gebhart/patrepeval huggingface dataset:
Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies (2017)

Effective immunotherapies for T-cell malignancies are lacking. We devised a novel approach based on chimeric antigen receptor (CAR)-redirected T lymphocytes. We selected CD7 as a target because of its consistent expression in T-cell acute lymphoblastic leukemia (T-ALL), including the most aggressive subtype, early T-cell precursor (ETP)-ALL. In 49 diagnostic T-ALL samples (including 14 ETP-ALL samples), median CD7 expression was >99%; CD7 expression remained high at relapse (n = 14), and during chemotherapy (n = 54). We targeted CD7 with a second-generation CAR (anti-CD7-41BB-CD3ζ), but CAR expression in T lymphocytes caused fratricide due to the presence of CD7 in the T cells themselves. To downregulate CD7 and control fratricide, we applied a new method (protein expression blocker [PEBL]), based on an anti-CD7 single-chain variable fragment coupled with an intracellular retention domain. Transduction of anti-CD7 PEBL resulted in virtually instantaneous abrogation of surface CD7 expression in all transduced T cells; 2.0% ± 1.7% were CD7<sup>+</sup> vs 98.1% ± 1.5% of mock-transduced T cells (n = 5; <i>P</i> < .0001). PEBL expression did not impair T-cell proliferation, interferon-γ and tumor necrosis factor-α secretion, or cytotoxicity, and eliminated CAR-mediated fratricide. PEBL-CAR T cells were highly cytotoxic against CD7<sup>+</sup> leukemic cells in vitro and were consistently more potent than CD7<sup>+</sup> T cells spared by fratricide. They also showed strong anti-leukemic activity in cell line- and patient-derived T-ALL xenografts. The strategy described in this study fits well with existing clinical-grade cell manufacturing processes and can be rapidly implemented for the treatment of patients with high-risk T-cell malignancies.
Development and Utility of Q-score for Characterizing Cotton Fiber Quality (2010)

Cotton (Gossypium hirsutum L.) fiber quality characteristics may be improved with an index that incorporates weighted values of multiple fiber measurements. Our objectives were to describe the logic and calculation of a numerical index (Q-score), to evaluate the relationship of Q-score to loan value, and to illustrate the use of Q-score in cotton breeding and cultivar testing. The Q-score is calculated by first normalizing fiber properties from 0 to 1 and then algebraically combining the normalized values by qualityweighting factors based upon input from textile processing experts. Fiber properties (weights) for Q-score calculations included fiber length (50%), micronaire (25%), length uniformity index (15%), and strength (10%). Q-scores and loan values were calculated for the 2001-2007 Arkansas Cotton Variety Tests (1478 observations). Economic analysis included summary statistics and correlations for the parameters. Q-score values were normally (or near normally) distributed, while loan values followed a Poisson or chi-square distribution. Q-score and loan value were positively correlated, and similarly correlated to the fiber parameters. Obtaining optimum loan values was more likely as Q-score increased. Q-score was more conservative and discriminating than loan values. Data for 16 cultivars at four sites over three years indicated that Q-score values were relatively consistent over years and sites. Q-score was normally distributed in data extracted from the 2005-2008 Arkansas cotton breeding trials. This distribution facilitates subsequent development of superior cotton lines. These results indicate that Q-score may assist with characterizing fiber quality. However, application of Q-score is limited because relative weights of four fiber traits are subjectively assigned, and measurement of trash and color are not included.
Synthesen in der Reihe der 1,4‐Diazepine (1988)

Abstract 2,3‐Diamino‐1,4‐naphthochinon ( 1 ) reagiert mit den Malonsäure‐Derivaten 2,5 und 7 je nach deren Substituenten zum Imidazolderivat 8 , zum Tetracarbonsäure‐tetraethylester des Typs 6 oder zu substituierten Diaminonaphthochinonen 3 , letztere reagieren im alkalischen Medium zu Diazepinen des Typs 4 . Das Diazepin 9 setzt sich mit aromatischen Aldehyden 10a–f zu 11a–f um. Methylierung von 11e–f liefert 12a–b .
Murine candidiasis: Sex differences in the severity of tissue lesions are not associated with levels of serum C3 and C5 (1991)

