gebhart/patrepeval huggingface dataset:
Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems Comparison with heparin and low-molecular-weight heparin (2004)

The abilities of three synthetic oligosaccharides to accelerate antithrombin inhibition of ten clotting or fibrinolytic proteinases were compared with those of unfractionated, fractionated high-affinity and low-molecular-weight heparins. The results show that the anticoagulant effects of the latter three heparins under conditions approximating physiologic are exerted almost exclusively by acceleration of the inactivation of thrombin, factor Xa and factor IXa to near diffusion-controlled rate constants of approximately 10(6) - 10(7) M(-1).s(-1). All other proteinases are inhibited with at least 20-fold lower rate constants. The anti-coagulant ability of the synthetic regular (fondaparinux) and high-affinity (idraparinux) pentasaccharides is due to a common mechanism, involving acceleration of only factor Xa inhibition to rate constants of approximately 10(6) M(-1).s(-1) . A synthetic hexadecasaccharide, containing both the pentasaccharide sequence and a proteinase binding site, exerts its anticoagulant effect by accelerating antithrombin inactivation of both thrombin and factor Xa to rate constants of approximately 10(6) - 10(7) M(-1).s(-1), although thrombin appears to be the more important target. In contrast, factor IXa inhibition is appreciably less stimulated. The conformational change of antithrombin induced both by the pentasaccharides and longer heparins contributes substantially, approximately 150-500-fold, to accelerating the inactivation of factors Xa, IXa and VIIa and moderately, approximately 50-fold, to that of factor XIIa and tissue plasminogen activator inhibition. The bridging effect due to binding of antithrombin and proteinase to the same, long heparin chain is dominating, approximately 1000-3000-fold, for thrombin inhibition and is appreciably smaller, although up to approximately 250-350-fold, for the inactivation of factors IXa and XIa. These results establish the proteinase targets of heparin derivatives currently used in or considered for thrombosis therapy and give new insights into the mechanism of heparin acceleration of antithrombin inhibition of proteinases.
Comparison of intranasal versus intravenous verapamil bioavailability. (1993)

Intranasal verapamil administration may limit intrasubject variability encountered due to the metabolism differences of the d and l-isomers. We simultaneously measured verapamil/norverapamil concentrations, PR interval, heart rate (HR), and mean arterial pressure (MAP) in six healthy volunteers receiving verapamil 5 mg intranasally and intravenously on two separate occasions. Two subjects achieved measurable verapamil concentrations after intranasal administration with a mean bioavailability of 16.1%. Intranasal bioavailability was limited secondary to instillation volume. No relationship between HR, MAP and verapamil concentration was noted. A relationship between mean intravenous verapamil concentration and mean PR interval was observed; however, extensive interpatient variability existed: two subjects demonstrated enough counterclockwise hysteresis to skew mean data. Mean data may falsely represent the verapamil concentration-effect relationship. Intranasal verapamil administration is limited by instillation volume. Development of a concentrated dosage form is necessary to assess bioavailability. Concentration-effect relationships are more accurately described using individual, rather than mean data.
The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet‐induced obesity (2007)

Obesity is one of the major health problems of our times. Elucidating the signaling mechanisms by which high-fat caloric diet induces obesity is critical for the understanding of this condition and for the development of therapeutic strategies for its treatment. Here, we demonstrate a novel role for protein CD38 as a regulator of body weight during a high-fat diet. CD38 is a ubiquitous enzyme that catalyzes the synthesis of second messengers and has been implicated in the regulation of a wide variety of signaling pathways. We report that CD38-deficient mice are protected against high-fat diet-induced obesity owing to enhanced energy expenditure. In fact, calorimetric studies indicate that CD38-deficient animals have a higher metabolic rate compared to control mice. Analysis of the mechanism revealed that this resistance to diet-induced obesity is mediated at least in part via a NAD-dependent activation of SIRT-PGC1alpha axis, a well-established cascade, involved in the regulation of mitochondrial biogenesis and energy homeostasis. Thus, together these results identify a novel pathway regulating body weight and clearly show that CD38 is a nearly obligatory component of the cellular cascade that led to diet-induced obesity.
Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA (2009)

