gebhart/patrepeval huggingface dataset:
Time for a Fully Integrated Nonclinical–Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective (2020)

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14-based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B-based "double-negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high-dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double-negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development.
Insights from the 2010 HIV Diagnostics Conference (2010)

The 2010 HIV Diagnostics Conference brought together approximately 260 representatives from public health laboratories, test manufacturers and federal agencies for a series of test method and technology presentations, as well as policy discussions related to HIV screening in the USA. The meeting was particularly substantive in the context of moving toward a consensus laboratory testing algorithm that capitalizes on the improved sensitivities and turnaround times associated with newer technologies. This article provides a brief overview of several meeting topics, including point-of-care testing algorithms, fourth-generation immunoassays, recency testing and new technologies.
<title>Variable phase-shift mask for deep-submicron optical lithography</title> (1991)

A variable phase-shift mask for optical lithography, which gives several kinds of optical phase shifting to light transmitted through the mask apertures, is proposed, and image quality obtained with this mask is investigated. Clear regions with some optical phase shiftings between 0 degree(s) and 180 degree(s) are inserted between the two connected apertures, which are 180 degree(s) out of phase. The role of these inserted regions is to decrease the dip in intensity distribution, which is occasionally needed for producing complicated features. The advantages of this variable phase-shift mask and the effect of wave-front aberrations on imaging characteristics are investigated.
Targeting glycogen synthase kinase-3 (GSK-3) in human melanoma (2008)

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA

A18 

In our functional survey of specific melanoma-associated alterations, we found a surprising anti-oncogenic role of beta-catenin signaling. Introduction of a protein-stabilized form of beta-catenin antagonized oncogene (activated Ras and c-Met)-driven transformation of human epidermal melanocytes (HEMs). Tracing the canonical beta-catenin pathway identified GSK-3, a negative regulator of beta-catenin, as a potential molecular target amenable to pharmacologic inhibition in melanoma cells. Treatment of oncogene-transformed HEMs with a small molecular GSK-3 inhibitor, BIO phenocopied the inhibitory effect of beta-catenin overexpression. Whereas the growth of primary HEMs and oncogene-transduced derivatives is exquisitely sensitive to inhibition by BIO treatment, the growth of patient-derived melanoma cell lines, in contrast, showed variable sensitivities (over two orders of magnitude) to pharmacologic GSK-3 inhibition. BIO synergized with the p53-MDM2 inhibitor, Nutlin-3, in the growth inhibition of susceptible melanoma cells. In addition, cell lines harboring NRAS mutations, compared to those with BRAF mutations or WT NRAS/BRAF alleles, are associated with increased resistance to GSK-3 inhibition. Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) of genomic mRNA profiles revealed enhanced cellular autophagy to be correlated with increased resistance to BIO-mediated growth inhibition. Relative BIO-resistance correlated with increased GFP-LC3 subcellular punctate localization, a reporter for enhanced autophagolysosomal flux. Additionally, pharmacologic inhibition of the autophagolysosomal pathway enhanced BIO-mediated growth inhibition. Thus, the growth of melanoma cells displays variable sensitivities to GSK-3 inhibition, and survival of melanoma cells in response to acute GSK-3 inhibition may be partially mediated by enhanced cellular autophagy.
Freeform Optical Surfaces: A Revolution in Imaging Optical Design (2012)

A revolutionary optical surface is the result of developments in the theory of aberrations, techniques in optical system optimization, computation speed, precision fabrication of surfaces without symmetry, and extensions to the range of the surface slopes allowed in optical testing.
Gene-Expression and Immunohistochemical Study of Specific T-Cell Subsets and Accessory Cell Types in the Transformation and Prognosis of Follicular Lymphoma (2007)

These results support the identification of FL as an immunologically functional disease in which an interaction of the tumor cells and the functional composition of the microenvironment determines the clinical behavior.
pH-Responsive Nanoparticle Superlattices with Tunable DNA Bonds (2018)

Stimuli-responsive nanomaterials with reconfigurable structures and properties have garnered significant interest in the fields of optics, electronics, magnetics, and therapeutics. DNA is a powerful and versatile building material that provides programmable structural and dynamic properties, and indeed, sequence-dependent changes in DNA have already been exploited in creating switchable DNA-based architectures. However, rather than designing a new DNA input sequence for each intended dynamic change, it would be useful to have one simple, generalized stimulus design that could provide multiple different structural outputs. In pursuit of this goal, we have designed, synthesized, and characterized pH-dependent, switchable nanoparticle superlattices by utilizing i-motif DNA structures as pH-sensitive DNA bonds. When the pH of the solution containing such superlattices is changed, the superlattices reversibly undergo: (i) a lattice expansion or contraction, a consequence of the pH-induced change in DNA length, or (ii) a change in crystal symmetry, a consequence of both pH-induced DNA "bond breaking" and "bond forming" processes. The introduction of i-motifs in DNA colloidal crystal engineering marks a significant step toward being able to dynamically modulate crystalline architectures and propagate local molecular motion into global structural change via exogenous stimuli.
Influence of severe protein malnutrition on rat lacrimal, salivary and gastrointestinal immune expression during development, adulthood and ageing. (1993)

