gebhart/patrepeval huggingface dataset:
Pharmacokinetics/pharmacodynamics (PK/PD) of ivosidenib in patients with IDH1-mutant advanced solid tumors from a phase 1 study. (2018)

2577 Background: Mutant isocitrate dehydrogenase 1 (mIDH1) produces the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (IVO; AG-120) is a targeted mIDH1 inhibitor under evaluation in an ongoing phase 1 study (NCT02073994) in mIDH1 advanced solid tumors including cholangiocarcinoma (CC), chondrosarcoma (CS), and glioma. We explored the PK profile of IVO, the relationship between IVO exposure and 2-HG inhibition, and the effect of intrinsic/extrinsic patient factors on IVO exposure. Methods: IVO was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles. As of May 12, 2017, 168 patients (pts) had received IVO 100 mg BID to 1200 mg QD in dose escalation (8 dose levels, n = 60) and 500 mg QD in expansion (n = 108). IVO was assessed in plasma and 2-HG in plasma and tumor biopsies using LC-MS/MS assays. Results: After single and multiple doses, IVO showed good oral exposure, was rapidly absorbed, and plasma levels declined bi-exponentially after peaking, with a mean terminal half-life of 40–102 h after a single dose. IVO exposure and half-life were lower in pts with glioma than with CC/CS. IVO exposure increased less than dose proportionally. Steady state (SS) was reached within 14 days, with moderate accumulation (1.5- to 1.7-fold for AUC at 500 mg QD) across all tumors. No intrinsic patient factors were identified that affected IVO exposure. Mild/moderate renal impairment, mild hepatic impairment, and concomitant administration of weak CYP3A4 inhibitors/inducers had no effect on IVO clearance at SS. After multiple doses in pts with CC/CS, plasma 2-HG was reduced by up to 98% to levels seen in healthy subjects. Maximal plasma 2-HG reduction occurred at 500 mg QD in most pts, with no additional inhibition at higher doses. Tumor 2-HG showed a substantial reduction and positive correlation with plasma 2-HG. There was no significant pretreatment elevation of plasma 2-HG in glioma pts. Conclusions: IVO demonstrated good oral exposure and a long half-life, enabling oral QD dosing, and robust, persistent 2-HG inhibition in pts with mIDH1 CC/CS. IVO 500 mg QD is appropriate for these pts irrespective of intrinsic patient factors or concomitant weak CYP3A4 inhibitors/inducers. Clinical trial information: NCT02073994.
Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion (2020)

Pancreatic cancer ranks high among the causes of cancer-related mortality. The prognosis of this grim condition has not improved significantly over the past 50 years, despite advancement in imaging techniques, cancer genetics and treatment modalities. Due to the relative difficulty in the early detection of pancreatic tumors, as low as 20% of patients are eligible for potentially curative surgery; moreover, chemotherapy and radiotherapy (RT) do not confer a great benefit in the overall survival of the patients. Currently, emerging developments in immunotherapy have yet to bring a significant clinical advantage among pancreatic cancer patients. In fact, pancreatic tumor-driven immune evasion possesses one of the greatest challenges leading to immunotherapeutic resistance. Most of the immune escape pathways are innate, while poor priming of hosts' immune response and immunoediting constitute the adaptive immunosuppressive machinery. In this review, we extensively discuss the pathway perturbations undermining the anti-tumor immunity specific to pancreatic cancer. We also explore feasible up-and-coming therapeutic strategies that may restore immunity and address therapeutic resistance, bringing hope to eliminate the status quo in pancreatic cancer prognosis.
Solution Synthesis of Thin Films in the SnO2−In2O3 System: A Case Study of the Mixing of Sol−Gel and Metal-Organic Solution Processes (2006)

