gebhart/patrepeval huggingface dataset:
P1–338: Safety, tolerability and immunogenicity of an immunotherapeutic vaccine (vanutide cridificar [ACC‐001]) and the QS‐21 adjuvant in Japanese individuals with mild‐to‐moderate Alzheimer's disease: A phase IIa, multicenter, randomized, adjuvant and placebo clinical trial (2013)

Vanutide cridificar (ACC-001) is a novel immunotherapeutic vaccine for the treatment of Alzheimer's Disease (AD) composed of amino-terminal peptides (1–7) of amyloid beta (Aβ) conjugated to a CRM 197 carrier, designed to elicit an anti-Aβ antibody response while avoiding an Aβ(1–42)-directed T-cell response. Objective: To assess the safety and tolerability of multiple doses of ACC-001 in Japanese subjects with mild to moderate AD. Immunogenicity and exploratory efficacy assessments were also conducted. Subjects were treated with 3μg of ACC-001 with QS-21 adjuvant (50μg), 10μg or 30μg of ACC-001 with/without QS-21, QS-21 alone, or PBS alone at day 1 and months 3, 6, 9, and 12, and followed for 12 months. Immunogenicity was evaluated by anti-Aβ IgG antibody titration. Exploratory efficacy evaluations included ADAS-Cog, DAD, NTB, and MMSE. Forty subjects were randomized and treated with either QS-21 50μg alone; 3μg, 10μg, or 30μg of ACC-001 with/without QS-21 (n=6 for each group); or PBS (n=4). Thirty-two subjects (80%) completed the study and 8 subjects (20%) discontinued the study for reasons other than adverse events (AEs) or lack of efficacy. The most common (≥2 subjects) treatment-emergent AEs (TEAEs) in the ACC-001 with/without QS-21 group were cataract, dental caries, injection site erythema/pain, pyrexia, nasopharyngitis, contusion, blood triglycerides increased, glucosuria, proteinuria, and back pain. Most TEAEs were mild (32 subjects) or moderate (3) in severity and self-limiting. Serious AEs were reported for 2 subjects: contusion, cholecystitis infective, and duodenal ulcer (ACC-001 3μg + QS-21, considered not related to study drug) and angina pectoris (ACC-001 30μg + QS-21, considered treatment related). No deaths occurred. High titer and sustained anti-Aβ IgG antibodies were observed in the ACC-001 with QS-21 groups. Addition of QS-21 was essential for high-titer responses. Due to a small number of subjects and intersubject variability, exploratory efficacy results did not support or refute a clinical benefit with ACC-001. Repeat administration of ACC-001 (3μg, 10μg, and 30μg) with/without QS-21 was generally safe and well tolerated. Addition of QS-21 was essential to elicit high-titer responses. High-titer, sustained, anti-Aβ IgG responses were observed with no apparent differences among the 3 ACC-001 doses tested.
The PI3K‐Akt pathway inhibits senescence and promotes self‐renewal of human skin‐derived precursors in vitro (2011)

Skin-derived precursors (SKPs) are embryonic neural crest- or somite-derived multipotent progenitor cells with properties of dermal stem cells. Although a large number of studies deal with their differentiation ability and potential applications in tissue damage repair, only a few studies have concentrated on the regulation of SKP self-renewal. Here, we found that after separation from their physiological microenvironment, human foreskin-derived SKPs (hSKPs) quickly senesced and lost their self-renewal ability. We observed a sharp decrease in Akt activity during this process, suggesting a possible role of the PI3K-Akt pathway in hSKP maintenance in vitro. Blocking this pathway with several inhibitors inhibited hSKP proliferation and sphere formation and increased hSKP senescence. In contrast, activating this pathway with PDGF-AA and a PTEN inhibitor, bpV(pic), promoted proliferation, improved sphere formation, and alleviated senescence of hSKPs, without altering their differentiation potential. Data also implied that this effect was associated with altered actions of FoxO3 and GSK-3β. Our results suggest an important role of the PI3K-Akt pathway in the senescence and self-renewal of hSKPs. These findings also provide a better understanding of the cellular mechanisms underlying hSKP self-renewal and stem cell senescence to allow more efficient expansion of hSKPs for regenerative medical applications.
Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping (2001)

1. Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its different regions), in the present study we examined the uptake of psychotropic drugs by vertically cut slices of whole brain, grey (cerebral cortex) and white (corpus callosum, internal capsule) matter of the brain and by neuronal and astroglial cell cultures. 2. Moreover, we assessed the contribution of lysosomal trapping to total drug uptake (total uptake=lysosomal trapping+phospholipid binding) by tissue slices or cells conducting experiments in the presence and absence of 'lysosomal inhibitors', i.e., the lysosomotropic compound ammonium chloride (20 mM) or the Na(+)/H(+)-ionophore monensin (10 microM), which elevated the internal pH of lysosomes. The initial concentration of psychotropic drug in the incubation medium was 5 microM. 3. Both total uptake and lysosomal trapping of the antidepressants investigated (imipramine, amitriptyline, fluoxetine, sertraline) and neuroleptics (promazine, perazine, thioridazine) were higher in the grey matter and neurones than in the white matter and astrocytes, respectively. Lysosomal trapping of the psychotropics occurred mainly in neurones where thioridazine sertraline and perazine showed the highest degree of lysosomotropism. 4. Distribution interactions between antidepressants and neuroleptics took place in neurones via mutual inhibition of lysosomal trapping of drugs. 5. A differential number of neuronal and glial cells in the brain may mask the lysosomal trapping and the distribution interactions of less potent lysosomotropic drugs in vertically cut brain slices. 6. A reduction (via a distribution interaction) in the concentration of psychotropics in lysosomes (depot), which leads to an increase in their level in membranes and tissue fluids, may intensify the pharmacological action of the combined drugs.
Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles. (1994)

L-692,429 is a substituted benzolactam that has recently been shown to stimulate GH secretion from rat pituitary cells in vitro with an ED50 of 60 nM. In the current studies, we evaluated the efficacy and specificity of L-692,429 as a GH secretagogue in beagles. L-692,429 at 0.1, 0.25, or 1.0 mg/kg or saline vehicle was administered iv to four male and four female beagles in a balanced cross-over design. Blood samples were collected up to 75 min posttreatment, and serum was assayed for GH, cortisol, PRL, and LH. Mean peak serum GH levels were significantly increased (P < 0.05) by L-692,429 to 13 +/- 2 (mean +/- SEM) ng/ml (0.1 mg/kg), 39 +/- 6 ng/ml (0.25 mg/kg), or 71 +/- 11 ng/ml (1.0 mg/kg) over the saline control value of 3.6 +/- 0.6 ng/ml. Mean peak GH levels occurred at 15 min and had returned to near-baseline levels by 75 min. There was no difference in response between sexes. Mean peak cortisol levels were significantly increased (P < 0.05) by 2.2-, 2.7-, and 3.1-fold above control levels (3.0 +/- 0.2 micrograms/dl) at 25-35 min and returned to near-baseline levels by 75 min. PRL was slightly decreased after L-692,429 treatment, whereas LH was not affected. In a second study, three groups of three male beagles each were administered 5.0 mg/kg L-692,429, iv; iv saline, or 2.2 U/kg ACTH, im. Blood was collected for 8 h posttreatment and assayed for GH, cortisol, ACTH, aldosterone, PRL, insulin, T3, and T4. L-692,429 administration significantly increased (P < 0.05) GH over the control level (6.0 +/- 3.6 ng/ml) to 133 +/- 14 ng/ml by 15 min, with a return to pretreatment levels by 120 min. Cortisol levels were significantly increased (P < 0.05) by 2.0-fold (L-692,429) or 2.9-fold (ACTH) over the saline control peak concentration of 5.6 +/- 1.6 micrograms/dl and were associated with concurrent increases in ACTH levels of 1.2-fold (L-692,429) or 2.1-fold (ACTH) over the saline control peak concentration of 67 +/- 20 pmol/L. Aldosterone, PRL, T3, and T4 were not significantly affected after L-692,429 administration; however, ACTH treatment significantly increased aldosterone (P < 0.05). These data demonstrate that L-692,429 is a novel nonpeptidyl secretagogue that stimulates a marked, but transient, increase in serum GH levels in the dog.(ABSTRACT TRUNCATED AT 400 WORDS)
Fabrication of Tailored Powder Structures by Electrophoretic Deposition and Sintering (2010)

