gebhart/patrepeval huggingface dataset:
The plinabulin/docetaxel combination to mitigate the known safety concerns of docetaxel. (2016)

e20595 Background: Docetaxel is currently approved in non-small cell lung Cancer (NSCLC) after a failure of first line chemotherapy. However, docetaxel has an unfavorable toxicity profile that limits its use. A docetaxel-containing regimen with an improved safety profile would therefore be attractive. Plinabulin, a first-in-class small molecule vascular disruptive agent with potent immuno-oncology effects, is being developed in combination with docetaxel to address this need. Methods: We conducted a Phase 2 study comparing the safety and efficacy of the plinabulin /docetaxel combination (n=90) with docetaxel alone (n=73) in patients with NSCLC entering 2nd or 3rd line therapy. Plinabulin was given intravenously at 20 mg/m2 (n= 40) or 30 mg/m2 (n=50) and docetaxel at 75 mg/m2(n=73). Results: Efficacy results of this study were presented at ASCO 2014. Baseline characteristics for age, gender, ECOG performance score, histology and disease status were comparable between groups. The plinabulin/docetaxel combination improved overall survival, in a subset of patients with large tumors (> 3 cm; HR=0.758, p =0.36), and also had duration of response benefit over docetaxel alone (12.7 vs 1.5 months; P<0.05). We are reporting on the safety profile of plinabulin/ docetaxel combination. Conclusions: In this Phase 2 study, the plinabulin/docetaxel combination mitigated some of the docetaxel toxicities. Most importantly it improved docetaxel dose intensity. The neutropenia benefit was likely due to plinabulin-induced release of cytokines such as IL-1 and IL-6 (data obtained in in-vitro plinabulin studies), which are known to increase neutrophil count. In addition, preliminary results indicated a potential efficacy benefit of the plinabulin/docetaxel combination over docetaxel alone. A global Phase 3 trial with the plinabulin/docetaxel combination vs docetaxel alone is currently underway in the US, China, Australia and New Zealand. Clinical trial information: NCT00630110.Adverse events. Plinabulin/Docetaxel Docetaxel Grade 3/4 Neutropenia * 7 % 25 % Use of G-CSF * 14 % 29 % Sepsis 0 % 3.6 % Severe infections 0 % 3.6 % Asthenia * 13 % 28 % Docetaxel dose reduction due to toxicity * 6 % 20 % *p<0.01; Plinabulin/docetaxel combination vs docetaxel alone.
Mapping of a gene for long QT syndrome to chromosome 4q25-27. (1995)

Long QT syndrome (LQTS) is a heterogeneous inherited disorder causing syncope and sudden death from ventricular arrhythmias. A first locus for this disorder was mapped to chromosome 11p15.5. However, locus heterogeneity has been demonstrated in several families, and two other loci have recently been located on chromosomes 7q35-36 and 3p21-24. We used linkage analysis to map the locus in a 65-member family in which LQTS was associated with more marked sinus bradycardia than usual, leading to sinus node dysfunction. Linkage to chromosome 11p15.5, 7q35-36, or 3p21-24 was excluded. Positive linkage was obtained for markers located on chromosome 4q25-27. A maximal LOD score of 7.05 was found for marker D4S402. The identification of a fourth locus for LQTS confirms its genetic heterogeneity. Locus 4q25-27 is associated with a peculiar phenotype within the LQTS entity.
Therapeutic targeting of Janus kinases (2008)

Cytokines play pivotal roles in immunity and inflammation, and targeting cytokines and their receptors is an effective means of treating such disorders. Type I and II cytokine receptors associate with Janus family kinases (JAKs) to effect intracellular signaling. These structurally unique protein kinases play essential and specific roles in immune cell development and function. One JAK, JAK3, has particularly selective functions. Mutations of this kinase underlie severe combined immunodeficiency, indicative of its critical role in the development and function of lymphocytes. Because JAK3 appears not to have functions outside of hematopoietic cells, this kinase has been viewed as an excellent therapeutic target for the development of a new class of immunosuppressive drugs. In fact, several companies are developing JAK3 inhibitors, and Phase II studies are underway. Mutations of Tyk2 cause autosomal recessive hyperIgE syndrome, and in principle, Tyk2 inhibitors might also be useful as immunosuppressive drugs. JAK2 gain-of-function mutations (V617F) underlie a subset of disorders collectively referred to as myeloproliferative diseases and phase 2 trials using JAK inhibitors are underway in this setting. Thus, we are learning a great deal about the feasibility and effectiveness of targeting Janus kinases, and it appears likely that this will be a fruitful strategy in a variety of settings.
CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies (1996)

