gebhart/patrepeval huggingface dataset:
Abstract 4543: High-throughput combination screening identifies novel drug-drug pairings for a Bruton's tyrosine kinase inhibitor against the ABC subtype of diffuse large B-cell lymphomas. (2013)

Abstract The vast majority of cancer treatments currently administered to patients consist of combinations of more than one drug via routine infusions that adhere to specific dosing schedules. It is thought that this multi-arm and time dependent approach will kill not only the tumor cells within the primary site, but also any metastatic lesions, and importantly, any circulating tumor cells (CTCs) which may still exist in the blood. Combination therapies have also been developed as a means to reduce general cytotoxic side effects and prevent resistance and recurrence. Our labs have recently developed a high throughput screening platform to test compounds in pair-wise combinations to rapidly and systematically identify additive, synergistic and antagonistic drug combinations. This HTS capability can easily generate hundreds of dose response matrices in a single study and can increase significantly when applied to multiple cell lines. We are using this combination screening platform with in vitro models from both established cell lines and primary patient material, and we expect it will serve as a very valuable tool and a starting point when designing clinical trials after these combinations show promise within in vivo models. In a proof of concept study, we tested combinations of compounds that effectively kill 2 established lines of the ABC sub-type of diffuse large B-cell lymphoma (DLBCL); TMD8 and HBL1. We will present the infrastructure and methods that we have developed to implement the combination screens, visualize data from the combination dose response comparisons and numerically compare combinations in terms of their response matrices. We will also describe how this approach allows us to investigate putative polypharmacological effects that play a role in compound combination responses. Finally, we will show the results of a combination screen with TMD8 and HBL1 cells, including the identification of a novel drug-drug combination for the BTK inhibitor ibrutinib (PCI-32765) which is of both basic and translational interest for the treatment of DLBCL. Citation Format: Lesley A. Mathews, Rajarshi Guha, Paul Shinn, Ryan M. Young, Kian-Huat Lim, Jonathan Keller, Dongbo Liu, Adam Yasgar, Crystal McKnight, Matthew B. Boxer, Damien Y. Duveau, Jian-kang Jiang, Sam Michael, Bryan T. Mott, Paresma R. Patel, William Leister, David J. Maloney, Christopher A. LeClair, Ganesha Rai, Ajit Jadhav, Brian D. Peyser, Christopher P. Austin, Scott Martin, Anton Simeonov, Marc Ferrer, Louis Staudt, Craig J. Thomas. High-throughput combination screening identifies novel drug-drug pairings for a Bruton's tyrosine kinase inhibitor against the ABC subtype of diffuse large B-cell lymphomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4543. doi:10.1158/1538-7445.AM2013-4543
New Technique for Measuring Low-Temperature Properties of Asphalt Binders with Small Amounts of Material (2010)

A new technique, which uses 4-mm parallel plates on a dynamic shear rheometer (DSR) with machine compliance corrections, was developed to measure low-temperature properties of asphalts. Good results have been achieved at test temperatures as low as −40°C. The test method requires only about 25 mg of material instead of 15 g for the bending beam rheometer (BBR). Also, no specimen premolding is needed, and a relatively low temperature (60°C to 70°C) is required to load the samples into the measuring system. The key to the new technique is correction for errors due to machine compliance. Two types of machine compliance correction were applied to the dynamic frequency sweep data in this work. The following areas were investigated: effects of machine compliance on the measured low-temperature properties, reproducibility of data, consistency among data collected on different sizes of plates after machine compliance corrections, and comparison between the corrected data from DSR and converted BBR data. Results show that this new technique is a reliable, rapid, and simple to perform test method, allowing for analysis of low-temperature properties of asphalt binder as well as extracted samples from pavements and other materials such as cold-mix asphalt and emulsion residue that require low-temperature operations and small samples.
Oligonucleotide‐peptide conjugates as potential antisense agents (1999)

