gebhart/patrepeval huggingface dataset:
Back to the future: a recent history of haemophilia treatment (2008)

In the last few decades, the management of patients with haemophilia has witnessed dramatic improvements, through the larger availability of safe plasma-derived and recombinant products for replacement therapy. Another important step forward is the progressively larger-scale implementation of primary prophylaxis in children. Currently, the main problem in patients with haemophilia is the onset of antibodies inactivating the infused clotting factor (inhibitors), even though immune tolerance regimens that are able to eradicate inhibitors and the availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of these patients. Cure of haemophilia through gene transfer is being attempted, but relatively, it is far from being implemented on a large scale. It is likely that further improvements in replacement therapy will occur in the near future, through the availability of new-therapeutic tools such as factors VIII and IX with longer half-lives, more potent bypassing agents and factors extracted from the milk of transgenic animals.
Viscoelastic Evaluation of Gemini Surfactant Gel for Hydraulic Fracturing (2013)

Abstract The viscoelastic surfactant (VES) fluids have been used in stimulation of low permeability oil and gas reservoir due to their low formation damage. The physical association and entanglement of wormlike like micelle gives viscoelastic properties, which gives similar properties as polymer. However, conventional viscoelastic surfactant fluids were used at much higher concentration than that of traditional polymer guar fluids. The more effective VES fluids that performed at lower concentration are unmet needs to be filled. Hence, new cationic Gemini viscoelastic surfactants with connecting spacer were studied. The Gemini surfactants have higher surface activity than that of conventional surfactants. Critical micelle concentration of Gemini surfactants is 10 times lower than that of conventional surfactants. Fluids of Gemini surfactants gave the desired viscosity by forming gel structure at lower concentration than that of conventional surfactants. The viscosity of new Gemini VES fluid can be maintained above 50 cps at 1% under 120 °C and shear rate of 100 s-1. The fluid is shear stable at the temperature for 2 hours. The dynamic rheological properties of the new VES fluid showed highly elastic properties, which elastic moduli G’ is higher than loss moduli G’ ‘at angular frequency 0.1 rad/s below 100 °C. It showed good proppant suspending properties. The solvent with high polarity has less effect on fluid viscosity than that of solvent with low polarity. The Gemini VES gel can be broken down upon contacting and mixing with hydrocarbons or dilution with formation brine. The Gemini VES gel is a better alterative fluid for low damaging hydraulic fracturing.
Smad4 Inactivation Promotes Malignancy and Drug Resistance of Colon Cancer (2011)

SMAD4 is localized to chromosome 18q21, a frequent site for loss of heterozygosity in advanced stage colon cancers. Although Smad4 is regarded as a signaling mediator of the TGFβ signaling pathway, its role as a major suppressor of colorectal cancer progression and the molecular events underlying this phenomenon remain elusive. Here, we describe the establishment and use of colon cancer cell line model systems to dissect the functional roles of TGFβ and Smad4 inactivation in the manifestation of a malignant phenotype. We found that loss of function of Smad4 and retention of intact TGFβ receptors could synergistically increase the levels of VEGF, a major proangiogenic factor. Pharmacologic inhibition studies suggest that overactivation of the TGFβ-induced MEK-Erk and p38-MAPK (mitogen-activated protein kinase) auxiliary pathways are involved in the induction of VEGF expression in SMAD4 null cells. Overall, SMAD4 deficiency was responsible for the enhanced migration of colon cancer cells with a corresponding increase in matrix metalloprotease 9 enhanced hypoxia-induced GLUT1 expression, increased aerobic glycolysis, and resistance to 5'-fluoruracil-mediated apoptosis. Interestingly, Smad4 specifically interacts with hypoxia-inducible factor (HIF) 1α under hypoxic conditions providing a molecular basis for the differential regulation of target genes to suppress a malignant phenotype. In summary, our results define a molecular mechanism that explains how loss of the tumor suppressor Smad4 promotes colorectal cancer progression. These findings are also consistent with targeting TGFβ-induced auxiliary pathways, such as MEK-ERK, and p38-MAPK and the glycolytic cascade, in SMAD4-deficient tumors as attractive strategies for therapeutic intervention.
Blood warms as it flows retrograde from a femoral cannulation site to the carotid artery during cardiopulmonary bypass (1994)