To enable sintering net-shape capabilities, a novel procedure for the fabrication of net-shape functionally graded composites by electrophoretic deposition and sintering are developed. The initial shape of the green specimen produced by electrophoretic deposition is designed in such a way so that the required final shape is achieved after sintering-imposed distortions. The shaped components can be metals, ceramics, polymers, and their combination as long as the material is in the form of powders. Through adjustment of an externally applied electric field and the shielding of electrical filed, the particles in the slurry are selectively deposited onto the porous mold which defines the desired geometry. By changing the slurries’ composition, the deposited component’s composition can be precisely tailored.
Secretin stimulates exocytosis in isolated bile duct epithelial cells by a cyclic AMP-mediated mechanism. (1992)

Intrahepatic bile duct epithelial cells, or cholangiocytes, contribute to bile secretion in response to hormones, including secretin. However, the mechanism by which secretin stimulates ductular bile flow is unknown. Since recent data in nonhepatic epithelia have suggested a role for exocytosis in fluid secretion, we tested the hypothesis that secretin stimulates exocytosis by isolated cholangiocytes. Cholangiocytes were isolated from normal rat liver by a newly described method employing enzymatic digestion and mechanical disruption followed by immunomagnetic separation using specific monoclonal antibodies, and exocytosis was measured using a fluorescence unquenching assay employing acridine orange. Secretin caused a dose-dependent (10(-12)-10(-7) M) increase in acridine orange fluorescence by acridine orange-loaded cholangiocytes with a peak response at 10 min; the half-maximal concentration of secretin was 7 x 10(-9) M. The secretin effect was inhibited by preincubation of cholangiocytes with colchicine (30% inhibition, p less than 0.05) or trypsin (90% inhibition, p less than 0.001); no inhibition was seen with lumicolchicine and heat-inactivated trypsin. Cholecystokinin, insulin, and somatostatin had no effect on fluorescence of acridine orange-loaded cholangiocytes; secretin had no effect on fluorescence of acridine orange-loaded hepatocytes or hepatic endothelial cells. Exposure of isolated cholangiocytes to secretin at doses that stimulated exocytosis caused a dose-dependent increase in cyclic AMP levels (218% maximal increase, p less than 0.05); moreover, an analogue of cyclic AMP stimulated exocytosis by cholangiocytes. Secretin had no effect on intracellular calcium concentration using Fura-2-loaded cholangiocytes assessed by digitized video microscopy. Our results demonstrate, for the first time, that secretin stimulates exocytosis by rat cholangiocytes. The effect is cell- and hormone-specific, dependent on intact microtubules, on a protein(s) on the external surface of cholangiocytes, and on changes in cellular levels of cyclic AMP. The results are consistent with the hypothesis that secretin-induced changes in bile flow may involve an exocytic process.
Thermogenic and Secondary Biogenic Gases, San Juan Basin, Colorado and New Mexico--Implications for Coalbed Gas Producibility (1994)

The San Juan basin is the most prolific coalbed gas basin in the world with 1992 production exceeding 440 Gcf (FOOTNOTE *) (12.4 billion m3), resources of approximately 50 Tcf (1.4 trillion m3), and proved reserves of over 6 Tcf (170 billion m3). Coalbed gas wells with the highest production (initial potential greater than 10 Mcf/day or 0.28 million m3/day) occur in the overpressured, north-central part of the basin. Hydrologic analysis indicates that overpressure in the Fruitland Formation is artesian in origin and represents repressuring that developed during the middle Pliocene. Highly permeable, laterally continuous coal beds override abandoned shoreline Pictured Cliffs sandstones and extend to the elevated recharge area in he northern basin to form a dynamic, regionally interconnected aquifer system. Coal rank and basin hydrodynamics control the composition of Fruitland coalbed gases, which varies significantly across the basin. Chemically dry gases in the north-central part of the basin coincide with meteoric recharge and regional overpressure. The consistency of methane ^dgr13C values across the basin, the presence of isotopically heavy carbon dioxide in coalbed gases and bicarbonate in formation waters, and biodegraded n-alkane distributions of some coal extracts indicate that coalbed gases in the north-central basin are a mixture of thermogenic (25-50%), secondary biogenic (15-30%), and migrated thermogenic (12-60%) gases. Migrated, conventionally and hydrodynamically trapped gases, in-situ generated secondary biogenic gases, and solution gases result in gas content that plot on or above the coal sorption isotherm. Bacteria transported basinward in groundwater flowing from the elevated northern basin margins metabolized wet gas components, n-alkanes, and organic compounds in the coal and generated secondary biogenic methane and carbon dioxide subsequent to coalification, uplift, erosion, and cooling. These gases may be limited to basin margins, where shallow depths and structural deformation result in higher permeability, or may extend more than 35 mi (56 km) basinward from the recharge zone. The presence of appreciable secondary biogenic gas indicates an active dynamic flow system with overall permeability sufficient for high productivity. Basin hydrogeology, reservoir heterogeneity, location of permeability barriers (no-flow boundaries), and the timing of biogenic gas generation and trap devel pment are critical for exploration and development of unconventional gas resources in organic-rich rocks.
A Human Antibody that Binds to the γ-carboxyglutamic Acid Domain of Factor IX Is a Potent Antithrombotic In Vivo (1999)