The objective of the present study was to examine and to compare the impact of severe protein malnutrition during development, adulthood and ageing on secretory immune expression in the eye, mouth and small intestine. In addition, we sought to determine whether potential abrogation of mucosal immunity by protein deprivation might be reversed by the administration of a balanced diet. Weanling, adult and aged rats were provided isocaloric diets containing 24% (control), 19%, 14%, 10%, 6% and/or 3.2% protein levels for defined periods and various immunological parameters were evaluated before, during and after the dietary regimen. Our results demonstrated the following. (1) Severe protein malnutrition (3.2%) dramatically suppressed the secretory immune system in eyes of weanling rats. After 8 weeks of protein insufficiency, tear IgA concentrations in young rats had undergone a precipitous decrease, such that IgA could not be detected in tears. This response was paralleled by a significant decline in the tear volume, tear secretory component (SC), IgG and total protein content, number of IgA-containing cells in lacrimal tissue, as well as the amounts of SC and/or IgA in saliva, intestinal secretions and serum. In contrast, the immunological effects of protein malnutrition in adult or aged animals varied considerably depending upon the specific mucosal site. (2) The influence of protein deprivation was dose dependent and reversible: maintenance of weanling rats on 10%, 6% or 3.2% protein diets interfered with the establishment of ocular and intestinal mucosal immunity, but later administration of optimal diets to these malnourished animals permitted a rapid immune recovery. (3) The impact of protein malnutrition on tear IgA levels in weanling animals, as shown by pair-feeding experiments, appeared to reflect primarily protein deficiency and not caloric restriction. Overall, these findings show that dietary protein plays a significant, site-specific role in the developmental expression of the secretory immune system.
perfbench (2018)

Network Virtualization (NV) provides low resource costs and high utilization, while ensuring bandwidth isolation in the data plane. Software-Defined Networks (SDNs) are a particularly interesting technology to implement NV, as tenants maintain control over their virtual Software-Defined Networks (vSDNs). However, bandwidth isolation alone may not be enough to provide a predictable application performance in virtual networks, as the virtualization layer itself is another source of potential performance interference. Today, we lack tools that help reveal and investigate such sources of interference and identify performance inefficiencies. In order to fill this gap, we developed a new tool --- perfbench. We report on the tool design and our initial findings.
Integrated testing of the SRL-165 glass waste form (1986)

Integrated testing of the important components of a glass waste form waste package has been performed in order to gain a better understanding of the processes of radionuclide release and transport in the near field environment. Based upon an interpretation of the depth of penetration of hydrogen in reacted SRL-165 glass we have modeled the radionuclide release from the glass as a combined process of (1) the diffusive exchange of alkalis and boron in the glass for hydrogen species in the solution (D = 10{sup -16} cm{sup 2}/s) and (2) surface dissolution. Surface dissolution controls the release of components not exchanged by diffusion and takes place at a rate of 1.5 to 3.0 {mu}m/yr. Subsequent to release the radionuclides may remain in the leach solution, diffuse into the tuff, or precipitate as secondary phases. Precipitation is particularly important for plutonium and americium. Diffusive transport of radionuclides through the tuff takes place at an extremely slow rate, D = 10{sup -16} cm{sup 2}/s. As such, the mass of radionuclides incorporated in the tuff by diffusion during the tests is inconsequential relative to that in the leach solution (with the exception of plutonium) and can be ignored in mass balance calculations. Mass balance calculations based upon the release of radionuclides by surface dissolution of the glass waste form are in good agreement with observed solution chemistry when allowances are made for a pulse of dissolution early in the tests. This pulse may be due to either the rapid dissolution of high-energy surface features early in the integrated tests, or an initially high surface dissolution rate that decreases with time as silica saturation is approached, or a combination of the two.
High-throughput size-based rare cell enrichment using microscale vortices (2011)