Oligonucleotide-peptide conjugates have several applications, including their potential use as improved antisense agents for interfering with the RNA function within cells. In order to provide robust and generally applicable conjugation chemistry, we developed a novel approach of fragment coupling of pre-synthesized peptides to the 2'-position of a selected nucleotide within an otherwise protected oligonucleotide chain attached to a solid support.
Effects of the HIV Protease Inhibitor Ritonavir on GLUT4 Knock-out Mice (2010)

HIV protease inhibitors acutely block glucose transporters (GLUTs) in vitro, and this may contribute to altered glucose homeostasis in vivo. However, several GLUT-independent mechanisms have been postulated. To determine the contribution of GLUT blockade to protease inhibitor-mediated glucose dysregulation, the effects of ritonavir were investigated in mice lacking the insulin-sensitive glucose transporter GLUT4 (G4KO). G4KO and control C57BL/6J mice were administered ritonavir or vehicle at the start of an intraperitoneal glucose tolerance test and during hyperinsulinemic-euglycemic clamps. G4KO mice exhibited elevated fasting blood glucose compared with C57BL/6J mice. Ritonavir impaired glucose tolerance in control mice but did not exacerbate glucose intolerance in G4KO mice. Similarly, ritonavir reduced peripheral insulin sensitivity in control mice but not in G4KO mice. Serum insulin levels were reduced in vivo in ritonavir-treated mice. Ritonavir reduced serum leptin levels in C57BL/6J mice but had no effect on serum adiponectin. No change in these adipokines was observed following ritonavir treatment of G4KO mice. These data confirm that a primary effect of ritonavir on peripheral glucose disposal is mediated through direct inhibition of GLUT4 activity in vivo. The ability of GLUT4 blockade to contribute to derangements in the other molecular pathways that influence insulin sensitivity remains to be determined.
Anti-Type V Collagen Humoral Immunity in Lung Transplant Primary Graft Dysfunction (2008)

Primary graft dysfunction (PGD) is a major complication following lung transplantation. We reported that anti-type V collagen (col(V)) T cell immunity was strongly associated with PGD. However, the role of preformed anti-col(V) Abs and their potential target in PGD are unknown. Col(V) immune serum, purified IgG or B cells from col(V) immune rats were transferred to WKY rat lung isograft recipients followed by assessments of lung pathology, cytokines, and PaO(2)/FiO(2), an index of lung dysfunction in PGD. Immune serum, purified IgG, and B cells all induced pathology consistent with PGD within 4 days posttransfer; up-regulated IFN-gamma, TNF-alpha, and IL-1beta locally; and induced significant reductions in PaO(2)/FiO(2). Depleting anti-col(V) Abs before transfer demonstrated that IgG2c was a major subtype mediating injury. Confocal microscopy revealed strong apical col(V) expression on lung epithelial, but not endothelial cells; which was consistent with the ability of col(V) immune serum to induce complement-dependent cytotoxicity only in the epithelial cells. Examination of plasma from patients with or without PGD revealed that higher levels of preformed anti-col(V) Abs were strongly associated with PGD development. This study demonstrates a major role for anti-col(V) humoral immunity in PGD, and identifies the airway epithelium as a target in PGD.
The First 100 Liver Transplants at UCLA (1987)

