gebhart/patrepeval huggingface dataset:
#3278 HUMAN PHARMACOKINETICS OF MULTIPLE, STEADY-STATE DOSING OF IPTACOPAN (2023)

Abstract Background and Aims Iptacopan (LNP023) is a first-in-class, oral, proximal complement inhibitor that specifically binds to Factor B and inhibits the alternative complement pathway (AP). Current Phase III studies of iptacopan focus on diseases associated with AP activation, such as paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis, IgA nephropathy, and atypical hemolytic uremic syndrome. Early modeling efforts suggested that an iptacopan concentration of ∼1000 ng/mL would provide near-maximal AP inhibition. The aim of this study was to evaluate the PK of oral iptacopan in healthy subjects to determine the dose that results in a ∼1000-ng/mL mean steady-state concentration over the entire 12-h dosing interval. Method In this blinded, controlled, randomized study, a total of 32 healthy subjects were enrolled into 5 cohorts receiving twice-daily dosing for 14 days: placebo (n = 8) or iptacopan 25, 50, 100, or 200 mg (n = 6 per group). Plasma iptacopan concentration was intensively measured for 72 hours post day 14 dose using a validated LC-MS/MS assay (LLOQ = 1 ng/mL). Results Iptacopan treatment was safe and well tolerated at all dose levels. Iptacopan steady-state concentration-time curves are shown below. Iptacopan was rapidly absorbed, with a median Tmax of approximately 2 hours (Figure 1). The mean half-life was moderately long at 18 to 25 hours. The inter-subject variability (CV%) of iptacopan Cmax and AUCinf was low at approximately 12% to 27%, and both parameters were under-dose proportional with increasing dose. At all time points from 0 to 12 hours, mean iptacopan concentration for the 200-mg dose cohort was &amp;gt;1000 ng/mL. Conclusion Iptacopan was rapidly absorbed, had low inter-subject variability, and a moderately long half-life. Only the 200-mg b.i.d dose produced mean iptacopan concentrations of ≥1000 ng/mL over the dosing interval, and thus is expected to result in near-complete, continuous AP inhibition. These results support the rationale for use of iptacopan 200 mg twice daily as the therapeutic dose in ongoing clinical trials and provide evidence of durable AP inhibition in patients administered oral iptacopan therapy.
An Interesting Case of Painless Jaundice: Primary Hepatic Lymphoma (2015)

A 77-year-old male with a history of a resolved hepatitis B infection, HTN, depression and a distant history of EtOH abuse presented with jaundice and an acute change in mental status. The patient also noted decreased appetite, weight loss and fatigue over the prior four weeks. He denied any abdominal pain, nausea, vomiting or change in bowel movements. Physical exam was notable for jaundice, hepatomegaly and mild abdominal distention without any tenderness to palpation. There was no palpable superficial lymphadenopathy. Laboratory findings showed deteriorated liver function, elevated lactate dehydrogenase (LDH), hypercalcemia and elevated blood lipid levels (Table 1). Serologic tests for hepatitis A and C and for HIV were negative. Serologic testing for hepatitis B showed evidence of a past infection. Tumor markers including serum α-fetoprotein and carcinoembryonic antigen were negative. CT of the abdomen and pelvis showed an enlarged and nodular liver without discrete parenchymal liver lesions. The pancreas, spleen and biliary tract were unremarkable. There was no evidence of abdominal lymphadenopathy. Core liver biopsy showed heavy infiltration of small, round cells with a high nuclear to cytoplasmic ratio, prominent nucleoli (Image 1) and which were strongly positive for CD20 and CD45, but negative for CD3. These indicated a large B-cell lymphoma. Given no signs of extra-hepatic involvement, a diagnosis of primary hepatic non-Hodgkin's lymphoma was made. Rituximab and prednisone were initiated with the intention of starting additional systemic chemotherapy agents upon signs of clinical improvement. Despite all attempts at therapy, the patient's liver failure progressed with rapidly worsening MELD scores (Table 2). The patient ultimately expired on hospital day twenty-one. Primary hepatic lymphoma (PHL) is a rare form of lymphoma, comprising < 1% of all extra-nodal lymphomas. It is most commonly found in middle-aged men and with varying presentations. HCV infection has been found in approximately 40% of patients with PHL. Presenting symptoms may vary and can be non-specific. Abdominal pain and nausea are most common, in addition to weight loss, fevers, B-symptoms and, less commonly, jaundice. 40% of PHL patients are found to have hypercalcemia for unknown reasons. Liver imaging is variable and can range from numerous, sometimes confluent lesions to a solitary mass. Biopsy showing lymphoma, and disease confinement to the liver is necessary for diagnosis. Treatment typically consists of combination chemotherapy, specifically R-CHOP. Our case presents a rare malignancy represented in literature mostly by way of case reports and case series.Figure 1Figure 2Figure 3
Enhancement by Activated Protein C of tPA-induced Lysis in a Cell-free System (1987)

