gebhart/patrepeval huggingface dataset:
Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models (2015)

Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition.
Epidemiology Of Murine Typhus (1990)

Although the insect circulatory system is involved in a multitude of vital physiological processes, it has gone grossly understudied. This review highlights this critical physiological system by detailing the structure and function of the circulatory ...Read More
LOGICAL DISK: A SIMPLE NEW APPROACH TO IMPROVING FILE SYSTEM PERFORMANCE (1993)

Making a file system efficient usually requires extensive modifications. For example, making a file system log-structured requires the introduction of new data structures that are tightly coupled with the general file system code. This paper describes a new organization for file systems, using a Logical Disk (LD); LD defines a simple new interface that separates file management and disk management. The interface simplifies the implementation of file systems and also improves performance. An implementation of a POSIX-compliant file system using LD confirms the benefits of this new organization. By trading main memory for a clean separation between file and disk management, LD allows file systems to achieve high performance.
Runs of homozygosity and inbreeding in thyroid cancer (2016)

Our results support the existence of recessive alleles in TC susceptibility. Although regions of homozygosity were rather small, it might be possible that variants within these ROHs affect TC risk and may function in a recessive manner.
What to do With Wake-Up Stroke (2015)

Wake-up stroke, defined as the situation where a patient awakens with stroke symptoms that were not present prior to falling asleep, represents roughly 1 in 5 acute ischemic strokes and remains a therapeutic dilemma. Patients with wake-up stroke were excluded from most ischemic stroke treatment trials and are often not eligible for acute reperfusion therapy in clinical practice, leading to poor outcomes. Studies of neuroimaging with standard noncontrast computed tomography (CT), magnetic resonance imaging (MRI), and multimodal perfusion-based CT and MRI suggest wake-up stroke may occur shortly before awakening and may assist in selecting patients for acute reperfusion therapies. Pilot studies of wake-up stroke treatment based on these neuroimaging features are promising but have limited generalizability. Ongoing randomized treatment trials using neuroimaging-based patient selection may identify a subset of patients with wake-up stroke that can safely benefit from acute reperfusion therapies.
Co-Administration of Molecular Adjuvants Expressing NF-Kappa B Subunit p65/RelA or Type-1 Transactivator T-bet Enhance Antigen Specific DNA Vaccine-Induced Immunity (2014)

DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent) or non-pathogen (i.e., cancer) antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP), a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity.
Influence of Pediococcus acidilactici as a starter on the flavour of tempoyak (fermented durian) (2009)

Pediococcus acidilactici UP02 was used as a starter for the fermentation of tempoyak ( Durio zibethinus Murr.), a traditional Indonesian fermented fruit. The flavour of tempoyak was compared to those in spontaneous fermentation (no starter added). The results showed that addition of P. acidilactici UP02 in tempoyak fermentation decreased the quantity of sulphur components, reduced the sugar content, and increased various non-sulphur compounds as well as, non-volatile acidity and contents of organic acids (lactic, malic, and acetic). Sensory evaluation showed that there was no significant difference among the samples for sourness and aroma. However, the P. acidilactici UP02-inoculated sample was more acceptable than the sample with no-starter treatment. On the basis of the results of GC-MS, the flavour components of tempoyak with P. acidilactici UP02 treatment were observed to have 48 compounds, mainly composed of dimethyl disulfide and diethyl disulfide followed by ethane,1-1-bis ethylthio.
Molecular Genetic Evidence that the Hydrophobic Anchors of Glycoproteins E2 and E1 Interact during Assembly of Alphaviruses (2002)

Chimeric alphaviruses in which the 6K and glycoprotein E1 moieties of Sindbis virus are replaced with those of Ross River virus grow very poorly, but upon passage, adapted variants arise that grow >100 times better. We have sequenced the entire domain encoding the E2, 6K, and E1 proteins of a number of these adapted variants and found that most acquired two amino acid changes, which had cumulative effects. In three independent passage series, amino acid 380 of E2, which is in the transmembrane domain, was mutated from the original isoleucine to serine in two instances and to valine once. We have now changed this residue to seven others by site-directed mutagenesis and tested the effects of these mutations on the growth of both the chimera [SIN(RRE1)] and of parental Sindbis. These results indicate that the transmembrane domains of glycoproteins E2 and E1 of alphaviruses interact in a sequence-dependent manner and that this interaction is required for efficient budding and assembly of infectious virions.
Cloning of TRAP, a ligand for CD40 on human T cells (1992)

