gebhart/patrepeval huggingface dataset:
Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes (2011)

Lixisenatide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist mimicking several favorable actions of endogenous GLP-1 that result in improved glycemic control with little or no hypoglycemia and weight loss. Phase II trials have shown that lixisenatide 20 μg once daily restores first-phase insulin release in patients with type 2 diabetes and improves the second-phase insulin response. Administered once or twice daily for 4 weeks, it significantly reduced postprandial and fasting blood glucose levels, and glycosylated hemoglobin (HbA(1c)). The efficacy and safety of lixisenatide once daily is being assessed in the GETGOAL Phase III clinical trial program. Results have shown beneficial effects on HbA(1c) compared with placebo in combination with commonly used antidiabetes agents, with no increased risk of hypoglycemia and with beneficial weight reduction. Adverse effects were similar to those observed for available GLP-1 receptor agonists, the most frequent being gastrointestinal. Both GLP-1 receptor agonists and long-acting insulin analogs have demonstrated protective effects on beta cells in preclinical studies. This, along with the pronounced effect of lixisenatide on postprandial plasma glucose, provides a rationale for combining it with long-acting basal insulin analogs, in the hope that the additive effects on glycemic control combined with a potential benefit on islet cells may lead to a new treatment approach to control blood glucose better and prevent long-term complications in patients with type 2 diabetes.
Distribution and properties of beta-adrenergic receptors in human iris-ciliary body. (1987)

beta-Adrenergic receptors from the iris-ciliary body of human eyes removed shortly after death were studied using membranes prepared by isopycnic centrifugation of tissue homogenates. This procedure separates uveal melanin pigment from plasma membranes and reduces nonspecific binding of 125I-iodopindolol. The observed binding of 125I-iodopindolol was of high affinity (Kd = 78 +/- 6.6 pM), saturable, and fully reversible (t1/2 = 4.6 min). Scatchard plots were linear and revealed a Bmax of 134 +/- 20 fmol/mg of protein from the whole iris-ciliary body. The affinities of the receptors for a series of agonists and antagonists were determined. The order of potency for the inhibition of the binding of the radioligand by antagonists was ICI 118,551 greater than MK950 greater than propranolol greater than ICI 89,406 greater than metoprolol. This order of potency is characteristic of beta-adrenergic receptors of the beta 2 subtype. Preparations of iris-ciliary body were also subjected to microdissection prior to density gradient centrifugation to permit the study of beta-adrenergic receptors in the ciliary processes, ciliary body, and iris. Each of these regions was found to contain approximately one third of the total number of beta-adrenergic receptors in the human iris-ciliary body. The highest density of receptors was located in the ciliary processes (180 +/- 40 fmol/mg of protein), while the density of receptors in the iris (98 +/- 7.5 fmol/mg of protein) and ciliary body (less the processes) (42 +/- 17 fmol/mg of protein) was notably lower. Only beta 2-adrenergic receptors are detectable by competition experiments in the iris-ciliary body as a whole, or in the individual preparations of iris, ciliary processes, or ciliary body; however, microdissection and analysis of beta-adrenergic receptor subtypes in isolated ciliary muscle permitted detection of a small number of beta 1-adrenergic receptors. beta 1-Adrenergic receptors comprised about 10% of the total number of beta-adrenergic receptors in the whole iris-ciliary body. The finding that most of the beta-adrenergic receptors in the human iris-ciliary body are of the beta 2 subtype may be of significant therapeutic importance in the medical management of glaucoma.
Long-term survival after embolization of potentially lethal bleeding malignant pelvic tumours (1995)

Transcatheter embolization was performed in 45 patients suffering from potentially lethal bleeding originating from malignant tumours in the pelvic region. In 21 cases, the basic disease was rectosigmoidal and in 20, gynaecological in origin. Uncommon bleeding sites were embolized in four other cases. The median survival time (Kaplan-Meier) was 6 months. Most patients died from tumour cachexia. In 10 cases (22%), recurrent bleeding occurred, in three of these with lethal consequences. Successful reembolization was performed on seven patients. The different embolization materials used showed a minor impact on the therapeutic result. Embolization therapy proved to be an effective measure in potentially lethal malignant pelvic bleeding. Gianturco, Anderson and Wallace (GAW) coils should be given preference where there is urgency, as they are accurate, easily and quickly insertable, and cause few complications.
Lipid G Protein-coupled Receptor Ligand Identification Using β-Arrestin PathHunter™ Assay (2009)