Mice deficient in the fifth component of complement are known to be extremely susceptible to lethal challenge with Candida albicans. However, male mice, that have significantly higher concentrations of serum C5 than females, were markedly more susceptible to infection. This difference was observed in both susceptible (CBA/H) and resistant (BALB/c) mice. Levels of serum C3 likewise showed no correlation with susceptibility.
Stochastic Gradient Hamiltonian Monte Carlo (2014)

Hamiltonian Monte Carlo (HMC) sampling methods provide a mechanism for defining distant proposals with high acceptance probabilities in a Metropolis-Hastings framework, enabling more efficient exploration of the state space than standard random-walk proposals. The popularity of such methods has grown significantly in recent years. However, a limitation of HMC methods is the required gradient computation for simulation of the Hamiltonian dynamical system-such computation is infeasible in problems involving a large sample size or streaming data. Instead, we must rely on a noisy gradient estimate computed from a subset of the data. In this paper, we explore the properties of such a stochastic gradient HMC approach. Surprisingly, the natural implementation of the stochastic approximation can be arbitrarily bad. To address this problem we introduce a variant that uses second-order Langevin dynamics with a friction term that counteracts the effects of the noisy gradient, maintaining the desired target distribution as the invariant distribution. Results on simulated data validate our theory. We also provide an application of our methods to a classification task using neural networks and to online Bayesian matrix factorization.
Colchicine site inhibitors of microtubule integrity as vascular disrupting agents (2008)

Abstract Drugs that bind to the colchicine binding site of tubulin and induce tubulin depolymerization hold promise as antitumor drugs through their ability to induce cell cycle arrest and to kill cancer cells through apoptosis and mitotic catastrophe. However, development of this group of compounds as direct antitumor cytotoxic agents has not proved successful. Over the last few years, the potential of these compounds to act as selective vascular disrupting agents has been recognized. Several agents have advanced to phase I and phase II clinical studies, and their capacity to suppress growth of the tumor vasculature has been confirmed. Toxicity in terms of cardiovascular and thromboembolic events remains a major concern and their therapeutic efficacy as single agents has been disappointing. Nevertheless, a more comprehensive understanding of tumor compensatory mechanisms and potential combination strategies with anti‐angiogenic agents suggest that vascular targeting therapy may be a fruitful direction for the further development of this class of drugs as anticancer agents. Drug Dev Res 69:352–358, 2008. © 2008 Wiley‐Liss, Inc.
Cell surface accumulation of overexpressed hamster lysosomal membrane glycoproteins. (1995)

We cloned and sequenced cDNAs encoding two lysosomal membrane glycoproteins, lgp-A and lgp-B, from Chinese hamster ovary cells. The deduced amino acid sequences of these proteins are similar to those of the other known members of this conserved family (also known as "LAMP" proteins). We used the cDNAs to generate stable lines of hamster lgp-expressing mouse NIH-3T3 cells, rat NRK cells, and monkey CV-1 cells. We also generated hybridomas that secrete antibodies specific for hamster lgp-A and lgp-B, enabling us to distinguish foreign from endogenous lgps in a wider variety of transfected cell lines. One line of mouse NIH-3T3 cells that expresses hamster lgp-B was studied in detail. Whereas most of the hamster lgp-B appeared to be transported to lysosomes in these cells, butyrate-induced overexpression resulted in the accumulation of a significant proportion of the total on the plasma membrane. In addition, overexpression of this foreign lgp-B also resulted in the appearance of the endogenous mouse lgp-A and lgp-B on the plasma membrane. Characterization of this accumulation suggested that it resulted from competition for one or more limited components in the transport pathway(s) to lysosomes. Endocytosis from the plasma membrane appeared to be one step that was saturable.
Biological Aspects of Alzheimer's Disease (1984)

Journal Article Biological Aspects of Alzheimer's Disease Get access Biological Aspects of Alzheimer's Disease, R. Katzman (Ed.). Cold Spring Harbor Laboratory, New York, 1983, 495 pp., $55.00 (hardcover). Journal of Gerontology, Volume 39, Issue 5, September 1984, Page 630, https://doi.org/10.1093/geronj/39.5.630a Published: 01 September 1984
Performance Improvement of a Wideband MIMO System by Using Two-Port RLWA (2009)