The profibrinolytic activity of human activated protein C (APC) was studied in a cell-free system using human plasma. Normal and Ba+* citrate adsorbed human plasmas were dialyzed against 150mM NaCl, 20mM Hepes, pH 7.4 and diluted to an A280 of 16. Reactions were initiated by the addition of aliquots of plasma to cuvettes containing human melanoma tPA and human thrombin at final concentrations of 1 and 30nM, respectively. The effects of Ca+* and varying concentrations of APC on clotlysis times were examined by monitoring turbidity at 600nM while maintaining the temperature at 37°C. The lysis time, defined as the midpoint of turbidity change, was 128 min for normal plasma containing 10 mM Ca+* and showed progressive and saturable shortening to about 90 min at &gt; 50nM APC. In the absence of Ca+*, lysis time was 55 min for normal plasma and did not shorten in response to APC. With Ba+* citrate adsorbed plasma, the lysis time was 82 min in the presence of 10mM Ca+*, and shortened to 42 min without Ca+*. APC had no effect on lysis time in Ba+* adsorbed plasma either with or without Ca+*. Both bovine and human APC were equally potent. Electrophoresis in DodSO4 and autoradiography of plasma samples containing 125I-labelled plasminogen indicated enhanced rates of plasminogen activation in the presence of APC. These data indicate that APC decreases lysis time in vitro at the level of plasminogen activation. This effect is dependent on Ca+* and may involve additional vitamin K-dependent protein ( s).
Understanding the Roles of FAK in Cancer (2014)

Focal adhesion kinase (FAK) is a protein tyrosine kinase that regulates cellular adhesion, motility, proliferation and survival in various types of cells. Interestingly, FAK is activated and/or overexpressed in advanced cancers, and promotes cancer progression and metastasis. For this reason, FAK became a potential therapeutic target in cancer, and small molecule FAK inhibitors have been developed and are being tested in clinical phase trials. These inhibitors have demonstrated to be effective by inducing tumor cell apoptosis in addition to reducing metastasis and angiogenesis. Furthermore, several genetic FAK mouse models have made advancements in understanding the specific role of FAK both in tumors and in the tumor environment. In this review, we discuss FAK inhibitors as well as genetic mouse models to provide mechanistic insights into FAK signaling and its potential in cancer therapy.
Formulation of Generalized Mass Transfer Correlations for Blood Oxygenator Design (2016)

