gebhart/patrepeval huggingface dataset:
Exploratory Pharmacokinetic/Pharmacodynamic and Tolerability Study of BCMAxCD3 in Cynomolgus Monkeys (2016)

Abstract JNJ-64007957 is a bispecific antibody that binds to CD3 on T cells, and BCMA on plasma cells, and should induce T cell mediated killing of BCMA expressing malignant plasma cells. The objectives of this study were to characterize the tolerability of JNJ-64007957 when given intravenously as either single- or repeated-doses (5 total doses) to male cynomolgus monkeys. Pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in the repeat-dose groups; the single dose arms allowed for PK evaluations through Day 56, and determination of key PK parameters to support FIH dose modeling. Methods: The cynomolgus monkey was chosen for this study as JNJ-64007957 binds to both cynomolgus monkey CD3 and BCMA and it is an accepted non-rodent species for nonclinical tolerability, PK and PD evaluations. In this study, male monkeys (3/group) were administered either control or JNJ-64007957 via slow intravenous bolus injection on Days 1, 8, 15, 22, and 29 for repeat dose groups (1-4) and on Day 1 for single dose groups (5-6). The JNJ-64007957 doses were 0, 0.1, 1 and 10 mg/kg/week for repeat dose administration, and 1 or 10 mg/kg for single dose administration. Monkeys were evaluated for general tolerability, and samples were collected for PK and PD evaluations. Results: JNJ-64007959 was well tolerated upto 10 mg/kg. PK assessments showed that Cmax and AUC increased in a dose proportional manner, and the overall PK profiles suggested very low anti-drug antibody responses. For repeat dose groups, accumulation ratio was approximately 2. This supports dosing frequency of more than one week. There were no toxicologically significant findings in the monkeys at doses up to 10 mg/kg/week. Some minor changes in lymphoid cellularity were noted including an apparent slight to minimal and non-dose dependent decreases in plasma cells within one or more of the lymphoid tissues. There were no changes in peripheral blood lymphocytes or cytokine release. The small number of animals in this study precludes making definitive conclusions regarding the pharmacodynamics effects of dual BCMA and CD3 engagement but this will be investigated in a larger study that will support first in human dosing. Conclusions: Overall, this exploratory cynomolgus monkey study was designed to evaluate JNJ-64007957 tolerability and PK/PD in one study. This study indicated that a BCMAxCD3 bispecific antibody showed no toxicologically significant effects when administered to monkeys once per week for 5-weeks and exposure was dose proportional. Disclosures Girgis: Janssen Research &amp; Development: Employment. Shetty:Janssen Research &amp; Development: Employment. Jiao:Janssen Research &amp; Development: Employment. Amuzie:Janssen Research &amp; Development: Employment. Weinstock:Janssen Research &amp; Development: Employment. Grimme Watson:Janssen Research &amp; Development: Employment. Ford:Janssen Research &amp; Development: Employment. Pillarisetti:Janssen: Employment. Baldwin:Janssen: Employment. Bellew:Janssen: Employment.
Structure and properties of porous hypercrosslinked polystyrene sorbents Styrosorb (1989)

Abstract
Net Primary Production of a Forest Ecosystem with Experimental CO 2 Enrichment (1999)

The concentration of atmospheric carbon dioxide was increased by 200 microliters per liter in a forest plantation, where competition between organisms, resource limitations, and environmental stresses may modulate biotic responses. After 2 years the growth rate of the dominant pine trees increased by about 26 percent relative to trees under ambient conditions. Carbon dioxide enrichment also increased litterfall and fine-root increment. These changes increased the total net primary production by 25 percent. Such an increase in forest net primary production globally would fix about 50 percent of the anthropogenic carbon dioxide projected to be released into the atmosphere in the year 2050. The response of this young, rapidly growing forest to carbon dioxide may represent the upper limit for forest carbon sequestration.
Spatial Impulse Response Rendering II: Reproduction of Diffuse Sound and Listening Tests (2006)

