tbuckley/cabot-search huggingface dataset:
MicroRNA-214 inhibits angiogenesis by targeting Quaking and reducing angiogenic growth factor release
Authors: Alain van Mil, Sebastian Grundmann, Marie-José Goumans, Zhiyong Lei, Martinus I. Oerlemans, Sridevi Jaksani, Pieter A. Doevendans, Joost P.G. Sluijter
Journal: Cardiovascular Research (2012)

Angiogenesis is a critical component of many pathological conditions in adult tissues and is essential for embryonic development. MicroRNAs are indispensable for normal vascular development, but their exact role in regulating angiogenesis remains unresolved. Previously, we have observed that miR-214 is differentially expressed in compensatory arteriogenesis. Here, we investigated the potential role of miR-214 in the process of angiogenesis.miR-214 is expressed in all major vascular cell types, and modulation of miR-214 levels in endothelial cells significantly affected tubular sprouting. In vivo silencing of miR-214 enhanced the formation of a perfused vascular network in implanted Matrigel plugs and retinal developmental angiogenesis in mice. miR-214 directly targets Quaking, a protein critical for vascular development. Quaking knockdown reduced pro-angiogenic growth factor expression and inhibited endothelial cell sprouting similar to miR-214 overexpression. In accordance, silencing of miR-214 increased the secretion of pro-angiogenic growth factors, including vascular endothelial growth factor, and enhanced the pro-angiogenic action of the endothelial cell-derived conditioned medium, whereas miR-214 overexpression had the opposite effect.Here, we report a novel role for miR-214 in regulating angiogenesis and identify Quaking as a direct target of miR-214. The anti-angiogenic effect of miR-214 is mediated through the down-regulation of Quaking and pro-angiogenic growth factor expression. This study presents miR-214 as a potential important target for pro- or anti-angiogenic therapies.
Thymocyte clones from 14-day mouse embryos. I. State of T cell receptor genes, surface markers, and growth requirements.
Authors: J Pelkonen, P Sideras, H G Rammensee, K Karjalainen, R Palacios
Journal: The Journal of Experimental Medicine (1987)

We have established in culture 13 clones from the thymus of a 14-d B10.BR mouse embryo and characterized 8 of them. All eight FT clones have the TCR-gamma and -beta genes in germline configuration. They express mRNA for the gamma, but not for the beta nor the alpha genes. All eight FT clones are Thy-1+, Ly-1+, LFA-1+, Pgp-1+, H-2K+, and T3-. Three phenotypes could be distinguished on the basis of Lyt-2, L3T4, and IL-2-R expression: Lyt-2+, L3T4-, IL-2-R+ (I); Lyt-2+, L3T4-, IL-2-R- (II); and Lyt-2+, L3T4+, IL-2-R+ (III) cells. All eight clones grow in rIL-4 and six clones also proliferate in rIL-2. Antibodies specific for IL-2-R inhibit their response to rIL-2 but not to rIL-4. The eight FT clones synthesize mRNA for IL-4 after stimulation in vitro and none of them exhibit cytolytic activity or helper function for B lymphocytes. We conclude that the FT clones are at a very early stage of T cell development, that the expression of Lyt-2 and L3T4 surface molecules can precede that of the antigen receptor, and that the same fetal thymocyte can use both IL-4 and IL-2 as growth factor.
Candidate Biomarkers of Response to an Experimental Cancer Drug Identified through a Large-scale RNA Interference Genetic Screen
Authors: Jasper Mullenders, Wolfgang von der Saal, Miranda M.W. van Dongen, Ulrike Reiff, Rogier van Willigen, Roderick L. Beijersbergen, Georg Tiefenthaler, Christian Klein, René Bernards
Journal: Clinical Cancer Research (2009)

