gebhart/patrepeval huggingface dataset:
CTNI-61. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA (2022)

Abstract Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson’s r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPK-pathway alterations, and patients with relatively high CBF.
Practical Synthesis of (3aR, 9bR)-8-Fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole: An Advanced Intermediate to Access the RORγt Inverse Agonist BMT-362265 (2021)

A practical and scalable route to (3aR, 9bR)-8-fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole 10, an advanced intermediate en route to the synthesis of the RORγt inverse agonist, BMT-362265, is described starting from fluorobenzene. The synthesis involved the screening of multiple synthetic routes for their feasibility and scalability. We also demonstrate the utility of an annulating reagent, (R)-N-(2-chloroethyl)-2-methylpropane-2-sulfinamide, for the diastereoselective synthesis of tricyclic pyrrolidine intermediates 24 and 36 on a multigram scale.
Multiplexed fiber Fabry–Perot temperature sensor system using white-light interferometry (2002)

A novel monitoring system for a fiber Fabry-Perot interferometer (FFPI) temperature sensor has yielded a resolution of 0.013 degrees C (0.0025 fringe). Light from a broadband source passes through a scanned Michelson interferometer and is reflected from a FFPI to produce a fringe pattern, the temporal position of which is proportional to a change in the optical length of the fiber interferometer. A second Michelson interferometer with a distributed-feedback laser source is used to correct for variations in the translation rate of the motor-driven scanning mirror. Coherence multiplexing of three such sensors has also been demonstrated.
Effect of Daunorubicin on Subcellular Pools of Glutathione in Cultured Heart Cells from Neonatal Rats (1988)

Alterations in cellular GSH and its compartmentation were investigated as a possible mechanism of toxicity of the anthracycline derivative daunorubicin in neonatal heart cells. Cultured beating heart cells from neonatal rats were exposed to daunorubicin at therapeutically relevant concentrations and the resulting changes in cellular GSH as well as cytosolic and mitochondrial pools of GSH were determined. Toxicity was estimated as an increased permeability of the plasma membrane to cytosolic enzymes, e.g., lactate dehydrogenase. Control heart cells were found to contain 12.2 +/- 1.8 nmoles GSH/10(6) cells. Daunorubicin caused a rapid initial decrease followed by a transient increase in cellular GSH. The extent of the latter increase was dependent on the concentration of daunorubicin. High concentrations of daunorubicin gave only a slight increase followed by a pronounced decrease in cellular GSH. By applying a digitonin-based method the effect of daunorubicin on the cytosolic and mitochondrial pools of GSH were separated. The concentration of cytosolic and mitochondrial reduced GSH was estimated to be 8.9 +/- 1.5 nmoles/10(6) cells and 3.3 +/- 0.6 nmoles/10(6) cells, respectively. The results indicate that daunorubicin caused a decrease of cytosolic GSH and, after a short lag period, a release of alctate dehydrogenase. No decrease of mitochondrial GSH occurred under these conditions indicating that daunorubicin influences selectively cytosolic GSH. No lipid peroxidation products were detected in DRB-treated cells under conditions when lactate dehydrogenase was released. Likewise, addition of the iron-chelator desferrioxamin did not influence the release of lactate dehydrogenase, whereas dithiothreitol offered partial protection.(ABSTRACT TRUNCATED AT 250 WORDS)
Diverse Mechanistic Pathways in Single-Site Heterogeneous Catalysis: Alcohol Conversions Mediated by a High-Valent Carbon-Supported Molybdenum-Dioxo Catalyst (2022)

With the increase in the importance of renewable resources, chemical research is shifting focus toward substituting petrochemicals with biomass-derived analogues and platform-molecule transformations such as alcohol processing. To these ends, in-depth mechanistic understanding is key to the rational design of catalytic systems with enhanced activity and selectivity. Here we discuss in detail the structure and reactivity of a single-site active carbon-supported molybdenum-dioxo catalyst (AC/MoO2) and the mechanism(s) by which it mediates alcohol dehydration. A range of tertiary, secondary, and primary alcohols as well as selected bio-based terpineols are investigated as substrates under mild reaction conditions. A combined experimental substituent effect/kinetic/kinetic isotope effect/EXAFS/DFT computational analysis indicates that (1) water assistance is a key element in the transition state; (2) the experimental kinetic isotopic effect and activation enthalpy are 2.5 and 24.4 kcal/mol, respectively, in good agreement with the DFT results; and (3) several computationally identified intermediates including Mo-oxo-hydroxy-alkoxide and cage-structured long-range water-coordinated Mo-dioxo species are supported by EXAFS. This structurally and mechanistically well-characterized single-site system not only effects efficient transformations but also provides insight into rational catalyst design for future biomass processes.
Expression of Chicken Hepatic Type I and Type III Iodothyronine Deiodinases during Embryonic Development1 (1997)

