gebhart/patrepeval huggingface dataset:
Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic (2015)

Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics.
Prevention of the Rapid Degradation of Subcutaneously Implanted Ag/AgCl Reference Electrodes Using Polymer Coatings (1994)

To assess the effect of the biological response to implanted Ag/AgCl reference electrodes on the electrode stability, uncoated and polymer-coated Ag/AgCl electrodes were implanted subcutaneously in rats. After 1 week of implantation, uncoated Ag/AgCl electrode potentials, measured in 0.1 M KCl, shifted by about -180 mV, and both voltammetry and electron microscopy showed that all the AgCl was removed. The electrodes could be significantly protected by coating with polyurethane or a perfluorinated ionomer (Nafion) cured at 120 degrees C for 1 h. Electron micrographs showed the 120 degrees C cured Nafion and polyurethane coatings remained intact over 2 weeks of implantation. Following 2 weeks of implantation the cured, Nafion-coated electrodes' potentials were shifted by -15 +/- 7 mV relative to the initial values. Voltammetry showed that they were still not polarizable. The current densities obtained with the coated reference electrodes are sufficient for their use as counter/pseudoreference electrodes with implantable two-electrode glucose sensor systems. The tissue response to coated electrodes was minimal in comparison to the response to uncoated reference electrodes.
Ketanserin analogs: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding (1992)

Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C receptors and even less is known about the influence of its structural features on 5-HT1C receptor affinity. The present study reveals that the fluoro and carbonyl groups of the 4-fluorobenzoyl portion of ketanserin make small contributions to 5-HT2 binding and that the intact benzoylpiperidine moiety is an important feature. Ring-opening of the piperidine ring reduces affinity. Although the quinazoline-2,4-dione moiety also contributes to binding, it appears to play a smaller role and can be structurally simplified with retention of 5-HT2 affinity. N-(4-Phenylbutyl)-4-(4-fluorobenzoyl)piperidine (39), for example, binds with nearly the same affinity (Ki = 5.3 nM) as ketanserin (Ki = 3.5 nM). All of the compounds examined bind at 5-HT1C sites with lower affinity than ketanserin, and some of the simplified analogues bind with nearly 10 times the 5-HT2 versus 5-HT1C selectivity of ketanserin; however, none displays > 120-fold selectivity. Several of the compounds, such as the amide 32 and the urea 33 represent examples of new structural classes of 5-HT2 ligands.
Guessing noise, not code-words (2018)

We introduce a new algorithm for Maximum Likelihood (ML) decoding for channels with memory. The algorithm is based on the principle that the receiver rank orders noise sequences from most likely to least likely. Subtracting noise from the received signal in that order, the first instance that results in an element of the code-book is the ML decoding. In contrast to traditional approaches, this novel scheme has the desirable property that it becomes more efficient as the code-book rate increases. We establish that the algorithm is capacity achieving for randomly selected code-books. When the code-book rate is less than capacity, we identify asymptotic error exponents as the block length becomes large. When the code-book rate is beyond capacity, we identify asymptotic success exponents. We determine properties of the complexity of the scheme in terms of the number of computations the receiver must perform per block symbol. Worked examples are presented for binary memoryless and Markovian noise. These demonstrate that block-lengths that offer a good complexity-rate tradeoff are typically smaller than the reciprocal of the bit error rate.
Isolation and characterization of monoclonal antibodies to Shiga-like toxin II of enterohemorrhagic Escherichia coli and use of the monoclonal antibodies in a colony enzyme-linked immunosorbent assay (1988)

The major obstacle in large-scale epidemiological investigations of the incidence of Shiga-like toxin (SLT)-producing Escherichia coli in diarrheal stools is the lack of a rapid, specific test to detect toxin. Enterohemorrhagic E. coli produces elevated levels of SLT-I, SLT-II, or both cytotoxins (also called Verotoxins). SLT-I but not SLT-II can be neutralized by antiserum to purified Shiga toxin and by monoclonal antibodies to the B subunit of SLT-I. In this study, monoclonal antibodies were generated against a crude preparation of SLT-II produced by an E. coli K-12 strain lysogenized with the 933W toxin-converting phage of enterohemorrhagic E. coli 933. Hybridoma culture supernatants were screened for anti-SLT-II antibodies by a cytotoxicity neutralization assay and by an enzyme-linked immunosorbent assay (ELISA). Of 53 ELISA-positive lines, 5 were capable of neutralizing the cytotoxicity of SLT-II but not of SLT-I, Shiga toxin, or a variant of SLT-II produced by E. coli that causes edema disease of swine. All five monoclonal antibodies immunoprecipitated the isolated A subunit of SLT-II but not the B subunit. Of these five neutralizing monoclonal antibodies, four were of the immunoglobulin M class and one belonged to the immunoglobulin G1 subclass. All five lines had kappa light chains. These neutralizing monoclonal antibodies have been used as probes in a colony ELISA to detect SLT-II-positive bacterial colonies. The colony ELISA with these monoclonal antibodies is a specific, sensitive test with potential diagnostic value.
Suboptimal magnesium status in the United States: are the health consequences underestimated? (2012)