A growing number of orphan G-protein-coupled receptors (GPCRs) have been reported to be activated by lipid ligands, such as lysophosphatidic acid, sphingosine 1-phosphate (S1P), and cannabinoids, for which there are already well established receptors. These new ligand claims are controversial due to either lack of independent confirmations or conflicting reports. We used the beta-arrestin PathHunter assay system, a newly developed, generic GPCR assay format that measures beta-arrestin binding to GPCRs, to evaluate lipid receptor and ligand pairing. This assay eliminates interference from endogenous receptors on the parental cells because it measures a signal that is specifically generated by the tagged receptor and is immediately downstream of receptor activation. We screened a large number of newly "deorphaned" receptors (GPR23, GPR92, GPR55, G2A, GPR18, GPR3, GPR6, GPR12, and GPR63) and control receptors against a collection of approximately 400 lipid molecules to try to identify the receptor ligand in an unbiased fashion. GPR92 was confirmed to be a lysophosphatidic acid receptor with weaker responses to farnesyl pyrophosphate and geranylgeranyl diphosphate. The putative cannabinoid receptor GPR55 responded strongly to AM251, rimonabant, and lysophosphatidylinositol but only very weakly to endocannabinoids. G2A receptor was confirmed to be an oxidized free fatty acid receptor. In addition, we discovered that 3,3'-diindolylmethane, a dietary molecule from cruciferous vegetables, which has known anti-cancer properties, to be a CB(2) receptor partial agonist, with binding affinity around 1 microm. The anti-inflammatory effect of 3,3'-diindolylmethane in RAW264.7 cells was shown to be partially mediated by CB(2).
ENDOTHELIAL CELL FUNCTIONS IN THE HEMODYNAMIC RESPONSES TO STRESS* (1982)

ACE is a function of the endothelial cell that appears vital to integrative homeostatic physiology in stress. The endothelial cell, both in the lung and in systemic tissues, is uniquely situated to detect changes in ambient oxygen tension; thereafter, as exemplified by the effects of altered oxygen tension on ACE, the cell is capable of initiating changes that modulate its functions to reflect the altered physiologic state. Based upon extensive studies of endothelial cells propagated in tissue culture, these altered functions are rapid in onset, rapidly reversible, and quite closely correlated to PO2. Integrity of the endothelial cell membrane is necessary for the modulating changes to occur, and indeed, ACE purified from the cell is insensitive to changes in oxygen tension: it is the cell, not the enzyme, that responds to changes in oxygen tension (FIGURE 5). It is important to emphasize the interdependent nature of the several vasoactive systems. The kallikrein-kinin system, in addition to its putative role in blood pressure regulation, is an intimate component of both the coagulation and fibrinolysis plasma protease cascades. The sympathetic nervous system has multiple points of interdigitation in both the kallikrein-kinin and the renin-angiotensin systems; high levels of epinephrine stimulate renin release and activate both plasma and tissue kallikrein. In turn, both of the vasoactive peptides of these systems, bradykinin and angiotensin II, stimulate epinephrine production from the adrenal medulla. Angiotensin II enhances the potency of norepinephrine released from postganglionic sympathetic nerve endings, increasing alpha-adrenergic tone. In addition, multiple interactions have been described between angiotensin II and bradykinin and the formation of prostaglandins by endothelial cells. Preliminary data indicate that the potency of these peptides in causing prostanoid release is, as might be expected, closely correlated to ACE activity, which itself is a function of ambient PO2. These multiple interactions are diagrammed in FIGURE 9. It is noteworthy that the two fundamental regulators of the circulation, pH and PO2, can be shown to interact at the most basic level with endothelial cell function.
Monoclonal antibodies reactive with the T cell receptor zeta chain: production and characterization using a new method. (1989)

