gebhart/patrepeval huggingface dataset:
Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models (2011)

Pancreatic cancer is one of the most lethal of human malignancies, and potent therapeutic options are lacking. Inhibition of cell cycle progression through pharmacological blockade of cyclin-dependent kinases (CDK) has been suggested as a potential treatment option for human cancers with deregulated cell cycle control. Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-β (TGF-β) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer.
Simultaneous Assessment of Asp Isomerization and Asn Deamidation in Recombinant Antibodies by LC-MS following Incubation at Elevated Temperatures (2012)

The degradation of proteins by asparagine deamidation and aspartate isomerization is one of several chemical degradation pathways for recombinant antibodies. In this study, we have identified two solvent accessible degradation sites (light chain aspartate-56 and heavy chain aspartate-99/101) in the complementary-determining regions of a recombinant IgG1 antibody susceptible to isomerization under elevated temperature conditions. For both hot-spots, the degree of isomerization was found to be significantly higher than the deamidation of asparagine-(387, 392, 393) in the conserved CH3 region, which has been identified as being solvent accessible and sensitive to chemical degradation in previous studies. In order to reduce the time for simultaneous identification and functional evaluation of potential asparagine deamidation and aspartate isomerization sites, a test system employing accelerated temperature conditions and proteolytic peptide mapping combined with quantitative UPLC-MS was developed. This method occupies the formulation buffer system histidine/HCl (20 mM; pH 6.0) for denaturation/reduction/digestion and eliminates the alkylation step. The achieved degree of asparagine deamidation and aspartate isomerization was adequate to identify the functional consequence by binding studies. In summary, the here presented approach greatly facilitates the evaluation of fermentation, purification, formulation, and storage conditions on antibody asparagine deamidation and aspartate isomerization by monitoring susceptible marker peptides located in the complementary-determining regions of recombinant antibodies.
The Set Point of Parathyroid Hormone Stimulation by Calcium Is Normal in Progressive Renal Failure (1998)

An increased set point of PTH stimulation by ionized calcium (Ca++) has been observed in renal failure patients with severe secondary hyperparathyroidism. The extension of this concept to all renal failure patients has remained problematic, even if it could explain elevated PTH levels in the absence of other biochemical abnormalities. We were particularly interested in seeing whether the concept could fit patients with progressive renal failure (PRF). To achieve this, we studied 26 normals (N), 9 patients with PRF, and 12 hemodialyzed patients (HD) in the basal state and during parathyroid function tests. The latter two groups were studied at the end of winter and end of summer, respectively. Patients with PRF had normal levels of Ca++, PO4, and 1,25(OH)2D, and they had low-normal concentrations of 25(OH)D; their basal I- and C-PTH levels were 3- and 4-fold higher than N, as were their creatinine levels. HD had significantly lower levels of Ca++ and 1,25(OH)2D, and they had higher levels of phosphate, creatinine, I-PTH, and C-PTH than N or PRF. Stimulated levels of I-PTH were similar in N (13.6 ± 4.3 pmol/L) and PFR (18 ± 3.3 pmol/L) and elevated in HD (37.1 ± 28.7 pmol/L; P < 0.001 vs. N, and P < 0.05 vs. PRF). Nonsuppressible I-PTH was increased 2-fold in PRF (N = 0.64 ± 0.19 vs. PRF = 1.28 ± 0.46 pmol/L; P < 0.01) and 6-fold in HD (3.95 ± 2.85 pmol/L; P < 0.001 vs. others). But the set point of I-PTH stimulation by Ca++ was normal in PRF (N = 1.18 ± 0.03 vs. PRF = 1.20± 0.04 mmol/L; not significant) and decreased in HD (1.09± 0.04 mmol/L; P < 0.001 vs. others). Similar results were obtained with the set point of C-PTH and of the C-PTH/I-PTH ratio. A positive correlation was observed between serum Ca++ concentration and the set point value when all three populations were analyzed together (r = 0.759, n = 47, P < 0.0001). These results indicate that the set point of PTH stimulation is normal in PRF and decreased in hypocalcemic HD. The set point seems to adjust to the ambient Ca++ concentration of the patients, by mechanisms yet to be elucidated. This does not suggest participation of this factor to the genesis of the secondary hyperparathyroidism of PRF.
Dynamic Graph Cuts for Efficient Inference in Markov Random Fields (2007)