To identify genetic events that characterize cancer progression, we conducted a comprehensive genetic evaluation of 161 primary breast tumors. Similar to the "mountain-and-hill" view of mutations, gene amplification also shows high- and low-frequency alterations in breast cancers. The frequently amplified genes include the well-known oncogenes ERBB2, FGFR1, MYC, CCND1, and PIK3CA, whereas other known oncogenes that are amplified, although less frequently, include CCND2, EGFR, FGFR2, and NOTCH3. More importantly, by honing in on minimally amplified regions containing three or fewer genes, we identified six new amplified genes: POLD3, IRAK4, IRX2, TBL1XR1, ASPH, and BRD4. We found that both the IRX2 and TBL1XR1 proteins showed higher expression in the malignant cell lines MCF10CA1h and MCF10CA1a than in their precursor, MCF10A, a normal immortalized mammary epithelial cell line. To study oncogenic roles of TBL1XR1, we performed knockdown experiments using a short hairpin RNA approach and found that depletion of TBL1XR1 in MCF10CA1h cells resulted in reduction of cell migration and invasion as well as suppression of tumorigenesis in mouse xenografts. Intriguingly, our mutation analysis showed the presence of activation mutations in the PIK3CA gene in a subset of tumors that also had DNA copy number increases in the PIK3CA locus, suggesting an additive effect of coexisting activating amino acid substitution and dosage increase from amplification. Our gene amplification and somatic mutation analysis of breast primary tumors provides a coherent picture of genetic events, both corroborating and novel, offering insight into the genetic underpinnings of breast cancer progression.
Pharmacological inhibition of TRα1 receptor potentiates the thyroxine effect on body weight reduction in rats: potential therapeutic implications in controlling body weight (2006)

It has been previously reported that thyroid hormone receptor alpha1 (TRalpha1) is involved in the regulation of food intake and heart rhythm. Herein, we show that pharmacological inhibition of TRalpha1 by dronedarone, an amiodarone like compound (shown to antagonize thyroid hormone binding to TRalpha1), prevented the thyroid hormone induced increase in food intake and heart rate acceleration in rats. This resulted in a marked reduction in body weight. It is likely that thyroid analogs may prove potential therapeutic agents for controlling body weight.
Quinupristin-dalfopristin (RP 59500): An injectable streptogramin combination (1996)

The pharmacology, pharmacokinetics, activity, and potential clinical role of quinupristin-dalfopristin (RP 59500) are described. Quinupristin-dalfopristin is the first injectable formulation of the streptogramin antibiotics. Streptogramin drug products are each composed of two chemically distinct compounds, which when administered together act synergistically by inhibiting bacterial protein synthesis. Quinupristin-dalfopristin has shown activity in vitro against many strains of streptococci and staphylococci, including methicillin- and erythromycin-resistant strains of staphylococci. The combination is more active against Enterococcus faecium than Enterococcus faecalis. It has also shown activity in vitro against certain gram-negative organisms and anaerobes. The mean maximum blood concentration at the end of a one-hour infusion ranged from 0.95 mg/L for a 1.4-mg/kg dose to 24.2 mg/L for a 29.4-mg/kg dose; there was a linear correlation between dose and mean area under the concentration-time curve. Mean half-life ranged from 1.27 to 1.53 hours. The drug is under investigation in the United States in Phase III trials. Of 60 evaluable patients with documented bacteremia involving E. faecium resistant to vancomycin, 40 (67%) had a favorable clinical response. Of 11 patients with bacteremia caused by methicillin-resistant Staphylococcus aureus, 78% had a favorable response. The efficacy of quinupristin-dalfopristin in treating resistant infections has also been suggested by smaller studies and case reports. The drug may be useful in the prophylaxis of endocarditis. Adverse reactions are generally mild and transient. Quinupristin-dalfopristin may be useful in treating serious gram-positive infections, but more clinical study is needed.
Hepatocytes as Immunological Agents (2015)