Cell isolation in designated regions or from heterogeneous samples is often required for many microfluidic cell-based assays. However, current techniques have either limited throughput or are incapable of viable off-chip collection. We present an innovative approach, allowing high-throughput and label-free cell isolation and enrichment from heterogeneous solution using cell size as a biomarker. The approach utilizes the irreversible migration of particles into microscale vortices, developed in parallel expansion-contraction trapping reservoirs, as the cell isolation mechanism. We empirically determined the critical particle∕cell diameter D(crt) and the operational flow rate above which trapping of cells∕particles in microvortices is initiated. Using this approach we successfully separated larger cancer cells spiked in blood from the smaller blood cells with processing rates as high as 7.5×10(6) cells∕s. Viable long-term culture was established using cells collected off-chip, suggesting that the proposed technique would be useful for clinical and research applications in which in vitro culture is often desired. The presented technology improves on current technology by enriching cells based on size without clogging mechanical filters, employing only a simple single-layered microfluidic device and processing cell solutions at the ml∕min scale.
Depinning-Induced Capillary Wave during the Sliding of a Droplet on a Textured Surface (2016)

Surfaces covered with hydrophobic micro-/nanoscale textures can allow water droplets to slide easily because of low contact angle hysteresis. In contrast to the case of a droplet sliding on a smooth surface, when a droplet slides on a textured surface, it must recede from the textures at its rear edge and the resultant depinning events induce a capillary wave on the surface of the droplet. Although this depinning-induced capillary wave can be observed to some extent through high-speed imaging, important parameters of the wave, such as the wavelength and frequency, and the factors that determine these parameters are not fully understood. We report direct measurements of this depinning-induced capillary wave using microelectromechanical systems (MEMS)-based force sensors fabricated on a textured surface. Such sensor measurements reveal the frequency of the vibration occurring on the surface of the droplet, from which it is possible to calculate the wavelength of the capillary wave. We show that the frequency and wavelength of the depinning-induced capillary wave during the sliding of a water droplet on a micropillar array depend upon neither the size of the droplet nor its sliding velocity. However, the frequency (wavelength) decreases (increases) as the pitch of the micropillar array increases. We argue that the wavelength of the depinning-induced capillary wave is equal to the maximum length of the liquid bridges that develop at the micropillars before depinning. This hypothesis is confirmed by comparing the wavelengths obtained from the sensor measurements to the maximum liquid-bridge lengths calculated from observations using a high-speed camera.
Non-additive impacts of covalent cross-linking on the viscoelastic nanomechanics of ionic polyelectrolyte complexes (2017)

This study elucidates the influences of adding covalent cross-linking on the nanomechanical viscoelasticity of ionically cross-linked polyelectrolyte networks.
A primary current distribution model of a novel micro-electroporation channel configuration (2010)

Traditional macro and micro-electroporation devices utilize facing electrodes, which generate electric fields inversely proportional to their separation distance. Although the separation distances in micro-electroporation devices are significantly smaller than those in macro-electroporation devices, they are limited by cell size. Because of this, significant potential differences are required to induce electroporation. These potential differences are often large enough to cause water electrolysis, resulting in electrode depletion and bubble formation, both of which adversely affect the electroporation process. Here, we present a theoretical study of a novel micro-electroporation channel composed of an electrolyte flowing over a series of adjacent electrodes separated by infinitesimally small insulators. Application of a small, non-electrolysis inducing potential difference between the adjacent electrodes results in radially-varying electric fields that emanate from these insulators, causing cells flowing through the channel to experience a pulsed electric field. This eliminates the need for a pulse generator, making a minimal power source (such as a battery) the only electrical equipment that is needed. A non-dimensional primary current distribution model of the novel micro-electroporation channel shows that decreasing the channel height results in an exponential increase in the electric field magnitude, and that cells experience exponentially greater electric field magnitudes the closer they are to the channel walls. Finally, dimensional primary current distribution models of two potential applications, water sterilization and cell transfection, demonstrate the practical feasibility of the novel micro-electroporation channel.
Harmonized microarray/mutation scanning analysis of TP53 mutations in undissected colorectal tumors (2004)

Both the mutational status and the specific mutation of TP53 (p53) have been shown to impact both tumor prognosis and response to therapies. Molecular profiling of solid tumors is confounded by infiltrating wild-type cells, since normal DNA can interfere with detection of mutant sequences. Our objective was to identify TP53 mutations in 138 stage I-IV colorectal adenocarcinomas and liver metastases without first enriching for tumor cells by microdissection. To achieve this, we developed a harmonized protocol involving multiplex polymerase chain reaction/ligase detection reaction (PCR/LDR) with Universal DNA microarray analysis and endonuclease V/ligase mutation scanning. Sequences were verified using dideoxy sequencing. The harmonized protocol detected all 66 mutations. Dideoxy sequencing detected 41 out of 66 mutations (62%) using automated reading, and 59 out of 66 mutations (89%) with manual reading. Data analysis comparing colon cancer entries in the TP53 database (http://p53.curie.fr) with the results reported in this study showed that distribution of mutations and the mutational events were comparable.
Silver-Promoted, Palladium-Catalyzed Direct Arylation of Cyclopropanes: Facile Access to Spiro 3,3′-Cyclopropyl Oxindoles (2013)