After autologous or allogeneic transplants of peripheral blood stem cells (PBSC), an adequate dose of CD34+ cells is necessary to ensure early and sustained hematopoietic engraftment and favorable clinical outcome. There are no comparable data on the relationship between CD34+ cell dose and recovery after allogeneic bone marrow transplants (BMT). Twenty-eight patients with hematologic malignancies received a BMT from an HLA-identical sibling, using T-cell depletion and cyclosporin for graft-versus-host disease prophylaxis and delayed donor lymphocyte transfusions in an attempt to prevent leukemia relapse. The treatment-related mortality (TRM), primarily due to infections and cytopenias, was significantly higher for 13 patients receiving less than 1 x 10(6) CD34+ cells/kg (64.9% +/- 12.8% v 6.9% +/- 6.4%, P = .003). Survival at a median follow-up of 1 year was also lower in the group receiving less than 1 x 10(6) CD34+ cells/kg (30.8% +/- 12.8 v 74.3% +/- 13.7%, P = .005). The CD34+ cell dose was the only variable significantly associated with TRM. The dose of CD34+ cells also correlated with speed of hematopoistic recovery. Patients receiving more than 2 x 10(6) CD34+ cells/kg showed significantly earlier recovery of monocytes and a trend for earlier recovery of lymphocytes. They achieved platelet and red blood cell transfusion independence earlier, required less granulocyte colony-stimulating factor support during ganciclovir treatment, and spent fewer days in the hospital after transplantation. These results suggest that, for allogeneic T-cell-depleted BMT, the higher CD34+ cell doses may improve outcome in engrafting patients.
Therapeutic Antibody Glycosylation Analysis: A Contract Research Organization Perspective in the Frame of Batch Release or Comparability Support (2013)

Glycosylation of the Fc moiety of a monoclonal antibody is a heterogeneous posttranslational process considered as a critical quality attribute of the purified drug substance due to its major impact on safety and efficacy (i.e., immunogenicity, CDC or ADCC effector functions, etc.). Glycosylation should thus be addressed for batch-to-batch comparability and for drug substance characterization, in terms of identity and/or purity testing. We present below a set of efficient, performing and complementary analytical tests that can be used alone or in combination, depending on the information needed and available laboratory instrumentation. The results obtained using these techniques for "global" glycosylation profile, N-glycans profiling, monosaccharides, and sialic acids determination are presented for the Trastuzumab (Herceptin)-humanized mAb produced in CHO.
Enhanced catalysis by active-site mutagenesis at aspartic acid 153 in Escherichia coli alkaline phosphatase (1992)

Bacterial alkaline phosphatase catalyzes the hydrolysis and transphosphorylation of phosphate monoesters. Site-directed mutagenesis was used to change the active-site residue Asp-153 to Ala and Asn. In the wild-type enzyme Asp-153 forms a second-sphere complex with Mg2+. The activity of mutant enzymes D153N and D153A is dependent on the inclusion of Mg2+ in the assay buffer. The steady-state kinetic parameters of the D153N mutant display small enhancements, relative to wild type, in buffers containing 10 mM Mg2+. In contrast, the D153A mutation gives rise to a 6.3-fold increase in kcat, a 13.7-fold increase in kcat/Km (50 mM Tris, pH 8), and a 159-fold increase in Ki for Pi (1 M Tris, pH 8). In addition, the activity of D153A increases 25-fold as the pH is increased from 7 to 9. D153A hydrolyzes substrates with widely differing pKa's of their phenolic leaving groups (PNPP and DNPP), at similar rates. As with wild type, the rate-determining step takes place after the initial nucleophilic displacement (k2). The increase in kcat for the D153A mutant indicates that the rate of release of phosphate from the enzyme product complex (k4) has been enhanced.
Binding and uptake of surfactant protein D by freshly isolated rat alveolar type II cells (2000)

