gebhart/patrepeval huggingface dataset:
Pharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Non-Peptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly (2021)

Abstract Depot injection formulations of peptide somatostatin receptor ligands (SRLs) are routinely used to treat acromegaly and neuroendocrine tumors (NETs). Paltusotine (CRN00808), an orally administered small molecule nonpeptide selective somatostatin receptor 2 (SST2) agonist has been shown to maintain GH and IGF-1 levels in acromegaly patients previously on depot SRLs (ACROBAT Edge NCT03789656). In this study, a capsule formulation was used, which did not exhibit dose proportional pharmacokinetics (PK) at doses &gt;40 mg, required a 2-hour post-dose fast in overnight fasted patients, and had the potential for reduced bioavailability when taken with proton-pump inhibitors (PPI). A spray-dried dispersion (SDD) tablet formulation was developed with improved solubility in the physiological pH range and its performance was evaluated in healthy volunteers. Male and female healthy volunteers who met inclusion/exclusion criteria were enrolled in a single-center Phase 1 study (ANZCTR registration ACTRN12619001562167). A Cohort of 12 subjects was administered a single dose of paltusotine in a four-period cross-over design. Periods 1 and 2 assessed the effect of lansoprazole (a PPI) on PK of 20 mg dose of paltusotine SDD tablets. In Period 3, 20 mg dose of paltusotine SDD tablets was co-administered with a high fat, high-calorie meal. In Period 4, a 60 mg dose of paltusotine SDD tablets was administered to assess dose proportionality. In a separate cohort of subjects (n=12; also, a 4-period cross-over design), the relative bioavailability of capsules and SDD tablets was assessed, and the effect of food administration 0.5, 1, and 2 hour post-dose was evaluated. Subsequently, in another cohort of 12 subjects (a 3-period cross-over design), dose proportionality of the SDD tablets was evaluated at 40 mg and 80 mg dose with a 1-hour post-dose fast. A 4 hours post-dose fast was also assessed for the 80 mg dose. Pharmacokinetics and safety of paltusotine were evaluated. Paltusotine was generally well tolerated in this study. SDD tablets exhibited dose proportional increase in total systemic exposure (AUC) up to a dose of 80 mg. Healthy volunteers pretreated with the PPI, lansoprazole (15 mg bid for 3 days), and co-administered with paltusotine SDD tablets exhibited a small decrease (approximately 25%) in systemic exposure to paltusotine compared with the same subjects that had washed out from the PPI-pretreatment. SDD tablets exhibited significant reduction in systemic exposure when co-administered with a high-fat, high-calorie meal. However, the SDD formulation was less sensitive to timing of post-dose food administration compared to the capsule formulation. These data suggest that the SDD tablet formulation of paltusotine improves flexibility in dose administration, can be co-administered with PPIs and other agents that increase stomach pH, and reduces the post-dose fasting requirement.
Common Themes of Dedifferentiation in Somatic Cell Reprogramming and Cancer (2008)

With its hallmarks of unregulated cell proliferation and compromised differentiation, cancer represents a derangement of normal tissue homeostasis. A common set of pathways are activated in the transformed state, through either mutation or altered epigenetic regulation, and both heritable effects sustain the tumor. Classical views of cancer have invoked tissue dedifferentiation in the oncogenic process, whereas modern views embodied in the cancer stem cell hypothesis hold that cancer emerges from primitive tissue stem cells or specific progenitor populations that through mutations assume the self-renewal properties of stem cells. Recently, somatic tissues have been reprogrammed to a pluripotent state resembling embryonic stem (ES) cells by ectopic expression of a cocktail of transcription factors. The factors that drive reprogramming are oncogenes or have been linked to cellular transformation, suggesting that tumorigenesis and somatic cell reprogramming might indeed share common mechanisms of dedifferentiation.
Multiple Iodine-125 radioactive seed localizations: single institution experience. (2015)

Poster: ECR 2015 / C-2363 / Multiple Iodine-125 radioactive seed localizations: single institution experience. by: E. L. Slomka, K. N. Glazebrook, J. Jakub, Z. Al Hilli, R. T. Fazzio, K. N. Jones; Rochester, MN/US
Use of a novel sonosensitizer in sonodynamic therapy of U251 glioma cells in vitro (2011)