Summary 10C12, a human antibody F(ab’)2, which specifically binds to the Gla domain of factor IX, interfered with all known coagulation processes that involve factor IX/IXa. These include the function of the intrinsic Xase complex and the activation of zymogen factor IX by factor XIa and by the tissue factor:factor VIIa complex. Furthermore, 10C12 potently inhibited activated partial thromboplastin clotting times (APTT) in plasma of guinea pig and rat, thus enabling in-vivo evaluation. In guinea pigs, a bolus administration of 10C12 (10 μg/kg) prevented cyclic flow variations in damaged carotid arteries without affecting coagulation or bleeding parameters. At a 100-fold higher dose, 10C12 had no effect on normal hemostasis as assessed by the cuticle bleeding time. At this dose, 10C12 was also efficacious in a rat arterial thrombosis model, substantially reducing clot weight and duration of vessel occlusion while prolonging ex-vivo APTT only 1.2-fold. The dose of heparin required to produce comparable antithrombotic effects prolonged the APTT by 12-fold and increased the tail bleeding time (TBT) by 8-fold. In contrast, 10C12 had no effect on TBT. However, rat tails showed a tendency for rebleeding which 10C12 exacerbated. In conclusion, the antithrombotic potency of the 10C12 antibody in two species provides evidence for an important role of F.IX, and its Gla domain in particular, during thrombogenesis under arterial flow conditions. The relative safety at effective doses of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders. Abbreviations Gla: γ-carboxyglutamic acid; CDRs: complementarity determining regions; CVFs: cyclic flow variations; TF:F.VIIa: tissue factor:factor VIIa; APTT: activated partial thromboplastin time; PT: prothrombin time; ACT: whole blood activated clotting time; CBT: cuticle bleeding time; TBT: tail bleeding time
Improved methods for calculating vectors of short length in a lattice, including a complexity analysis (1985)

The standard methods for calculating vectors of short length in a lattice use a reduction procedure followed by enumerating all vectors of <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="bold upper Z Superscript m"> <mml:semantics> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:msup> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mi mathvariant="bold">Z</mml:mi> </mml:mrow> </mml:mrow> <mml:mi>m</mml:mi> </mml:msup> </mml:mrow> <mml:annotation encoding="application/x-tex">{{\mathbf {Z}}^m}</mml:annotation> </mml:semantics> </mml:math> </inline-formula> in a suitable box. However, it suffices to consider those <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="bold x element-of bold upper Z Superscript m"> <mml:semantics> <mml:mrow> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mi mathvariant="bold">x</mml:mi> </mml:mrow> </mml:mrow> <mml:mo>∈</mml:mo> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:msup> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mi mathvariant="bold">Z</mml:mi> </mml:mrow> </mml:mrow> <mml:mi>m</mml:mi> </mml:msup> </mml:mrow> </mml:mrow> <mml:annotation encoding="application/x-tex">{\mathbf {x}} \in {{\mathbf {Z}}^m}</mml:annotation> </mml:semantics> </mml:math> </inline-formula> which lie in a suitable ellipsoid having a much smaller volume than the box. We show in this paper that searching through that ellipsoid is in many cases much more efficient. If combined with an appropriate reduction procedure our method allows to do computations in lattices of much higher dimensions. Several randomly constructed numerical examples illustrate the superiority of our new method over the known ones.
Mechanism of the inhibitory effect of surfactants on intramuscular absorption of drugs. (1977)