A cDNA clone, designated TRAP (TNF-related activation protein) was isolated from a collection of T cell activation genes. The polypeptide encoded by a mRNA of approx. 2.3 kb is 261 amino acids long with a calculated M(r) of 29.3 kDa. The structural features predict a type II transmembrane protein, but are also compatible with a secreted form. TRAP is highly similar to an identified murine CD40 ligand both at the cDNA (82.8% identity) and the protein (77.4% identity) levels, and related to tumor necrosis factor/lymphotoxin. Expressed in a murine myeloma, TRAP was identified as a ligand for CD40 by binding to a soluble CD40 construct. TRAP mRNA is expressed in a T cell-specific fashion with a maximum at 8 h after stimulation. The TRAP gene is located in the q26.3-q27.1 region of the X chromosome.
Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations (2006)

Wilson disease protein (ATP7B) is a copper-transporting P(1B)-type ATPase that regulates copper homeostasis and biosynthesis of copper-containing enzymes in human tissues. Inactivation of ATP7B or related ATP7A leads to severe neurodegenerative disorders, whereas their overexpression contributes to cancer cell resistance to chemotherapeutics. Copper-transporting ATPases differ from other P-type ATPases in their topology and the sequence of their nucleotide-binding domain (N-domain). To gain insight into the structural basis of ATP7B function, we have solved the structure of the ATP7B N-domain in the presence of ATP by using heteronuclear multidimensional NMR spectroscopy. The N-domain consists of a six-stranded beta-sheet with two adjacent alpha-helical hairpins and, unexpectedly, shows higher similarity to the bacterial K(+)-transporting ATPase KdpB than to the mammalian Ca(2+)-ATPase or Na(+),K(+)-ATPase. The common core structure of P-type ATPases is retained in the 3D fold of the N-domain; however, the nucleotide coordination environment of ATP7B within this fold is different. The residues H1069, G1099, G1101, I1102, G1149, and N1150 conserved in the P(1B)-ATPase subfamily contribute to ATP binding. Analysis of the frequent disease mutation H1069Q demonstrates that this mutation does not significantly affect the structure of the N-domain but prevents tight binding of ATP. The structure of the N-domain accounts for the disruptive effects of >30 known Wilson disease mutations. The unique features of the N-domain provide a structural basis for the development of specific inhibitors and regulators of ATP7B.
Rapid humanization of the Fv of monoclonal antibody B3 by using framework exchange of the recombinant immunotoxin B3(Fv)-PE38. (1994)

B3(Fv)-PE38 is a recombinant single-chain immunotoxin in which the Fv region of carcinoma-specific antibody B3 is fused to a truncated form of Pseudomonas exotoxin (PE). The efficacy of monoclonal antibody B3 and B3 immunotoxins in cancer therapy and diagnosis may be limited by the human anti-mouse response. Here we describe the humanization of the Fv of B3(Fv)-PE38 by "framework exchange." The variable domains of the heavy (VH) and light (VL) chains were aligned with their best human homologs to identify framework residues that differ. Initially, 11 framework residues in VH and six in VL were changed by site-specific mutagenesis to human residues and introduced simultaneously into a preassembled single-chain Fv expression cassette. Six VH and five VL residues that differ were not changed because they were buried, in the interdomain interface, or previously found to result in decreased affinity when mutated. This basic design resulted in some 20-fold loss of activity. Changing VL residues at the interdomain interfacial position 100 and at the buried position 104 to the human sequence increased the activity 8-fold. Changing VH residue at position 82b from the human sequence back to that of the mouse restored the activity 2- to 3-fold to the full binding and cytotoxic activity of the mouse sequence. Humanized B3(Fv)-PE38 lost immunogenic epitopes recognized by sera from monkeys that had been immunized with B3(Fv)-PE38.
Estrogen Receptor (ER) mRNA and ER-Related Gene Expression in Breast Cancers That Are 1% to 10% ER-Positive by Immunohistochemistry (2012)

A minority of the 1% to 9% IHC ER-positive tumors show molecular features similar to those of ER-positive, potentially endocrine-sensitive tumors, whereas most show ER-negative, basal-like molecular characteristics. The safest clinical approach may be to use both adjuvant endocrine therapy and chemotherapy in this rare subset of patients.
Invertible Micellar Polymer Assemblies for Delivery of Poorly Water-Soluble Drugs (2012)