We have developed a novel method for the production and characterization of monoclonal antibodies reactive with lineage-restricted intracellular Ag. Using this technique, we have produced a panel of antibodies that react specifically with permeabilized T lymphocytes but not with permeabilized B lymphocytes or native T cells. One of these antibodies, designated TIA-2, was found to react with greater than 98% of peripheral blood T lymphocytes. Immunoblotting experiments showed TIA-2 to recognize a 32 kd protein that was reduced to 16 kDa in the presence of 2-mercaptoethanol. Immunoprecipitates analyzed on non-reducing/reducing diagonal polyacrylamide gels showed the homodimeric structure recognized by TIA-2 to be associated with additional structures whose pattern closely resembled that of the T cell receptor complex. When immunoprecipitates formed using antibodies reactive with CD3 epsilon were immunoblotted with TIA-2, the homodimeric TCR zeta chain was specifically recognized. Using TIA-2 as a TCR zeta specific reagent, we show that whole cell expression of this TCR subunit is dramatically reduced following exposure to mAb reactive with CD3. mAb reactive with activating epitopes of CD2 were also capable of down-modulating the expression of TCR zeta, but to a lesser degree. Exposure to Con A or IL-2, on the other hand, did not reduce the whole cell expression of TCR zeta. Given the central importance of TCR zeta in the expression of a functionally competent Ag receptor, its reduced expression in response to certain activating stimuli is likely to play an important role in regulating T cell responsiveness.
Minimal Amino Acid Exchange in Human TCR Constant Regions Fosters Improved Function of TCR Gene-Modified T Cells (2010)

TCR gene therapy using adoptive transfer of TCR gene-modified T cells is a new strategy for treatment of cancer. One critical prerequisite for TCR gene therapy is sufficient expression of transferred TCRs. Several strategies to achieve optimal expression were developed, including "murinization," which replaces the human TCRalpha and TCRbeta constant regions by their murine counterparts. Using a series of mouse-human hybrid constructs, we have identified nine amino acids responsible for the improved expression of murinized TCRs. Five essential amino acid exchanges were identified in the TCRbeta C region, with exchange of a glutamic acid (human) for a basic lysine (mouse) at position 18 of the C region, being most important. For the TCRalpha C region, an area of four amino acids was sufficient for improved expression. The minimally murinized TCR variants (harboring only nine residues of the mouse sequence) enhanced expression of human TCRs by supporting preferential pairing of transferred TCR chains and a more stable association with the CD3 proteins. Most important, usage of minimally murinized TCR chains improved the function of transduced primary human T cells in comparison with cells transduced with wild-type TCRs. For TCR gene therapy, the utilization of minimally instead of completely murinized constant regions dramatically reduces the number of foreign residues and thereby the risk for immunogenicity of therapeutic TCRs.
Regularizing informal mining - a summary of the proceedings of the international roundtable on artisanal mining (1996)

Artisinal mining is the most primitive type of mining, characterized by individuals or groups exploiting deposits - usually illegally - with the simplest equipment. Although it provides an important source of income to the poor, artisinal mining engenders a host of problems: environmental; health and safety concerns; labor and gender issues; and technical, financial, regulatory, and legal issues. A key conclusion was that no real solutions are possible unless artisinal miners are given full legal and transferable mining titles to their claims.
NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo (2003)

Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD).In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid protein (A42) in a human H4 cell line.Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid protein precursor (APP) transgenic mice, and plasma and brain levels of A and the drug were evaluated.These studies show that (a) eight FDA-approved NSAIDs lower A42 in vivo, (b) the ability of an NSAID to lower A42 levels in cell culture is highly predicative of its in vivo activity, (c) in vivo A42 lowering in mice occurs at drug levels achievable in humans, and (d) there is a significant correlation between A42 lowering and levels of ibuprofen.Importantly, flurbiprofen and its enantiomers selectively lower A42 levels in broken cell -secretase assays, indicating that these compounds directly target the -secretase complex that generates A from APP.Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered A42 levels to the greatest extent.Because R-flurbiprofen reduces A42 levels by targeting -secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an A42 lowering agent.
Iron Oxide Nanoparticles for Sustained Delivery of Anticancer Agents (2005)