Abstract-In this paper we present a fast new fully dynamic algorithm for the st-mincut/max-flow problem. We show how this algorithm can be used to efficiently compute MAP solutions for certain dynamically changing MRF models in computer vision such as image segmentation. Specifically, given the solution of the max-flow problem on a graph, the dynamic algorithm efficiently computes the maximum flow in a modified version of the graph. The time taken by it is roughly proportional to the total amount of change in the edge weights of the graph. Our experiments show that, when the number of changes in the graph is small, the dynamic algorithm is significantly faster than the best known static graph cut algorithm. We test the performance of our algorithm on one particular problem: the object-background segmentation problem for video. It should be noted that the application of our algorithm is not limited to the above problem, the algorithm is generic and can be used to yield similar improvements in many other cases that involve dynamic change.
The passive transfer of immunoglobulin G serum antibodies from patients with longstanding Complex Regional Pain Syndrome (2010)

These results lend support to a pathophysiological role for IgG autoantibodies in CRPS.
Sandalwood Fragrance Biosynthesis Involves Sesquiterpene Synthases of Both the Terpene Synthase (TPS)-a and TPS-b Subfamilies, including Santalene Synthases (2011)

Sandalwood oil is one of the worlds most highly prized fragrances. To identify the genes and encoded enzymes responsible for santalene biosynthesis, we cloned and characterized three orthologous terpene synthase (TPS) genes SaSSy, SauSSy, and SspiSSy from three divergent sandalwood species; Santalum album, S. austrocaledonicum, and S. spicatum, respectively. The encoded enzymes catalyze the formation of α-, β-, epi-β-santalene, and α-exo-bergamotene from (E,E)-farnesyl diphosphate (E,E-FPP). Recombinant SaSSy was additionally tested with (Z,Z)-farnesyl diphosphate (Z,Z-FPP) and remarkably, found to produce a mixture of α-endo-bergamotene, α-santalene, (Z)-β-farnesene, epi-β-santalene, and β-santalene. Additional cDNAs that encode bisabolene/bisabolol synthases were also cloned and functionally characterized from these three species. Both the santalene synthases and the bisabolene/bisabolol synthases reside in the TPS-b phylogenetic clade, which is more commonly associated with angiosperm monoterpene synthases. An orthologous set of TPS-a synthases responsible for formation of macrocyclic and bicyclic sesquiterpenes were characterized. Strict functionality and limited sequence divergence in the santalene and bisabolene synthases are in contrast to the TPS-a synthases, suggesting these compounds have played a significant role in the evolution of the Santalum genus.
Decorin-Type I Collagen Interaction (1995)

Interactions between the core protein of the small dermatan sulfate proteoglycan decorin and type I collagen have been considered to influence the kinetics of collagen fibrillogenesis and the diameter of and the distance between the fibrils. A variety of recombinant core protein fragments were expressed in Escherichia coli, extracted from inclusion bodies, and renatured in the presence of bovine serum albumin, which was essential for obtaining functional activity. A recombinant protein lacking the first 14 amino acids of the mature core protein (P15-329) interacted with reconstituted type I collagen fibrils and inhibited collagen fibrillogenesis almost as efficiently as intact decorin purified from fibroblast secretions under non-denaturing conditions. Peptides comprising amino acids 15-183 (P15-183) and 185-329 (P185-329) were able to compete for the binding of wild-type decorin, with P15-183 being more active than P185-329. Several other peptides were much less effective. Binding studies using radioactively labeled peptides P15-183 and P185-329 gave direct evidence for the independent binding of both peptides. Peptides 15-183 and 15-125 had the capability of inhibiting collagen fibrillogenesis, whereas peptide 185-329 was inactive. These data suggest (i) that there are at least two separate binding domains for the interaction between decorin core protein and type I collagen and (ii) that binding is not necessarily correlated with an alteration of collagen fibrillogenesis.
Forskolin: a unique diterpene activator of cyclic AMP-generating systems. (1981)

Forskolin, a diterpene of the labdane family, activates adenylate cyclase in broken cell preparations as well as in intact tissues. This activation does not require the guanine nucleotide regulatory subunit of the enzyme and probably occurs via an interaction with the catalytic subunit of adenylate cyclase. Activation of adenylate cyclase by forskolin results in marked increases in levels of intracellular cyclic AMP in a variety of eukaryotic cells. Low concentrations of forskolin which alone elicit small increases in intracellular cyclic AMP greatly potentiate hormonal activation of adenylate cyclase in a number of intact cells. Forskolin elicits cellular responses which have been proposed to be dependent o cyclic AMP as a second messenger. Forskolin, thus provides an invaluable tool for the investigation of the role of cyclic AMP in physiological responses to hormones, both through it direct activation of adenylate cyclase and through its ability to potentiate hormonal activation of adenylate cyclase.
Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray (2000)