Alveolar type II cells secrete, internalize, and recycle pulmonary surfactant, a lipid and protein complex that increases alveolar compliance and participates in pulmonary host defense. Surfactant protein (SP) D, a collagenous C-type lectin, has recently been described as a modulator of surfactant homeostasis. Mice lacking SP-D accumulate surfactant in their alveoli and type II cell lamellar bodies, organelles adapted for recycling and secretion of surfactant. The goal of current study was to characterize the interaction of SP-D with rat type II cells. Type II cells bound SP-D in a concentration-, time-, temperature-, and calcium-dependent manner. However, SP-D binding did not alter type II cell surfactant lipid uptake. Type II cells internalized SP-D into lamellar bodies and degraded a fraction of the SP-D pool. Our results also indicated that SP-D binding sites on type II cells may differ from those on alveolar macrophages. We conclude that, in vitro, type II cells bind and recycle SP-D to lamellar bodies, but SP-D may not directly modulate surfactant uptake by type II cells.
Heparan Sulfate 3-O-Sulfotransferase Isoform 5 Generates Both an Antithrombin-binding Site and an Entry Receptor for Herpes Simplex Virus, Type 1 (2002)

Heparan sulfate 3-O-sulfotransferase transfers sulfate to the 3-OH position of a glucosamine residue of heparan sulfate (HS) to form 3-O-sulfated HS. The 3-O-sulfated glucosamine residue contributes to two important biological functions of HS: binding to antithrombin and thereby carrying anticoagulant activity, and binding to herpes simplex viral envelope glycoprotein D to serve as an entry receptor for herpes simplex virus 1. A total of five HS 3-O-sulfotransferase isoforms were reported previously. Here we report the isolation and characterization of a novel HS 3-O-sulfotransferase isoform, designated as HS 3-O-sulfotransferase isoform 5 (3-OST-5). 3-OST-5 cDNA was isolated from a human placenta cDNA library and expressed in COS-7 cells. The disaccharide analysis of 3-OST-5-modified HS revealed that 3-OST-5 generated at least three 3-O-sulfated disaccharides as follows: IdoUA2S-AnMan3S, GlcUA-AnMan3S6S, and IdoUA2S-AnMan3S6S. Transfection of the plasmid expressing 3-OST-5 rendered wild type Chinese hamster ovary cells susceptible to the infection by herpes simplex virus 1, suggesting that 3-OST-5-modified HS serves as an entry receptor for herpes simplex virus 1. In addition, 3-OST-5-modified HS bound to herpes simplex viral envelope protein glycoprotein D. Furthermore, we found that 3-OST-5-modified HS also bound to antithrombin, suggesting that 3-OST-5 also produces anticoagulant HS. In summary, our results indicate that a new member of 3-OST family generates both anticoagulant HS and an entry receptor for herpes simplex virus 1. These results provide a new insight regarding the mechanism for the biosynthesis of biologically active HS.
Etch-pit initiation by dissolved oxygen on terraces of H-Si(111) (1997)

Dissolved oxygen in 40% aqueous ammonium fluoride solution initiates the formation of etch pits in the terraces of the otherwise ideal H-Si(111) surface. The etch pits are observed byex situ scanning tunneling microscopy in an argon atmosphere following emersion from the aqueous fluoride solution. Removal of O2from the fluoride solution by sparging with argon substantially reduces the initiation of etch pits. We propose the following mechanism of etch-pit initiation. Oxygen molecules are reduced to superoxide anion radicals at the negative open-circuit potential of the silicon surface. A small fraction (less than 0.4%) of these superoxide anions abstract hydrogen atoms from the H-Si(111) terraces to form silicon radicals (dangling bonds), which are then susceptible to etching in neutral to basic aqueous solutions. Hydrogen atom abstraction by aqueous superoxide anion radical also explains the known enhancement by water of oxide growth on hydrogen-terminated silicon surfaces.
Potential Photoaffinity Labels for Tubulin. Synthesis and Evaluation of Diazocyclohexadienone and Azide Analogs of Colchicine, Combretastatin, and 3,4,5-Trimethoxybiphenyl (1994)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPotential Photoaffinity Labels for Tubulin. Synthesis and Evaluation of Diazocyclohexadienone and Azide Analogs of Colchicine, Combretastatin, and 3,4,5-TrimethoxybiphenylJohn D. Olszewski, Mary Marshalla, Michal Sabat, and Richard J. SundbergCite this: J. Org. Chem. 1994, 59, 15, 4285–4296Publication Date (Print):July 1, 1994Publication History Published online1 May 2002Published inissue 1 July 1994https://pubs.acs.org/doi/10.1021/jo00094a048https://doi.org/10.1021/jo00094a048research-articleACS PublicationsRequest reuse permissionsArticle Views866Altmetric-Citations39LEARN 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-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Evaluation of the Bacterial Vaginal Flora of 20 Postmenopausal Women by Direct (Nugent Score) and Molecular (Polymerase Chain Reaction and Denaturing Gradient Gel Electrophoresis) Techniques (2002)