Thin films with nominal molar compositions ranging from 98% In2O3−2% SnO2 to 2% In2O3−98% SnO2 were prepared by mixing solutions of Sn(II) 2-ethylhexanoate in butanol with In2O3 sols prepared by a chemical complexation-based sol−gel process. The starting solutions were characterized by Fourier transform infrared spectroscopy, while the thin films, prepared by spin coating on silicon substrates and subsequent heat treatments up to 500 or 800 °C, were characterized by X-ray diffraction, field emission scanning electron microscopy, Auger spectroscopy, Fourier transform infrared spectroscopy, high-resolution transmission electron microscopy, and electron energy loss spectroscopy. It was concluded that the main factor governing the film formation is the lack of cross-linking reactions between the Sn and In species in the starting solutions. This may result in phase separation already during the spinning stage, in particular, for compositions with comparable concentrations of the two components. During the heat treatment, In2O3 crystallization is favored and is able to prevent that of SnO2 even when the concentration of the former is 10%. This result is explained by referring to the different chemistry involved in the solution processing of the Sn precursor with respect to the sol−gel processing of In2O3. Upon heat treatment up to 800 °C, a peculiar structure forms in the film with 30% In2O3, constituted by a mixture of nanocrystals of SnO2, In2O3, and a mixed phase.
Interindividual variability in sensitivity to warfarin-Nature or nurture? (2001)

At optimized steady state, individual sensitivity to warfarin is determined by CYP2C9 genotype and age with no effect of vitamin K. Prospective studies will determine the impact of these findings in clinical practice.
Near-field alignment of phased-array antennas (1999)

This paper describes the algorithms and equipment used to apply near-field scanning techniques to the phase alignment of phased-array antennas. This procedure achieves a level of precision not previously available. The electronic scanning property of the antenna is used to bring different sections of the antenna spectrum within range of the near-field scanning process. These partial spectra are then merged to define the entire spectrum of the antenna. This process provides the resolution needed to determine the excitation at individual elements by the inverse Fourier transformation operation. The process described here has been used in the production of a very large number of phased-array antennas currently in service.
Deficiency of acylpeptide hydrolase in small-cell lung carcinoma cell lines. (1992)

During protein biosynthesis, processing of the N terminus of many proteins may occur through acetylation and deacetylation. The enzyme acylpeptide hydrolase is likely involved in deacetylation of nascent peptide chains or of bioactive peptides. The related enzyme, acylase, hydrolyzes the acetyl amino acid product of the acylpeptide hydrolase reaction to acetate and a free amino acid. There is a reciprocal relationship between the substrates for these enzymes (i.e., substrates for one enzyme are competitive inhibitors for the other). In several cultured cell lines, including normal and malignant cells, the ratio of acylpeptide hydrolase to acylase enzyme activities appears to be coordinated and characteristic for a given cell type. Thus, in normal cultured lung cells, hamster ovary cells, hepatoma cells, and lymphocyte cells, nearly equal amounts of these enzymes are expressed, conducive to optimal processing of acetylated N-terminal residues. Four lines of erythroleukemic cell lines were found to express nearly twice as much acylase as acylpeptide hydrolase activity. In the Ehrlich ascites tumor cell line, where 80% of the proteins have been reported to remain acetylated at their N terminus, acylpeptide hydrolase is hardly expressed but acylase activity is not reduced. The 3p21 region of human chromosome 3, which contains the DNF15S2 locus that encodes acylpeptide hydrolase (Jones et al., Proc Natl Acad Sci USA 1991;88:2194), undergoes deletion in some carcinoma cells; the gene that encodes for the acylase is also present on region 3p of the same chromosome. We found that both acylpeptide hydrolase and acylase activities are practically absent in six small-cell lung carcinoma cell lines tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Anaerobic Growth of Escherichia coli K12 with Fumarate as Terminal Electron Acceptor. Genetic Studies with Menaquinone and Fluoroacetate-resistant Mutants (1979)