Strategically designed amphiphilic invertible polymers (AIPs) are capable of (i) self-assembling into invertible micellar assemblies (IMAs) in response to changes in polarity of environment, polymer concentration, and structure, (ii) accommodating (solubilizing) substances that are otherwise insoluble in water, and (iii) inverting their molecular conformation in response to changes in the polarity of the local environment. The unique ability of AIPs to invert the molecular conformation depending on the polarity of the environment can be a decisive factor in establishing the novel stimuli-responsive mechanism of solubilized drug release that is induced just in response to a change in the polarity of the environment. The IMA capability to solubilize lipophilic drugs and deliver and release the cargo molecules by conformational inversion of polymer macromolecules in response to a change of the polarity of the environment was demonstrated by loading IMA with a phytochemical drug, curcumin. It was demonstrated that four sets of micellar vehicles based on different AIPs were capable of delivering the curcumin from water to an organic medium (1-octanol) by means of unique mechanism: AIP conformational inversion in response to changing polarity from polar to nonpolar. The IMAs are shown to be nontoxic against human cells up to a concentration of 10 mg/L. On the other hand, the curcumin-loaded IMAs are cytotoxic to breast carcinoma cells at this concentration, which confirms the potential of IMA-based vehicles in controlled delivery of poorly water-soluble drug candidates and release by means of this novel stimuli-responsive mechanism.
Raptor Forward Error Correction Scheme for Object Delivery (2007)

This document specifies an Internet standards track protocol for the Internet community, and requests discussion and suggestions for improvements.
Blood-brain barrier transport of cationized immunoglobulin G: enhanced delivery compared to native protein. (1989)

IgG molecules are potential neuropharmaceuticals that may be used for therapeutic or diagnostic purposes. However, IgG molecules are excluded from entering brain, owing to a lack of transport of these plasma proteins through the brain capillary wall, or blood-brain barrier (BBB). The possibility of enhanced IgG delivery through the BBB by cationization of the proteins was explored in the present studies. Native bovine IgG molecules were cationized by covalent coupling of hexamethylenediamine and the isoelectric point was raised to greater than 10.7 based on isoelectric focusing studies. Native and cationized IgG molecules were radiolabeled with 125I and chloramine T. Cationized IgG, but not native IgG, was rapidly taken up by isolated bovine brain microvessels, which were used as an in vitro model system of the BBB. Cationized IgG binding was time and temperature dependent and was saturated by increasing concentrations of unlabeled cationized IgG (dissociation constant of the high-affinity binding site, 0.90 +/- 0.37 microM; Bmax, 1.4 +/- 0.4 nmol per mg of protein). In vivo studies documented enhanced brain uptake of 125I-labeled cationized IgG relative to [3H]albumin, and complete transcytosis of the 125I-labeled cationized IgG molecule through the BBB and into brain parenchyma was demonstrated by thaw-mount autoradiography of frozen sections of rat brain obtained after carotid arterial infusions of 125I-labeled cationized IgG. These studies demonstrate that cationization of IgG molecules greatly facilitates the transport of these plasma proteins through the BBB in vivo, and this process may provide a new strategy for IgG delivery through the BBB.
IMGT, the international ImMunoGeneTics database(R) (2003)

The international ImMunoGeneTics database (IMGT) (http://imgt.cines.fr), is a high quality integrated information system specializing in Immunoglobulins (IG), T cell Receptors (TR) and Major Histocompatibility Complex (MHC) of human and other vertebrates, created in 1989, by the Laboratoire d'ImmunoGénétique Moléculaire (LIGM), at the Université Montpellier II, CNRS, Montpellier, France. IMGT provides a common access to standardized data which include nucleotide and protein sequences, oligonucleotide primers, gene maps, genetic polymorphisms, specificities, 2D and 3D structures. IMGT includes three sequence databases (IMGT/LIGM-DB, IMGT/MHC-DB, IMGT/PRIMER-DB), one genome database (IMGT/GENE-DB) with different interfaces (IMGT/GeneSearch, IMGT/GeneView, IMGT/LocusView), one 3D structure database (IMGT/3Dstructure-DB), Web resources comprising 8000 HTML pages ('IMGT Marie-Paule page') and interactive tools for sequence analysis (IMGT/V-QUEST, IMGT/JunctionAnalysis, IMGT/Allele-Align, IMGT/PhyloGene). IMGT data are expertly annotated according to the rules of the IMGT Scientific chart, based on IMGT-ONTOLOGY. IMGT tools are particularly useful for the analysis of the IG and TR repertoires in physiological normal and pathological situations. IMGT has important applications in medical research (autoimmune diseases, AIDS, leukemias, lymphomas, myelomas), biotechnology related to antibody engineering (phage displays, combinatorial libraries) and thera-peutic approaches (graft, immunotherapy). IMGT is freely available at http://imgt.cines.fr.
Complex signals in the genomic 3′ nontranslated region of bovine viral diarrhea virus coordinate translation and replication of the viral RNA (2004)