To monitor the bacterial vaginal microflora of postmenopausal women, several approaches were used: (1) Nugent scoring of Gram-stained smears from vaginal swabs; (2) testing for bacteria, using specific polymerase chain reaction (PCR) primers; (3) PCR-denaturing gradient gel electrophoresis (DGGE) analysis of total bacterial DNA, amplified using eubacterial and Lactobacillus-specific primers; and (4) sequence analysis of amplified DNA fragments of interest from denaturing gradient gels. Of 20 women studied, 70% had either intermediate-grade bacterial colonization or bacterial vaginosis (BV), as defined by Nugent criteria, at the first sampling point. Subjects with normal Nugent scores had >/=1 species of Lactobacillus detected by sequencing of dominant DNA fragments from denaturing gradient gels generated using eubacterial primers. Samples from women with Nugent scores that indicated BV had varied bacterial DGGE profiles, which emphasizes the diverse nature of such infections. This study indicates that asymptomatic BV appears to be much more common than is currently perceived; these findings may have implications for the health of postmenopausal women.
Metal–Ge-Si heterostructures for near-infrared light detection (1999)

We report on Ge Schottky photodiodes epitaxially grown on Si (100) exhibiting a good responsivity in the near infrared up to 1.55 μm. The Ge epitaxial layers, grown by ultrahigh vacuum chemical vapor deposition, were deposited in two steps differing by the substrate temperature. With this procedure it was possible to obtain films thicknesses comparable with light penetration depth in the 1.3–1.6 μm range. The photodiodes have a photocurrent which increases as a function of voltage bias, reaching a maximum responsivity of 0.12 A/W at 1.3 μm under a reverse bias of 4 V. The leakage current density at the saturation voltage is 1 nA/μm2. The results show that the proposed approach is promising for the fabrication of 1.3–1.55 μm near-infrared photodetectors integrated on silicon chips.
Improved antisense oligonucleotide induced exon skipping in the mdx mouse model of muscular dystrophy (2002)

These results demonstrate the increasing feasibility of an AO-based therapy for treatment of DMD. By refining AO design we have been able to reduce the size and the effective dose of the AOs and have dramatically improved the efficiency of the technique.
Interaction of Peptide YY with Rat Intestinal Epithelial Plasma Membranes: Binding of the Radioiodinated Peptide (1986)

High affinity binding sites for peptide YY (PYY) have been identified and characterized in plasma membranes prepared from rat jejunal epithelium by studying the kinetics, stoichiometry, and chemical specificity of the interaction of 125I-labeled PYY with membranes. Binding of [125I]PYY was rapid, saturable, reversible, specific, and depended on temperature, pH, and ionic strength. In optimized steady state conditions of binding (2 h of incubation at 15 C), the degradation of both [125I] PYY and binding sites did not exceed 20%. The concentration dependence of PYY binding, determined by adding increasing concentrations of [125I]PYY, indicated that specific binding saturated at 2-3 nM peptide. Scatchard analysis revealed a single class of binding sites with a dissociation constant (Kd) of 434 +/- (SE) 56 pM and a binding capacity of 336 +/- 41 fmol/mg protein (n = 11). Identical results were obtained when increasing concentrations of unlabeled PYY were added to a fixed concentration of [125I]PYY, indicating that the radioiodinated peptide has the same apparent affinity as native PYY. Peptides structurally unrelated to PYY, such as members of the vasoactive intestinal peptide family, insulin, or cholecystokinin octapeptide, were unable to compete with [125I]PYY for binding to membranes. Rat, human, and avian pancreatic polypeptides, which display, respectively, 42%, 47%, and 53% homology with PYY, did inhibit [125I]PYY binding but with an approximate or equal to 100,000-fold lower potency than PYY, indicating the strict structural requirement for recognition by PYY binding sites. In contrast, natural or synthetic neuropeptide Y, which has 25 out of 36 amino acids in common with PYY, retained a high affinity for PYY binding sites [only 4.7 +/- 1.2 (n = 5) times lower than that of PYY]. Specific [125I]PYY binding was particularly high in the upper small intestine and could not be detected in stomach, large intestine, or liver. These findings indicate that rat small intestinal epithelium expresses specific binding sites for the candidate gut hormone PYY that also binds the neuropeptide Y with high affinity, suggesting that the two peptides may regulate the function of small intestinal epithelium, through interaction with a common receptor site.
Laboratory Operations, Specimen Processing, and Handling for Viral Load Testing and Surveillance (2010)