A major impediment in the optimal selection of cancer patients for the most effective therapy is the lack of suitable biomarkers that foretell the response of a patient to a given drug. In the present study, we have used large-scale RNA interference-based genetic screens to find candidate biomarkers of resistance to a new acyl sulfonamide derivative, R3200. This compound inhibits the proliferation of tumor cells in vitro and in vivo, but its mechanism of action is unknown.We used a large-scale RNA interference genetic screen to identify modulators of the efficacy of R3200. We searched for genes whose suppression in an in vitro cell system could cause resistance to the anticancer effects of R3200.We report here that knockdown of either RBX1 or DDB1 causes resistance to the anticancer effects of R3200, raising the possibility that these two genes may have utility as biomarkers of response to this drug in a clinical setting. Interestingly, both RBX1 and DDB1 are part of an E3 ubiquitin ligase complex.We propose that suppression of the activity of a RBX1 and DDB1-containing E3 ligase complex leads to the stabilization of certain proteins, the increased abundance of which is in turn responsible for resistance to R3200. Moreover, our data suggest that RBX1 and DDB1 could potentially be developed into biomarkers of resistance to acyl sulfonamide-based cancer drugs. This will require clinical validation in a series of patients treated with R3200.
Factor Analysis of the Electrocardiogram
Authors: A. M. SCHER, A. C. YOUNG, W. M. MEREDITH
Journal: Circulation Research (1960)

The factor analysis of electrocardiograms from 17 normal individuals indicates that over 95 per cent of all the electrocardiographic "information" is accounted for by 3 factors. In the entire series, all individual leads were more than 93 per cent accounted for by 3 factors. These results indicate that there are no significant voltages at the body surface in normal individuals which can be ascribed to more than 3 internal generators. While these results indicate a 3-function system, they do not indicate a dipolar system since a dipole is a special case of a more general 3-function system.
Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/– mice
Authors: Evis Harja, De-xiu Bu, Barry I. Hudson, Jong Sun Chang, Xiaoping Shen, Kellie Hallam, Anastasia Z. Kalea, Yan Lu, Rosa H. Rosario, Sai Oruganti, Zana Nikolla, Dmitri Belov, Evanthia Lalla, Ravichandran Ramasamy, Shi Fang Yan, Ann Marie Schmidt
Journal: Journal of Clinical Investigation (2008)

Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE–/– mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.
Subtypes of intestinal metaplasia and Helicobacter pylori.
Authors: M E Craanen, P Blok, W Dekker, J Ferwerda, G N Tytgat
Journal: Gut (1992)

To determine whether there is a relationship between the presence of H pylori and the various subtypes of intestinal metaplasia in the gastric antrum, 2274 antral gastroscopic biopsies from 533 patients were examined. H pylori was found in 289 patients. Intestinal metaplasia in general was found in 135 patients. Type I intestinal metaplasia was found in 133 patients (98.5%), type II in 106 patients (78.5%) and type III in 21 patients (15.6%). Ninety eight of these 135 patients (72.6%) were H pylori positive and 37 patients (27.4%) were H pylori negative. No statistically significant difference was found in the prevalence of type I and II intestinal metaplasia between the intestinal metaplasia positive and H pylori positive and intestinal metaplasia negative and H pylori negative patients. Type III intestinal metaplasia was found less often in the intestinal metaplasia positive and H pylori positive patients (11.2%) as compared with intestinal metaplasia positive and H pylori negative patients (27%) (p less than 0.05). In contrast with type I and II intestinal metaplasia type III intestinal metaplasia was found more often in moderate/severe intestinal metaplasia than in mild intestinal metaplasia (p less than 0.02). Within the group of patients with moderate/severe intestinal metaplasia, type III was found less often in the H pylori positive patients (p less than 0.05). We suggest that the gastric milieu for H pylori is less appropriate in type III intestinal metaplasia positive patients. As type III intestinal metaplasia might be regarded as a marker of possibly increased gastric cancer risk, the lower prevalence of H pylori in these type III intestinal metaplasia positive patients might be the result of severe changes in mucosal architecture.
Antiviral effect of prolonged intermittent lymphoblastoid alpha interferon treatment in chronic hepatitis B.
Authors: H L Janssen, L Berk, S W Schalm, R A Heijtink, G Hess, S Rossol, K H Meyer zum Buschenfelde, R A Chamuleau, P L Jansen, H W Reesink
Journal: Gut (1992)