This paper numerically investigates non-Newtonian blood flow with oxygen and carbon dioxide transport across and along an array of uniformly square and staggered arranged fibers at various porosity (ε) levels, focussing on a low Reynolds number regime (Re < 10). The objective is to establish suitable mass transfer correlations, expressed in the form of Sherwood number (Sh = f(ε, Re, Sc)), that identifies the link from local mass transfer investigations to full-device analyses. The development of a concentration field is initially investigated and expressions are established covering the range from a typical deoxygenated condition up to a full oxygenated condition. An important step is identified where a cut-off point in those expressions is required to avoid any under- or over-estimation on the Sherwood number. Geometrical features of a typical commercial blood oxygenator is adopted and results in general show that a balance in pressure drop, shear stress, and mass transfer is required to avoid potential blood trauma or clotting formation. Different definitions of mass transfer correlations are found for oxygen/carbon dioxide, parallel/transverse flow, and square/staggered configurations, respectively. From this set of correlations, it is found that transverse flow has better gas transfer than parallel flow which is consistent with reported literature. The mass transfer dependency on fiber configuration is observed to be pronounced at low porosity. This approach provides an initial platform when one is looking to improve the mass transfer performance in a blood oxygenator without the need to conduct any numerical simulations or experiments.
Stabilization of the output power of intracavity frequency-doubled lasers (2002)

Intracavity frequency-doubled solid-state lasers exhibit intensity fluctuations of their light output, which are cause by nonlinear dynamical processes. Up to now, there are different solutions to this problem, but they reduce the output power, increase the size of the laser and/or make them more complicated to assemble. One focus of current research in nonlinear dynamics is derivation of control strategies from mathematical models and their experimental realization. We suggest a method to stabilize the output power by means of an electronic feedback of the emitted infrared light intensity to the pump power. First we show the theoretical predictions of a recently published stability analysis of a rate equation model with feedback. The presented experimental observation show systematic deviations from theory. This makes it necessary to refine the model to explain the deviations. The refinement has direct impact on the improvement of the feedback loop and, therefore, on the application of such a control scheme.
Naphthoquinone glycosides for bioelectroanalytical enumeration of the faecal indicator Escherichia coli (2016)

Microbial water quality monitoring for the presence of faecal indicator bacteria (FIB) is a mandatory activity in many countries and is key in public health protection. Despite technological advances and a need for methodological improvements, chromogenic and fluorogenic enzymatic techniques remain the mainstays of water quality monitoring for both public health agencies and regulated utilities. We demonstrated that bioelectroanalytical approaches to FIB enumeration are possible and can be achieved using commercially available enzyme-specific resorufin glycosides, although these are expensive, not widely available or designed for purpose. Following this, we designed two naphthoquinone glycosides which performed better, achieving Escherichia coli detection in the range 5.0 × 10<sup>2</sup> to 5.0 × 10<sup>5</sup> CFU ml<sup>-1</sup> 22-54% quicker than commercially available resorufin glycosides. The molecular design of the naphthoquinone glycosides requires fewer synthetic steps allowing them to be produced for as little as US$50 per kg. Tests with environmental samples demonstrated the low tendency for abiotic interference and that, despite specificity being maintained between β-glucuronidase and β-galactosidase, accurate enumeration of E. coli in environmental samples necessitates development of a selective medium. In comparison to a commercially available detection method, which has U.S. Environmental Protection Agency (EPA) approval, our approach performed better at high organism concentrations, detecting 500 organisms in 9 h compared with 13.5 h for the commercial method. Bioelectroanalytical detection is comparable to current approved methods and with further development could result in improved detection times. A recent trend for low-cost open-source hardware means that automated, potentiostatically controlled E. coli detection systems could be constructed for less than US$100 per channel.
Coiled Tubing Best Practices in Conjunction with Multistage Completions in the Tight Gas Fields of Saudi Arabia (2012)