Hepatocytes are targeted for infection by a number of major human pathogens, including hepatitis B virus, hepatitis C virus, and malaria. However, hepatocytes are also immunological agents in their own right. In systemic immunity, they are central in the acute-phase response, which floods the circulation with defensive proteins during diverse stresses, including ischemia, physical trauma, and sepsis. Hepatocytes express a variety of innate immune receptors and, when challenged with pathogen- or damage-associated molecular patterns, can deliver cell-autonomous innate immune responses that may result in host defense or in immunopathology. Important human pathogens have evolved mechanisms to subvert these responses. Finally, hepatocytes talk directly to T cells, resulting in a bias toward immune tolerance.
CW operation of corner cavity semiconductor lasers (1993)

Etched facet semiconductor lasers have been fabricated and tested under CW operating conditions. The lasers consist of stripes formed by proton implantation, a total internal reflection (TIR) corner, and an output coupling facet. Devices with a variety of output coupling geometries were fabricated. Laser threshold currents and spectral characteristics were measured. Threshold current levels of devices with several different aperture sizes are compared to those of structures with standard Fabry-Perot reflectors.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
IBA PROTON PENCIL BEAM SCANNING: AN INNOVATIVE SOLUTION FOR CANCER TREATMENT (2000)

Particles are used in medical application for cancer treatment. Radiotherapy aims to deliver a high dose in a well-defined target volume while sparing the healthy surrounding tissues. Compared to the conventional radiotherapy (X-ray), protons show superior clinical performances thanks to their inherent depth dose characteristic (Bragg peak). In proton therapy, several techniques can be used to deliver the dose into the target volume. The most auspicious method, the one that allows the best conformation with the tumor, is called “Pencil Beam Scanning”. This method consists in directing lots of small pencil beam into the target in order to cover the 3D volume. IBA is developing an innovative pencil beam scanning method. The beam position is adjusted in X & Y by 2 scanning magnets while the depth depends on the beam energy. The 3D volume is divided in several slices parallel to the body surface. The dose in each slice is delivered by controlling simultaneously the beam intensity and the speed of the beam spot in the X & Y direction. The major advantage of the pencil beam scanning developed by IBA will be the pliancy in dose distribution shapes in an optimum way in term of minimizing the total treatment time.
Identification of an immunodominant cytotoxic T-lymphocyte recognition site in glycoprotein B of herpes simplex virus by using recombinant adenovirus vectors and synthetic peptides (1991)

Cytotoxic T-lymphocyte (CTL) responses to herpes simplex virus (HSV) polypeptides play an important role in recovery from infection and in preventing latency. We have previously shown that glycoprotein B (gB) is a major target recognized by HSV-specific CTLs in C57BL/6 (H-2b) and BALB/c (H-2d) mice but not in CBA/J (H-2k) mice (L. A. Witmer, K. L. Rosenthal, F. L. Graham, H. M. Friedman, A. Yee, and D. C. Johnson, J. Gen. Virol. 71:387-396, 1990). In this report, we utilize adenovirus vectors expressing gB with various deletions to localize an immunodominant site in gB, recognized by H-2b-restricted anti-HSV CTLs, to a region between residues 462 and 594. Overlapping peptides spanning this region were synthesized and used to further localize the immunodominant site to residues 489 to 515, a region highly conserved in HSV type 1 (HSV-1) and HSV-2 strains. The 11-amino-acid peptide was apparently associated exclusively with the Kb major histocompatibility complex gene product and not the Db gene product. In contrast, H-2d-restricted CTLs recognized an immunodominant site between residues 233 and 379.
The macrophage, TNF, and other cytokines. (1995)

A complex interplay of peptides known as the cytokines may have a tremendous influence over a number of inflammatory related conditions. Tumor necrosis factor occupies an early and central role in the initiation of cascades that ultimately influences a number of cell types involved in tissue inflammation, tissue rejection, cancer, and injuries from ischemia reperfusion. Only now are the cascades being defined and therapies being designed to interrupt the toxic effects of these cytokines and to treat malignancy.
Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide. (1991)