In a European multicentre study 40 patients with HBeAg positive chronic hepatitis B virus (HBV) infection were treated with 5 mega units of lymphoblastoid alpha-interferon daily according to the following regimen: a four week primer course, four weeks of rest and a second course lasting 16 to 30 weeks. After 52 weeks of follow up, a response (HBeAg seroconversion and HBV-DNA negativity) was observed in 22 patients (55%). HBsAg seroconversion occurred in five patients (12.5%). One patient exhibited a relapse for serum HBeAg and HBV-DNA after cessation of treatment. According to a response prediction model, the observed response rate was not related to the selection of patients likely to respond. The initial interferon course induced a reduction of the serum HBV-DNA and HBeAg levels of 87% and 18%, respectively, leading to a significantly lower level of viral replication activity at the start of the second longterm course compared with baseline. After 24 weeks of follow up (week 16 of the second course), 19 (48%) patients exhibited a response, 13 (32%) a partial response (HBeAg &lt; 50% of initial level or HBV-DNA negative) and 8 (20%) no response. For eight of the 13 partial responders treatment was stopped at week 24 and viral replication rebounded to pretreatment values. In the last five partial responders prolongation of therapy up to week 38 led to a definite response and HBsAg seroconversion in three of the five patients. The results of this study suggest that a short primer course and prolongation of therapy may help to enhance the response rate of alpha-interferon therapy for chronic hepatitis type B.
Targeting the Mitotic Checkpoint for Cancer Therapy with NMS-P715, an Inhibitor of MPS1 Kinase
Authors: Riccardo Colombo, Marina Caldarelli, Milena Mennecozzi, Maria Laura Giorgini, Francesco Sola, Paolo Cappella, Claudia Perrera, Stefania Re Depaolini, Luisa Rusconi, Ulisse Cucchi, Nilla Avanzi, Jay Aaron Bertrand, Roberto Tiberio Bossi, Enrico Pesenti, Arturo Galvani, Antonella Isacchi, Francesco Colotta, Daniele Donati, Jürgen Moll
Journal: Cancer Research (2010)

MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells.
The Spinal Phospholipase-Cyclooxygenase-Prostanoid Cascade in Nociceptive Processing
Authors: Camilla I. Svensson, Tony L. Yaksh
Journal: The Annual Review of Pharmacology and Toxicology (2002)

Intrathecal phospholipase A 2 (PLA 2 ) and cyclooxygenase-2 (COX-2), but not COX-1, inhibitors attenuate facilitated pain states generated by peripheral injury/inflammation and by direct activation of spinal glutamate and substance P receptors. These results are consistent with the constitutive expression of PLA 2 and COX-2 in spinal cord, the spinal release of prostaglandins by persistent afferent input, and the effects of prostaglandins on spinal excitability. Whereas the acute actions of COX-2 inhibitors are clearly mediated by constitutively expressed spinal COX-2, studies of spinal COX-2 expression indicate that it is upregulated by neural input and circulating cytokines. Given the intrathecal potency of COX-2 inhibitors, the comparable efficacy of intrathecal versus systemic COX-2 inhibitors in hyperalgesic states not associated with inflammation, and the onset of antihyperalgesic activity prior to COX-2 upregulation, it is argued that a principal antihyperalgesic mechanism of COX-2 inhibitors lies with modulation of constitutive COX-2 present at the spinal level.
Lymphoscintigraphy of a Breast Tumor Showing Focal Tracer Accumulation Along the Falciform Ligament of the Liver
Authors: L. Vermeeren, P. J. Tanis, O. E. Nieweg, R. A. Valdés Olmos
Journal: Clinical Nuclear Medicine (2010)

Technetium-99m nanocolloid was injected intratumorally in a patient with a left breast carcinoma. Sequential planar images showed drainage to an axillary and a left parasternal sentinel node. The liver showed faint homogeneous tracer uptake but there was also focal tracer accumulation adjacent to the liver. Single photon emission computed tomography–computed tomography (SPECT/CT) visualized the 2 sentinel nodes, but also intense tracer accumulation along the falciform ligament. Lymph from the breast can follow unpredictable pathways and may travel retrograde via the internal mammary chain towards lymphatic channels along the falciform ligament. This phenomenon might also explain incidental observations of umbilical metastasis in breast cancer.
Regulation of <i>HMGA1</i> Expression by <i>MicroRNA-296</i> Affects Prostate Cancer Growth and Invasion
Authors: Jian-Jun Wei, Xinyu Wu, Yi Peng, Guizhi Shi, Basturk Olca, Ximing Yang, Garrett Daniels, Iman Osman, Jiangyong Ouyang, Eva Hernando, Angel Pellicer, Johng S. Rhim, Jonathan Melamed, Peng Lee
Journal: Clinical Cancer Research (2010)

