-Maroto, Justo P. Castaño, Jose Aneiros-Fernandez, Luis de Lecea, Michael D. Culler, Pedro Hernandez-Cortes, Francisco O’Valle, Mario Delgado
Journal: Circulation Research (2013)

Proliferation and migration of smooth muscle cells (SMCs) are key steps for the progression of atherosclerosis and restenosis. Cortistatin is a multifunctional neuropeptide belonging to the somatostatin family that exerts unique functions in the nervous and immune systems. Cortistatin is elevated in plasma of patients experiencing coronary heart disease and attenuates vascular calcification.To investigate the occurrence of vascular cortistatin and its effects on the proliferation and migration of SMCs in vitro and in vivo and to delimitate the receptors and signal transduction pathways governing its actions.SMCs from mouse carotid and human aortic arteries and from human atherosclerotic plaques highly expressed cortistatin. Cortistatin expression positively correlated with the progression of arterial intima hyperplasia. Cortistatin inhibited platelet-derived growth factor-stimulated proliferation of human aortic SMCs via binding to somatostatin receptors (sst2 and sst5) and ghrelin receptor, induction of cAMP and p38-mitogen-activated protein kinase, and inhibition of Akt activity. Moreover, cortistatin impaired lamellipodia formation and migration of human aortic SMCs toward platelet-derived growth factor by inhibiting, in a ghrelin-receptor-dependent manner, Rac1 activation and cytosolic calcium increases. These effects on SMC proliferation and migration correlated with an inhibitory action of cortistatin on the neointimal formation in 2 models of carotid arterial ligation. Endogenous cortistatin seems to play a critical role in regulating SMC function because cortistatin-deficient mice developed higher neointimal hyperplasic lesions than wild-type mice.Cortistatin emerges as a natural endogenous regulator of SMCs under pathological conditions and an attractive candidate for the pharmacological management of vascular diseases that course with neointimal lesion formation.
Purification of 3α-hydroxysteroid and 3β-hydroxysteroid dehydrogenases from human liver cytosol
Authors: Hajime Takikawa, Makoto Fujiyoshi, Kou Nishikawa, Masami Yamanaka
Journal: Hepatology (1992)

We previously reported that the human Y' bile acid binder, which has higher bile acid binding affinities than rat Y' binders (3 alpha-hydroxysteroid dehydrogenases), has dihydrodiol dehydrogenase activity and is different from 3 alpha-hydroxysteroid dehydrogenases. In this study, 3 alpha-hydroxysteroid dehydrogenases and 3 beta-hydroxysteroid dehydrogenase were purified from human liver, and bile acid binding affinities and enzyme kinetics of the 3 alpha-hydroxysteroid dehydrogenases were studied. On chromatofocusing of pooled Affigel blue fraction of the Y' fraction, three 3 alpha-hydroxysteroid dehydrogenase peaks eluted at pH 6.0, 5.7 and 5.4. These peaks did not bind bile acids, and further purification by hydroxyapatite-high-performance liquid chromatography gave pure 3 alpha-hydroxysteroid dehydrogenases with identical M(r) (36,000) having dihydrodiol dehydrogenase activity. 3 beta-Hydroxysteroid dehydrogenase was eluted together with Y' bile acid binder at pH 7.2 on chromatofocusing and was separated from Y' bile acid binder on hydroxyapatite-high-performance liquid chromatography as a pure protein with M(r) 32,000. The apparent Kms of 3 alpha-hydroxysteroid dehydrogenases were similar to those of rat enzymes. In conclusion, we purified human hepatic 3 alpha-hydroxysteroid dehydrogenases, which have similar characteristics to rat enzymes, but do not bind bile acids or reduce bile acid precursors. These data further support the importance of human bile acid binder in intracellular bile acid transport in the human liver.
Clinical Significance of Tumor-Associated Inflammatory Cells in Metastatic Neuroblastoma
Authors: Shahab Asgharzadeh, Jill A. Salo, Lingyun Ji, André Oberthuer, Matthias Fischer, Frank Berthold, Michael Hadjidaniel, Cathy Wei-Yao Liu, Leonid S. Metelitsa, Roger Pique-Regi, Peter Wakamatsu, Judith G. Villablanca, Susan G. Kreissman, Katherine K. Matthay, Hiroyuki Shimada, Wendy B. London, Richard Sposto, Robert C. Seeger
Journal: Journal of Clinical Oncology (2012)

Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature.Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts.Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively.These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
Stable Knockdown of Polycystin-1 Confers Integrin-α2β1–Mediated Anoikis Resistance
Authors: Lorenzo Battini, Elena Fedorova, Salvador Macip, Xiaohong Li, Patricia D. Wilson, G. Luca Gusella
Journal: Journal of the American Society of Nephrology (2006)

The mechanisms of action of polycystin-1 (PC1) have been difficult to dissect because of its interaction with multiple factors, the heterogeneity of the genetic mutations, and the complexity of the experimental animal models. Here, stable knockdown of PC1 in MDCK epithelial cells was achieved by lentiviral-mediated delivery of a specific small interfering RNA for PKD1. The reduction of PC1 expression prevented tubulogenesis in three-dimensional collagen type I culture in response to hepatocyte growth factor and induced formation of cysts. PC1 knockdown created a condition of haploinsufficiency that led to hyperproliferation, increased adhesion to collagen type I, and increased apoptosis. It was shown that the suppression of PC1 was associated with the increased expression of integrin-alpha2beta1 and reduced apoptosis in cells grown on collagen type I. The engagement of integrin-alpha2beta1 seemed to be essential for the survival because PC1 knockdown cells were significantly less susceptible to anoikis by a mechanism that was reversible by anti-integrin-alpha2beta1 blocking antibodies. Overall, these data link integrin-alpha2beta1 to some of the biologic functions that are ascribed to PC1 and establish the potential of this approach for the direct study of PC1 functions in a genetically defined background. Furthermore, these findings indicate that reduction of PC1 expression levels, rather than the loss of heterozygosity, may be sufficient to induce cystogenesis.
Temporal Change in Risk of Metachronous Contralateral Renal Cell Carcinoma: Influence of Tumor Characteristics and Demographic Factors
Authors: Farhang Rabbani, Harry W. Herr, Taghreed Almahmeed, Paul Russo
Journal: Journal of Clinical Oncology (2002)

To determine the relative risk (RR) of developing a metachronous contralateral renal tumor after an initial diagnosis of renal cell carcinoma (RCC), with stratification by renal tumor characteristics, demographic factors, and follow-up duration, in order to develop an improved risk-based surveillance strategy.The 1973 to 1997 Surveillance, Epidemiology, and End Results database was used to determine the observed and expected number of metachronous contralateral renal tumors developing after an initial diagnosis of RCC.A total of 43,483 patients had a first diagnosis of RCC. Contralateral RCC developed subsequently in 155 (0.4%) of 40,049 patients with follow-up who had no synchronous diagnosis of RCC, with 10.81 expected cases (RR, 14.3; 95% CI, 12.2 to 16.8). The respective RRs (and 95% CIs) for contralateral RCC for white men and women were 16.0 (11.1 to 22.3) and 13.7 (7.7 to 22.6) at less than 2 years, 8.8 (5.0 to 14.3) and 10.5 (5.0 to 19.3) at 2 to 5 years, 13.5 (8.1 to 21.0) and 5.1 (1.4 to 13.2) at 5 to 10 years, and 13.0 (6.2 to 23.9) and 13.7 (5.0 to 29.9) at > or = 10 years, respectively. The RRs were significantly higher in black compared with white men for the first 5 years, with the RRs (and 95% CIs) in the former group of 95.3 (58.2 to 146.7) at less than 2 years and 41.9 (16.8 to 86.3) at 2 to 5 years.The incidence of metachronous contralateral RCC is stable on long-term follow-up, suggesting that surveillance of the contralateral kidney should remain rigorous on extended follow-up. Black men are at a significantly higher risk of developing contralateral RCC in the first 5 years of follow-up.
Pulmonary Microvascular Permeability
Authors: Mary I. Townsley, Zhenxing Fu, Odile Mathieu-Costello, John B. West
Journal: Circulation Research (1995)