Fifteen independent menaquinone biosynthesis mutants (men) of Escherichia coli K12, selected for their inability to use fumarate as terminal electron acceptor, were investigated. Two nutritionally distinct groups were detected. The major group (13 mutants) responded to 1,4-dihydroxy-2-naphthoate (DHN), 2-succinylbenzoate (SB) and its dilactone, whereas the minor group (2 mutants) only responded to DHN. DHN was at least five times more effective than SB but it inhibited growth at concentrations greater than 10 microM. For anaerobic growth on glucose minimal medium the auxotrophs responded to much lower concentrations of DHN and SB and these intermediates could be replaced by uracil. Anaerobic growth tests showed that glycerol, formate and H2 are good substrates for E. coli when fumarate is the ultimate electron acceptor but growth with lactate or with fumarate alone is poor. All 15 men mutations were located between glpT and purF at approximately 49 min in the E. coli linkage map. Cotransduction frequencies with relevant markers were: nalA (21%), glpT (35%) and purF (15%). The presence of at least three genetically distinct classes (menC and menD, SB-requirers; menB, DHN-requirers) was indicated using abortive transduction as a complementation test and three-factor genetic analysis. The relative orientation nalA...menC-(D,B)...purF was indicated. Fluoroacetate-resistant mutants were isolated and four different classes were identified: ack, lacking acetate kinase; pta, lacking phosphotransacetylase; facA, lacking both of these activities; and facB, which retained both of these enzyme activities. Some of the pta mutants and all of the facA mutants failed to grow on media containing fumarate as terminal electron acceptor or anaerobically on glucose minimal medium. All four types had genetic lesions clustered between the men and purF sites. Average cotransduction frequencies with relevant markers were: nalA (4%), men (27 to 35%) and purF (71 to 80%).
Observation of high c n 2 and turbulent path length on OTS space-Earth link (1988)

Simple models have been used to estimate characteristic height and intensity of tropospheric refractive turbulence from fluctuations of the field amplitude received by two antennas of diverse sizes on the OTS space-Earth path. Data refer to particular events of high scintillation, probably associated with the presence of nonprecipitating clouds, and yield elevated values of cn2.
Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps (2010)

Neutrophils release decondensed chromatin termed neutrophil extracellular traps (NETs) to trap and kill pathogens extracellularly. Reactive oxygen species are required to initiate NET formation but the downstream molecular mechanism is unknown. We show that upon activation, neutrophil elastase (NE) escapes from azurophilic granules and translocates to the nucleus, where it partially degrades specific histones, promoting chromatin decondensation. Subsequently, myeloperoxidase synergizes with NE in driving chromatin decondensation independent of its enzymatic activity. Accordingly, NE knockout mice do not form NETs in a pulmonary model of Klebsiella pneumoniae infection, which suggests that this defect may contribute to the immune deficiency of these mice. This mechanism provides for a novel function for serine proteases and highly charged granular proteins in the regulation of chromatin density, and reveals that the oxidative burst induces a selective release of granular proteins into the cytoplasm through an unknown mechanism.
Probabilistic enrichment of knowledge graph entities for relation detection in conversational understanding (2014)

Knowledge encoded in semantic graphs such as Freebase has been shown to benefit semantic parsing and interpretation of natural language user utterances. In this paper, we propose new methods to assign weights to semantic graphs that reflect common usage types of the entities and their relations. Such statistical information can improve the disambiguation of entities in natural language utterances. Weights for entity types can be derived from the populated knowledge in the semantic graph, based on the frequency of occurrence of each type. They can also be learned from the usage frequencies in real world natural language text, such as related Wikipedia documents or user queries posed to a search engine. We compare the proposed methods with the unweighted version of the semantic knowledge graph for the relation detection task and show that all weighting methods result in better performance in comparison to using the unweighted version.
N1-linked melatonin dimers as bivalent ligands targeting dimeric melatonin receptors (2014)

A novel series of dimeric melatonin analogues obtained by connecting two melatonin molecules through N1 with spacers of 15–24 atoms was synthesized and characterized in 2-[125-I]-iodomelatonin binding and bioluminescence resonance energy transfer (BRET) experiments at MT1 and MT2 receptors. Compounds 4 (16 atoms spacer) and 13 (24 atoms spacer) are among the ligands inducing the maximal BRET at MT2-homodimers as well as at both types of MT1/MT2 heterodimers. Notably, ligand-induced BRET changes observed for compounds linked through spacers of 22–24 atoms could be attributed to ligand-induced conformational changes between the two protomers of MT1 and MT2 homo- and heterodimers providing evidence for the binding of both pharmacophores of dimeric melatonin analogues to the two protomers of receptor dimers.
The Bacillus subtilis iron-sparing response is mediated by a Fur-regulated small RNA and three small, basic proteins (2008)