High-motility group AT-hook gene 1 (HMGA1) is a non-histone nuclear binding protein that is developmentally regulated. HMGA1 is significantly overexpressed in and associated with high grade and advance stage of prostate cancer (PC). The oncogenic role of HMGA1 is at least mediated through chromosomal instability and structural aberrations. However, regulation of HMGA1 expression is not well understood. Identification of microRNA-mediated HMGA1 regulation will provide a promising therapeutic target in treating PC.In this study, we examined the functional relation between miR-296 and HMGA1 expression in several PC cell lines and a large PC cohort. We further examined the oncogenic property of HMGA1 regulated by miR-296.Here we report that miR-296, a microRNA predicted to target HMGA1, specifically represses HMGA1 expression by promoting degradation and inhibiting HMGA1translation. Repression of HMGA1 by miR-296 is direct and sequence specific. Importantly, ectopic miR-296 expression significantly reduced PC cell proliferation and invasion, in part through the downregulation of HMGA1. Examining PC patient samples, we found an inverse correlation between HMGA1 and miR-296 expression: high levels of HMGA1 were associated with low miR-296 expression and strongly linked to more advanced tumor grade and stage.Our results indicate that miR-296 regulates HMGA1 expression and is associated with PC growth and invasion.
Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia.
Authors: C J Mann, F T Yen, A M Grant, B E Bihain
Journal: Journal of Clinical Investigation (1991)

Plasma net cholesteryl ester (CE) transfer and optimum cholesteryl ester transfer protein (CETP) activity were determined in primary hypertriglyceridemic (n = 11) and normolipidemic (n = 15) individuals. The hypertriglyceridemic group demonstrated threefold greater net CE transfer leading to enhanced accumulation of CE in VLDL. This increased net transfer was not accompanied by a change in CETP activity. In normolipidemia, but not in hypertriglyceridemia, net CE transfer correlated with VLDL triglyceride (r = 0.92, P less than 0.001). In contrast, net CE transfer in hypertriglyceridemia, but not in normolipidemia, correlated with CETP activity (r = 0.73, P less than 0.01). Correction of hypertriglyceridemia with bezafibrate reduced net CE transfer towards normal and restored the correlation with VLDL triglyceride (r = 0.90, P less than 0.005) while suppressing the correlation with CETP activity. That net CE transfer depends on VLDL concentration was confirmed by an increase of net CE transfer in normolipidemic plasma supplemented with purified VLDL. Supplementation of purified CETP to normolipidemic plasma did not stimulate net CE transfer. In contrast, net CE transfer was enhanced by addition of CETP to both plasma supplemented with VLDL and hypertriglyceridemic plasma. Thus, in normal subjects, VLDL concentration determines the rate of net CE transfer. CETP becomes rate limiting as VLDL concentration increases, i.e., in hypertriglyceridemia.
Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype
Authors: Renee M. Balliet, Gang Chen, Carla J. Gallagher, Ryan W. Dellinger, Dongxiao Sun, Philip Lazarus
Journal: Cancer Research (2009)