The aim of the present study was to investigate the effect of ZnPcS(2)P(2)-meditated sonodynamic therapy (SDT) on U251 human glioma cells and to identify its underlying biological mechanism. The growth inhibition rate was determined by MTT assay. The apoptotic rate was examined by flow cytometry. Fine structures were observed with transmission electron microscopy (TEM). Generation of reactive oxygen species (ROS) was detected spectrophotometrically. Caspase-3, -8 and -9 expression was detected by Western blot analysis. The growth inhibition rate of U251 human glioma cells indicated that ZnPcS(2)P(2)-meditated SDT had a better growth inhibition rate of tumor cells at a concentration of 5.0 μg/ml ZnPcS(2)P(2), at a 4-h incubation time with ZnPcS(2)P(2), and at 6 h re-incubation following SDT. At 6 h after SDT, the growth inhibition rate of cells was significantly higher compared to other groups, apoptosis could be detected in SDT by flow cytometry. TEM examination revealed morphological features of apoptosis or necrosis. Furthermore, caspase-3, -8 and -9 expression following SDT was found to be increased by Western blot analysis. Finally, generation of ROS in cells was also elevated. In conclusion, ZnPcS(2)P(2)-SDT is capable of inducing U251 cell apoptosis or necrosis and has satisfying antitumor effects. The mechanism of ZnPcS(2)P(2)-meditated SDT involves ROS generation in U251 cells, which initiates subsequent apoptosis through the mitochondrial and death receptor pathways.
Rare Tautomer Hypothesis Supported by Theoretical Studies:  Ab Initio Investigations of Prototropic Tautomerism in the <i>N</i>-Methyl-P Base (2005)

Density functional theory calculations were applied to the prediction of the tautomeric properties of N-methyl-P (6-methyl-3,4-dihydro-8H-pyrimido[4,5-c][1,2]oxazin-7-one), a base of the nucleoside analogue dP (6-(2-deoxy-beta-D-ribofuranosyl)-3,4-dihydro-8H-pyrimido[4,5-c][1,2]oxazin-7-one), for which water-solution experimental data have become available recently. The calculations have been performed for three tautomers in the gas phase, with various numbers of water molecules, and within the polarizable continuum model (PCM) of solvation. The obtained results correctly predict the presence of two tautomers and reproduce accurately the experimentally obtained ratio of the two most stable tautomeric forms when using a combination of explicit water molecules and the PCM of solvation. This lends additional support to the rare tautomer hypothesis of substitution mutagenesis in DNA replication.
Extensible Pre-authentication Kerberos (2007)

Kerberos is a well-established authentication system. As new authentication methods arise, incorporating them into Kerberos is desirable. However, extending Kerberos poses challenges due to a lack of source code availability for some implementations and a lengthy standardization process. This paper presents Extensible Pre-Authentication in Kerberos (EPAK), a Kerberos extension that enables many authentication methods to be loosely coupled with Ker- beros, without further modification to Kerberos. To demon- strate the utility of the framework, two authentication meth- ods for open systems are presented that have been imple- mented as Kerberos extensions using EPAK. These exten- sions illustrate the flexibility EPAK brings to Kerberos while maintaining backwards compatibility.
High-temperature chemical stability of plasma-sprayed Ca{sub 0.5}Sr{sub 0.5}Zr{sub 4}P{sub 6}O{sub 24} coatings on Nicalon/SiC ceramic matrix composite and Ni-based superalloy substrates (1996)

The potential application of Ca{sub 0.5}Sr{sub 0.5}Zr{sub 4}P{sub 6}O{sub 24} (CS50) as a corrosion-resistant coating material for Si-based ceramics and as a thermal barrier coating material for Ni-based superalloys was explored. A {approximately}200 {micro}m thick CS50 coating was prepared by air plasma spray with commercially available powder. A Nicalon/SiC ceramic matrix composite and a Ni-based superalloy coated with a {approximately}200 {micro}m thick metallic bond coat layer were used as substrate materials. Both the powder and coating contained ZrP{sub 2}O{sub 7} as an impurity phase, and the coating was highly porous as-deposited. The coating deposited on the Nicalon/SiC substrate was chemically stable upon exposure to air and Na{sub 2}SO{sub 4}/O{sub 2} atmospheres at 1,000 C for 100 h. In contrast, the coating sprayed onto the superalloy substrate significantly reacted with the bond coat surface after similar oxidation in air.
A Critical Analysis of the Tumor Volume Threshold for Clinically Insignificant Prostate Cancer Using a Data Set of a Randomized Screening Trial (2010)

