gebhart/patrepeval huggingface dataset:
Adaptive design methods in clinical trials – a review (2008)

In recent years, the use of adaptive design methods in clinical research and development based on accrued data has become very popular due to its flexibility and efficiency. Based on adaptations applied, adaptive designs can be classified into three categories: prospective, concurrent (ad hoc), and retrospective adaptive designs. An adaptive design allows modifications made to trial and/or statistical procedures of ongoing clinical trials. However, it is a concern that the actual patient population after the adaptations could deviate from the originally target patient population and consequently the overall type I error (to erroneously claim efficacy for an infective drug) rate may not be controlled. In addition, major adaptations of trial and/or statistical procedures of on-going trials may result in a totally different trial that is unable to address the scientific/medical questions the trial intends to answer. In this article, several commonly considered adaptive designs in clinical trials are reviewed. Impacts of ad hoc adaptations (protocol amendments), challenges in by design (prospective) adaptations, and obstacles of retrospective adaptations are described. Strategies for the use of adaptive design in clinical development of rare diseases are discussed. Some examples concerning the development of Velcade intended for multiple myeloma and non-Hodgkin's lymphoma are given. Practical issues that are commonly encountered when implementing adaptive design methods in clinical trials are also discussed.
Microspectrophotometry of Nitric Oxide--Dependent Changes in Hemoglobin in Single Red Blood Cells Incubated with Stimulated Macrophages (1997)

A highly sensitive microspectrophotometer was developed to measure spectral changes of oxyhemoglobin (oxy Hb) in single red blood cells (RBC) incubated with stimulated macrophages as a model of nitric oxide (NO) dependent cytotoxicity. Our microspectrophotometer, using a modified acousto-optic tunable filter (AOTF) and a 2-dimensional CCD array, allows fast spectrophotometric data acquisition. Human RBC treated with various concentrations of NO showed spectral changes due to the conversion of oxy Hb to methemoglobin (met Hb), in which the change in absorption differences at alpha (557 590 nm) and beta (542-525 nm) bands showed a linear relationship with the concentration of NO up to 100 microM. In contrast to highly diffusible NO, nitrite ions (NO2-) seem to enter RBC very slowly, resulting in negligible formation of met Hb in the presence of 5 mM glucose even during a prolonged incubation period. RBC were incubated with murine macrophages with and without lipopolysaccharide (LPS) in the presence of glucose for 24 and 40 h and subjected to the microspectrophotometric assay. The RBC incubated with LPS-stimulated macrophages showed significant changes in the spectrum due to NO-dependent conversion of oxy Hb to met Hb, which corresponded to the spectral changes of RBC treated with a several times higher concentration of NO than that in the culture medium. The trapping efficiency was calculated from the amounts of the NO released from macrophages and of the met Hb formed in the RBC, which gave a high efficiency (43%). The results suggest that RBC trap NO directly by cell cell interaction with macrophages. This spectrophotometric system is available for use with just a few drops of samples to study NO-specific cytotoxicity as a model of RBC without the use of any chemical reagent, in parallel with microscopic observations on changes of the cellular morphology under physiological conditions, such as membrane damage leading to hemolysis, adherence, and phagocytosis.
Parity striping of disc arrays: low-cost reliable storage with acceptable throughput (1990)

Abstract: ~n analysis of mirrored discs and of RAID5 shows that mirrors have considerably better throughput, measured as requests/second, on random requests of arbitrary size (up to 1MB). Mirrors have comparable or better response time for requests of reasonable size (less than looKB). But mirrors have a 100 % storage penalty: storing the data twice. Parity striping is a data layout that stripes the parity across the discs, but does not stripe the data. Parity striping has throughput almost as good as mirrors, and has costlGB comparable to RAIDS designs-- combing the advantages of both for high-traffic disc resident data. Parity striping has additional fault containment and software benefits as well. Parity striping sacrifices the high data transfer rates of RAID designs for high throughput. It is argued that response time and throughput are preferable performance
Structure of Penicillium citrinum α1,2-Mannosidase Reveals the Basis for Differences in Specificity of the Endoplasmic Reticulum and Golgi Class I Enzymes (2002)