Abstract The pressure threshold for injury of pulmonary capillaries is ≈50 to 55 cm H 2 O in the canine lung, as measured by changes in the filtration coefficient ( K f,c ). Since the pulmonary endothelial basement membrane has been observed to thicken in patients with heart failure and pulmonary venous hypertension, we hypothesized that both baseline permeability and the threshold for high-vascular-pressure injury would be altered as a result. Dogs (n=12) were chronically paced at 245 beats per minute for ≈4 weeks, then were paced at 225 beats per minute for an additional 3 weeks. Lung lobes from anesthetized paced dogs and additional control dogs (n=14) were then isolated, ventilated, and perfused with blood. Although vascular resistance was increased nearly threefold and vascular compliance reduced by 50% in the paced group, K f,c referenced to 1 g blood-free dry weight was no different from control. Despite this lack of difference at normal pulmonary vascular pressures, several significant results were obtained. First, in the paced group there was a significant increase in the threshold for high-vascular-pressure injury: K f,c measured at pulmonary vascular pressures commonly seen in heart failure (20 to 50 cm H 2 O) were significantly less in this group compared with control. Model predictions showed that in vivo, this difference in K f,c would result in a 50% reduction in the amount of water and protein cleared across the pulmonary capillary endothelial barrier in the paced group. Next, challenge with high vascular pressure resulted in less accumulation of residual blood in this group compared with control. Finally, in separate groups of animals, morphometric analysis of the alveolocapillary barrier showed that after either 4 or 7 to 8 weeks of pacing, endothelial, interstitial, and epithelial thicknesses were increased compared with control. Together, these results suggest that vascular remodeling confers a modest but important increase in the resistance of these lungs to high-vascular-pressure injury and the development of alveolar edema.
DOG PLASMA PROTEIN GIVEN BY VEIN UTILIZED IN BODY METABOLISM OF DOG
Authors: W. T. Pommerenke, H. B. Slavin, D. H. Kariher, G. H. Whipple
Journal: The Journal of Experimental Medicine (1935)

Foreign plasma protein (horse) introduced parenterally into the protein fasting dog is not utilized in the body economy. Its fate appears to be disintegration and elimination as excess urinary nitrogen. This is totally different from the fate of dog plasma protein under similar conditions. Dog hemoglobin given parenterally to the protein fasting dog is not utilized as is dog plasma protein to keep the animal in nitrogen equilibrium but the globin is largely broken down and discarded as excess urinary nitrogen. A small part of the injected hemoglobin is probably utilized to maintain the red cell concentration in the blood at high levels. Dog plasma given parenterally in a protein fasting dog will maintain the dog in nitrogen equilibrium and there is no surplus nitrogen elimination in the after periods. It is apparent that the introduced plasma protein is utilized efficiently in body metabolism to replace or repair tissue protein. It is suggested that although this is an emergency reaction the same reactions may go on in normal internal metabolism. The observation that foreign plasma and dog hemoglobin cannot be utilized when given parenterally actually strengthens this last argument for a normal contribution from plasma proteins to body proteins.
Dietary flaxseed meal reduces proteinuria and ameliorates nephropathy in an animal model of type II diabetes mellitus
Authors: Manuel T. Velasquez, S.A.M. J. Bhathena, Tedine Ranich, Arnold M. Schwartz, David E. Kardon, A.L.I. A. Ali, Christian C. Haudenschild, Carl T. Hansen
Journal: Kidney International (2003)
Shiga Toxin Promotes Podocyte Injury in Experimental Hemolytic Uremic Syndrome via Activation of the Alternative Pathway of Complement
Authors: Monica Locatelli, Simona Buelli, Anna Pezzotta, Daniela Corna, Luca Perico, Susanna Tomasoni, Daniela Rottoli, Paola Rizzo, Debora Conti, Joshua M. Thurman, Giuseppe Remuzzi, Carlamaria Zoja, Marina Morigi
Journal: Journal of the American Society of Nephrology (2014)