We confirmed the original value of the index tumor volume threshold of 0.5 ml for insignificant prostate cancer, and we demonstrated that clinically insignificant prostate cancer may include index Gleason score 6, pT2 tumors with volumes up to at least 1.3 ml. These results suggest a reconsideration of current methods and nomograms used for pretreatment risk assessment.
Absorbing boundary conditions for the Schrödinger equation on finite intervals (1992)

The absorbing boundary conditions for the one- and two-dimensional Schr\"odinger equation on a finite interval are considered by using a rational-function approximation for the dispersion relation. The approximation gives good results over a wide range of input parameters. A finite-difference approximation is used to solve the Schr\"odinger equation and the resulting boundary conditions.
• Conducting (2003)

During Felix Mendelssohn's time, the art of conducting was still very much in its infancy. He played a major role in its development by being at the forefront of developments in conducting, particularly in Germany and England. At an early age, Mendelssohn acquired his practical skill in directing ensembles by participating in the private performances, involving members of the Royal Orchestra, held regularly in the family home. Despite his effectiveness as a conductor, however, his choice of tempo was the target of criticism. Robert Schumann commented on the rapidity with which he took the first movement of Ludwig van Beethoven's Ninth Symphony, while Richard Wagner took him to task for his tendency to hurry through pieces to the detriment of the music. Many other contemporaries questioned his propensity for fast tempos, not only in conducting but also in piano playing. Mendelssohn's conducting ability was fully realized in Leipzig following the establishment of the Gewandhaus orchestra.
Collaboration of tRNA modifications and elongation factor eEF1A in decoding and nonsense suppression (2018)

Transfer RNA (tRNA) from all domains of life contains multiple modified nucleosides, the functions of which remain incompletely understood. Genetic interactions between tRNA modification genes in Saccharomyces cerevisiae suggest that different tRNA modifications collaborate to maintain translational efficiency. Here we characterize such collaborative functions in the ochre suppressor tRNA SUP4. We quantified ochre read-through efficiency in mutants lacking either of the 7 known modifications in the extended anticodon stem loop (G26-C48). Absence of U34, U35, A37, U47 and C48 modifications partially impaired SUP4 function. We systematically combined modification defects and scored additive or synergistic negative effects on SUP4 performance. Our data reveal different degrees of functional redundancy between specific modifications, the strongest of which was demonstrated for those occurring at positions U34 and A37. SUP4 activity in the absence of critical modifications, however, can be rescued in a gene dosage dependent fashion by TEF1 which encodes elongation factor eEF1A required for tRNA delivery to the ribosome. Strikingly, the rescue ability of higher-than-normal eEF1A levels extends to tRNA modification defects in natural non-suppressor tRNAs suggesting that elevated eEF1A abundance can partially compensate for functional defects induced by loss of tRNA modifications.
Experimental and Numerical Investigations on the Air-Pumping Phenomenon in High-Speed Spur and Helical Gears (2005)

An approximate hydrodynamic model of the air-lubricant pumping by spur and helical gears, which makes it possible to predict the compression-expansion process by the meshing teeth, is presented. The simulated pressure patterns correlate well with the experimental evidence obtained from a specific test rig for both spur and helical gears. Finally, it is shown that this pumping phenomenon can generate significant power losses, especially for high-speed applications.
Mechanism of pain in osteoid osteomas: an immunohistochemical study (1993)