The mechanism of the absorption inhibitory effect of surfactants on the intramuscular absorption of drugs was investigated. The following observations were demonstrated. 1) All surfactants used in this study whether nonionic or ionic caused solubilization of muscle protein. A good correlation between the solubilization of muscle protein and the absorption inhibitory effect was also found except in the case of the nonionic surfactant HCO-120. 2) The effect of hyaluronidase in the absence or presence of various concentrations of polysorbate 80 on the intramuscular absorption of drugs of different molecular weight was examined. The coexistence of hyaluronidase and polysorbate 80 greatly affected the absorption of drugs. This was depending upon the molecular size of diffused drug and the concentration of surfactant. It was found that increasing the concentrations of polysorbate 80 in the presence of hyaluronidase was accompanied by an inhibition in the absorption of isonicotinamide and abolishment of the accelerating effect of hyaluronidase on the absorption of 14C-sucrose, but it could not show any effect on the absorption of 14C-inulin. 3) The permeability coefficient of gelatin-sodium chondroitin sulfate mixed membrane in the presence of polysorbate 80 was decreased significantly. From these results, it can be concluded that the surfactants interacted with proteins and mucopolysaccharides which are the main components of connective tissue, consequently the intramuscular absorption of drugs was extremely inhibited.
Hostile takeovers: viral appropriation of the NF-kB pathway (2001)

Transcriptional regulators of the NF-kB/IkB family promote the expression of well over 100 target genes, the majority of which participate in the host immune response (1). These proteins include a multitude of cytokines and chemokines, receptors required for immune recognition, proteins involved in antigen presentation, and adhesion receptors involved in transmigration across blood vessels walls. Because of this extensive role in immune action, NF-kB has been termed the central mediator of the immune response. Gene knockout and other studies establish roles for NF-kB in the ontogeny of the immune system but also demonstrate that NF-kB participates at multiple steps during oncogenesis (2) and the regulation of programmed cell death (3).

For several reasons, the NF-kB pathway provides an attractive target to viral pathogens. Activation of NF-kB is a rapid, immediate early (IE) event that occurs within minutes after exposure to a relevant inducer, does not require de novo protein synthesis, and results in a strong transcriptional stimulation of several early viral as well as cellular genes. In this review, we will describe strategies that viruses have evolved to modulate the NF-kB pathway, to enhance viral replication, host cell survival, and evasion of immune responses. Activation of NF-kB constitutes an obvious target because many of its target genes — growth factors, cytokines and their receptors, and proto-oncogenes — profoundly influence the host cell cycle. In addition, some viruses exploit the antiapoptotic properties of NF-kB to evade the host defense mechanisms that limit replication by killing infected cells, or conversely to trigger apoptosis as a mechanism to increase virus spread.

Perhaps not surprisingly, the persistent activation of the NF-kB pathway maintained by certain viruses contributes to oncogenic transformation (2). In addition to the classic studies with the avian REV-T retrovirus which contains the v-Rel oncoprotein and induces a rapid and fatal B-cell lymphoma in young birds (4), several lines of evidence demonstrate that NF-kB family members contribute to human oncogenesis. Localization of NF-kB–encoding genes at sites of chromosomal translocations and genomic rearrangements in cancer, high levels of NF-kB activity in many breast cancer cells, and constitutive nuclear NF-kB complexes in Hodgkin’s lymphoma cells all support this view (2). Furthermore, as discussed below, viral oncogene products, including human T-cell leukemia virus type 1 (HTLV-1) Tax protein and Epstein-Barr virus latent infection membrane protein 1 (EBV LMP1), each act by unique mechanisms to disrupt NF-kB regulation and initiate viral transformation.
Overexpression of Exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs (2004)

Plasmids or viral vectors that express short hairpin RNAs (shRNAs) have emerged as important tools for the stable inhibition of specific genes by RNA interference. shRNAs are structural and functional homologs of pre-microRNAs, intermediates in the production of endogenously encoded microRNAs (miRNAs). Therefore, overexpressed shRNAs could inhibit miRNA function by competing for a limiting level of one or more factors involved in miRNA biogenesis or function. Here, we demonstrate that overexpressed shRNAs can saturate the activity of endogenous Exportin 5, a factor required for nuclear export of both shRNAs and pre-miRNAs. While shRNA overexpression can therefore inhibit miRNA function, simultaneous overexpression of Exportin 5 reverses this effect. Moreover, Exportin 5 overexpression can significantly enhance RNA interference mediated by shRNAs. These data have implications for the future clinical utilization of shRNAs and also provide a simple method to enhance RNA interference by shRNAs in culture.