cDNA microarray technology has been increasingly used to monitor global gene expression patterns in various tissues and cell types. However, applications to mammalian development have been hampered by the lack of appropriate cDNA collections, particularly for early developmental stages. To overcome this problem, a PCR-based cDNA library construction method was used to derive 52,374 expressed sequence tags from pre- and peri-implantation embryos, embryonic day (E) 12.5 female gonad/mesonephros, and newborn ovary. From these cDNA collections, a microarray representing 15,264 unique genes (78% novel and 22% known) was assembled. In initial applications, the divergence of placental and embryonic gene expression profiles was assessed. At stage E12.5 of development, based on triplicate experiments, 720 genes (6.5%) displayed statistically significant differences in expression between placenta and embryo. Among 289 more highly expressed in placenta, 61 placenta-specific genes encoded, for example, a novel prolactin-like protein. The number of genes highly expressed (and frequently specific) for placenta has thereby been increased 5-fold over the total previously reported, illustrating the potential of the microarrays for tissue-specific gene discovery and analysis of mammalian developmental programs.
Role of chloride in angiotensin II-induced salt-sensitive hypertension. (1991)

The present study investigated the effect of the anion accompanying sodium on the development of angiotensin II-induced hypertension in rats and the role of the sympathetic nervous system and extracellular fluid volume in its mechanism. Hypertension was induced by intraperitoneal infusion of angiotensin II (125 ng/min) for 12 days via miniosmotic pump. High dietary intake of sodium chloride significantly augmented the angiotensin II-induced hypertension (mean blood pressure on day 13, 165 +/- 6 versus 142 +/- 6 mm Hg, p less than 0.05), but equimolar sodium loading provided as sodium citrate failed to enhance angiotensin II hypertension (140 +/- 6 mm Hg). Plasma norepinephrine concentration in the conscious, resting state increased with sodium chloride loading in angiotensin II-infused rats (594 +/- 42 versus 312 +/- 37 pg/ml, p less than 0.01), but it remained unchanged with sodium citrate loading (324 +/- 23 pg/ml). Correspondingly, maximum response to hexamethonium bromide, a ganglion blocker, was greater in sodium chloride-loaded angiotensin II rats (77.7 +/- 4.6 mm Hg) than that in angiotensin II (59.7 +/- 5.1 mm Hg) or in sodium citrate-loaded angiotensin II (57.7 +/- 4.2 mm Hg) rats. Moreover, extracellular fluid volume, measured as Na2(35)SO4 space, increased in sodium chloride-loaded angiotensin II rats (427 +/- 18 ml/kg body wt) as compared with that in angiotensin II rats (375 +/- 15 ml/kg body wt) but not when compared with volume in sodium citrate-loaded angiotensin II (389 +/- 7 ml/kg body wt) rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Numerical Simulation of Separation of Circulating Tumor Cells from Blood Stream in Deterministic Lateral Displacement (DLD) Microfluidic Channel (2015)

Abstract Deterministic Lateral Displacement (DLD) microfluidic devices provide a reliable label-free separation method for detection of circulating tumor cells (CTCs) in blood samples based on their biophysical properties. In this paper, we proposed an effective design of the DLD microfluidic device for the CTC separation in the blood stream. A typical DLD array is designed and numerical simulations are performed to separate the CTC and leukocyte (white blood cells) in different fluid flow conditions. Fluid-Solid Interaction method is used to investigate the behaviour of these deformable cells in fluid flow. In this study, the effects of critical parameters affecting cell separation in the DLD microfluidic devices ( e.g. flow condition, cell deformability, and stress) have been investigated. The obtained results show that unlike leukocytes, the CTC’s motion is independent of the flow condition and is laterally displaced even in higher Reynolds number. Larger cells (CTCs) cannot intercept the low-velocity fluid near the wall of the posts; thus, they move faster and become separated from leukocytes. To reduce the cellular stress during separation process, which causes increase of cell viability and more effective design of microfluidic device, the results obtained here may be used as a significant design parameter for the DLD fabrication.
Linking of 2‐Oxoglutarate and Substrate Binding Sites Enables Potent and Highly Selective Inhibition of JmjC Histone Demethylases (2012)

Select an isoform: Linking of cosubstrate and substrate binding sites enables highly selective inhibiton of isoforms of human histone lysine demethylases. The results should provide a basis for the development of potent and selective JmjC inhibitors, possibly suitable for clinical use. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Cardiac hypertrophy and histone deacetylase–dependent transcriptional repression mediated by the atypical homeodomain protein Hop (2003)

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. Repression of antihypertrophic pathways has rarely been demonstrated to cause cardiac hypertrophy in vivo. Hop is an unusual homeodomain protein that is expressed by embryonic and postnatal cardiac myocytes. Unlike other homeodomain proteins, Hop does not bind DNA. Rather, it modulates cardiac growth and proliferation by inhibiting the transcriptional activity of serum response factor (SRF) in cardiomyocytes. Here we show that Hop can inhibit SRF-dependent transcriptional activation by recruiting histone deacetylase (HDAC) activity and can form a complex that includes HDAC2. Transgenic mice that overexpress Hop develop severe cardiac hypertrophy, cardiac fibrosis, and premature death. A mutant form of Hop, which does not recruit HDAC activity, does not induce hypertrophy. Treatment of Hop transgenic mice with trichostatin A, an HDAC inhibitor, prevents hypertrophy. In addition, trichostatin A also attenuates hypertrophy induced by infusion of isoproterenol. Thus, chromatin remodeling and repression of otherwise active transcriptional processes can result in hypertrophy and heart failure, and this process can be blocked with chemical HDAC inhibitors.
A code decompression architecture for VLIW processors (2001)