Osteoid osteoma is a benign bone tumour characterized by pain which is relieved by non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin. To clarify the mechanism of the pain, five osteoid osteomas were studied immunohistochemically using polyclonal antibodies against prostaglandin E2 (PGE2), S-100 protein and protein gene product 9.5 (PGP 9.5). In all five cases, the pain had been relieved by NSAIDs. Nerve fibres positive for S-100 protein and PGP 9.5 were observed in the fibrous zone, especially close to the blood vessels, around the nidus in all the lesions and also within the nidus in three lesions. PGE2 immunoreactivity was variably positive in the nidus of three lesions. In one case a large number of actively proliferating osteoblasts reacted with this antibody. The other cases showed unevenly distributed PGE2 positivity which tended to be prominent in the plump osteoblasts. As control material we examined fibrous dysplasia (3 cases), osteosarcomas (3) and giant-cell tumours of bone (3). The plump osteoblastic tumour cells of three osteosarcomas and the bone-forming cells in two cases of fibrous dysplasia gave a positive reaction for PGE2. No S-100 or PGP 9.5 immunoreactive nerve fibres were seen in these lesions. It is concluded that the presence of nerve fibres alone might play a more important role in mediation of pain in osteoid osteomas than some effects of osteoblast-produced PGE2 on the nerves and proliferated blood vessels.
Detection of mycobacterial lipoarabinomannan with an antigen-capture ELISA in unprocessed urine of Tanzanian patients with suspected tuberculosis (2005)

A direct antigen-capture ELISA based on the detection of mycobacterial lipoarabinomannan (LAM) in unprocessed urine was evaluated for its usefulness in clinical practice. In Tanzania, 231 patients with suspected pulmonary tuberculosis (TB) and 103 healthy volunteers were screened with standard TB tests and with the new LAM-ELISA. Of 132 patients with confirmed pulmonary mycobacterial disease (positive sputum culture), 106 were positive using the LAM-ELISA (sensitivity 80.3%). In comparison, the sensitivity of acid-fast bacilli (AFB) sputum microscopy was 62.1% (82 of 132 confirmed cases). Of the 231 patients, 17 were both culture- and AFB-negative, but had typical radiographic signs of pulmonary mycobacterial infection and did not respond to antibiotic treatment. Of these 17 patients, 13 (76.5%) had positive LAM-ELISA test results. To define the specificity of the assay, urine samples from 103 healthy volunteers were also screened using LAM-ELISA. All but one had an optical density below the cut-off (specificity 99%). Of interest was a significant correlation between level of microscopic density of mycobacteria in sputum and LAM antigen concentration in urine (chi2=8.44). The LAM-ELISA is a field-adapted tool that can improve screening standards in countries with a high incidence of TB.
Memory size estimation for multimedia applications (1998)

Memory modules dominate the cost, performance, and power of embedded systems that process multidimensional signals, typically present in image and video processing. Therefore, studying the impact of parallelism on memory size is crucial for trading off system performance against area cost to enable intelligent system partitioning and exploration. We propose a memory size estimation method for algorithmic specifications containing multidimensional arrays and parallel constructs, intended as part of a high-level partitioning and exploration methodology. The system designer can trade-off estimation accuracy for increased run time. We present the results of our estimation approach on a number of image and video processing kernels, and discuss some preliminary results on the influence of parallelism on storage requirement.
Human Cytochrome P450 2A13: Correlation between a 2.35 Å Structure and Ligand Binding (2006)

Cytochrome P450 enzymes catalyze the biotransformation of xenobiotics including drugs and toxins. The human lung cytochrome P450 2A13 activates the nicotine‐derived procarcinogen 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) into DNAaltering compounds that can cause lung cancer. Another P450, 2A6, is also present in human lung, but at much lower levels. These two enzymes are 94% identical, but 2A13 metabolizes NNK and the marker substrate coumarin with much lower K m values than does 2A6. A truncated version of 2A13 was used to investigate its ligand binding properties and X‐ray structure. The structure of 2A13 was determined to 2.35 Å and solved by molecular replacement using 2B4 (PDB 1SUO ) as a search model. The global structures of 2A13 and 2A6 (PDB 1Z10 ) are very similar with an r.m.s. deviation of 0.4 Å for the C α atoms. The 2A13 active site cavity is small and highly hydrophobic with a cluster of Phe residues composing the active site roof. Active site residue Asn297 is positioned to hydrogen bond with ligands. Substitution of Ala117 in 2A13 with the Val found in 2A6 at this position interchanges the kinetics of coumarin metabolism, likely due to reorientation of the substrate by the larger Val side chain. This substitution and other amino acid differences between these two active sites cause significant variation in binding for many 2A ligands. These studies explore the molecular basis for differences in enzyme activity between two closely related human P450s. Research was supported by the NIH RR017708 (EES), GM076343 (EES), and RR016475 (JLS).
Stains for the Differential Diagnosis of Degenerative Dementias (1999)