Class I alpha1,2-mannosidases (glycosylhydrolase family 47) are key enzymes in the maturation of N-glycans. This protein family includes two distinct enzymatically active subgroups. Subgroup 1 includes the yeast and human endoplasmic reticulum (ER) alpha1,2-mannosidases that primarily trim Man(9)GlcNAc(2) to Man(8)GlcNAc(2) isomer B whereas subgroup 2 includes mammalian Golgi alpha1,2-mannosidases IA, IB, and IC that trim Man(9)GlcNAc(2) to Man(5)GlcNAc(2) via Man(8)GlcNAc(2) isomers A and C. The structure of the catalytic domain of the subgroup 2 alpha1,2-mannosidase from Penicillium citrinum has been determined by molecular replacement at 2.2-A resolution. The fungal alpha1,2-mannosidase is an (alphaalpha)(7)-helix barrel, very similar to the subgroup 1 yeast (Vallée, F., Lipari, F., Yip, P., Sleno, B., Herscovics, A., and Howell, P. L. (2000) EMBO J. 19, 581-588) and human (Vallée, F., Karaveg, K., Herscovics, A., Moremen, K. W., and Howell, P. L. (2000) J. Biol. Chem. 275, 41287-41298) ER enzymes. The location of the conserved acidic residues of the catalytic site and the binding of the inhibitors, kifunensine and 1-deoxymannojirimycin, to the essential calcium ion are conserved in the fungal enzyme. However, there are major structural differences in the oligosaccharide binding site between the two alpha1,2-mannosidase subgroups. In the subgroup 1 enzymes, an arginine residue plays a critical role in stabilizing the oligosaccharide substrate. In the fungal alpha1,2-mannosidase this arginine is replaced by glycine. This replacement and other sequence variations result in a more spacious carbohydrate binding site. Modeling studies of interactions between the yeast, human and fungal enzymes with different Man(8)GlcNAc(2) isomers indicate that there is a greater degree of freedom to bind the oligosaccharide in the active site of the fungal enzyme than in the yeast and human ER alpha1,2-mannosidases.
Targeting the myostatin signaling pathway to treat muscle wasting diseases (2011)

Muscle wasting increases the risks of morbidity and mortality. But, the reliability of estimates of the degree of muscle wasting is controversial as are definitions of terms like cachexia. Much information has been learnt about the pathophysiology of muscle wasting, including the major role of the ubiquitin-proteasome system (UPS) which along with other proteases degrades protein and limits protein synthesis. In contrast, few successful strategies for reversing muscle loss have been tested. Several catabolic conditions are characterized by inflammation, increased glucocorticoid production, and impaired intracellular signaling in response to insulin and IGF-1. These characteristics lead to activation of the UPS and other proteases producing muscle wasting. Another potential initiator of muscle wasting is myostatin and its expression is increased in muscles of animal models and patients with certain catabolic conditions. Myostatin is a member of the TGF-β family; it suppresses muscle growth and its absence stimulates muscle growth substantially. Recently, pharmacologic suppression of myostatin was found to counteract inflammation, increased glucocorticoids and impaired insulin/IGF-1 signaling and most importantly, prevents muscle wasting in rodent models of cancer and kidney failure. Myostatin antagonism as a therapy for patients with muscle wasting should become a topic of clinical investigation.
Specificity, diversity, and regulation in TGF-beta superfamily signaling. (1999)

Transforming growth factor-beta (TGF-beta) superfamily members are multifunctional cell-cell signaling proteins that play pivotal roles in tissue homeostasis and development of multicellular animals. They mediate their pleiotropic effects from membrane to nucleus through distinct combinations of type I and type II serine/threonine kinase receptors and their downstream effectors, known as Smad proteins. Certain Smads, termed receptor-regulated Smads, become phosphorylated by activated type I receptors and form heteromeric complexes with a common-partner Smad4, which translocates into the nucleus to control gene transcription. In addition to these signal transducing Smads, inhibitory Smads have been identified that inhibit the activation of receptor-regulated Smads. In contrast to the still growing TGF-beta superfamily (with approximately 30 members in mammals), relatively few type I and type II receptors as well as Smads have been identified. We will focus on recent insights into the molecular mechanisms by which signaling specificity between different TGF-beta superfamily members is achieved and regulated, and how a single family member can elicit a broad scala of biological responses.-Piek, E., Heldin, C.-H., ten Dijke, P. Specificity, diversity, and regulation in TGF-beta superfamily signaling.
Active origami by 4D printing (2014)