RNA remains the most informative and accurate biomarker for human immunodeficiency virus type 1 load diagnostics and for surveillance of drug resistance markers. Viral load testing by nucleic acid amplification currently is a complex and expensive test that is restricted to centralized laboratory testing. Successful extension of centralized viral load testing to rural or remote settings is a major challenge. Emerging nucleic acid-based technologies are progressing rapidly toward platforms appropriate for field use in low-resource settings, leaving a growing gap for sample processing technologies that complement them. One area in which new technologies could be applied to improve access is clinical specimen preservation and processing. Novel technologies that extract nucleic acid from clinical specimens and stabilize it at the point of specimen collection could fill this gap. In addition, these technologies may provide alternative viral load detection and surveillance solutions to the current centralized laboratory testing paradigm.
The5ESSSwitching System: System Development Environment (1985)

This article describes the elements of the system development environment that support each phase of the 5ESS™ digital switching system product development. The elements themselves are complex hardware/software systems that are specialized to meet the particular needs of the different phases of development but integrated to smooth the transition through the phases. The requirements and design phases are supported by general-purpose UNIX™ systems that provide a rich set of tools for document preparation. The design is transformed into executable software for the 5ESS system, primarily in the C programming language, augmented by C-based extension languages to support the special needs of database and diagnostic programming. This software is created, compiled, combined, and packaged for the 5ESS switch test models by large UNIX systems running on IBM System/370-compatible hardware. Unit testing of developed software takes place on smaller support computer systems in an environment that closely resembles the test model. The test models, actual 5ESS switching systems, are used for the integration and system test of the product. A dedicated computer system for each test model supports testing at the C language level. A number of actual and simulated load generators are used to stress and regression test the system. All the support systems are interconnected with high-speed data transmission networks that support remote command execution as well as file transfer.
Mutational analysis of the transcription activation domain of RelA: identification of a highly synergistic minimal acidic activation module. (1994)

The potent C-terminal activation domain of the RelA (p65) subunit of the cellular transcription factor NF-kappa B is shown to contain several discrete acidic activation modules. These short, approximately 11-amino-acid modules were able to give rise to only a low level of transcription activation when fused to the GAL4 DNA-binding domain as monomers. However, dimers and higher-order multimers activated the transcription of minimal promoter elements as effectively as the full-length RelA or VP16 activation domain. Therefore, this 11-amino-acid RelA-derived acidic module appears to contain all of the sequence information required to fully activate a target promoter element as long as it is presented in a form that permits functional synergy. Critical primary sequence requirements for acidic activation module function included a core phenylalanine residue and flanking bulky hydrophobic residues. Overall negative charge was necessary but not sufficient for function. While dimeric forms of the 11-amino-acid acidic activation module bound to either TFIIB or TATA-binding protein efficiently in vitro, a similarly charged peptide lacking the core phenylalanine residue failed to interact. Overall, these data demonstrate that the biological activity of the RelA activation domain is dependent on acidic activator sequences that are closely comparable to those detected in the activation domain of the viral VP16 regulatory protein. We hypothesize that the ability of these acidic activators to specifically interact with multiple components of the transcription initiation complex likely underlies the dramatic functional synergy exhibited by this class of activation domains in vivo.