A clinical program in liver transplantation was begun at UCLA in 1984 after a period of laboratory investigation. The first 100 orthotopic liver transplants (OLT) were performed in 83 patients (43 adults and 40 children) between February 1, 1984 and November 1, 1986. Donors and recipients were matched only for size and ABO blood group compatibility, with OLT performed across blood groups in 28 patients. Standard operative techniques were used, including venous-venous bypass in adults. Arterial reconstruction was performed using an aortic Carrel patch or "branch patch" in 65% of cases and by end-to-end or aortic conduit techniques in the remainder. The hepatic artery thrombosis rate was 5%. Biliary reconstruction was choledochocholedochostomy in 67 OLT and Roux-en-Y choledochojejunostomy in 33 (complication rate of 24% and 24%, respectively). Average lengths and ranges of donor liver ischemia, operating time, and blood replacement were 4 hours (range: 1-10 hours), 7.6 hours (range: 4-15 hours), and 17 units packed cells (range: 2-220 units). Immunosuppressive regimen was cyclosporine-steroid combination, with monoclonal anti-T-cell antibody (OKT3) used for refractory rejection. All patients had one or more complications: pulmonary (78%), infectious (51%), renal dialysis (25%), neurologic (22%). All patients had at least one episode of acute rejection, and 3.6% had chronic rejection. Retransplantation was needed in nine patients once and in four patients twice. The overall retransplant survival rate was 54%, and two of four patients who received a second retransplant are alive. Sixty-three of the 83 patients (76%) are alive (adults 72%, children 80%). The 1- and 2-year actuarial survival rate is 73% (adults 68%, children 78%). Thirty-eight of 43 patients (88%) who had transplantation in the past year are alive. Of 14 perioperative variables assessed as predictors of early mortality, only postoperative dialysis (p less than 0.0005) and presence of severe rejection (p less than 0.01) had statistical significance. Seventy per cent of adults returned to work, and 84% of children had normal or accelerated growth. A new program in liver transplantation provides a dramatic option in patient care and an academic stimulus to the entire medical center.
Weak bases and ionophores rapidly and reversibly raise the pH of endocytic vesicles in cultured mouse fibroblasts. (1982)

It has been shown that endocytic vesicles in BALB/c 3T3 cells have a pH of 5.0 (Tycko and Maxfield, Cell, 28:643-651). In this paper, a method for measuring the effect of various agents, including weak bases and ionophores, on the pH of endocytic vesicles is presented. The method is based on the increase in fluorescein fluorescence with 490-nm excitation as the pH is raised above 5.0. Intensities of cells were measured using a microscope spectrofluorometer after internalization of fluorescein-labeled alpha 2-macroglobulin by receptor-mediated endocytosis. The increase in endocytic vesicle pH was determined from the increase in fluorescence after addition of various concentrations of the test agents. The following agents increased endocytic vesicle pH above 6.0 at the indicated concentrations: monensin (6 microM), FCCP (10 microM), chloroquine (140 microM), ammonia (5 mM), methylamine (10 mM). The ability of many of these agents to raise endocytic vesicle pH may account for many of their effects on receptor-mediated endocytosis. Dansylcadaverine caused no effect on vesicle pH at 1 mM. The observed increases in vesicle pH were rapid (1-2 min) and could be reversed by removal of the perturbant. This reversibility indicates that the vesicles themselves contain a mechanism for acidification. The increase in vesicle pH due to these treatments can be observed visually using an SIT video camera. Using this method, it is shown that endocytic vesicles become acidic at very early times (i.e., within 5-7 min of continuous uptake at 37 degrees C).
Transmission-Line Properties of Parallel Wide Strips by a Conformal-Mapping Approximation (1964)

A transmission line is made of a symmetrical pair of strip conductors, face-to-face, or a single strip parallel to a ground plane. The strip width is nominally greater than the separation, but may be somewhat less than the separation. The field configuration is evaluated by a conformal mapping procedure which gives a very close approximation in terms of ordinary functions (exponential and hyperbolic) rather than the exact solution in terms of difficult functions (elliptic). Computation procedures are given for synthesis or analysis, the former following more naturally from the derivation. For the transitional case of strip width equal to separation, the mapping approximation is found to leave a relative error of the order of 10/sup -8/, in the wave resistance or shape ratio. Simple, explicit, practical formulas are developed for practical use with slide-rule accuracy. Emphasis is placed on establishing and specifying the residual error of each formula.
Navigated DENSE strain imaging for post-radiofrequency ablation lesion assessment in the swine left atria (2013)

Magnetic resonance imaging strain may be a non-contrast alternative to 3D-MDE in intra-procedural monitoring of atrial ablation lesions.
Automatic encoding into SNOMED III: a preliminary investigation. (1994)

The Linguistic String Project (LSP) medical language processing (MLP) system converts narrative clinical reports into database tables of patient data. A procedure for mapping the output of the LSP MLP system into SNOMED III codes was developed. Preliminary results and further requirements are discussed.
Rheology of Viscoelastic Solutions of Cationic Surfactant. Effect of Added Associating Polymer (2005)