Macrophage-derived nitric oxide (NO) is cytostatic to tumor cells and microbial pathogens. We tested whether one molecular target for the cytostatic action of NO may be ribonucleotide reductase (RR), a rate-limiting enzyme in DNA synthesis. In a concentration-dependent manner, NO gas and lysates of activated macrophages that generated comparable amounts of NO led to the same degree of inhibition of partially purified RR from L1210 mouse lymphoma cells. Lysates from nonactivated macrophages, which do not produce NO, were noninhibitory. With lysates from activated macrophages, RR was protected by omitting L-arginine or by adding the NO synthase inhibitors diphenyleneiodonium, N omega-methyl-L-arginine, or N omega-amino-L-arginine. L-Arginine, but not D-arginine, abolished the protective effect of N omega-amino-L-arginine. The prototypic pharmacologic inhibitor of RR is hydroxyurea. Its structural resemblance to N omega-hydroxy-L-arginine, a reaction intermediate of NO synthase, prompted us to test if hydroxyurea can generate NO. In the presence of H2O2 and CuSO4, hydroxyurea produced NO2-/NO3-, aerobic reaction products of NO. Addition of morpholine blocked NO2-/NO3- generation from hydroxyurea and led to formation of nitrosomorpholine, as detected by gas chromatography/mass spectrometry. Thus, hydroxyurea can produce an NO-like, nitrosating rectant. L1210 cell DNA synthesis was inhibited completely by activated macrophages or by hydroxyurea, and was partially restored to the same degree in both settings by providing deoxyribonucleosides to bypass the block in RR. Thus, both NO gas and NO generated by activated macrophage lysates inhibit tumor cell RR. The RR inhibitor hydroxyurea can also generate an NO-like species. Similar, partial restoration of tumor cell DNA synthesis by deoxyribonucleosides in the presence of activated macrophages or hydroxyurea suggests that cytostasis by activated macrophages and by hydroxyurea has comparable mechanisms, including, but probably not limited to, inhibition of RR.
Synthesis of an Acyloxymethyl Prodrug of the Inositol Phosphate α-Trinositol (1996)

ABSTRACT Acyloxymethylation of an acylated silver salt of α-trinositol gives, after deprotection, membrane permeable 1D-myo-inositol 1,2,6-tris(ethoxycarbonyloxymethyl sodium phosphate). The acyl groups, 3-(4,5-methylenedioxy-2-nitrophenyl)propanoyl, are cleaved by hydrogenolysis.
CEMENT SLURRIES FOR GEOTHERMAL WELLS CEMENTING (1994)

During a well cementing special place belongs to the cement slurry design.To ensure the best quality of cementing, a thorough understanding of well parameters is essential, as well as behaviour of cement slurry (especially at high temperatures) and application of proven cementing techniques.Many cement jobs fail because of bad job planning.Well cementing without regarding what should be accomplished, can lead to well problems (channels in the cement, unwanted water, gas or fluid production, pipe corrosion) and expensive well repairs.Cementing temperature conditions are important because bottomhole circulating temperatures affect slurry thickening time, arheology, set time and compressive strength development.Knowing the actual temperature which cement encounters durin placement allows the selection of proper cementing materiak for a specific application.Slurry design is affected by well depth, bottom hole circulating temperature and static temperature, type of drilling fluid, slurry density, pumping time, quality of mix water, fluid loss control, flow regime, settling and free water, quality of cement, dry or liquid additives, strength development, and quality of the lab cement testing and equipment.Most Portland cements and Class J cement have shown suitable performances in geothermal wells.Cement system designs for geothermal wells differ from those for conventional high temperature oil and gas wells in the exclusive use of silica flour instead of silica sand, and the avoidance of fly ash as an extender.In this paper, Portland cement behaviour at high temperatures is described.Cement slurry and set cement properties are also described.Published in literature, the composition of cement slurries which were tested in geothermal conditions and which obtained required compressive strength and water permeability are listed.As a case of our practice geothermal wells Velika Ciglena-1 and Velika Ciglena-la are described.
A four-level storage 4-Gb DRAM (1997)