Abstract Open hole multistage fracturing (MSF) completions are becoming standard practice in the south gas fields development in Saudi Arabia with more than 25 wells completed to date using open hole packers and selective port technology. Overall, the production results from the use of MSF completions have been very positive and the forecast is that MSF technology usage will grow considerably over the next several years. In general, MSF completions provide an excellent advantage in that they are intervention-less in their standard mode of operation. An aspect that is evolving is the secondary use of coiled tubing (CT) to handle the planned and unplanned (contingency) operations occasionally required to reach well production objectives. Without optimum operational planning and the selection of correct CT downhole tools, completion problems can be encountered and this ultimately can result in the job objective not being reached at all or only at increased costs. This paper presents MSF case studies where CT has been deployed and investigates the operational impact and productivity enhancement. Correlations taken from the key hardware variables, such as fracturing port size and type, motor type, mill bit type, and CT size, are also considered and analyzed. Following the lessons learned and best practices from these experiences, with correct implementation, the findings from this paper should increase the potential for successful multistage completion operations and ultimate improvements in productivity.
Boosted binary features for noise-robust speaker verification (2010)

The standard approach to speaker verification is to extract cepstral features from the speech spectrum and model them by generative or discriminative techniques. We propose a novel approach where a set of client-specific binary features carrying maximal discriminative information specific to the individual client are estimated from an ensemble of pair-wise comparisons of frequency components in magnitude spectra, using Adaboost algorithm. The final classifier is a simple linear combination of these selected features. Experiments on the XM2VTS database strictly according to a standard evaluation protocol have shown that although the proposed framework yields comparatively lower performance on clean speech, it significantly outperforms the state-of-the-art MFCC-GMM system in mismatched conditions with training on clean speech and testing on speech corrupted by four types of additive noise from the standard Noisex-92 database.
DOME (2012)

The computational and storage demands for the future Square Kilometer Array (SKA) radio telescope are significant. Building on the experience gained with the collaboration between ASTRON and IBM with the Blue Gene based LOFAR correlator, ASTRON and IBM have now embarked on a public-private exascale computing research project aimed at solving the SKA computing challenges. This project, called DOME, investigates novel approaches to exascale computing, with a focus on energy efficient, streaming data processing, exascale storage, and nano-photonics. DOME will not only benefit the SKA, but will also make the knowledge gained available to interested third parties via a Users Platform. The intention of the DOME project is to evolve into the global center of excellence for transporting, processing, storing and analyzing large amounts of data for minimal energy cost: the 'ASTRON & IBM Center for Exascale Technology'.
Bacterial aminopeptidases: Properties and functions (1996)

Aminopeptidases are exopeptidases that selectively release N-terminal amino acid residues from polypeptides and proteins. Bacteria display several aminopeptidasic activities which may be localised in the cytoplasm, on membranes, associated with the cell envelope or secreted into the extracellular media. Studies on the bacterial aminopeptide system have been carried out over the past three decades and are significant in fundamental and biotechnological domains. At present, about one hundred bacterial aminopeptidases have been purified and biochemically studied. About forty genes encoding aminopeptidases have also been cloned and characterised. Recently, the three-dimensional structure of two aminopeptidases, the methionine aminopeptidase from Escherichia coli and the leucine aminopeptidase from Aeromonas proteolytica, have been elucidated by crystallographic studies. Most of the quoted studies demonstrate that bacterial aminopeptidases generally show Michaelis-Menten kinetics and can be placed into either of two categories based on their substrate specificity: broad or narrow. These enzymes can also be classified by another criterium based on their catalytic mechanism: metallo-, cysteine- and serine-aminopeptidases, the former type being predominant in bacteria. Aminopeptidases play a role in several important physiological processes. It is noteworthy that some of them take part in the catabolism of exogenously supplied peptides and are necessary for the final steps of protein turnover. In addition, they are involved in some specific functions, such as the cleavage of N-terminal methionine from newly synthesised peptide chains (methionine aminopeptidases), the stabilisation of multicopy ColE1 based plasmids (aminopeptidase A) and the pyroglutamyl aminopeptidase (Pcp) present in many bacteria and responsible for the cleavage of the N-terminal pyroglutamate.
Off-resonance artifact correction for magnetic resonance imaging: a review (2022)