Rheological studies were performed with aqueous salt solutions of viscoelastic cationic surfactant erucyl bis(hydroxyethyl)methylammonium chloride (EHAC) and its mixtures with hydrophobically modified polyacrylamide. The solutions of surfactant itself above the concentration of crossover of wormlike micelles exhibit two regions of rheological response. In the first region, they behave like polymer solutions in semidilute regime characterized by viscoelastic behavior with a spectrum of relaxation times. In the second region, unlike polymer solutions their relaxation after shear is dominated by a single relaxation time. Being composed of "living" micelles, the EHAC solutions easily lose their viscosity at the variation of the external conditions. For instance, heating from 20 to 60 degrees C reduces viscosity by up to 2 orders of magnitude, while added hydrocarbons induce a sudden drop of viscosity by 3-6 orders of magnitude. Polymer profoundly affects the rheological properties of EHAC solutions. The polymer/surfactant system demonstrates a 10,000-fold increase in viscosity as compared to pure-component solutions, the effect being more pronounced for polymer with less blocky distribution of hydrophobic units. A synergistic enhancement of viscosity was attributed to the formation of common network, in which some subchains are made up of elongated surfactant micelles, while others are composed of polymer. At cross-links the hydrophobic side groups of polymer anchor EHAC micelles. In contrast to surfactant itself, the polymer/surfactant system retains high viscosity at elevated temperature; at the same time it keeps a high responsiveness to hydrocarbon medium inherent to EHAC.
Detection of Borrelia burgdorferi using the polymerase chain reaction (1990)

Segments of the ospA gene of Borrelia burgdorferi were amplified by the polymerase chain reaction (PCR). Oligonucleotide primers used in the reaction flank a 309-base-pair segment within the ospA gene. After 35 cycles of amplification, the product could be detected by agarose gel electrophoresis or dot hybridization with a 32P-labeled probe. This segment was amplified in all strains of B. burgdorferi tested, but it was not detected in other bacterial species. An additional primer pair which has a broad specificity for conserved 16S rRNA sequences that are present in eubacteria amplified a 215-base-pair fragment in all organisms tested. The sensitivity of PCR for the detection of B. burgdorferi in clinical samples was evaluated by seeding blood and urine specimens with B. burgdorferi and subjecting them to amplification. We were able to detect 10 organisms per ml of blood or urine, using PCR with dot hybridization detection. DNA extraction is not required for sample preparation. Blood and urine specimens were obtained from canines with clinical and serologic evidence of Lyme disease and subjected to PCR analysis. Of 17 clinical specimens from 15 animals, one blood specimen showed reactivity in the PCR.
Rotavirus-Specific Cytotoxic T Lymphocyte Response of Mice after Oral Inoculation with Candidate Rotavirus Vaccine Strains RRV or WC3 (1989)

The immunologic basis of homotypic and heterotypic protection by immunization with two candidate rotavirus vaccine strains (simian strain RRV and bovine strain WC3, respectively) was investigated. Mice were orally inoculated with RRV, and 6 d later splenic lymphocytes lysed target cells infected with RRV (serotype 3) but not with human rotavirus serotypes 1 or 2; 4 w after inoculation, cytotoxic T lymphocytes (CTLs) generated in vitro from CTL precursors were also strain-specific. Also, the frequency of RRV-specific CTLs from CTLp after RRV immunization was 20-fold greater than that of cross-reactive CTLs. Inoculation of mice with WC3 (serotype 6), on the other hand, produced cross-reactive CTLs from CTLp at 4 w; CTLs lysed target cells infected with WC3 or human serotypes 1, 2, or 3 to the same extent. The frequency of cross-reactive CTLs after WC3 immunization was greater than or equal to 20-fold greater than that of WC3-specific CTLs. Cross-reactive, rotavirus-specific CTLs induced after WC3 immunization may in part explain the immunologic basis of protection against heterotypic challenge.
LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling:Arrows point the way (2004)