Hypothermia protects the brain from injury during cardiopulmonary bypass and hypothermic circulatory arrest. However, when the arterial cannula is at sites other than the ascending aorta, brain cooling before circulatory arrest may be incomplete, contributing to poor neurological outcome. The authors performed an experiment using a rabbit model of cardiopulmonary bypass with femoral arterial perfusion. Arterial perfusate and carotid artery temperatures were simultaneously measured in six rabbits undergoing cardiopulmonary bypass, three with femoral artery cannulation, and three with subclavian artery cannulation. The subclavian artery site was chosen as a surrogate for ascending aortic cannulation. Carotid blood temperature was 3.7 degrees C to 0.3 degree C warmer than arterial perfusate temperature during femoral arterial perfusion. The temperature difference decreased over time (p = 0.0007). The temperature gradient was significantly less (p = 0.002) when subclavian arterial perfusion was used. Carotid blood temperature was 1.1 degrees C to 0.0 degree C warmer than arterial perfusate temperature during subclavian cannulation. The authors conclude that when femoral perfusion cooling is used, blood is warmed as it flows in a retrograde direction in the descending aorta to the carotid artery.
Effect of Insulin in the Induction and Regression of Atherosclerosis in the Chick (1960)

Insulin administration to intact cockerels made atherosclerotic by the feeding of a cholesterol-oil-containing diet prevented regression of coronary atherosclerosis. Insulin administration during the induction of atherosclerosis had no effect on the development of lesions. In some experiments, insulin slightly inhibited estrogen-induced protection of the coronary arteries when the birds were on a high cholesterol-oil diet.
A novel one-pot three-step synthesis of 2-(1-Benzofuran-2-yl)quinoline-3-carboxylic acid derivatives (2010)

Neste trabalho descrito um protocolo eficiente e simples para a sntese de cidos 2-(1-benzofurano-2-il)quinolina-3-carboxlicos, envolvendo trs etapas realizadas em um nico pote: sntese de ter de Williamson, hidrlise do grupo ster na posio 2 da quinolina e ciclizao por condensao intramolecular entre o aldedo e o metileno na posio 2 da quinolina
AAIR Versus DDDR Pacing in Patients with Impaired Sinus Node Chronotropy: An Echocardiographic and Cardiopulmonary Study (1997)

The aim of this study was to compare AAIR and DDDR pacing at rest and during exercise. We studied 15 patients (10 men, age 65 +/- 6 years) who had been paced for at least 3 months with activity sensor rate modulated dual chamber pacemakers. All had sick sinus syndrome (SSS) with impaired sinus node chronotropy. The patients underwent a resting echocardiographic evaluation of systolic and diastolic LV function at 60 beats/min during AAIR and DDDR pacing with an AV delay, which ensured complete ventricular activation capture. Cardiac output (CO) was also measured during pacing at 100 beats/min in both pacing modes. Subsequently, the oxygen consumption (VO2AT) and VO2AT pulse at the anaerobic threshold were measured during exercise in AAIR mode and in DDDR mode with an AV delay of 120 ms. The indices of diastolic function showed no significant differences between the two pacing modes, except for patients with a stimulus-R interval > 220 ms, for whom the time velocity integral of LV filling and LV inflow time were significantly lower under AAI than under DDD pacing. At 60 beats/min, CO was higher under AAI than under DDD mode only when the stimulus-R interval was below 220 ms. For stimulus-R intervals longer than 220 ms, and also during pacing at 100 beats/min, the CO was higher in DDD mode. The stimulus-R interval decreased in all patients during exercise. The time to anaerobic threshold, VO2AT, and VO2AT pulse showed no significant differences between the two pacing modes. Our results indicate that, at rest, although AAIR pacing does not improve diastolic function in patients with SSS, it maintains a higher CO than does DDDR pacing in cases where the stimulus-R interval is not excessively prolonged. On exertion, the two pacing modes appear to be equally effective, at least in cases where the stimulus-R interval decreases in AAIR mode.
Synthesis of 5-Hydroxyectoine from Ectoine: Crystal Structure of the Non-Heme Iron(II) and 2-Oxoglutarate-Dependent Dioxygenase EctD (2010)