Spatial impulse response rendering (SIRR) is a method for reproducing room impulse responses over multichannel loudspeaker setups. The applied analysis and synthesis methods were introduced in a companion paper. Time-frequency analysis is used to obtain directional and diffuseness information from the recorded sound field. Nondiffuse sound is then reproduced as pointlike virtual sources, and diffuse sound is synthesized with a decorrelation technique. The proposed synthesis methods for diffuse sound are examined in more detail and a hybrid method is derived. The relationship between diffuseness and interaural coherence is also studied. In addition, results of two listening tests are presented. It is shown that with a large loudspeaker setup under anechoic conditions, SIRR reproduction is at best indistinguishable from the original sample. Furthermore, in a listening test conducted in a standard listening room with real measured responses, SIRR reproduction is evaluated as the most natural one of the systems studied.
mRNAs from human adenovirus 2 early region 4 (1984)

The molecular structure of the mRNAs from early region 4 of human adenovirus 2 has been studied by Northern blot analysis, S1 nuclease analysis, and sequence analysis of cDNA clones. The results make it possible to identify four different splice donor sites and six different splice acceptor sites. The structure of 12 different mRNAs can be deduced from the analysis. The mRNAs have identical 5' and 3' ends and are thus likely to be processed from a common mRNA precursor by differential splicing. The different mRNA species are formed by the removal of one to three introns, and they all carry a short 5' leader segment. The introns appear to serve two functions; they either place a 5' leader segment in juxtaposition with an open reading frame or fuse two open translational reading frames. The early region 4 mRNAs can encode at least seven unique polypeptides.
Transient Kinetics of Heparin-catalyzed Protease Inactivation by Antithrombin III (1989)

The kinetics of alpha-factor Xa inhibition by antithrombin III (AT) were studied in the absence and presence of heparin (H) with high affinity for antithrombin by stopped-flow fluorometry at I 0.3, pH 7.4 and 25 degrees C, using the fluorescence probe p-aminobenzamidine (P) and intrinsic protein fluorescence to monitor the reactions. Active site binding of p-aminobenzamidine to factor Xa was characterized by a 200-fold enhancement and 4-nm blue shift of the probe fluorescence emission spectrum (lambda max 372 nm), 29-nm red shift of the excitation spectrum (lambda max 322 nm), and dissociation constant (KD) of about 80 microM. Under pseudo-first order conditions [( AT]0, [H]0, [P]0 much greater than [Xa]0), the observed factor Xa inactivation rate constant (kobs) measured by p-aminobenzamidine displacement or residual enzymatic activity increased linearly with the "effective" antithrombin concentration (i.e. corrected for probe competition) up to 300 microM in the absence of heparin, indicating a simple bimolecular process with a rate constant of 2.1 x 10(3) M-1 s-1. In the presence of heparin, a similar linear dependence of kobs on effective AT.H complex concentration was found up to 25 microM whether the reaction was followed by probe displacement or the quenching of AT.H complex protein fluorescence due to heparin dissociation, consistent with a bimolecular reaction between AT.H complex and free factor Xa with a 300-fold enhanced rate constant of 7 x 10(5) M-1 s-1. Above 25 microM AT.H complex, an increasing dead time displacement of p-aminobenzamidine and a downward deviation of kobs from the initial linear dependence on AT.H complex concentration were found, reflecting the saturation of an intermediate Xa.AT.H complex with a KD of 200 microM and a limiting rate of Xa-AT product complex formation of 140 s-1. Kinetic studies at catalytic heparin concentrations yielded a kcat/Km for factor Xa at saturating antithrombin of 7 x 10(5) M-1 s-1 in agreement with the bimolecular rate constant obtained in single heparin turnover experiments. These results demonstrate that 1) the accelerating effect of heparin on the AT/Xa reaction is at least partly due to heparin promoting the ordered assembly of antithrombin and factor Xa in an intermediate ternary complex and that 2) heparin catalytic turnover is limited by the rate of conversion of the ternary complex intermediate to the product Xa-AT complex with heparin dissociation occurring either concomitant with this step or in a subsequent faster step.
Drugs from the Sea (2000)