In comparison with calcium, magnesium is an "orphan nutrient" that has been studied considerably less heavily. Low magnesium intakes and blood levels have been associated with type 2 diabetes, metabolic syndrome, elevated C-reactive protein, hypertension, atherosclerotic vascular disease, sudden cardiac death, osteoporosis, migraine headache, asthma, and colon cancer. Almost half (48%) of the US population consumed less than the required amount of magnesium from food in 2005-2006, and the figure was down from 56% in 2001-2002. Surveys conducted over 30 years indicate rising calcium-to-magnesium food-intake ratios among adults and the elderly in the United States, excluding intake from supplements, which favor calcium over magnesium. The prevalence and incidence of type 2 diabetes in the United States increased sharply between 1994 and 2001 as the ratio of calcium-to-magnesium intake from food rose from <3.0 to >3.0. Dietary Reference Intakes determined by balance studies may be misleading if subjects have chronic latent magnesium deficiency but are assumed to be healthy. Cellular magnesium deficit, perhaps involving TRPM6/7 channels, elicits calcium-activated inflammatory cascades independent of injury or pathogens. Refining the magnesium requirements and understanding how low magnesium status and rising calcium-to-magnesium ratios influence the incidence of type 2 diabetes, metabolic syndrome, osteoporosis, and other inflammation-related disorders are research priorities.
Intracranial Injection of Recombinant Adeno-associated Virus Improves Cognitive Function in a Murine Model of Mucopolysaccharidosis Type VII (2001)

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by the lack of beta-glucuronidase (GUSB) activity. GUSB deficiency leads to the progressive accumulation of undegraded glycosaminoglycans (GAGs) in cells of most tissues, including the brain, and is associated with mental retardation. Reduction of lysosomal storage in the central nervous system and prevention of cognitive dysfunction may require intracranial delivery of a therapeutic agent during the newborn period that provides a continuous source of GUSB. Therefore, we injected recombinant adeno-associated virus encoding human GUSB into both the anterior cortex and the hippocampus of newborn MPS VII mice. Total GUSB activity in the brain approached normal levels by 18 weeks. Although GUSB activity was concentrated near the injection sites, lysosomal distension was reduced in most areas of the brain. In addition to histopathologic evidence of GAG reduction, the previously undescribed accumulation of GM2 and GM3 gangliosides in the brain was also prevented. Furthermore, GUSB expression and reduced lysosomal distension correlated with improvements in cognitive function as measured in the Morris Water Maze test. These findings indicate that localized overexpression of GUSB has positive effects on the pathology and cognitive function and does not have overt toxicity.
Epidemiology of multiple sclerosis in US veterans (1985)

World War II or Korean Conflict veterans with MS (5,305 in number) and pre-illness-matched controls were compared for residence at birth and entry on active duty (EAD) within three north-south tiers of states in the United States. A strong north-south gradient of MS risk was present. Migrants were defined as those whose birth and EAD tier differed. For white men of World War II, all white men, and all whites, there were highly significant reductions in risk for moves southward from either the north or middle tier, and increases in risk for moves northward from the middle tier. Increases similar in magnitude of middle to north did not attain statistical significance in the few southern-born migrants. For the small groups of black men and white men of Korean service, trends were similar but did not attain significance, whereas for white women, they were of borderline significance. Findings imply an environmental cause for MS, with acquisition years before symptom-onset.
Acetaminophen Toxicity (1999)