The Pd-catalyzed, Ag(I)-mediated intramolecular direct arylation of cyclopropane C-H bonds is described. Various spiro 3,3'-cyclopropyl oxindoles can be obtained in good to excellent yields from easily accessible 2-bromoanilides. The kinetic isotope effect was determined and epimerization studies were conducted, suggesting that the formation of a putative Pd-enolate is not operative and that the reaction proceeds via a C-H arylation pathway.
Investigation of Flow Patterns in Continuous‐flow Stirred Vessels by Laser Doppler Velocimetry (2002)

Abstract The flow structure of a continuous‐flow reactor stirred by a Rushton turbine was investigated by laser Doppler velocimetry for two different mean residence time‐mixing time ratios. Velocity measurements were obtained for two inlet locations, corresponding to the incoming liquid stream being fed co‐currently or counter‐currently to the flow discharged by the turbine. In all investigated configurations and for all operating conditions, it was found that the flow disruption caused by the incoming liquid stream was observable mainly in the first vessel quarter, which followed the feed‐tube plane. From comparison of the velocities encountered in the various planes in the continuous‐flow reactor to the velocities of the batch reactor, it was also concluded that it may be possible to intensify the usage of the turbine‐stirred vessel by decreasing the characteristic times ratio, without considerable flow by‐pass and/or short‐circuiting problems.
Investigation of Material Constants of CaTiO3 Doped (K,Na)NbO3 Film by MEMS-Based Test Elements (2018)

A CaTiO₃-doped (K,Na)NbO₃ (KNN-CT) film is a lead-free piezoelectric film that is expected to substitute Pb(Zr,Ti)O₃ (PZT) film in piezoelectric micro electro mechanical systems (MEMS). However, the full set of the material constants (elastic constants, piezoelectric constants and dielectric constants) of the KNN-CT film have not been reported yet. In this study, all the material constants of a sputter-deposited blanket KNN-CT film were investigated by the resonance responses of MEMS-based piezoelectric resonators and the phase velocities of leaky Lamb waves on a self-suspended membrane. The phase velocities measured by a line-focus-beam ultrasonic material characterization (LFB-UMC) system at different frequencies were fitted with theoretical ones, which were calculated from the material constants, including fitting parameters. A genetic algorithm was used to find the best-fitting parameters. All the material constants were then calculated. Although some problems arising from the film quality and the nature of deliquescence are observed, all the material constants were obtained exhibiting accuracy within 16 m/s in the phase velocity of leaky Lamb wave.
Photonic High-Power 160-GHz Signal Generation by Using Ultrafast Photodiode and a High-Repetition-Rate Femtosecond Optical Pulse Train Generator (2014)

We demonstrate photonic high-power MMW generation at subTHz (160 GHz) frequencies by using ultrafast near-ballistic unitraveling carrier photodiodes (NBUTC-PD), which have a miniaturized active area (24 μm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> ) and flip-chip bonding package for good heat-sinking. Under optical sinusoidal signal excitation with a ~85% modulation depth, 165-GHz optical-to-electrical 3-dB bandwidth, 18-mA saturation current, +5.11-dBm maximum output power at 160-GHz operating frequency has been demonstrated. In order to further mitigate device-heating, we developed a high-power pulsed optical signal source with increased optical modulation depth: a femtosecond optical short-pulse generator with extremely high repetition rate (160 GHz) and pulsewidth as short as 285 fs. With this novel source, we generated high MMW power (+7.8 dBm) with an effective 120% optical modulation depth at 160 GHz directly from the NBUTC-PD.
Supplementary Information from Heterochromatin Protein 1α Mediates Development and Aggressiveness of Neuroendocrine Prostate Cancer (2023)

&lt;p&gt;Supplementary materials and methods used in this study. Supplementary table with primer sequences. Figure S1, Histological feature of PDX models and heatmaps of PDX and clinical cohorts. Figure S2, IHC staining of HP1α in PDX models, and expression of Hp1α mRNA in NPp53 CRPC GEM models. Figure S3, Additional analyses of HP1α function in NEPC cells. Figure S4, Additional analyses of HP1α function in NE transdifferentiation. Figure S5, Additional analyses of the repressive function of HP1α on AR and REST expression. Figure S6, Additional analyses of the function of HP1α. Supplementary references.&lt;/p&gt;