Marine organisms have attracted much attention as potential sources for drugs over recent years. This timely book covers the discovery, development and production of drugs from marine bacteria, fungi, microalgae, sponges and opisthobranch mollusks. A recent highlight of marine natural product research described here is the development of a painkill
The design of an asynchronous MIPS R3000 microprocessor (2002)

The design of an asynchronous clone of a MIPS R3000 microprocessor is presented. In 0.6 /spl mu/m CMOS, we expect performance close to 280 MIPS, for a power consumption of 7 W. The paper describes the structure of a high-performance asynchronous pipeline, in particular precise exceptions, pipelined caches, arithmetic, and registers, and the circuit techniques developed to achieve high throughput.
Very high detectability in two-photon spectroscopy (1990)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTVery high detectability in two-photon spectroscopyMary J. Wirth and H. O. FatunmbiCite this: Anal. Chem. 1990, 62, 9, 973–976Publication Date (Print):May 1, 1990Publication History Published online1 May 2002Published inissue 1 May 1990https://pubs.acs.org/doi/10.1021/ac00208a015https://doi.org/10.1021/ac00208a015research-articleACS PublicationsRequest reuse permissionsArticle Views94Altmetric-Citations28LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis (2015)

The results of this phase 2 trial suggest that guselkumab may be an effective therapy for plaque psoriasis and that control of psoriasis can be achieved with specific anti-interleukin-23 therapy. (Funded by Janssen Research and Development; X-PLORE ClinicalTrials.gov number, NCT01483599.).
Angiotensin-converting enzyme inhibitor therapy in chronic hemodialysis patients: Any evidence of erythropoietin resistance? (1996)

Exacerbation of anemia associated with angiotensin-converting enzyme (ACE) inhibitor therapy has been noted to occur in patients with chronic renal failure, end-stage renal disease, and renal transplantation. Angiotensin-converting enzyme inhibitors appear to cause anemia through induction of decreased red blood cell production. There are data suggesting that ACE inhibitors may impair erythropoiesis via either suppression of angiotensin-mediated erythropoietin (EPO) production or bone marrow response to EPO. Patients on chronic hemodialysis receive recombinant human EPO (rHuEPO) for therapy of anemia and may also receive an ACE inhibitor for hypertension or congestive heart failure. We undertook a retrospective study to evaluate whether patients treated with ACE inhibitors developed a more severe anemia or required a higher dose of rHuEPO to maintain a similar hematocrit. Ninety-five of 108 chronic hemodialysis patients met study criteria (hemodialysis for 4 months and no treatment with an ACE inhibitor for at least 4 months = group 1; therapy with an ACE inhibitor for at least 4 months = group 2). Forty-eight patients (group 1, n = 24; group 2, n = 24) were available for analysis after exclusion for a variety of factors. There was no difference between the two groups in terms of baseline characteristics, number of blood transfusions or hospital days, or other laboratory parameters. There was no statistically significant difference in average hematocrit between group 1 (33.5% +/- 3.9%) and group 2 (32.6% +/- 1.6%). Similarly, no significant difference was observed for the average rHuEPO dose/treatment between group 1 (3,272 +/- 1,532 IU/treatment; 50.69 +/- 26.94 IU/kg/treatment) and group 2 (3,401 +/- 1,009 IU/treatment; 52.87 +/- 19.38 IU/kg/treatment). These results suggest that ACE inhibitors do not significantly induce more severe anemia or alter rHuEPO response in chronic hemodialysis patients.
p-n junction heterostructure device physics model of a four junction solar cell (2006)