Wnt signaling through the canonical beta-catenin pathway plays essential roles in development and disease. Low-density-lipoprotein receptor-related proteins 5 and 6 (Lrp5 and Lrp6) in vertebrates, and their Drosophila ortholog Arrow, are single-span transmembrane proteins that are indispensable for Wnt/beta-catenin signaling, and are likely to act as Wnt co-receptors. This review highlights recent progress and unresolved issues in understanding the function and regulation of Arrow/Lrp5/Lrp6 in Wnt signaling. We discuss Arrow/Lrp5/Lrp6 interactions with Wnt and the Frizzled family of Wnt receptors, and with the intracellular beta-catenin degradation apparatus. We also discuss the regulation of Lrp5/Lrp6 by other extracellular ligands, and LRP5 mutations associated with familial osteoporosis and other disorders.
Mass Spectrometric Methods for Evaluating Point Mutations (1998)

Two methods for internally calibrating spectra resulting from the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry analysis of partially digested proteins are described. Partial digestion of proteins results in a large number of ion signals present in the MALDI-TOF mass spectrum, which in turn represent a significant over-sampling of each amino acid present in the analyte. This over-sampling allows ion signals of undisputed origin to be used as internal calibrants for the evaluation of fragments suspected to contain point mutations. Correlated with the correct amino acid sequence, the mass values of all ion signals (calibrants and analytes) are observed to fall into a single low-error data set. Conversely, empirically derived data applied to an incorrect sequence split the data into subsets of different errors. The methods take advantage of the self-consistent nature of data generated during the enzymatic mass mapping of proteins using MALDI-TOF, and they aid in the rapid, sensitive and accurate evaluation of point mutations present in proteins.
Stress, Corticotropin‐Releasing Hormone, Glucocorticoids, and the Immune/Inflammatory Response: Acute and Chronic Effectsa (1999)

Corticotropin-releasing hormone (CRH) influences the immune system indirectly, through activation of the hypothalamic-pituitary-adrenal axis and sympathetic system, and directly, through local modulatory actions of peripheral (immune) CRH. We recently demonstrated that catecholamines and histamine potently inhibited interleukin (IL)-12 and stimulated IL-10, whereas glucocorticoids suppressed IL-12, but did not affect IL-10 production ex vivo. Thus, both glucocorticoids and catecholamines, the end products of the stress system, and histamine, a product of activated mast cells, may selectively suppress cellular immunity and favor humoral immune responses. We localized immunoreactive CRH in experimental carrageenin-induced aseptic inflammation and, in humans, in inflamed tissues from patients with several autoimmune disease. In addition, we demonstrated that CRH activated mast cells via a CRH receptor type 1-dependent mechanism, leading to release of histamine and hence vasodilatation and increased vascular permeability. Thus, activation of the stress system, through direct and indirect effects of CRH, may influence the susceptibility of an individual to certain autoimmune, allergic, infectious or neoplastic diseases. Antalarmin, a novel nonpeptide CRH antagonist, prevented several proinflammatory effects of CRH, thus revealing its therapeutic potential in some forms of inflammation.
Projecting Lower Competence to Maintain Moral Warmth in the Avoidance of Prosocial Requests (2017)

When faced with prosocial requests, consumers face a difficult decision between taking on the request's burden or appearing unwarm (unkind, uncaring). We propose that the desire to refuse such requests while protecting a morally warm image leads consumers to under‐represent their competence. Although consumers care strongly about being viewed as competent, five studies showed that they downplayed their competence to sidestep a prosocial request. This effect occurred across both self‐reported and behavioral displays of competence. Further, the downplaying competence effect only occurred when facing an undesirable prosocial request, not a similarly undesirable proself request. The final studies showed that people specifically downplayed competence and not warmth. We further distinguished between social warmth (e.g., humor) and moral warmth (e.g., kindness), showing that when competence, social warmth, and moral warmth were all requisite skills for a prosocial task, people downplayed competence and social warmth more than moral warmth. These findings underscore that although people care strongly about being viewed as competent, they willingly trade off competence evaluations if evaluations of warmth—particularly moral warmth—are at risk.