Shiga toxin (Stx)-producing Escherichia coli is the offending agent of postdiarrhea-associated hemolytic uremic syndrome (HUS), a disorder of glomerular ischemic damage and widespread microvascular thrombosis. We previously documented that Stx induces glomerular complement activation, generating C3a responsible for microvascular thrombosis in experimental HUS. Here, we show that the presence of C3 deposits on podocytes is associated with podocyte damage and loss in HUS mice generated by the coinjection of Stx2 and LPS. Because podocyte adhesion to the glomerular basement membrane is mediated by integrins, the relevance of integrin-linked kinase (ILK) signals in podocyte dysfunction was evaluated. Podocyte expression of ILK increased after the injection of Stx2/LPS and preceded the upregulation of Snail and downregulation of nephrin and α-actinin-4. Factor B deficiency or pretreatment with an inhibitory antibody to factor B protected mice against Stx2/LPS-induced podocyte dysregulation. Similarly, pretreatment with a C3a receptor antagonist limited podocyte loss and changes in ILK, Snail, and α-actinin-4 expression. In cultured podocytes, treatment with C3a reduced α-actinin-4 expression and promoted ILK-dependent nuclear expression of Snail and cell motility. These results suggest that Stx-induced activation of the alternative pathway of complement and generation of C3a promotes ILK signaling, leading to podocyte dysfunction and loss in Stx-HUS.
High-Resolution 3-Dimensional Reconstruction of the Infarct Border Zone
Authors: Sally L. Rutherford, Mark L. Trew, Gregory B. Sands, Ian J. LeGrice, Bruce H. Smaill
Journal: Circulation Research (2012)

Slow nonuniform electric propagation in the border zone (BZ) of a healed myocardial infarct (MI) can give rise to reentrant arrhythmia. The extent to which this is influenced by structural rather than cellular electric remodeling is unclear.To determine whether structural remodeling alone in the infarct BZ could provide a substrate for re-entry by (i) characterizing the 3-dimensional (3D) structure of the myocardium surrounding a healed MI at high spatial resolution and (ii) modeling electric activation on this structure.Anterior left ventricular (LV) infarcts were induced in 2 rats by coronary artery ligation. Three-dimensional BZ volume (4.1 mm(3) and 5.6 mm(3)) were imaged at 14 days using confocal microscopy. Viable myocytes were identified, and their connectivity and orientation were quantified. Preserved cell networks were observed in the subendocardium and subepicardium of the infarct. Myocyte tracts traversed the BZ, and there was heavy infiltration of collagen into the adjacent myocardium. Myocyte connectivity decreased by ≈65% over 250 μm across the BZ. This structure was incorporated into 3D network models on which activation was simulated using Luo-Rudy membrane dynamics assuming normal cellular electric properties. Repetitive stimulation was imposed at selected BZ sites. Stimulus site-specific unidirectional propagation occurred in the BZ with rate-dependent slowing and conduction block, and reentry was demonstrated in one substrate. Activation times were prolonged because of tract path length and local slowing.We have used a detailed image-based model of the infarct BZ to demonstrate that structural heterogeneity provides a dynamic substrate for electric reentry.
INDUCED RESISTANCE OF THE CENTRAL NERVOUS SYSTEM TO EXPERIMENTAL INFECTION WITH EQUINE ENCEPHALOMYELITIS VIRUS
Authors: R. Walter Schlesinger, Peter K. Olitsky, Isabel M. Morgan
Journal: The Journal of Experimental Medicine (1944)