We present results from a p-n junction device physics model for GaInP/GaAs/GaInAsP/GaInAs four junction solar cells. The model employs subcells whose thicknesses have an upper bound of 5&#956;m and lower bound of 200nm, which is just above the fully depleted case for the assumed doping of N<sub>A</sub> = 1 x 10<sup>18</sup> cm<sup>-3</sup> and N<sub>D</sub> = 1 x 10<sup>17</sup> cm<sup>-3</sup>. The physical characteristics of the cell model include: free carrier absorption, temperature and doping effects on carrier mobility, as well as recombination via Shockley-Read-Hall recombination from a single midgap trap level and surface recombination. Upper bounds on cell efficiency set by detailed balance calculations can be approached by letting the parameters approach ideal conditions. However whereas detailed balance calculations always benefit from added subcells, the current matching requirements for series connected p-n multi-junctions indicate a minimum necessary performance from an added subcell to yield a net increase in overall device efficiency. For the four junction cell considered here, optimizing the subcell thickness is an important part of optimizing the efficiency. Series resistance limitations for concentrator applications can be systematically explored for a given set of subcells. The current matching limitation imposed by series connection reduces efficiency relative to independently-connected cells. The overall trend indicates an approximately 5% drop in efficiency for series connected cells relative to identical independently connected cells. The series-connected devices exhibit a high sensitivity to spectral changes and individual subcell performance. If any single subcell within the series-connected device is degraded relative to its optimal design, the entire device is severely hindered. This model allows complex heterostructure solar cell structures to be evaluated by providing device physics-based predictions of performance limitations.
2‘,3‘-Dideoxy-3‘-thionucleoside Triphosphates:  Syntheses and Polymerase Substrate Activities (2007)

All four 2',3'-dideoxy-3'-thio-nucleosides (ddtNTPs) function as substrates for the Y410F mutant of Deep Vent (exo-) DNA polymerase. Not only are the ddtNTPs incorporated to form the N + 1 product, but further elongations are observed in which the key step is attack of the 3'-thiol on the 5'-triphosphate. Although other polymerases are likely to differ in their use of the ddtNTPs, there does not appear to be a fundamental prohibition against using a thiol nucleophile on a phosphate anhydride electrophile. The syntheses of four ddtNTPs (C, T, A, G) are described. [structure: see text]
Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. (1991)

A partial cDNA was isolated that encoded a protein kinase, termed rac (related to the A and C kinases). This cDNA was subsequently used to screen libraries derived from the human cell lines MCF-7 and WI38 and led to the isolation of full-length cDNA clones. DNA sequence analysis identified an open reading frame of 1440 base pairs encoding a protein of 480 amino acids (Mr, 55,716). This result was supported by the synthesis of a Mr 58,000 protein in an in vitro translation system that used RNA transcribed from cloned cDNAs with SP6 RNA polymerase. The predicted protein contains consensus sequences characteristic of a protein kinase catalytic domain and shows 73% and 68% similarity to protein kinase C and the cAMP-dependent protein kinase, respectively. Northern (RNA) analysis revealed a single mRNA transcript of 3.2 kilobases that varied up to 300-fold between different cell lines. Specific antisera directed towards the carboxyl terminal of the rac protein kinase were prepared and used to identify that phosphorylated several substrates in immunoprecipitates prepared with the rac-specific antisera.
Gel Scaffolds of BMP‐2‐Binding Peptide Amphiphile Nanofibers for Spinal Arthrodesis (2014)

Peptide amphiphile (PA) nanofibers formed by self-assembly can be customized for specific applications in regenerative medicine through the use of molecules that display bioactive signals on their surfaces. Here, the use of PA nanofibers with binding affinity for the bone promoting growth factor BMP-2 to create a gel scaffold for osteogenesis is reported. With the objective of reducing the amount of BMP-2 used clinically for successful arthrodesis in the spine, amounts of growth factor incorporated in the scaffolds that are 10 to 100 times lower than that those used clinically in collagen scaffolds are used. The efficacy of the bioactive PA system to promote BMP-2-induced osteogenesis in vivo is investigated in a rat posterolateral lumbar intertransverse spinal fusion model. PA nanofiber gels displaying BMP-2-binding segments exhibit superior spinal fusion rates relative to controls, effectively decreasing the required therapeutic dose of BMP-2 by 10-fold. Interestingly, a 42% fusion rate is observed for gels containing the bioactive nanofibers without the use of exogenous BMP-2, suggesting the ability of the nanofiber to recruit endogenous growth factor. Results obtained here demonstrate that bioactive biomaterials with capacity to bind specific growth factors by design are great targets for regenerative medicine.
Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles’ Heel of Targeted Therapy (2015)