Recent advances in three dimensional (3D) printing technology that allow multiple materials to be printed within each layer enable the creation of materials and components with precisely controlled heterogeneous microstructures. In addition, active materials, such as shape memory polymers, can be printed to create an active microstructure within a solid. These active materials can subsequently be activated in a controlled manner to change the shape or configuration of the solid in response to an environmental stimulus. This has been termed 4D printing, with the 4th dimension being the time-dependent shape change after the printing. In this paper, we advance the 4D printing concept to the design and fabrication of active origami, where a flat sheet automatically folds into a complicated 3D component. Here we print active composites with shape memory polymer fibers precisely printed in an elastomeric matrix and use them as intelligent active hinges to enable origami folding patterns. We develop a theoretical model to provide guidance in selecting design parameters such as fiber dimensions, hinge length, and programming strains and temperature. Using the model, we design and fabricate several active origami components that assemble from flat polymer sheets, including a box, a pyramid, and two origami airplanes. In addition, we directly print a 3D box with active composite hinges and program it to assume a temporary flat shape that subsequently recovers to the 3D box shape on demand.
Siren: catching evasive malware (2006)

With the growing popularity of anomaly detection systems, which is due partly to the rise in zero-day attacks, a new class of threats have evolved where the attacker mimics legitimate activity to blend in and avoid detection. We propose a new system called Siren that injects crafted human input alongside legitimate user activity to thwart these mimicry attacks. The crafted input is specially designed to trigger a known sequence of network requests, which Siren compares to the actual traffic. It then flags unexpected messages as malicious. Using this method, we were able to detect ten spyware programs that we tested, many of which attempt to blend in with user activity. This paper presents the design, implementation, and evaluation of the Siren activity injection system, as well as a discussion of its potential limitations
Synthesis of Anthracene End-Capped Poly(methyl methacrylate)s via Atom Transfer Radical Polymerization and Its Kinetic Analyses (2002)

The synthesis of anthracene end-capped poly(methyl methacrylate)s via atom transfer radical polymerization (ATRP) and the kinetic analyses thereof are reported. Methyl methacrylate was polymerized in toluene at 90 °C (or 60 °C) via ATRP using 9-anthracenemethyl-2-bromoisobutyrate as the initiator and CuBr/N-(n-hexyl)pyridylmethanimine as the catalyst. Anthracene end-capped polymers with predetermined molecular weights and low polydispersities (PDI < 1.3) were obtained and characterized by 1H NMR and UV−vis. The initiator and Cu(I) concentrations, initially added Cu(II) concentration, and reaction temperature of the ATRP system have a decisive effect on the kinetics of the reaction. When the initiator and Cu(I) concentrations or the reaction temperature are relatively high, or the initially added Cu(II) concentration is relatively low, and consequently the radical concentration in the system is relatively high, the kinetics of the polymerization fits Fischer's equation (ln([M]0/[M]) ∝ t2/3). On the other hand, Matyjaszewski's equation (ln([M]0/[M]) ∝ t) can be fitted quite well when the initiator and Cu(I) concentrations or the reaction temperature are so low or the initially added Cu(II) concentration becomes so high that radical termination is negligible. This kinetic transition is of great importance for better understanding the mechanism of ATRP. The equilibrium and termination constants (Keq and kt) for the studied ATRP system at 90 °C are 9.1 × 10-8 and 1.3 × 108 M-1 s-1, respectively. The experimental evidence for Fischer's theoretically derived threshold Cu(II) concentration for the kinetic transition, i.e., [Cu(II)]0,t = (3Keq[RX]0[Cu(I)]0kt/kp)1/2, is provided.
Neuere Methoden der präparativen organischen Chemie IV Mit Sekundär‐Reaktionen gekoppelte α‐Additionen von Immonium‐Ionen und Anionen an Isonitrile (1962)

Abstract Die mit Sekundär‐Reaktionen gekoppelte α‐Addition von Immonium‐Ionen und Anionen (OH − , SeH − , S 2 O 3 2− , N 3 − , NCO − , NCS − , R‐CO 2 − , RO‐CO 2 − ) an Isonitrile ermöglicht einstufige Synthesen organischer Stickstoff‐Verbindungen aus zwei bis fünf Komponenten. Durch Kondensation von Aminen (Ammoniak, prim. und sek. aliphatische und aromatische Amine, Hydrazine) und Aldehyden oder Ketonen mit Isonitrilen und Säuren sind so beispielsweise α‐Amino‐carbonsäure‐amide, ‐thioamide, ‐selenoamide, 1.5‐disubstituierte Tetrazole, Hydantoin‐ und Thiohydantoin‐imide, α‐Acylamino‐carbonsäure‐amide, Oligopeptid‐Derivate, β‐Lactame, Penicillansäure‐Derivate, Urethane, Diacylimide und Hydrazin‐Abkömmlinge zugänglich. Die Umsetzungen sind einfach auszuführen und verlaufen unter schonenden Bedingungen. Ausbeuten über 90% sind nicht selten.
Measurement of Single-Molecule Resistance by Repeated Formation of Molecular Junctions (2003)