In embryonic chicken liver (ECL) two types of iodothyronine deiodinases are expressed: D1 and D3. D1 catalyzes the activation as well as the inactivation of thyroid hormone by outer and inner ring deiodination, respectively. D3 only catalyzes inner ring deiodination. D1 and D3 have been cloned from mammals and amphibians and shown to contain a selenocysteine (Sec) residue. We characterized chicken D1 and D3 complementary DNAs (cDNAs) and studied the expression of hepatic D1 and D3 messenger RNAs (mRNAs) during embryonic development. Oligonucleotides based on two amino acid sequences strongly conserved in the different deiodinases (NFGSCTSecP and YIEEAH) were used for reverse transcription-PCR of poly(A+) RNA isolated from embryonic day 17 (E17) chicken liver, resulting in the amplification of two 117-bp DNA fragments. Screening of an E17 chicken liver cDNA library with these probes led to the isolation of two cDNA clones, ECL1711 and ECL1715. The ECL1711 clone was 1360 bp long and lacked a translation start site. Sequence alignment showed that it shared highest sequence identity with D1s from other vertebrates and that the coding sequence probably lacked the first five nucleotides. An ATG start codon was engineered by site-directed mutagenesis, generating a mutant (ECL1711M) with four additional codons (coding for MGTR). The open reading frame of ECL1711M coded for a 249-amino acid protein showing 58-62% identity with mammalian D1s. An in-frame TGA codon was located at position 127, which is translated as Sec in the presence ofa Sec insertion sequence (SECIS) identified in the 3'-untranslated region. Enzyme activity expressed in COS-1 cells by transfection with ECL1711M showed the same catalytic, substrate, and inhibitor specificities as native chicken D1. The ECL1715 clone was 1366 bp long and also lacked a translation start site. Sequence alignment showed that it was most homologous with D3 from other species and that the coding sequence lacked approximately the first 46 nucleotides. The deduced amino acid sequence showed 62-72% identity with the D3 sequences from other species, including a putative Sec residue at a corresponding position. The 3'-untranslated region of ECL1715 also contained a SECIS element. These results indicate that ECL1711 and ECL1715 are near-full-length cDNA clones for chicken D1 and D3 selenoproteins, respectively. The ontogeny of D1 and D3 expression in chicken liver was studied between E14 and 1 day after hatching (C1). D1 activity showed a gradual increase from E14 until C1, whereas D1 mRNA level remained relatively constant. D3 activity and mRNA level were highly significantly correlated, showing an increase from E14 to E17 and a strong decrease thereafter. These results suggest that the regulation of chicken hepatic D3 expression during embryonic development occurs predominantly at the pretranslational level.
Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma (2019)

Most clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), resulting in the accumulation of hypoxia-inducible factor α-subunits (HIF-α) and their downstream targets. HIF-2α expression is particularly high in ccRCC and is associated with increased ccRCC growth and aggressiveness. In the canonical HIF signaling pathway, HIF-prolyl hydroxylase 3 (PHD3) suppresses HIF-2α protein by post-translational hydroxylation under sufficient oxygen availability. Here, using immunoblotting and immunofluorescence staining, qRT-PCR, and siRNA-mediated gene silencing, we show that unlike in the canonical pathway, PHD3 silencing in ccRCC cells leads to down-regulation of HIF-2α protein and mRNA. Depletion of other PHD family members had no effect on HIF-2α expression, and PHD3 knockdown in non-RCC cells resulted in the expected increase in HIF-2α protein expression. Accordingly, PHD3 knockdown decreased HIF-2α target gene expression in ccRCC cells and expression was restored upon forced HIF-2α expression. The effect of PHD3 depletion was pinpointed to <i>HIF2A</i> mRNA stability. In line with these <i>in vitro</i> results, a strong positive correlation of <i>PHD3</i> and <i>HIF2A</i> mRNA expression in ccRCC tumors was detected. Our results suggest that in contrast to the known negative regulation of HIF-2α in most cell types, high PHD3 expression in ccRCC cells maintains elevated HIF-2α expression and that of its target genes, which may enhance kidney cancer aggressiveness.
Paraprotein–Related Kidney Disease: Kidney Injury from Paraproteins—What Determines the Site of Injury? (2016)

Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated nephropathies provides a framework that aids clinicians in prompt diagnosis and appropriate adjunctive treatment of these disorders. Glomerular diseases that may be associated with paraproteinemias include amyloid deposition, monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, C3 glomerulopathy caused by alterations in the complement pathway, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemia. Tubular lesions include the classic Fanconi syndrome, light-chain proximal tubulopathy, interstitial fibrosis, and cast nephropathy. These paraproteinemic renal diseases are distinct in their pathogenesis as well as their urinary and kidney biopsy findings. Renal pathology is usually initiated by deposition and direct involvement of the intact monoclonal Ig or Ig fragments with resident cells of the nephron. Our review summarizes current insights into the underlying molecular pathogenesis of these interesting kidney lesions.
Introduction (2021)

This introduction presents an overview of the key concepts discussed in the subsequent chapters of this book. The book deals with the competing interests of globalization and internationalization. It focuses on instilling skills of global citizenship through critical studies of intercultural musical encounters. The book discusses the College Music Society’s 2014 call for universities to include diversity as one of the main pillars of a new approach to college music curricula, an approach that aims to “lead organically to essential encounters with the diverse musics of the world.” It examines Bela Bartok’s boundary-crossing musical encounters to highlight the risks of adopting ahistorical frameworks when expanding classes to be more global. The book describes how in Brazil the historically fragile state of music history as a discipline and political developments have constrained the teaching of music history, especially efforts to meaningfully broaden pedagogies to include a more diverse cross-section of Brazilian musics.
Region-Based Location-Service-Management Protocol for VANETs (2009)

The efficiency by which a node of a vehicular ad hoc network (VANET) can route messages to destinations heavily depends on the VANET's ability to keep track of the locations of its nodes (vehicles). Current location-management schemes lack scalability and, hence, are proven unable to work in large-scale networks. Therefore, location management in VANETs remains a major challenge. In this paper, we propose a new region-based location-service-management protocol (RLSMP) that uses mobility patterns as means to synthesize node movement and, thus, can be used in large VANET applications. The protocol attempts to relax the scalability issue suffered by other protocols by employing message aggregation in location updating and in querying. Furthermore, due to the protocol's intrinsic locality awareness, it achieves minimum control overhead. To evaluate the efficiency of the protocol, we study its performance analytically and by using simulation for a 2-D random-walk model, as well as on real mobility patterns. The performance of the protocol is compared with that of other prominent location-management protocols.
High-resolution tandem mass spectrometry of carbonic anhydrase (1994)

Electrospray ionization of carbonic anhydrase with ion dissociation yields a mass spectrum from which the masses of > 100 isotopic clusters are determined accurately, with the number of charges assigned directly from resolved isotopic peaks. Of these clusters, 80% correspond to fragmentation at or near the amino acid proline. The masses of combinations of two, three, and four of these clusters sum to the molecular mass with 0.1-Da accuracy, while further fragment ion dissociation provides additional sequence information. The capability of this methodology to detect sequence variations is illustrated with an isozyme having a single amino acid replacement.
Anti‐inflammatory Cyclooxygenase‐2 Selective Inhibitors (2004)

The arachidonic acid cascade (Fig. 1) plays an important role in the inflammation process. All of the conventional NSAIDs are inhibitors of the COX enzymes. This enzyme catalyzes the transformation of arachidonic acid to prostaglandin H2. In 1991, a novel isoform of cyclooxygenase in the arachidonic acid/prostaglandin pathway was discovered. This inducible enzyme associated with the inflammatory process was named cyclooxygenase II (COX-2) or prostaglandin G/H synthase II. COX-2 is localized mainly in inflammatory cells and tissues, and becomes up-regulated during the acute inflammatory response; whereas COX-1 is mainly responsible for the production of homeostatic prostaglandins which are associated with gastrointestinal ulceration, perforation and hemorrhage. The synthesis of celecoxib (Celebrex®) involve the following steps: Claisen condensation of 4-methylacetophenone with ethyl trifluoroacetate in the presence of NaOMe in methanol under reflux. Subsequent diarylpyrazole formation from the condensation of dione 7 and 4-sulfonamidophenylhydrazine hydrochloride then delivered celecoxib. The synthesis of rofecoxib (Vioxx®) involve the following steps: 2-Bromo-1-(4-(methylsulfonyl)phenyl)ethanone was cyclo-condensed with phenylacetic acid under the influence of DBU to deliver rofecoxib.
Experimental and numerical thermo-mechanical analysis of wire-based laser metal deposition of Al-Mg alloys (2021)