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor used in the treatment of cutaneous T-cell lymphoma and in clinical trials for treatment of multiple other cancers. A major mode of SAHA metabolism is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To characterize the UGTs active against SAHA, homogenates from HEK293 cell lines overexpressing UGT wild-type or variant UGT were used. The hepatic UGTs 2B17 and 1A9 and the extrahepatic UGTs 1A8 and 1A10 exhibited the highest overall activity against SAHA as determined by V(max)/K(M) (16+/-6.5, 7.1+/-2.2, 33+/-6.3, and 24+/-2.4 nL x min(-1) x microg UGT protein(-1), respectively), with UGT2B17 exhibiting the lowest K(M) (300 micromol/L) against SAHA of any UGT in vitro. Whereas the UGT1A8p.Ala173Gly variant exhibited a 3-fold (P<0.005) decrease in glucuronidation activity against SAHA compared with wild-type UGT1A8, the UGT1A8p.Cys277Tyr variant exhibited no detectable glucuronidation activity; a similar lack of detectable glucuronidation activity was observed for the UGT1A10p.Gly139Lys variant. To analyze the effects of the UGT2B17 gene deletion variant (UGT2B17*2) on SAHA glucuronidation phenotype, human liver microsomes (HLM) were analyzed for glucuronidation activity against SAHA and compared with UGT2B17 genotype. HLM from subjects homozygous for UGT2B17*2 exhibited a 45% (P<0.01) decrease in glucuronidation activity and a 75% (P<0.002) increase in K(M) compared with HLMs from subjects homozygous for the wild-type UGT2B17*1 allele. Overall, these results suggest that several UGTs play an important role in the metabolism of SAHA and that UGT2B17-null individuals could potentially exhibit altered SAHA clearance rates with differences in overall response.
Utility of Fluorescence In Situ Hybridization as a Non-invasive Technique in the Diagnosis of Upper Urinary Tract Urothelial Carcinoma
Authors: Mercedes Marín-Aguilera, Lourdes Mengual, María José Ribal, Mireia Musquera, Elisabet Ars, Humberto Villavicencio, Ferran Algaba, Antonio Alcaraz
Journal: European Urology (2006)
Jumping ability and change of jumping ability as a risk factor for developing jumper's knee? Data from the patellar tendinopathy cohort 2006-2010
Authors: H Visnes, R Bahr
Journal: British Journal of Sports Medicine (2011)

Background Previous studies on high level athletes has shown that players with jumper's knee jumps as high and perhaps even higher than the symptom-free athletes. The reason for this difference is unknown, and we know little about when this difference occurs. Objective Assess the Jumping ability and change of this ability as a risk factor for developing jumper's knee. Design Prospective cohort study. Participants Elite volleyball players at junior high school (Top Volley Norway) at Sand, Norway. Method Standardised jumping on the power platform (Boscotest). Standing jump (SJ) and countermovement jump (CMJ) were tested at baseline and then twice a year. The jumper's knee diagnosis was based on a standardised clinical examination. Results A total of 113 symptom-free students were included, with a mean observation time of 1.8 years. 19 of these developed jumper's knee (16 boys and three girls). The three symptomatic women these were excluded in the analysis. The groups were equal at baseline; asymptomatic athletes had SJ of mean 27.5 cm and CMJ at 35.0 cm, while the jumper's knee group had SJ at 28.0 cm (p=0.67 vs asymptomatic) and CMJ (37.2 cm (p=0.10). Jumping ability changed in both groups. For the asymptomatic it was SJ: 5.5 cm (95% CI 1.9 to 9.1) for and CMJ: 6.0 cm (4.1–7.9) while the corresponding results in jumper's knee group was SJ: 3.7 cm (−1.8 to 9.3) (ANOVA, p=0.003) and CMJ: 4.5 cm (0.3 to 8.8) (ANOVA, p=0.001). Conclusion There is no difference at baseline between the men who developed jumper's knee with those who remained asymptomatic. Those who remained asymptomatic, however, increased their jumping ability more than those who developed a finding that conflict with data from previous cross-sectional studies.
Cardiovascular response during severe acute asthma and its treatment in children.
Authors: A T Edmunds, S Godfrey
Journal: Thorax (1981)

Heart rate, blood pressure, pulsus paradoxus, and cardiac output measured by means of transthoracic electrical impedance cardiography have been recorded in 29 children mean age 10 years +/- 2 SD during status asthmaticus. Changes were recorded over the first two hours of treatment during which all patients received oxygen, intravenous fluid, and hydrocortisone, and were randomly assigned to receive aminophylline, salbutamol, or both. Admission values showed significant correlation of pulsus paradoxus with PaCO2 (r = 0.66). Pulsus paradoxus was greater than 20 mmHg for all patients with PaCO2 above 5.5 kPa. Mean stroke volume and cardiac output were 89% and 131% of the resting convalescent values in the same children. Stroke volume cardiac output and heart rate did not correlate with peak expiratory flow rate or blood gas measurements. Aminophylline and salbutamol together were associated with significantly greater increase in PEF than aminophylline alone (P less than 0.05). Nebulised salbutamol was just as effective as intravenous salbutamol. Heart rate and systolic blood pressure declined significantly after nebulised salbutamol and aminophylline, but not after intravenous salbutamol and aminophylline. Stroke volume and cardiac output did not change significantly in any treatment group.