In magnetic resonance imaging (MRI), inhomogeneity in the main magnetic field used for imaging, referred to as off-resonance, can lead to image artifacts ranging from mild to severe depending on the application. Off-resonance artifacts, such as signal loss, geometric distortions, and blurring, can compromise the clinical and scientific utility of MR images. In this review, we describe sources of off-resonance in MRI, how off-resonance affects images, and strategies to prevent and correct for off-resonance. Given recent advances and the great potential of low field and/or portable MRI, we also highlight the advantages and challenges of imaging at low field with respect to off-resonance.
Active-shape-model-based segmentation of abdominal aortic aneurysms in CTA images (2002)

An automated method for the segmentation of thrombus in abdominal aortic aneurysms from CTA data is presented. The method is based on Active Shape Model (ASM) fitting in sequential slices, using the contour obtained in one slice as the initialisation in the adjacent slice. The optimal fit is defined by maximum correlation of grey value profiles around the contour in successive slices, in contrast to the original ASM scheme as proposed by Cootes and Taylor, where the correlation with profiles from training data is maximised. An extension to the proposed approach prevents the inclusion of low-intensity tissue and allows the model to refine to nearby edges. The applied shape models contain either one or two image slices, the latter explicitly restricting the shape change from slice to slice. To evaluate the proposed methods a leave-one-out experiment was performed, using six datasets containing 274 slices to segment. Both adapted ASM schemes yield significantly better results than the original scheme (p&lt;0.0001). The extended slice correlation fit of a one-slice model showed best overall performance. Using one manually delineated image slice as a reference, on average a number of 29 slices could be automatically segmented with an accuracy within the bounds of manual inter-observer variability.
Design for Decision (1967)

Even though the principalship may be under going some redefinition, the principal is going to remain a significant decision-maker. Making decisions, however, is a process that calls for more form and style than many administrators customarily accord it.
Output Power Optimization for Electromagnetic Vibration Energy Harvesters (2010)

In this work, we present a procedure to optimize the output power of electromagnetic vibration energy harvesters, or micropower generators (MPGs). The procedure is based on optimizing both the electrical damping coefficient and the coil configuration, wire gauge and number of turns, to maximize the power flow from the input mechanical source to the electrical load for different load values. Also, we present a closed analytical form for the maximum efficiency of the electromagnetic MPGs.
Effect of high fat consumption on cell proliferation activity of colorectal mucosa and on soluble faecal bile acids. (1988)

To assess the effect of fat consumption on the proliferation of the rectal mucosa, 30 normal volunteers (22 to 71 years) were randomly allocated to three groups: (a) basal low fat diet containing 30 g of fat per day; (b) the basal diet with doses of 30 g corn oil taken with each of the three meals: 120 g fat/day; (c) the basal diet with one dose of 90 g corn oil after the last meal: 120 g fat/day. Rectal biopsies were taken 15 cm from the anal verge after five days on the diets and mucosal cell proliferation was measured by labelling index (LI). The LI was significantly (p less than 0.01) higher in group (c) (9.2) than in group (a) (5.9), with group (b) intermediate (6.8). In multiple stepwise regression analysis, the data were best fitted with age and the variable indicating fat consumed as a bolus as predictors of LI (r2 = 0.39, p less than 0.001). In separate analyses the regression coefficient with age in the fat bolus group was 0.23, p less than 0.001. There was some tendency towards lower bile acids in the faecal water in group (a) than in groups (b) and (c) following the diets and between the bile acids and LI (for lithocholic acid r = 0.48, p = 0.01). These data show that dietary fat given as a bolus can lead to an increase in the proliferation of human colonic cells, possibly as a consequence of raised levels of cytotoxic acidic lipids in the faecal stream.
Site‐Selective Late‐Stage Aromatic [18F]Fluorination via Aryl Sulfonium Salts (2019)

Site-selective functionalization of C-H bonds in small complex molecules is a long-standing challenge in organic chemistry. Herein, we report a broadly applicable and site-selective aromatic C-H dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two-step C-H [<sup>18</sup> F]fluorination of a series of marketed small-molecule drugs.