In this letter, we demonstrate the performance achievable with a highly reconfigurable leaky-wave antenna (RLWA) when used as a building block of a wideband multiple-input-multiple-output (MIMO) communication system. The antenna design consists of a periodic structure, composed of cascaded composite right/left-hand (CRLH) microstrip unit cells with tunable electrical characteristics, that is capable of steering its radiation beam over a wide angular range. Field measurements collected in an indoor environment employing an array of dipoles at the transmitter and the RLWA and an array of dipoles at the receiver are used to measure the RLWA achievable gains. We show that the proposed antenna is capable of providing significant gains, with respect to a traditional array of dipoles, while reducing the space occupied by the antenna on the communication device.
Combining Bupropion SR With Venlafaxine, Paroxetine, or Fluoxetine (2002)

Bupropion had an effect on the pharmacokinetics of venlafaxine but not those of the SSRIs. Further investigation of combination treatments under randomized, double-blind conditions is recommended.
Genetic Recombination in Pseudomonas aeruginosa (1955)

SUMMARY: Genetic recombination has been shown to occur in Pseudomonas aeruginosa. Crosses between 18 biochemical mutants of 4 strains were studied and, although non-random segregation was found for non-selective markers, it has not yet been possible to draw conclusions concerning gene order or linkage. The progeny obtained from crosses tended to resemble one parent more than the other. The 4 strains of P. aeruginosa used were interfertile in certain combinations but self-sterile. There was no evidence for an infectious principle affecting fertility but fertility changes may occur amongst recombinant progeny.
Effect of Anaplerotic Fluxes and Amino Acid Availability on Hepatic Lipoapoptosis (2009)

To identify metabolic pathways involved in hepatic lipoapoptosis, metabolic flux analysis using [U-(13)C(5)]glutamine as an isotopic tracer was applied to quantify phenotypic changes in H4IIEC3 hepatoma cells treated with either palmitate alone (PA-cells) or both palmitate and oleate in combination (PA/OA-cells). Our results indicate that palmitate inhibited glycolysis and lactate dehydrogenase fluxes while activating citric acid cycle (CAC) flux and glutamine uptake. This decoupling of glycolysis and CAC fluxes occurred during the period following palmitate exposure but preceding the onset of apoptosis. Oleate co-treatment restored most fluxes to their control levels, resulting in steatotic lipid accumulation while preventing apoptosis. In addition, palmitate strongly increased the cytosolic NAD(+)/NADH ratio, whereas oleate co-treatment had the opposite effect on cellular redox. We next examined the influence of amino acids on these free fatty acid-induced phenotypic changes. Increased medium amino acids enhanced reactive oxygen species (ROS) generation and apoptosis in PA-cells but not in PA/OA-cells. Overloading the medium with non-essential amino acids induced apoptosis, but essential amino acid overloading partially ameliorated apoptosis. Glutamate was the most effective single amino acid in promoting ROS. Amino acid overloading also increased cellular palmitoyl-ceramide; however, ceramide synthesis inhibitors had no effect on measurable indicators of apoptosis. Our results indicate that free fatty acid-induced ROS generation and apoptosis are accompanied by the decoupling of glycolysis and CAC fluxes leading to abnormal cytosolic redox states. Amino acids play a modulatory role in these processes via a mechanism that does not involve ceramide accumulation.
CID3: an extension of ID3 for attributes with ordered domains (1991)

Quinlan's ID3 is a popular and efficient algorithm for inducing decision trees from concept examples, where the examples are presented as vectors of attribute-value pairs. If some attributes have integer or real domains ID3 tends to generate very complex decision trees. This is due to: (1) an attribute selection heuristic biased towards attributes with domains of large cardinality (2) strong constraints (bias) imposed on decision trees generated and (3) the fact that ID3 does not distinguish between attributes with unordered domains and attributes with linearly ordered (integer or real) domains. ID3- IV and GID3 address the first and second problem respectively. We propose CID3, a generalization of GID3, which addresses the third problem. These algorithms are compared with respect to five criteria for decision tree quality and computational efficiency. The test domain consists of normal and abnormal electrocardiograms (ECGs) described mainly by integer and real attributes. CID3, which implements the weakest bias and uses the most domain knowledge,&#13;\ngenerates a superior quality decision tree for the ECGs.
Christian Perspectives on Jerusalem (1999)