In embedded system design, memory has been one of the most restricted resources. Reducing program size has been an important goal when designing an embedded system. Most of the previous work on code compression has targeted RISC architectures. Recently VLIW processors became very popular, particularly for signal processing. Decompression speed is especially important for VLIW architectures given that the length of the instruction word is long. Furthermore, modern VLIW architectures use flexible instruction formats, which require new code compression approaches. Previous work has assumed that instruction positions within the long instruction word correspond to specific functional units. In contrast, our code compression algorithm is capable of compressing flexible instruction formats, where any functional unit can be used for any position in the instruction word. We demonstrate our methods by applying it to the TMS320C6x architecture. We also compare two techniques for decompressing the VLIW instruction packet to reduce the decompression time. A fast parallel decompression architecture is described, which is implemented in TSMC 0.25 technology.
Beneficial effects of a leukotriene antagonist on endotoxin-induced acute hemodynamic alterations. (1987)

The role of lipoxygenase metabolites of arachidonic acid as inflammatory mediators of endotoxin shock remains uncertain. In this study the effect of LY171883, a selective leukotriene D4/E4 antagonist, on the hemodynamic alterations of endotoxin shock was assessed. Adult male rats were given an intraperitoneal injection of LY171883 (30 mg/kg) or vehicle 10 minutes prior to intravenous injection of endotoxin (15 mg/kg) or vehicle. Cardiac output, mean arterial pressure, and multiple organ blood flows were determined at 30 minutes after endotoxin or vehicle administration with 85Sr-radiolabeled microspheres. Cardiac output decreased from 32.1 +/- 2.7 ml/min/100 g in the control group to 16.3 +/- 2.7 ml/min/100 g in endotoxin-treated animals (P less than .05). Pretreatment with LY171883 blunted significantly (P less than .05) this fall in cardiac output (26.3 +/- 2.6 ml/min/100 g). Endotoxin reduced mean arterial pressure from 95 +/- 8 mm Hg in controls to 57 +/- 8 (P less than .05), which was not, however, different from control values in rats receiving the LTD4/E4 antagonist. There was also significant (P less than .05) blunting of the endotoxin-induced fall in blood flow to the heart, gastrointestinal tract, and kidneys in animals pretreated with LY171883. Our data demonstrate that this selective leukotriene D4/E4 antagonist has significant salutary actions in endotoxin shock and suggest that LTD4 and/or E4 mediate, in part, the acute hemodynamic sequelae of endotoxin shock.
Distinguishing Androgen Receptor Agonists and Antagonists: Distinct Mechanisms of Activation by Medroxyprogesterone Acetate and Dihydrotestosterone (1999)

Natural and pharmacological androgen receptor (AR) ligands were tested for their ability to induce the AR NH2-terminal and carboxyl-terminal (N/C) interaction in a two-hybrid protein assay to determine whether N/C complex formation distinguishes in vivo AR agonists from antagonists. High-affinity agonists such as dihydrotestosterone, mibolerone, testosterone, and methyltrienolone at concentrations between 0.1 and 1 nM induce the N/C interaction more than 40-fold. The lower affinity anabolic steroids, oxandrolone and fluoxymesterone, require concentrations of 10-100 nM for up to 23-fold induction of the N/C interaction. However no N/C interaction was detected in the presence of the antagonists, hydroxyflutamide, cyproterone acetate, or RU56187, at concentrations up to 1 microM, or with 1 microM estradiol, progesterone, or medroxyprogesterone acetate; each of these steroids at 1-500 nM inhibited the dihydrotestosterone-induced N/C interaction, with medroxyprogesterone acetate being the most effective. In transient and stable cotransfection assays using the mouse mammary tumor virus reporter vector, all ligands displayed concentration-dependent AR agonist activity that paralleled induction of the N/C interaction, with antagonists and weaker agonists failing to induce the N/C interaction. AR dimerization and DNA binding in mobility shift assays and AR stabilization reflected, but were not dependent on, the N/C interaction. The results indicate that the N/C interaction facilitates agonist potency at low physiological ligand concentrations as detected in transcription, dimerization/DNA binding, and stabilization assays. However the N/C interaction is not required for agonist activity at sufficiently high ligand concentrations, nor does its inhibition imply antagonist activity.