Regulation of bacterial iron homeostasis is often controlled by the iron-sensing ferric uptake repressor (Fur). The Bacillus subtilis Fur protein acts as an iron-dependent repressor for siderophore biosynthesis and iron transport proteins. Here, we demonstrate that Fur also coordinates an iron-sparing response that acts to repress the expression of iron-rich proteins when iron is limiting. When Fur is inactive, numerous iron-containing proteins are down-regulated, including succinate dehydrogenase, aconitase, cytochromes, and biosynthetic enzymes for heme, cysteine, and branched chain amino acids. As a result, a fur mutant grows slowly in a variety of nutrient conditions. Depending on the growth medium, rapid growth can be restored by mutations in one or more of the molecular effectors of the iron-sparing response. These effectors include the products of three Fur-regulated operons that encode a small RNA (FsrA) and three small, basic proteins (FbpA, FbpB, and FbpC). Extensive complementarity between FsrA and the leader region of the succinate dehydrogenase operon is consistent with an RNA-mediated translational repression mechanism for this target. Thus, iron deprivation in B. subtilis activates pathways to remodel the proteome to preserve iron for the most critical cellular functions.
An overview of the SPHINX-II speech recognition system (1993)

In the past year at Carnegie Mellon steady progress has been made in the area of acoustic and language modeling. The result has been a dramatic reduction in speech recognition errors in the SPHINX-II system. In this paper, we review SPHINX-II and summarize our recent efforts on improved speech recognition. Recently SPHINX-II achieved the lowest error rate in the November 1992 DARPA evaluations. For 5000-word, speaker-independent, continuous, speech recognition, the error rate was reduced to 5%.
Enhancing Performance While Avoiding Damage: A Contribution of Macular Pigment (2013)

MP simultaneously reduces visual discomfort and protects from light damage at short wavelengths. As a result, MP increases the range of safe and comfortable light levels. Because higher light levels enable improved visual sensitivity for fine detail, these findings indicate that the spectral absorption properties and spatial distribution of MP combine to protect the retina while enhancing visual performance. The action spectrum for visual discomfort closely matches the risk for acute light damage to the retinal pigment epithelium, and it is consistent with a major influence from the intrinsically photosensitive retinal ganglion cells containing melanopsin. We suggest that MP interacts with nonimage-forming retinal input to achieve the dual outcomes of visual discomfort reduction and protection from light damage.
Synthesis of Oxytocin Analogues with Replacement of Sulfur by Carbon Gives Potent Antagonists with Increased Stability (2005)

[Chemical reaction: See text] The neuropeptide oxytocin 1 controls mammary and uterine smooth muscle contraction. Atosiban 2, an oxytocin antagonist, is used for prevention of preterm labor and premature birth. However, the metabolic lifetimes of such peptide drugs are short because of in vivo degradation. Facile production of oxytocin analogues with varying ring sizes wherein sulfur is replaced by carbon (methylene or methine) could be achieved by standard solid-phase peptide synthesis using olefin-bearing amino acids followed by on-resin ring-closing metathesis (RCM). These were tested for agonistic and antagonistic uteronic activity using myometrial strips taken from nonpregnant female rats. Peptide 8 showed agonistic activity in vitro (EC50= 1.4 x 10(3) +/- 4.4 x 10(2) nM) as compared to 1 (EC50= 7.0 +/- 2.1 nM). Atosiban analogues 17 (pA2= 7.8 +/- 0.1) and 18 (pA2= 8.0 +/- 0.1) showed substantial activity compared to the parent oxytocin antagonist 2 (pA2= 9.9 +/- 0.3). Carba analogue 35 (pA2= 6.1 +/- 0.1) had an agonistic activity over 2 orders of magnitude less than its parent 3 (8.8 +/- 0.5). A comparison of biological stabilities of 1,6-carba analogues of both an agonist 8 and antagonist 18 versus parent peptides 1 and 2 was conducted. The half-lives of peptides 8 and 18 in rat placental tissue were shown (Table 2) to be greatly improved versus their parents oxytocin 1 and atosiban 2, respectively. These results suggest that peptides 8 and 18 and analogues thereof may be important leads into the development of a long-lasting, commercially available therapeutic for initiation of parturition and treatment of preterm labor.
Vascular cell adhesion molecule-1 expressed by bone marrow stromal cells mediates the binding of hematopoietic progenitor cells (1992)