We have developed a novel water-dispersible oleic acid (OA)-Pluronic-coated iron oxide magnetic nanoparticle formulation that can be loaded easily with high doses of water-insoluble anticancer agents. Drug partitions into the OA shell surrounding iron oxide nanoparticles, and the Pluronic that anchors at the OA-water interface confers aqueous dispersity to the formulation. Neither the formulation components nor the drug loading affected the magnetic properties of the core iron oxide nanoparticles. Sustained release of the incorporated drug is observed over 2 weeks under in vitro conditions. The nanoparticles further demonstrated sustained intracellular drug retention relative to drug in solution and a dose-dependent antiproliferative effect in breast and prostate cancer cell lines. This nanoparticle formulation can be used as a universal drug carrier system for systemic administration of water-insoluble drugs while simultaneously allowing magnetic targeting and/or imaging.
Identification of Tumorsphere- and Tumor-Initiating Cells in HER2/Neu-Induced Mammary Tumors (2007)

A variety of human malignancies, including breast cancer, are thought to be organized in a hierarchy, whereby a relatively minor population of tumor initiating cells (TIC) is responsible for tumor growth and the vast majority of remaining cells is nontumorigenic. Analysis of TICs in model systems of breast cancer would offer uniform and accessible source of tumor cells and the power of mouse genetics to dissect these rare cells. The HER2/Neu proto-oncogene is overexpressed in an aggressive form of human breast cancer. Mouse mammary tumor virus (MMTV)-Neu transgenic mice develop mammary tumors that mimic human HER2 subtype breast cancer. Here, we report on the functional identification of mouse HER2/Neu TICs that can induce tumors after transplantation into the mammary gland of recipient mice. Secondary tumors formed after injecting MMTV-Neu TICs resemble primary tumors in the original transgenic mice and are organized in a hierarchy containing TICs as well as their nontumorigenic descendants. To study MMTV-Neu TICs in vitro, we grew tumorspheres under nonadherent culture conditions. Tumorsphere forming units (TFU) capable of producing tumorspheres retained tumorigenic potential and were indistinguishable by several criteria from TICs. Interestingly, MMTV-Neu TICs and TFUs were committed to the luminal cell fate when induced to differentiate in vitro. Our data define reproducible characteristics of the MMTV-Neu TIC and TFU, which help to explain marker expression profiles of HER2-positive breast cancer. In addition, the similarity between TICs and TFUs in this system provides a rationale for TFU-based screens to target tumor-initiating cells in HER2(+) breast cancer.
High-rate deposition of amorphous hydrogenated silicon: effect of plasma excitation frequency (1987)

The effect of plasma excitation frequency on the deposition of amorphous hydrogenated silicon in a silane glow-discharge system is investigated. A large increase in the deposition rate up to 21 Å/s is observed in the range between 25 and 150 MHz. Optical and electrical film parameters remain practically unchanged over this frequency range.
Isolation of two interferon-induced translational inhibitors: a protein kinase and an oligo-isoadenylate synthetase. (1978)

Large-scale purification of translational inhibitors present in interferon-treated mouse L cells, but not in untreated cells, led to the isolation of two interferon-induced activities. One is a protein kinase system that is activatable by double-stranded RNA and ATP and that phosphorylates a Mr 67,000 protein and the smallest subunit of eukaryotic initiation factor-2. The purified protein kinase is a strong translational inhibitor. The second activity is an enzyme that, with double-stranded RNA, slowly polymerizes ATP into oligoadenylate with a 2'-5' phosphodiester linkage. The oligo-isoadenylate in turn activates a potent inhibitor of mRNA translation.
The contribution of bovine Factor V and Factor Va to the activity of prothrombinase. (1979)