A finite element model is employed to perform a sequentially coupled thermo-mechanical analysis for enabling rapid process simulations of temperature fields, residual stresses and distortions for the production of additively manufactured parts via laser metal deposition. Experimental identification of characteristic process features such as temperature distribution, melt pool dimensions and bead geometries were used for the initial built-up and calibration of the model. The addition of material during process simulation is realised through reactivating inactive elements during the transient heat transfer analysis and through reactivating a combination of inactive and quiet elements during the mechanical analysis. The travelling heat source is geometrically bounded to precisely control the volume of its energy distribution. The results of the transient heat transfer analysis are sequentially coupled to a mechanical analysis for obtaining information on the resulting residual stresses and deformation. Based on the good agreement between numerical and experimental results of the thermal analysis, conclusions on the corresponding residual stress distributions and deformation are made. It is shown that the model represents an efficient tool for process prediction regarding thermal history, residual stresses and final-part deformations. Finally, the model is utilised to identify parameters and conditions of the process that lead to reduced residual stresses and deformations of the investigated additive part.
First animal evaluation of the “ReinHeart”, a new lineary driven total artificial heart (2009)

Finocchiaro, Thomas; Laumen, Marco; Cuenca-Navalon, E.; Fritschi, Andreas; Timms, Daniel; Schulte-Eistrup, S.; Morshuis, M.; Lessmann, M.; Hameyer, K.; Korfer, R.; Meyns, Bart; Schmitz-Rode, Thomas; Steinseifer, Ulrich
Oxidative decomposition mechanisms of lithium peroxide clusters: an Ab Initio study (2019)

Oxidative decomposition of solid lithium peroxide is an important part of the charging process in a Li-O2 battery. In this paper, we investigate oxidative decomposition mechanisms of lithium peroxide clusters as molecular models for solid lithium peroxide using density functional methods to understand charging processes in advanced energy storage systems. Most calculations are done using a (Li2O2)4 cluster with similar results obtained from a larger (Li2O2)16 cluster. Reaction pathways of the clusters involving different sequences of oxidation, oxygen evolution, lithium cation removal, and spin excitation are investigated. The computations suggest that certain oxidative decomposition routes may not have dependence on the oxygen evolution or Li-ion removal kinetics due to the exothermicity of oxygen removal and Li+ removal (by solvent) upon oxidation. The computed charge potentials evaluated using a tetramer model indicates that it is possible to have low overcharge potential provided there exists a good electronic conductivity to facilitate the oxidative decomposition. Finally, oxidation potentials of a series of LixOy clusters are investigated to assess their dependence on stoichiometry and how the local site from which the electrons are being removed affects the charge potentials.
Comparative behavior of polybutadiene and polynorbornene‐based latices prepared by dispersion ring‐opening metathesis polymerization with a poly(ethylene oxide) macromonomer (2004)

Abstract This study critically examines the similarities and differences between poly(ethylene oxide) (PEO) stabilized latices of polynorbornene and polybutadiene. Features such as the kinetics of copolymerization of norbornene and cyclooctadiene with a macromonomer of PEO, the particles' size and morphology, the type of copolymer formed, and the stability of these latices were investigated and the results obtained are considered. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2705–2716, 2004
Explaining and improving a machine-learning based printer identification system (2019)

Counterfeiting of currency globally remains a significant problem to this day. According to the authorities, a large portion of this fake currency is produced by Small Office or Home Office inkjet printers. In this paper, we explain why a previously developed machine learning based Printer Identification System works with high accuracy and we investigate to improve the stability and generalization of the classifier. We study the print patterns of 8 inkjet printers from different manufacturers. We look at the features of the data by reducing its dimensions using Principle Component Analysis. This shows significant separation between printers which implies that the Deep Neural Network was able to pick up on key differences. The results are also comparable with that of reducing dimensions with Linear Discriminant Analysis. The model however does have some limitations regarding ink density and print media. It always classifies an image amongst the trained printers and does not show anomalies. For this, we consider the Gaussian distribution of target printers to see how the probabilities fared when trained and fitted separately for each printer, thus having a set of images that do not fit in with any of the printers for which the classifier was trained. The results acquired from these methods have contributed to making a more real-world implementation of our classifier, named LAPIS (machine-Learning Applied Printer Identification System), for printer forensics.