As a response to high osmolality, many microorganisms synthesize various types of compatible solutes. These organic osmolytes aid in offsetting the detrimental effects of low water activity on cell physiology. One of these compatible solutes is ectoine. A sub-group of the ectoine producer's enzymatically convert this tetrahydropyrimidine into a hydroxylated derivative, 5-hydroxyectoine. This compound also functions as an effective osmostress protectant and compatible solute but it possesses properties that differ in several aspects from those of ectoine. The enzyme responsible for ectoine hydroxylation (EctD) is a member of the non-heme iron(II)-containing and 2-oxoglutarate-dependent dioxygenases (EC 1.14.11). These enzymes couple the decarboxylation of 2-oxoglutarate with the formation of a high-energy ferryl-oxo intermediate to catalyze the oxidation of the bound organic substrate. We report here the crystal structure of the ectoine hydroxylase EctD from the moderate halophile Virgibacillus salexigens in complex with Fe(3+) at a resolution of 1.85 A. Like other non-heme iron(II) and 2-oxoglutarate dependent dioxygenases, the core of the EctD structure consists of a double-stranded beta-helix forming the main portion of the active-site of the enzyme. The positioning of the iron ligand in the active-site of EctD is mediated by an evolutionarily conserved 2-His-1-carboxylate iron-binding motif. The side chains of the three residues forming this iron-binding site protrude into a deep cavity in the EctD structure that also harbours the 2-oxoglutarate co-substrate-binding site. Database searches revealed a widespread occurrence of EctD-type proteins in members of the Bacteria but only in a single representative of the Archaea, the marine crenarchaeon Nitrosopumilus maritimus. The EctD crystal structure reported here can serve as a template to guide further biochemical and structural studies of this biotechnologically interesting enzyme family.
Coupled Site-Directed Mutagenesis/Transgenesis Identifies Important Functional Domains of the Mouse Agouti Protein (1996)

The agouti locus encodes a novel paracrine signaling molecule containing a signal sequence, an N-linked glycosylation site, a central lysine-rich basic domain, and a C-terminal tail containing 10 cysteine (Cys) residues capable of forming five disulfide bonds. When overexpressed, agouti causes a number of pleiotropic effects including yellow coat and adult-onset obesity. Numerous studies suggest that agouti causes yellow coat color by antagonizing the binding of alpha-melanocyte-stimulating hormone (alpha-MSH) to the alpha-MSH-(Melanocortin-1) receptor. With the goal of identifying functional domains of agouti important for its diverse biological activities, we have generated 14 agouti mutations by in vitro site-directed mutagenesis and analyzed these mutations in transgenic mice for their effects on coat color and obesity. These studies demonstrate that the signal sequence, the N-linked glycosylation site, and the C-terminal Cys residues are important for full biological activity, while at least a portion of the lysine-rich basic domain is dispensable for normal function. They also show that the same functional domains of agouti important to coat color determination are important for inducing obesity, consistent with the hypothesis that agouti induces obesity by antagonizing melanocortin binding to other melanocortin receptors.
Dietary Administration of the Proapoptotic Vitamin E Analogue α-Tocopheryloxyacetic Acid Inhibits Metastatic Murine Breast Cancer (2006)