Acetaminophen is one of the most extensively used analgesics/antipyretics worldwide, and overdose or idiopathic reaction causes major morbidity and mortality in its victims. Research into the mechanisms of toxicity and possible therapeutic intervention is therefore essential. In this study, the response of transgenic mice overexpressing human antioxidant enzymes to acute acetaminophen overdose was investigated. Animals overexpressing superoxide dismutase or plasma glutathione peroxidase demonstrated dramatic resistance to acetaminophen toxicity. Intravenous injection of glutathione peroxidase provided normal mice with nearly complete protection against a lethal dose of acetaminophen. Surprisingly, animals overexpressing intracellular glutathione peroxidase in the liver were significantly more sensitive to acetaminophen toxicity compared with nontransgenic littermates. This sensitivity appears to be due to the inability of these animals to efficiently recover glutathione depleted as a result of acetaminophen metabolism. Finally, the results suggest that glutathione peroxidase overexpression modulates the synthesis of several acetaminophen metabolites. Our results demonstrate the ability of glutathione peroxidase levels to influence the outcome of acetaminophen toxicity.
Composite lithium metal anode by melt infusion of lithium into a 3D conducting scaffold with lithiophilic coating (2016)

Lithium metal-based battery is considered one of the best energy storage systems due to its high theoretical capacity and lowest anode potential of all. However, dendritic growth and virtually relative infinity volume change during long-term cycling often lead to severe safety hazards and catastrophic failure. Here, a stable lithium-scaffold composite electrode is developed by lithium melt infusion into a 3D porous carbon matrix with "lithiophilic" coating. Lithium is uniformly entrapped on the matrix surface and in the 3D structure. The resulting composite electrode possesses a high conductive surface area and excellent structural stability upon galvanostatic cycling. We showed stable cycling of this composite electrode with small Li plating/stripping overpotential (<90 mV) at a high current density of 3 mA/cm(2) over 80 cycles.
Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo (2001)

Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon gamma and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.
Structure of the N-Linked Glycan Present on Multiple Glycoproteins in the Gram-negative Bacterium, Campylobacter jejuni (2002)

Mass spectrometry investigations of partially purified Campylobacter jejuni protein PEB3 showed it to be partially modified with an Asn-linked glycan with a mass of 1406 Da and composed of one hexose, five N-acetylhexosamines and a species of mass 228 Da, consistent with a trideoxydiacetamidohexose. By means of soybean lectin affinity chromatography, a mixture of glycoproteins was obtained from a glycine extract, and two-dimensional gel proteomics analysis led to the identification of at least 22 glycoproteins, predominantly annotated as periplasmic proteins. Glycopeptides were prepared from the glycoprotein mixture by Pronase digestion and gel filtration. The structure of the glycan was determined by using nano-NMR techniques to be GalNAc-alpha1,4-GalNAc-alpha1,4-[Glcbeta1,3-]GalNAc-alpha1,4-GalNAc-alpha1,4-GalNAc-alpha1,3-Bac-beta1,N-Asn-Xaa, where Bac is bacillosamine, 2,4-diacetamido-2,4,6-trideoxyglucopyranose. Protein glycosylation was abolished when the pglB gene was mutated, providing further evidence that the enzyme encoded by this gene is responsible for formation of the glycopeptide N-linkage. Comparison of the pgl locus with that of Neisseria meningitidis suggested that most of the homologous genes are probably involved in the biosynthesis of bacillosamine.
Retargeting of Coronavirus by Substitution of the Spike Glycoprotein Ectodomain: Crossing the Host Cell Species Barrier (2000)

Coronaviruses generally have a narrow host range, infecting one or just a few species. Using targeted RNA recombination, we constructed a mutant of the coronavirus mouse hepatitis virus (MHV) in which the ectodomain of the spike glycoprotein (S) was replaced with the highly divergent ectodomain of the S protein of feline infectious peritonitis virus. The resulting chimeric virus, designated fMHV, acquired the ability to infect feline cells and simultaneously lost the ability to infect murine cells in tissue culture. This reciprocal switch of species specificity strongly supports the notion that coronavirus host cell range is determined primarily at the level of interactions between the S protein and the virus receptor. The isolation of fMHV allowed the localization of the region responsible for S protein incorporation into virions to the carboxy-terminal 64 of the 1,324 residues of this protein. This establishes a basis for further definition of elements involved in virion assembly. In addition, fMHV is potentially the ideal recipient virus for carrying out reverse genetics of MHV by targeted RNA recombination, since it presents the possibility of selecting recombinants, no matter how defective, that have regained the ability to replicate in murine cells.
Activity-based costing for clinical paths. An example to improve clinical cost & efficiency. (1996)