Christian Perspectives on Jerusalem. by: Michael Prior. , Language: English
The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. (1995)

The receptor of Hepatocyte Growth Factor-Scatter Factor (HGF) is a tyrosine kinase which regulates cell motility and growth. After ligand-induced tyrosine phosphorylation, the HGF receptor associates with the Shc adaptor, via the SH2 domain. Site-directed mutagenesis of the HGF receptor indicates that phosphotyrosines Y1349VHV and Y1356VNV can work as docking sites for Shc. The Kd of this interaction, measured in real time using synthetic phosphopeptides and recombinant Shc on a BIAcore biosensor, is 150 nm for both sites. After stimulation of the HGF receptor, Shc is phosphorylated on Y317VNV, generating an high affinity binding site for Grb2 (Kd = 15 nM). This duplicates the high affinity binding site for Grb2 present on the HGF receptor (Y1356VNV). Thus HGF stimulation can trigger the Ras pathway by recruiting Grb2 both directly through the receptor, and indirectly, through Shc. Overexpression of wild-type Shc, but not of the Y317-->F mutant, enhances cell migration and growth in response to HGF. These data show that Shc is a relevant substrate of the HGF receptor, and works as an 'amplifier' of the motogenic as well as of the mitogenic response.
In vitro study of farnesyltransferase inhibitor SCH 66336, in combination with chemotherapy and radiation, in non-small cell lung cancer cell lines (2004)

K-ras alterations have been reported in 20-30% of non-small cell lung cancer (NSCLC) and represent a suitable target for the development of novel anticancer agents, such as Farnesyl transferase inhibitors (FTi), a new class of agents inhibiting the post-translational modification of the K-ras proteins. The effectiveness of FTi SCH66336 in inhibiting cell proliferation and deranging cell cycle of NSCLC cell lines as well as its interaction with chemotherapy or radiation have been evaluated. The activity of FTi SCH66336, alone or in combination with paclitaxel, gemcitabine, and radiotherapy, was examined in 3 cell lines, A-549, LX-1 and CaLu-6, by colorimetric MTT assay. Cell cycle perturbation and apoptosis were also assessed by cytofluorimetric analysis. The activity of SCH 66336 was found to be concentration- and time-dependent. The effect of SCH 66336, as demonstrated by cell growth recovery experiments, resulted cytostatic and it was superimposable in both cell lines bearing 2 different K-ras mutations (A-549 and LX-1) and in K-ras wild-type Ca-Lu-6. In all cell lines the combination of SCH 66336 and paclitaxel resulted in a synergism of action when SCH 66336 followed paclitaxel treatment, whereas, antagonism was found when SCH 66336 preceded paclitaxel treatment. No significant synergism or addition with SCH 66336 followed by radiation treatment was noted. Different cell cycle phase blocks at various drug concentrations were observed. In conclusion, SCH 66336 displays concentration-dependent cytostatic antitumour activity and schedule-dependent synergy with 2 commonly used anticancer agents in NSCLC cell lines. Further clinical testing of these combinations is warranted.
Cellular role of yeast Apn1 apurinic endonuclease/3'-diesterase: repair of oxidative and alkylation DNA damage and control of spontaneous mutation. (1991)