Our understanding of the structural substrates underlying the dementia syndrome has been transformed by the introduction of the Gallyas silver stain and the application of immunostains for tau, ubiquitin, and alpha-synuclein. Visualization of sequential changes in Alzheimer's disease and the recognition of a new substrate for dementia and dementia with argyrophilic grains, are two of the advances related to the application of the Gallyas method. The specificity of alpha-synuclein for recognizing Lewy bodies enables the unequivocal diagnosis of dementia with Lewy bodies. The diverse entities that constitute the Pick complex can be identified by applying immunostains for tau and ubiquitin in addition to the Gallyas silver stain.
Sequential Deprotection for Control of Orientation in the Self-Assembly of Asymmetric Molecules for Molecular Electronic Devices (2004)

We present a demonstration of molecular rectification in a metal−molecule−metal junction created by self-assembly where endgroup chemistry does not influence the observed conductance asymmetry. Using a protection scheme which allows for stepwise deprotection of aryl thiols, the deposition of α,ω-dithio-molecules with a preferred polar order can be achieved. Quartz crystal microgravimetry was used to demonstrate the sequential nature of the deprotection and the preferred orientation of absorption of the monodeprotected dithiols. Current−voltage measurements of metal−molecule−metal junctions reveal a bias polarity asymmetry resulting solely from the internal molecular asymmetry and not from the initial protecting group chemistry.
Analysis of the Decision-Directed SNR Estimator for Speech Enhancement With Respect to Low-SNR and Transient Conditions (2010)

Because of their many applications and their relative ease of implementation, single-channel speech enhancement algorithms have received much attention. As a consequence, a vast amount of publications on estimation procedures and their implementation in noise reduction systems exists. However, there has been little systematic research on the theoretic performance of such estimators. In this paper, we provide a systematic analysis of the performance of noise reduction algorithms in low signal-to-noise ratio (SNR) and transient conditions, where we consider approaches using the well-known decision-directed SNR estimator. We show that the smoothing properties of the decision-directed SNR estimator in low SNR conditions can be analytically described and that the limits of noise reduction for widely used spectral speech estimators based on the decision-directed approach can be predicted. We also illustrate that achieving both a good preservation of speech onsets in transient conditions on one side and the suppression of musical noise on the other can be especially problematic when the decision-directed SNR estimation is used.
Storage Management Solutions for Distributed Computing Environments (1996)

Storage management is fast becoming one of the most important issues information technology (IT) managers face today. With data accumulating at enormous rates, and with end users demanding faster access to more information, storage management has moved from an operation that was done only at night to a mission-critical concern that requires full-time attention. Storage management consists of all the activities related to the effective deployment, accessibility, and use of stored information across a computing infrastructure. Storage management involves several major disciplines, including backing up and restoring data, storing data online across multiple classes of storage devices such as disks and tape, archiving data for legal and historical purposes, and managing storage resources such as tape or optical media for optimal use. Managing these storage disciplines takes an effective combination of organization, processes, and technologies to meet end-user data-availability expectations. In today’s distributed computing environments, IT managers need consistent storage management strategies and processes across the enterprise. In addition, storage management processes cannot be separated from an integrated network and system strategy. Therefore, IT managers need complete solutions that integrate the various storage management components and technologies such as databases, file systems, storage peripherals, storage management applications, and network and system management strategies. In the past, storage management solutions have been proprietary (mainframes) or piecemeal (early client/server point products), with specific peripherals working only with specific software and hardware. It was difficult to expand a solution to meet the demands of rapidly growing collections of data. In this article we will describe trends driving storage management technology and the components that make up an ideal storage management solution. Finally, we’ll introduce HP hardware and software products, services, and partners and describe how they work together providing storage solutions for our customers.