Human fibroblast growth factor receptors (FGFRs) 1-4 are a family of receptor tyrosine kinases that can serve as drivers of tumorigenesis. In particular, FGFR1 gene amplification has been implicated in squamous cell lung and breast cancers. Tyrosine kinase inhibitors (TKIs) targeting FGFR1, including AZD4547 and E3810 (Lucitanib), are currently in early phase clinical trials. Unfortunately, drug resistance limits the long-term success of TKIs, with mutations at the "gatekeeper" residue leading to tumor progression. Here we show the first structural and kinetic characterization of the FGFR1 gatekeeper mutation, V561M FGFR1. The V561M mutation confers a 38-fold increase in autophosphorylation achieved at least in part by a network of interacting residues forming a hydrophobic spine to stabilize the active conformation. Moreover, kinetic assays established that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. Structural analyses of these TKIs with wild type (WT) and gatekeeper mutant forms of FGFR1 offer clues to developing inhibitors that maintain potency against gatekeeper mutations. We show that AZD4547 affinity is preserved by V561M FGFR1 due to a flexible linker that allows multiple inhibitor binding modes. This is the first example of a TKI binding in distinct conformations to WT and gatekeeper mutant forms of FGFR, highlighting adaptable regions in both the inhibitor and binding pocket crucial for drug design. Exploiting inhibitor flexibility to overcome drug resistance has been a successful strategy for combatting diseases such as AIDS and may be an important approach for designing inhibitors effective against kinase gatekeeper mutations.
Thrombomodulin blocks the ability of thrombin to activate platelets. (1983)

When thrombin is complexed to the endothelial cell surface receptor thrombomodulin, it loses its procoagulant activities in that it no longer clots fibrinogen or activates factor V. Studies were initiated to determine if complex formation also blocks thrombin's other major procoagulant function, the activation of platelets. When bound to thrombomodulin, thrombin no longer induces platelets to either aggregate or release [14C] serotonin. Binding studies using 125I-labeled thrombin or diisopropyl phosphorothrombin indicate that the complex does not bind to the platelet. When thrombomodulin is added after thrombin has bound to the platelets, the thrombin rapidly redistributes onto the thrombomodulin. These data suggest that in addition to its other anticoagulant effects, thrombomodulin may also act to inhibit and/or reverse platelet activation by thrombin.
ErbB3 Inhibitory Surrobodies Inhibit Tumor Cell Proliferation In Vitro and In Vivo (2012)

ErbB3 is an important regulator of tumorigenesis and is implicated in development of resistance to several currently used oncology drugs. We have identified ErbB3 inhibitors based on a novel biologic scaffold termed a surrobody. Two of these inhibitors appear to work by a previously unrecognized mechanism of action. As a consequence, they not only inhibited cell proliferation and intracellular signaling driven by stimulation with the ErbB3 ligand neuregulin (NRG), but also inhibited signaling and proliferation that was driven by overexpression of ErbB2 in the absence of ligand stimulation. In addition, the surrobodies inhibited tumor growth in vivo in both ErbB2-overexpressing and nonoverexpressing cells. In ErbB2-overexpressing cells, both of the anti-ErbB3 surrobodies significantly augmented the activities of trastuzumab, lapatinib, and GDC-0941, agents that inhibit cell proliferation by different mechanisms. Moreover, although NRG diminished the efficacy of these agents, when they were combined with anti-ErbB3 surrobodies the affect of NRG was abrogated. In this capacity, the anti-ErbB3 surrobodies were more effective than the ErbB2/ErbB3 dimerization inhibitory antibody pertuzumab. Despite the fact that these surrobodies appear to engage ErbB3 differently than previously described anti-ErbB3 antibodies, they retain all of the beneficial characteristics of this class of agents, including the ability to augment drugs that inhibit EGF receptor. These anti-ErbB3 agents, therefore, show substantial promise for development as single agents or in combination with other ErbB-directed antibodies or small molecules and may provide for a broader range of therapeutic indications than previously described anti-ErbB3 antibodies.