The genomes of positive-strand RNA viruses strongly resemble cellular mRNAs. However, besides operating as a messenger to generate the virus-encoded proteins, the viral RNA serves also as a template during replication. A central issue of the viral life cycle, the coordination of protein and RNA synthesis, is yet poorly understood. Examining bovine viral diarrhea virus (BVDV), we report here on the role of the variable 3'V portion of the viral 3' nontranslated region (3'NTR). Genetic studies and structure probing revealed that 3'V represents a complex RNA motif that is composed of synergistically acting sequence and structure elements. Correct formation of the 3'V motif was shown to be an important determinant of the viral RNA replication process. Most interestingly, we found that a proper conformation of 3'V is required for accurate termination of translation at the stop-codon of the viral open reading frame and that efficient termination of translation is essential for efficient replication of the viral RNA. Within the viral 3'NTR, the complex 3'V motif constitutes also the binding site of recently characterized cellular host factors, the so-called NFAR proteins. Considering that the NFAR proteins associate also with the 5'NTR of the BVDV genome, we propose a model where the viral 3'NTR has a bipartite functional organization: The conserved 3' portion (3'C) is part of the nascent replication complex; the variable 5' portion (3'V) is involved in the coordination of the viral translation and replication. Our data suggest the accuracy of translation termination as a sophisticated device determining viral adaptation to the host.
Optically matched trilevel resist process for nanostructure fabrication (1995)

A novel trilevel resist process has been developed which enables high-contrast imaging of periodic structures with spatial periods down to 200 nm in thick resist on highly reflective substrates, using λ=351.1 nm argon-ion laser exposure. The process utilizes a 200-nm-thick, high-contrast, imaging resist layer, a thin (∼15-nm) evaporated dielectric interlayer, and a 300–600-nm-thick bottom antireflection coating (ARC) which suppresses reflections from the substrate. Our trilevel resist scheme has been implemented in a manufacturing process which utilizes a high-contrast interferometric lithography system for the formation of large-area, 200–1000 nm period grating and dot array images. The choice of interlayer is the most critical feature of this process. This material must have good deposition and adhesion properties, must be optically matched to the resist and ARC, must etch quickly during the reactive-ion etching (RIE) pattern transfer from the resist into the interlayer, must display very high selectivity to the ARC during the RIE pattern transfer into the bottom layer, and must be easily stripped after the trilevel resist structure has served its purpose. We also report on computer modeling which elucidates the factors influencing standing wave formation and present results of tests with several interlayer materials which display good optical matching and selectivities of up to 240:1 during RIE of the ARC.
A rapid one-tube genomic DNA extraction process for PCR and RAPD analyses (1995)

Journal Article A rapid one-tube genomic DNA extraction process for PCR and RAPD analyses Get access J. J. Steiner, J. J. Steiner * National Forage Seed Production Research Center, USDA-ARS, 3450 SW Campus WayCorvallis, OR 97331, USA * To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar C. J. Polemba, C. J. Polemba National Forage Seed Production Research Center, USDA-ARS, 3450 SW Campus WayCorvallis, OR 97331, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar R. G. Fjellstrom, R. G. Fjellstrom National Forage Seed Production Research Center, USDA-ARS, 3450 SW Campus WayCorvallis, OR 97331, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar L. F. Elliott L. F. Elliott National Forage Seed Production Research Center, USDA-ARS, 3450 SW Campus WayCorvallis, OR 97331, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 23, Issue 13, 11 July 1995, Pages 2569–2570, https://doi.org/10.1093/nar/23.13.2569-a Published: 11 July 1995 Article history Received: 24 March 1995 Accepted: 18 May 1995 Published: 11 July 1995
Purification and Properties of Streptococcus pneumoniaeNeuraminidase (1989)

Considerable amounts (200 units/ml) of neuraminidase activity were detected in middle ear effusion of children (age 1 month-10 years) and its presence was highly correlated with the presence of Streptococcus pneumoniae. When isolates of this organism are cultured, neuraminidase activity appears in the growth medium during the exponential phase of growth. In order to study the role of this enzyme in the pathology of otitis media we have developed a method for its purification. The enzyme was purified over 5,800-fold by removing the organism and passing the culture broth through a series of affinity and ion-exchange columns. The overall yield was 2 mg enzyme protein and the final specific activity was 1.8 X 10(6) units/mg protein. A molecular weight of 65,000 was estimated by SDS-PAGE and gel filtration chromatography. The Stokes radius of neuraminidase was calculated to be 32 A, its isoelectric point was 7.2, and its pH optimum was 6.0. In terms of specificity, the enzyme catalyzed the hydrolysis of sialic acid linkages in mucin, glycoproteins, and gangliosides: bovine submaxillary mucin supported the highest catalytic efficiency, and alpha-1-antitrypsin the lowest. Neuraminidase acted on at least three linkage classes of substrates, alpha-2,6 and alpha-2,3 linkages of N-acetylneuraminic acid to galactose, and alpha-2,6 linkages to N-acetyl-galactosamine.