Although vaccination of guinea pigs with formalin-inactivated Western equine encephalomyelitis virus rendered them specifically immune to an intracerebral challenge dose of 1,000 M.L.D. of Western virus, it failed to protect their central nervous system against the initial effects of the virus: the intracerebral challenge dose was followed by an abortive infection of 20 to 30 hours' duration characterized by fever and histopathological changes which simulated the response at that early stage of non-vaccinated control animals. During the abortive infection of immune animals, virus could occasionally be demonstrated in their brains; indeed, it was detected with about the same frequency it was isolated from brains of similarly inoculated, non-immune guinea pigs during corresponding early phases of the infection. About one week after the abortive infection there was found a marked transitory accumulation of specific neutralizing antibody in the brain tissue. See PDF for Equation equalled at this time 1:1 to 1:10 instead of the value of about 1:300 found under physiological conditions. Guinea pigs which had recovered from an abortive infection with Western virus were resistant for a limited period of time to the effects of intracerebral inoculations of the immunologically distinct viruses of Eastern equine encephalomyelitis or vesicular stomatitis.
Laboratory Markers in the Diagnosis of Venous Thromboembolism
Authors: Joseph A. Caprini, Catherine J. Glase, Christopher B. Anderson, Karen Hathaway
Journal: Circulation (2004)

Selected blood tests may be useful in the diagnosis of venous thromboembolism (VTE), or in the identification of a congenital or acquired defect associated with the development of VTE. Several studies have shown the D-dimer assay to have a high negative predictive value but poor specificity when used in the detection of VTE. Yet in the emergency room setting, the D-dimer test may be useful if a detailed risk factor analysis for each patient is included in the diagnosis. The presence of such genetic thrombophilia markers as factor V Leiden, prothrombin 20210A mutation, and antiphospholipid antibodies significantly increases a patient's risk of a thrombotic event. The relative risk of thrombosis in factor V heterozygotes is at least 3 times higher than in the general population, whereas the increased risk of thrombosis in homozygotes is estimated to be 50- to 80-fold greater than those without the defect. Thromboembolic events are reported in approximately one third of antiphospholipid-positive patients. Other markers such as hyperhomocysteinemia and deficiencies of antithrombin, protein C, or protein S, when combined with the previous mutations, significantly increase a patient's risk of a thrombotic event. We feel that it is important to identify these ultra-high-risk patients to provide adequate counseling about the risk of thrombosis before elective surgical procedures. Often, lifelong anticoagulation may be needed as these patients and family members may need testing before taking birth control pills or hormonal replacement.
Therapeutic aerosols 1--physical and practical considerations.
Authors: S P Newman, S W Clarke
Journal: Thorax (1983)

Therapeutic aerosols 1-Physical and practical considerationsThe inhaled route is a logical means of treating respiratory disorders since drugs may be delivered directly to the large surface area of the tracheobron- chial tree and alveoli.The value of inhalation treatment was recognised by ancient civilisations in India, China, and the Middle East, as well as by Hippocrates and Galen.' Since those times, and par- ticularly recently, inhalation treatment has increased greatly in sophistication, and the advantages of this route for the delivery of specific drugs have become well recognised.The drugs often begin to act very rapidly, and as a smaller dose can be used than with oral or intravenous delivery there is generally a reduction in the incidence of systemic side effects.This review is in two parts.This first part will discuss the physical nature of therapeutic aerosols and the importance of ensuring correct use of the various inhalation devices if aerosols are to reach their required site of action-so far as that is known.The second part will describe the wide range of drugs which may be given in aerosol form as topical treatment for pulmonary disorders and in some instances as a form of systemic treatment.
Compression of the Left Main Coronary Artery by a Giant Pulmonary Artery Aneurysm
Authors: Alfonso Jurado-Román, Felipe Hernández-Hernández, María J. Ruíz-Cano, María T. Velázquez-Martín, José M. Medina, Inés Pérez-López, Elvira Barrios-Garrido-Lestache, José M. Montero-Cabezas, Pilar Escribano-Subías
Journal: Circulation (2013)