The rates of prothrombin activation under initial conditions of invariant concentrations of prothrombin and Factor Xa were studied in the presence of various combinations of Ca2+, homogeneous bovine Factor V, Factor Va, phosphatidylcholine-phosphatidylserine vesicles, and activated bovine platelets. Reactions were monitored continuously through the enhanced fluorescence accompanying the interaction of newly formed thrombin with dansylarginine-N-(3-ethyl-1,5-pentanediyl) amide. The complete prothrombinase (Factor Xa, Ca2+, phospholipid, and Factor Va) behaved as a "typical" enzyme and catalyzed the activation of prothrombin with an apparent Vmax of 2100 mol of thrombin/min/mol of Factor Va or Factor Xa, whichever was the rate-limiting component. Regardless of whether the enzymatic complex was composed of Factor Xa, Ca2+, and plasma Factor Va plus phospholipid vesicles, or activated platelets in the place of the latter components, similar specific activity values were observed. The combination of Factor Va, Ca2+, and phospholipid enhanced the rate of the Factor Xa-catalyzed activation of prothrombin by a factor of 278,000. Factor Va itself when added to Factor Xa, Ca2+, and phospholipid, enhanced the rate of prothrombin activation by a factor of 13,000. Unactivated Factor V appears to possess 0.27% of the procoagulant activity of thrombin-activated Factor Va. From the kinetics of prothrombinase activity, an interaction between Factor Xa and both Factor V and Factor Va was observed, with apparent 1:1 stoichiometries and dissociation constants of 7.3 x 10(-10) M for Factor Va and 2.7 x 10(-9) M for Factor V. The present data, combined with data on the equilibrium binding of prothrombinase components to phospholipid, indicate that the model prothrombinase described in this paper consists of a phospholipid-bound, stoichiometric complex of Factor Va and Factor Xa, with bound Factor Va serving as the "binding site" for Factor Xa, in concert with its proposed role in platelets.
Cell Adhesion Molecule Expression by Vascular Endothelial Cells as an Immune/Inflammatory Reaction in Human Colon Carcinoma (1995)

The cell adhesion of inflammatory cells to vascular endothelial cells is an important process in the recruitment of inflammatory cells to the site. In cancer tissue, infiltration of inflammatory cells has been suggested to be a mechanism of host resistance. To clarify this infiltration mechanism, we investigated cell adhesion molecule expression (E-selectin, P-selectin, and ICAM-1) in vascular endothelial cells by immunohistochemistry in colon carcinoma. Venules distributed along the invasive margin expressed E- and P-selectins and ICAM-1. These phenotypical features are identical to those of endothelial cells observed in active inflammatory lesions, and the vessels can, therefore, be designated as immunologically activated vessels. Nevertheless, the majority of blood vessels within the tumor lacked immunoreactivity for all these adhesion molecules and, therefore, could be designated as immunologically inactive vessels. Granulocytes, lymphocytes and macrophages, bearing the counter-receptors of these adhesion molecules, were more densely distributed along the invasive margin. In contrast, few inflammatory cells were present within the tumor. In conclusion, the present study has demonstrated the phenotypical heterogeneity of tumor vessels; those for inflammatory cell infiltration to the tumor and those for the nutrient supply to the tumor.
Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models (2012)

Systemic chemotherapy using two-drug platinum-based regimens for the treatment of advanced stage non-small cell lung cancer (NSCLC) has largely reached a plateau of effectiveness. Accordingly, efforts to improve survival and quality of life outcomes have more recently focused on the use of molecularly targeted agents, either alone or in combination with standard of care therapies such as taxanes. The molecular chaperone heat shock protein 90 (Hsp90) represents an attractive candidate for therapeutic intervention, as its inhibition results in the simultaneous blockade of multiple oncogenic signaling cascades. Ganetespib is a non-ansamycin inhibitor of Hsp90 currently under clinical evaluation in a number of human malignancies, including NSCLC. Here we show that ganetespib potentiates the cytotoxic activity of the taxanes paclitaxel and docetaxel in NSCLC models. The combination of ganetespib with paclitaxel, docetaxel or another microtubule-targeted agent vincristine resulted in synergistic antiproliferative effects in the H1975 cell line in vitro. These benefits translated to improved efficacy in H1975 xenografts in vivo, with significantly enhanced tumor growth inhibition observed in combination with paclitaxel and tumor regressions seen with docetaxel. Notably, concurrent exposure to ganetespib and docetaxel improved antitumor activity in 5 of 6 NSCLC xenograft models examined. Our data suggest that the improved therapeutic indices are likely to be mechanistically multifactorial, including loss of pro-survival signaling and direct cell cycle effects resulting from Hsp90 modulation by ganetespib. Taken together, these findings provide preclinical evidence for the use of this combination to treat patients with advanced NSCLC.