The conductance of a single molecule connected to two gold electrodes was determined by repeatedly forming thousands of gold-molecule-gold junctions. Conductance histograms revealed well-defined peaks at integer multiples of a fundamental conductance value, which was used to identify the conductance of a single molecule. The resistances near zero bias were 10.5 +/- 0.5, 51 +/- 5, 630 +/- 50, and 1.3 +/- 0.1 megohms for hexanedithiol, octanedithiol, decanedithiol, and 4,4' bipyridine, respectively. The tunneling decay constant (betaN) for N-alkanedithiols was 1.0 +/- 0.1 per carbon atom and was weakly dependent on the applied bias. The resistance and betaN values are consistent with first-principles calculations.
Crystal Structure of the Dual Specificity Protein Phosphatase VHR (1996)

Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. Here, the crystal structure of a human DSP, vaccinia H1-related phosphatase (or VHR), was determined at 2.1 angstrom resolution. A shallow active site pocket in VHR allows for the hydrolysis of phosphorylated serine, threonine, or tyrosine protein residues, whereas the deeper active site of protein tyrosine phosphatases (PTPs) restricts substrate specificity to only phosphotyrosine. Positively charged crevices near the active site may explain the enzyme's preference for substrates with two phosphorylated residues. The VHR structure defines a conserved structural scaffold for both DSPs and PTPs. A "recognition region," connecting helix alpha1 to strand beta1, may determine differences in substrate specificity between VHR, the PTPs, and other DSPs.
Protein Displays of the Human Immunoglobulin Heavy, Kappa and Lambda Variable and Joining Regions (1999)

'Protein displays of the Human Immunoglobulin Heavy, Kappa and Lambda Variable and Joining Regions', the 6th report of the 'IMGT Locus on Focus' section, comprises 4 figures: (1) 'Protein display of human IGH V-REGIONs'; (2) 'Protein display of human IGK V-REGIONs'; (3) 'Protein display of human IGL V-REGIONs and V-PREB REGION'; (4) 'Protein display of human IGH, IGK and IGL J-REGIONs', and 1 table entitled: 'FR-IMGT and CDR-IMGT length of the human IGHV, IGKV, IGLV and V-PREB genes'. These figures and table are available at the IMGT Marie-Paule page from IMGT, the international ImMunoGeneTics database (http://imgt.cnusc.fr: 8104) created by Marie-Paule Lefranc, Université Montpellier II, CNRS, France.
SQL open heterogeneous data access (1998)

We describe the open, extensible architecture of SQL for accessing data stored in external data sources not managed by the SQL engine. In this scenario, SQL engines act as middleware servers providing access to external data using SQL DML statements and joining external data with SQL tables in heterogeneous queries. We describe the state-of-the art in object-relational systems and their companion products, and provide an outlook on future directions.
Monogene and Polygene Therapy for the Treatment of Experimental Prostate Cancers by Use of Apoptotic Genes bax and bad Driven by the Prostate-Specific Promoter ARR 2 PB (2002)