The ability of the vitamin E (RRR-alpha-tocopherol) derivatives alpha-tocopheryl succinate (alpha-TOS) and alpha-tocopheryloxyacetic acid (alpha-TEA) to suppress tumor growth in preclinical animal models has recently led to increased interest in their potential use for treating human cancer. To make the use of these vitamin E analogues more clinically relevant, we compared the antitumor efficacy of orally and i.p. delivered forms of alpha-TEA and alpha-TOS against a murine mammary cancer (4T1) that bears resemblance to human breast cancer because of its poor immunogenicity and high metastatic potential. In cell culture studies, we showed that both compounds inhibited tumor colony formation and induced apoptotic death of tumor cells. To avoid solubility concerns associated with the hydrophobicity of alpha-TEA and alpha-TOS, we used the vesiculated forms of alpha-TEA (V alpha-TEA) and alpha-TOS (V alpha-TOS) for the in vivo tumor studies. Both compounds inhibited the growth of preestablished 4T1 tumors when given i.p. However, when given by oral gavage, only the esterase-resistant V alpha-TEA was able to suppress primary tumor growth and reduce lung metastasis. To make this approach more translatable to the clinic, alpha-TEA was incorporated into the diet and fed to tumor-bearing mice. We report here for the first time that dietary alpha-TEA delivery significantly inhibited primary tumor growth and dramatically reduced spontaneous metastatic spread to the lung in prophylactic and therapeutic settings. This study suggests that dietary alpha-TEA could prove useful as a relatively easy and effective modality for treating metastatic breast cancer.
Actions of Rho Family Small G Proteins and p21-Activated Protein Kinases on Mitogen-Activated Protein Kinase Family Members (1996)

The mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that are regulated by distinct extracellular stimuli. The currently known members include extracellular signal-regulated protein kinase 1 (ERK1), ERK2, the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), and p38 MAP kinases. We find that overexpression of the Ste20-related enzymes p21-activated kinase 1 (PAK1) and PAK2 in 293 cells is sufficient to activate JNK/SAPK and to a lesser extent p38 MAP kinase but not ERK2. Rat MAP/ERK kinase kinase 1 can stimulate the activity of each of these MAP kinases. Although neither activated Rac nor the PAKs stimulate ERK2 activity, overexpression of either dominant negative Rac2 or the N-terminal regulatory domain of PAK1 inhibits Ras-mediated activation of ERK2, suggesting a permissive role for Rac in the control of the ERK pathway. Furthermore, constitutively active Rac2, Cdc42hs, and RhoA synergize with an activated form of Raf to increase ERK2 activity. These findings reveal a previously unrecognized connection between Rho family small G proteins and the ERK pathway.
A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis (1996)

We have examined the prothrombin gene as a candidate gene for venous thrombosis in selected patients with a documented familial history of venous thrombophilia. All the exons and the 5'- and 3'-UT region of the prothrombin gene were analyzed by polymerase chain reaction and direct sequencing in 28 probands. Except for known polymorphic sites, no deviations were found in the coding regions and the 5'-UT region. Only one nucleotide change (a G to A transition) at position 20210 was identified in the sequence of the 3'-UT region. Eighteen percent of the patients had the 20210 AG genotype, as compared with 1% of a group of healthy controls (100 subjects). In a population-based case-control study, the 20210 A allele was identified as a common allele (allele frequency, 1.2%; 95% confidence interval, 0.5% to 1.8%), which increased the risk of venous thrombosis almost threefold {odds ratio, 2.8; 95% confidence interval, 1.4 to 5.6}. The risk of thrombosis increased for all ages and both sexes. An association was found between the presence of the 20210 A allele and elevated prothrombin levels. Most individuals (87%) with the 20210 A allele are in the highest quartile of plasma prothrombin levels (> 1.15 U/mL). Elevated prothrombin itself also was found to be a risk factor for venous thrombosis.
Inhibition of Angiogenesis Mediated by Extremely Low-Frequency Magnetic Fields (ELF-MFs) (2013)

The formation of new blood vessels is an essential therapeutic target in many diseases such as cancer, ischemic diseases, and chronic inflammation. In this regard, extremely low-frequency (ELF) electromagnetic fields (EMFs) seem able to inhibit vessel growth when used in a specific window of amplitude. To investigate the mechanism of anti-angiogenic action of ELF-EMFs we tested the effect of a sinusoidal magnetic field (MF) of 2 mT intensity and frequency of 50 Hz on endothelial cell models HUVEC and MS-1 measuring cell status and proliferation, motility and tubule formation ability. MS-1 cells when injected in mice determined a rapid tumor-like growth that was significantly reduced in mice inoculated with MF-exposed cells. In particular, histological analysis of tumors derived from mice inoculated with MF-exposed MS-1 cells indicated a reduction of hemangioma size, of blood-filled spaces, and in hemorrhage. In parallel, in vitro proliferation of MS-1 treated with MF was significantly inhibited. We also found that the MF-exposure down-regulated the process of proliferation, migration and formation of tubule-like structures in HUVECs. Using western blotting and immunofluorescence analysis, we collected data about the possible influence of MF on the signalling pathway activated by the vascular endothelial growth factor (VEGF). In particular, MF exposure significantly reduced the expression and activation levels of VEGFR2, suggesting a direct or indirect influence of MF on VEGF receptors placed on cellular membrane. In conclusion MF reduced, in vitro and in vivo, the ability of endothelial cells to form new vessels, most probably affecting VEGF signal transduction pathway that was less responsive to activation. These findings could not only explain the mechanism of anti-angiogenic action exerted by MFs, but also promote the possible development of new therapeutic applications for treatment of those diseases where excessive angiogenesis is involved.
An Image Processing Method for Cardiac Motion Analysis (1987)