The APN1 gene of Saccharomyces cerevisiae encodes the major apurinic/apyrimidinic endonuclease and 3'-repair DNA diesterase in yeast cell extracts. The Apn1 protein is a homolog of Escherichia coli endonuclease IV, which functions in the repair of some oxidative and alkylation damages in that organism. We show here that yeast strains lacking Apn1 (generated by targeted gene disruption or deletion-replacement) are hypersensitive to both oxidative (hydrogen peroxide and t-butylhydroperoxide) and alkylating (methyl- and ethylmethane sulfonate) agents that damage DNA. These cellular hypersensitivities are correlated with the accumulation of unrepaired damages in the chromosomal DNA of apn1 mutant yeast cells. Hydrogen peroxide-treated APN1+ but not apn1 mutant cells regenerate high-molecular-weight DNA efficiently after the treatment. The DNA strand breaks that accumulate in the Apn1-deficient mutant contain lesions that block the action of DNA polymerase but can be removed in vitro by purified Apn1. An analogous result with DNA from methylmethane sulfonate-treated cells corresponded to the accumulation of unrepaired DNA apurinic sites in the apn1 mutant cells. The rate of spontaneous mutation in apn1 mutant S. cerevisiae was 6- to 12-fold higher than that measured for wild-type yeast cells. This increase indicates that under normal growth conditions, the production of DNA damages that are targets for Apn1 is substantial and that such lesions can be mutagenic when left unrepaired.
Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors (2017)

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.
How Phase Transformations during Cooling Affect Li-Mn-Ni-O Positive Electrodes in Lithium Ion Batteries (2013)

The Li-Mn-Ni-O system has received much attention for potential positive electrode materials in lithium ion batteries. This article is an executive summary of a large project that used combinatorial samples synthesized at over 500 compositions to determine the entire Li-Mn-Ni-O and Li-Co-Mn-O pseudo-ternary systems under various synthesis conditions. During slow cooling, the boundaries of the single phase layered region in the Li-Mn-Ni-O system move significantly making the solid-solution area smaller, while the complex co-existence region, made up of two 3-phase regions, transforms dramatically. The impact of these phase transformations on battery performance is presented here for the first time. The electrochemical data for three new materials present in the co-existence region demonstrates why efforts to design a spinel-layered composite electrode have been so difficult. Furthermore, the layered region is considerably larger than previously discussed in the literature implying that a portion of the region remains unexplored. Additionally, matching published lattice parameters with contour plots obtained from the combinatorial studies shows that the common practice of using excess lithium during synthesis may result in single phase compounds with more lithium than the target stoichiometry, which helps explain the large variation in electrochemical performance seen in the literature. This study is therefore a significant contribution toward a complete understanding of how synthesis conditions affect Li-Mn-Ni-O structures and their electrochemistry.
Sequence-Specific Conjugates of Oligo(2′-O-methylribonucleotides) and Hairpin Oligocarboxamide Minor-Groove Binders: Design, Synthesis, and Binding Studies with Double-Stranded DNA (2005)

New conjugates of triplex-forming pyrimidine oligo(2'-O-methylribonucleotides) with one or two 'head-to-head' hairpin oligo(N-methylpyrrole carboxamide) minor-groove binders (MGBs) attached to the terminal phosphate of the oligonucleotides with a oligo(ethylene glycol) linker were synthesized. It was demonstrated that, under appropriate conditions, the conjugates form stable complexes with double-stranded DNA (dsDNA) similarly to triplex-forming oligo(deoxyribonucleotide) (TFO) conjugates containing 5-methylated cytosines. Kinetic and thermodynamic parameters of the complex formation were evaluated by gel-shift assay and thermal denaturation. Higher melting temperatures (Tm), faster complex formation, and lower dissociation constants (Kd) of the triple helices (6-7 nM) were observed for complexes of MGB-oligo(2'-O-methylribonucleotide) conjugates with the target dsDNA compared to the nonconjugated individual components. Interaction of MGB moieties with the HIV proviral DNA fragment was indicated by UV/VIS absorption changes at 320 nm in the melting curves. The introduction of thymidine via a 3',3'-type 'inverted' phosphodiester linkage at the 3'-end of oligo(2'-O-methylribonucleotide) conjugates (3'-protection) had no strong influence on triplex formation, but slightly affected complex stability. At pH 6.0, when one or two hairpin MGBs were attached to the oligonucleotide, both triplex formation and minor-groove binding played important roles in complex formation. When two 'head-to-head' oligo(N-methylpyrrole) ligands were attached to the same terminal phosphate of the oligonucleotide or the linker, binding was observed at pH >7.5 and at high temperatures (up to 74 degrees). However, under these conditions, binding was retained only by the MGB part of the conjugate.