How much does this medical service or surgical procedure cost the hospital to provide? What is the most efficient clinical pathway that maximizes the quality of patient care while minimizing costs? More and more hospitals are discovering that they don't have solid answers to these critically important questions. In an age of managed care and capitation, however, it is imperative for management to know if the patient care services they provide are making or losing money-and by how much. This article discusses how a powerful new tool called activity-based costing (ABC) can be used to help hospitals accurately determine patient care costs. We show how to build a model that combines both clinical and financial data to measure how efficiently the operation allocates human, material and capital resources to provide its services. The modeling approach described in this article can be used to better analyze a wide range of important operational and financial issues, including: How to efficiently allocate resources, and what resources will be needed as patient demand changes-ideal for operational management and planning; How efficiently activities and processes are performed to meet patient needs-effective for measuring performance and improving quality; Determining clinical pathway profitability-essential for understanding where you're making or losing money; Cycle time, throughput and the impact of resource capacity constraints-critical for meeting patient demand; Costs of idle capacity-important for using resources more efficiently. We will illustrate with an example how this modeling technique can be used to develop and implement efficient clinical pathways.
Molecular classification of cancer types from microarray data using the combination of genetic algorithms and support vector machines (2003)

Simultaneous multiclass classification of tumor types is essential for future clinical implementations of microarray-based cancer diagnosis. In this study, we have combined genetic algorithms (GAs) and all paired support vector machines (SVMs) for multiclass cancer identification. The predictive features have been selected through iterative SVMs/GAs, and recursive feature elimination post-processing steps, leading to a very compact cancer-related predictive gene set. Leave-one-out cross-validations yielded accuracies of 87.93% for the eight-class and 85.19% for the fourteen-class cancer classifications, outperforming the results derived from previously published methods.
CD20-Specific Engineered Toxin Body Demonstrates Direct Cell Kill Of Multiple B-Cell Non-Hodgkin's Lymphoma Types (2013)

Abstract The B-cell membrane protein CD20 is expressed by both benign and neoplastic lymphocytes. It has been a superb target for immunotherapies targeting B-cell derived diseases. There are several anti-CD20 antibodies which have been developed for B-cell lymphoma therapy. The most successful example of this targeted approach is rituximab, which is approved for front and second line therapy of Non-Hodgkin lymphoma (NHL). However, rituximab has limited direct cell-kill effects, acting primarily through indirect immune responses induced by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC). While CD20-targeted radiotherapeutics have shown promise, their administrative challenges have curtailed their clinical utility. Thus, a therapeutic approach with direct cell-kill activity against CD20-expressing cells would be clinically useful. We have developed an engineered toxin body (ETB) comprising a CD20 specific scFv and a modified Shiga-like Toxin A (3F7) capable of specifically recognizing and killing CD20 expressing cells. 3F7 is selectively cytotoxic against B-cell NHL cell lines and against NHL cells obtained from patients. It demonstrated potent cytotoxicity against Burkitt’s lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma with IC (50) values ranging from 1.4 nM to 12 nM. Through immunofluorescent tracking, 3F7 internalizes within one hour after binding to CD20 (+) B cells. Consistent with the in vitro activity, 3F7 demonstrated anti-tumor efficacy in mice bearing Raji xenograft tumors. These results show that 3F7 is a promising targeted therapeutic agent against CD20 positive B-cell lymphomas and is currently under further development. Disclosures: Rajagopalan: Molecular Templates: Employment. Wirth:Molecular Templates: Employment. Erdman:Molecular Templates: Employment. Brieschke:Molecular Templates: Employment. Null: Molecular Templates: Employment. Liu:Molecular Templates: Employment. Willert:Molecular Templates: Employment. Higgins:Molecular Templates: Employment.
HTTP streaming of JPEG2000 images (2002)

JPEG2000 is a new image compression standard. One of the goals of JPEG2000 is to support large images. Since even the compressed image file can be very big for large images, downloading the entire image can take a long time depending upon the user's connection speed. Thus, we propose to use streaming of JPEG2000 images. We use the Hypertext Transfer Protocol (HTTP) for streaming. The use of HTTP to stream JPEG2000 images will ease its deployment. Thus, JPEG2000 images can be hosted by a Web server and can be streamed to the client helper application. The solution is scalable, so client devices with different capabilities, a variety of screen resolutions, and heterogeneous bandwidths can all achieve a scalable viewing of the same content stored in a single file. It is also possible to stream only selected regions of the image at a particular resolution and decode this partial stream and display it at the client. Thus, the proposed approach can handle resolution, quality and region of interest scalability feature of JPEG2000 images.