A new image processing method is developed to process two-dimensional ultrasound B-scan echo images which makes possible the delineation of the displacement of cardiac boundaries for the precise assessment of infarcted/ischemic regions. An economic image processing system is designed for the purpose. An algorithm to compute the direction and amplitude of the displacement vector at any point in the cardiac image, given two frames of the image at two different time instants, is developed. The performance of the algorithm is examined with synthesized images. Displacement amplitudes along the boundaries of the left ventricle are plotted and compared for normal and diseased conditions.
Fast IR laser mapping ellipsometry for the study of functional organic thin films (2015)

Fast infrared mapping with sub-millimeter lateral resolution as well as time-resolved infrared studies of kinetic processes of functional organic thin films require a new generation of infrared ellipsometers. We present a novel laboratory-based infrared (IR) laser mapping ellipsometer, in which a laser is coupled to a variable-angle rotating analyzer ellipsometer. Compared to conventional Fourier-transform infrared (FT-IR) ellipsometers, the IR laser ellipsometer provides ten- to hundredfold shorter measurement times down to 80 ms per measured spot, as well as about tenfold increased lateral resolution of 120 μm, thus enabling mapping of small sample areas with thin-film sensitivity. The ellipsometer, equipped with a HeNe laser emitting at about 2949 cm(-1), was applied for the optical characterization of inhomogeneous poly(3-hexylthiophene) [P3HT] and poly(N-isopropylacrylamide) [PNIPAAm] organic thin films used for opto-electronics and bioapplications. With the constant development of tunable IR laser sources, laser-based infrared ellipsometry is a promising technique for fast in-depth mapping characterization of thin films and blends.
Soluble heparin proteoglycans released from stimulated mast cells induce uptake of low density lipoproteins by macrophages via scavenger receptor-mediated phagocytosis. (1992)

Stimulation of rat serosal mast cells in vitro triggers exocytosis of secretory granules from their cytoplasm. Thereupon, the granules lose their perigranular membranes, and about 40% of the heparin proteoglycans and all of the chondroitin sulfate proteoglycans that they initially contained are released into the incubation medium. At physiologic ionic strength and calcium ion concentration, the solubilized heparin proteoglycans, but not the chondroitin sulfate proteoglycans, form insoluble complexes with the low density lipoproteins (LDL) present. We calculated that the heparin proteoglycans could bind approximately seven times their own mass (Mr about 1 x 10(6)) of LDL cholesterol. Using gold-labeled LDL, we observed massive phagocytosis of the heparin proteoglycan-LDL complexes by cultured mouse macrophages in vitro, which was inhibited by cytochalasin B. Uptake of LDL by mouse macrophages was 45-fold higher in the presence of solubilized heparin proteoglycans than in their absence, and continued unabated over a 72-h period, indicating that the uptake process was not under negative feedback control. Excess amounts of acetyl-LDL or polyinosinic acid inhibited the uptake of these insoluble heparin proteoglycan-LDL complexes, indicating that their phagocytosis was mediated by scavenger receptors of the acetyl-LDL receptor type. The experiments reveal the following pathophysiologic mechanism relevant to atherogenesis: stimulated mast cells secrete soluble heparin proteoglycans capable of forming insoluble complexes with LDL and thereby trigger uptake of LDL by macrophages through scavenger receptor-mediated phagocytosis.