We have shown that adenovirus-mediated manipulation of apoptotic genes such as bax could be a therapeutic option for prostate cancer. Unfortunately, the response of experimental prostate tumors to a single therapeutic gene of the apoptotic pathway is short-lived, and most of these tumors relapse after a short period of time. In this investigation we present data generated with adenovirus AvARR(2)PB-Bad, in which the apoptotic gene bad was placed under the control of the dihydrotestosterone (DHT)-inducible third-generation probasin-derived promoter ARR(2)PB. This therapeutic virus was given alone or in combination with other therapeutic viruses to a variety of in vitro and in vivo experimental models of prostate cancer. On infection with AvARR(2)PB-Bad, DHT-induced Bad overexpression occurred specifically in androgen receptor-positive (AR(+)) cells of prostatic derivation. The apoptotic effect of AvARR(2)PB-Bad (group 1) was compared with that of AvARR(2)PB-Bax (which overexpresses the apoptotic protein Bax) (group 2), with that of the combination AvARR(2)PB-Bad plus AvARR(2)PB-Bax (group 3), and with that of the control virus AvARR(2)PB-CAT (group 4) in the cell line LNCaP. In addition to identifying the modality of apoptosis induction by overexpressed Bad, the results suggested that group 3 contained more apoptotic cells than any other group. In additional studies, AR(+) androgen-dependent LNCaP cells or AR(+) and androgen-independent C4-2 cells were injected subcutaneously into nude mice. Four groups of six LNCaP or C4-2 tumors were treated with the same combinations of viruses discussed above for groups 1, 2, 3, and 4. Treatment resulted in decreased tumor size in groups 1, 2, and 3 compared with group 4. There was a better response in group 3 compared with group 2, and in group 2 compared with group 1. A better response in group 3 was confirmed during a 8-week follow-up period, in which no treatment was administered. Two LNCaP and C4-2 tumors of group 3 disappeared at the end of treatment and did not recur after an 8-week follow-up period. The data suggest that polygene therapy with apoptotic molecules is more effective in experimental models of androgen-dependent or -independent prostate cancer than monogene therapy.
Inhibiting viral proteases: Challenges and opportunities (2002)

Inhibitor design against viral targets must take into account the peculiar characteristics of viral biology-in particular, the plasticity of their replicative machinery. This includes maturational cleavage of the polyprotein, which is mediated by virally encoded proteases. Designing against a movable target is particularly challenging, but at the same time it offers new opportunities. Here we describe our experience with the NS3/4A (NS: nonstructural) serine protease of human hepatitis C virus (HCV). By extensive use of combinatorial peptide libraries, various inhibitor types were generated, including product inhibitors, serine traps, P-P' inhibitors, and prime side inhibitors. The latter represent a first case for a serine protease. A key finding, derived from structural studies utilizing these inhibitors, was that NS3 is an induced-fit protease, requiring both the NS4A cofactor protein and the substrate to fully activate its catalytic machinery. In the absence of cofactor and/or substrate, NS3 exists in solution as a large conformational ensemble, which can be matched by a correspondingly large set of peptide inhibitors, each one stabilizing a given conformer. In the perspective of inhibiting viral proteases in general, we suggest that combinatorial ligand ensembles may be a powerful tool, to contrast the adaptive potential of the viral quasispecies.
Propagation and Retention of Viscoelastic Surfactants Following Matrix Acidizing Treatments in Carbonate Cores (2010)

Abstract Viscoelastic surfactants have been applied extensively in the field, because of their unique characteristics of forming rod-like micelles with the increase of pH and calcium concentration. There is continuous debate in the industry on whether the gel generated by these surfactants causes formation damage or not. This is especially true in dry gas wells. The objective of the present study is to conduct core flood experiments using surfactant-based acids and measure the concentration of the surfactant concentration in the core effluent. Material balance on the surfactant will shed lights on the amount of surfactant recovered, which will help in assessing damage due to surfactant gel retention in the cores. Core flood tests were performed using calcium carbonate cores 1.5 in. diameter and 20 in. length. The cores were injected with a surfactant-based acid of 15 wt% HCl that contained 7 vol% surfactant and other acid additives. Core flood test were conducted at constant injection flow rate that was varied from 3 to 40 cm3/min. Carbonate cores of various initial permeability were used. In all core tests, surfactant concentration was measured in the injected acid and core effluent using the two-phase titration method. Mutual solvent was used to break surfactant gels. Considerable amounts of viscoelastic surfactant were retained in the carbonate cores after the acid treatments, and the retained surfactant gel is a source of formation damage if not effectively removed. The amount of surfactant-based acid required to create wormhole in carbonate matrix is high at both low shear rate (&amp;lt; 900 s-1) and high shear rate (&amp;gt; 3,000 s-1), and is low at intermediate shear rates with the minimum value at shear rate of 1,500 to 2,000 s-1. The surfactant retention in the carbonate matrix is lowest at shear rates near 2,000 s-1, and is high at both high and low shear rates. Surfactant was retained in gelled form. Mutual solvent was able to remove as much as 21% of the total amount of surfactant injected into the core.