A 4-Gb DRAM with multilevel-storage memory cells has been developed. This large memory capacity is achieved by storing data at four levels, each corresponding to two-bit-data storage in a single memory cell. The four-level storage reduces the effective cell size by 50%. A sense amplifier using charge coupling and charge sharing was developed for the four-level sensing and restoring. The sense amplifier uses a hierarchical bit-line scheme and operates in a time-sharing mode, thus reducing the sense amplifier area. A 4-Gb DRAM fabricated using 0.15-/spl mu/m CMOS technology measures 986 mm/sup 2/. The memory cell is 0.23 /spl mu/m/sup 2/. Its capacitance of 60 fF is achieved by using a high-dielectric-constant material BST.
Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update (2011)

Despite advances in resuscitation and surgical management of combat wounds, infection remains a concerning and potentially preventable complication of combat-related injuries. Interventions currently used to prevent these infections have not been either clearly defined or subjected to rigorous clinical trials. Current infection prevention measures and wound management practices are derived from retrospective review of wartime experiences, from civilian trauma data, and from in vitro and animal data. This update to the guidelines published in 2008 incorporates evidence that has become available since 2007. These guidelines focus on care provided within hours to days of injury, chiefly within the combat zone, to those combat-injured patients with open wounds or burns. New in this update are a consolidation of antimicrobial agent recommendations to a backbone of high-dose cefazolin with or without metronidazole for most postinjury indications, and recommendations for redosing of antimicrobial agents, for use of negative pressure wound therapy, and for oxygen supplementation in flight.
Flow cytometric analysis of human bone marrow. II. Normal B lymphocyte development (1987)

A panel of B lymphoid-reactive monoclonal antibodies was used to analyze the phenotypic changes that accompany B lymphocyte development in normal human bone marrow. The B lymphoid cells were identified using light scattering and the expression of CD19 on a flow cytometer. Quantitative three-color immunofluorescence was then used to correlate other cell surface antigens on these cells identified as B lymphoid in normal marrow. CD10 and CD20 identified almost exclusive populations and provided a convenient means of discriminating between the less and more mature B lineage cells. The CD10+ cells could be further subdivided using CD34. The population of CD19+, CD10+, CD34+ cells comprised only 0.6% of marrow cells, but these contained the majority of terminal deoxynucleotidyl transferase (TdT+) cells. In the assessment of class II antigens, HLA-DR was expressed on all B lineage cells whereas HLA-DP preceded HLA-DQ in appearance during the developmental process. Among the later antigens expressed on B lineage cells, cell surface IgM, CD20, and HLA-DQ were expressed at essentially the same time. Cell surface CD10 was lost at the time when CD21 and CD22 were acquired on the cell surface. These data illustrate that multiparameter flow cytometry can be used to define a continuous progression of stages of B lymphocyte development based on cell surface antigen expression even though these cells represent a minor fraction of normal marrow cells.
Generation of a FasL-based Proapoptotic Fusion Protein Devoid of Systemic Toxicity due to Cell-surface Antigen-restricted Activation (2003)

We describe the construction of a FasL fusion protein devoid of systemic toxicity, inducing apoptosis only on cell-surface antigen-positive cells. The fusion protein consists carboxyl-terminally of the extracellular domain of FasL and amino-terminally of a fibroblast activation protein (FAP)-specific single chain antibody fragment (sc40-FasL). The latter allows immobilization-dependent conversion of the inactive soluble FasL fusion protein into an entity with membrane FasL-like activity. Thus, sc40-FasL efficiently induced apoptosis only in FAP-expressing cells. In accordance with a strict target-selective activity of sc40-FasL, the intravenous application of this reagent in mice revealed no signs of systemic toxicity and prevented growth of xenotransplanted FAP-positive (but not FAP-negative) tumor cells. The principle described here for the first time, in which cell-surface antigen-mediated activation of Fas permits local activation of Fas in vivo, opens novel avenues for the use of Fas signaling in cancer therapy.