Human bone marrow-derived CD34+ cells were analyzed for the expression of the beta 1-family of integrin adhesion molecules. Integrin alpha 4 beta 1 was consistently expressed by greater than 90% of CD34+ cells, including essentially all assayable granulocyte-macrophage colony- forming cells (CFU-GM) and erythroid bursts (BFU-E) as shown by fluorescence-activated cell sorting studies. Adhesion of highly enriched CD34+ cells to cultured allogeneic marrow stromal cells was largely inhibited both by monoclonal antibody to alpha 4 beta 1 and to vascular cell adhesion molecule-1 (VCAM-1), a ligand for alpha 4 beta 1. VCAM-1 was found to be expressed by bone marrow stromal elements in vitro both constitutively at low level and at high levels after treatment with cytokines. Induction of VCAM-1 was cytokine- and time- dependent with maximum levels being obtained after 4 hours of exposure to a combination of interleukin-4 and tumor necrosis factor-alpha. Cytokine-induced stromal cells bound threefold higher numbers of CFU-GM and BFU-E, this increase being abrogated by anti-alpha 4 beta 1 and anti-VCAM-1 antibodies. In addition, the adhesion to stroma of more immature progenitors, the long-term culture initiating cells, also occurred through an alpha 4 beta 1/VCAM-1-dependent mechanism. These studies identify an adhesion mechanism of potential importance in the localization of primitive progenitors within the hematopoietic microenvironment.
Usage of T cell receptor (TCR) V beta gene in ulcerative colitis. (1996)

Ulcerative colitis (UC) is an inflammatory disease of unknown etiology. In this study, the expression of TCRV beta gene in UC patients was examined. The present study included 11 consecutive Japanese patients with UC. The control group comprised 10 healthy people. The usage of T Cell Receptor (TCR) V beta chain gene segments in peripheral blood was examined using RT-PCR. In addition, HLA-DR DNA typing was performed for the 11 patients with UC. The average of the positive expression rates in the UC group was 0.617 +/- 0.126, which was significantly higher than that of the control group (0.829 +/- 0.080) (p < 0.01). In the UC group, the usage of V beta chain gene in the active phase was almost same as that in the inactive phase. No specific distribution of V beta repertoire was observed in the UC group. In UC patients, no distinct correlation was found between any certain HLA-DR type and TCRV B gene usage. UC patients had a significantly lower rate of the expression of TCR V beta genes compared to normal controls. There is a possibility that the restricted usage of TCR V beta repertoire is possibly related to the existence of oligoclonal TCR repertoire in UC patients.
Effect of Macrolides on In Vivo Ion Transport across Cystic Fibrosis Nasal Epithelium (2005)

Fourteen- and 15-member macrolide antibiotics are under investigation as potential therapeutic agents for cystic fibrosis (CF). The nonantibiotic mechanisms of action of these compounds in CF are not understood. We used nasal potential difference (NPD) measurements to test the effect of macrolides on airway epithelial ion (chloride, sodium) transport of CF mice and humans. We tested clarithromycin and azithromycin in mice, and clarithromycin in patients with CF. Baseline and post-treatment NPD was measured in two strains (C57Bl6 and BalbC) of CF transmembrane regulator "knockout" and littermate control mice, and in DeltaF508/DeltaF508 mice. In addition, NPD was measured in 18 human subjects with CF (17 DeltaF-508/DeltaF-508 and 1 DeltaF-508/other) who were undergoing a 12-month, randomized, double-blind crossover study of the effects of clarithromycin on pulmonary outcome in CF. Neither clarithromycin nor azithromycin affected ion transport characteristics of normal or CF nasal epithelium in either mouse or humans. We conclude that the apparent beneficial effects of macrolides on pulmonary outcome in CF are not mediated by their modulation of ion transport.