gebhart/patrepeval huggingface dataset:
Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition (2016)

<b>Purpose:</b> Using gene-disrupted allogeneic T cells as universal effector cells provides an alternative and potentially improves current chimeric antigen receptor (CAR) T-cell therapy against cancers and infectious diseases.<b>Experimental Design:</b> The CRISPR/Cas9 system has recently emerged as a simple and efficient way for multiplex genome engineering. By combining lentiviral delivery of CAR and electro-transfer of Cas9 mRNA and gRNAs targeting endogenous TCR, β-2 microglobulin (B2M) and PD1 simultaneously, to generate gene-disrupted allogeneic CAR T cells deficient of TCR, HLA class I molecule and PD1.<b>Results:</b> The CRISPR gene-edited CAR T cells showed potent antitumor activities, both <i>in vitro</i> and in animal models and were as potent as non-gene-edited CAR T cells. In addition, the TCR and HLA class I double deficient T cells had reduced alloreactivity and did not cause graft-versus-host disease. Finally, simultaneous triple genome editing by adding the disruption of PD1 led to enhanced <i>in vivo</i> antitumor activity of the gene-disrupted CAR T cells.<b>Conclusions:</b> Gene-disrupted allogeneic CAR and TCR T cells could provide an alternative as a universal donor to autologous T cells, which carry difficulties and high production costs. Gene-disrupted CAR and TCR T cells with disabled checkpoint molecules may be potent effector cells against cancers and infectious diseases. <i>Clin Cancer Res; 23(9); 2255-66. ©2016 AACR</i>.
Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery (2006)

Impressive progress in genome sequencing, protein expression and high-throughput crystallography and NMR has radically transformed the opportunities to use protein three-dimensional structures to accelerate drug discovery, but the quantity and complexity of the data have ensured a central place for informatics. Structural biology and bioinformatics have assisted in lead optimization and target identification where they have well established roles; they can now contribute to lead discovery, exploiting high-throughput methods of structure determination that provide powerful approaches to screening of fragment binding.
Circulating Activated and Effector Memory T Cells Are Associated with Calcification and Clonal Expansions in Bicuspid and Tricuspid Valves of Calcific Aortic Stenosis (2011)

We sought to delineate further the immunological significance of T lymphocytes infiltrating the valve leaflets in calcific aortic stenosis (CAS) and determine whether there were associated alterations in circulating T cells. Using clonotypic TCR β-chain length and sequence analysis we confirmed that the repertoire of tricuspid CAS valves contains numerous expanded T cell clones with varying degrees of additional polyclonality, which was greatest in cases with severe calcification. We now report a similar proportion of clonal expansions in the much younger bicuspid valve CAS cases. Peripheral blood flow cytometry revealed elevations in HLA-DR(+) activated CD8 cells and in the CD8(+)CD28(null)CD57(+) memory-effector subset that were significantly greater in both bicuspid and tricuspid CAS cases with more severe valve calcification. Lesser increases of CD4(+)CD28(null) T cells were identified, principally in cases with concurrent atherosclerotic disease. Upon immunostaining the CD8 T cells in all valves were mainly CD28(null), and CD8 T cell percentages were greatest in valves with oligoclonal repertoires. T cell clones identified by their clonotypic sequence as expanded in the valve were also found expanded in the circulating blood CD28(null)CD8(+) T cells and to a lesser degree in the CD8(+)CD28(+) subset, directly supporting the relationship between immunologic events in the blood and the valve. The results suggest that an ongoing systemic adaptive immune response is occurring in cases with bicuspid and tricuspid CAS, involving circulating CD8 T cell activation, clonal expansion, and differentiation to a memory-effector phenotype, with trafficking of T cells in expanded clones between blood and the valve.
Tumor necrosis factor production in patients with leprosy (1992)

The spectrum of host responses to Mycobacterium leprae provides a model for investigating the role of cytokines in the pathogenesis of mycobacterial disease. Of particular interest is tumor necrosis factor (TNF), a cytokine which may have both antimycobacterial and immunopathologic effects. To evaluate the potential role of TNF in leprosy, we measured TNF production in response to M. leprae and its defined constituents by peripheral blood mononuclear cells from patients across the spectrum of disease. The levels of TNF induced through the stimulation of cells with M. leprae or its dominant "lipopolysaccharide," lipoarabinomannan, were higher in patients with the tuberculoid form of the disease than in those with the lepromatous form. In patients with erythema nodosum leprosum (ENL), a reactional state of lepromatous leprosy, the levels of TNF release by peripheral blood mononuclear cells were higher than in any other form of the disease. Treatment of ENL patients with thalidomide reduced TNF secretion by more than 90%. The mycolylarabinogalactan-peptidoglycan complex of Mycobacterium species, the protein-peptidoglycan complex, and muramyl dipeptide all elicited significant TNF release. Therefore, TNF release appears to be triggered by at least two major cell wall structural constituents of M. leprae, lipoarabinomannan and segments of the cell wall skeleton. The prominent TNF release in patients with the paucibacillary tuberculoid form of the disease compared with that in patients with the multibacillary lepromatous form suggests that this cytokine contributes to a resistant immune response to mycobacterial infection. However, the marked TNF release in patients with ENL indicates that TNF may also mediate immunopathologic effects, such as fever and tissue damage.
A ray‐propagation fast multipole algorithm (1994)

Abstract A new technique is presented for accelerating the fast multipole method, allowing rapid solution of surface integral equations for wave‐scattering problems. A nonnested, ray‐propagation approach is used to compute a matrix‐vector multiply in O(N 4/3 ) operations, where N is the number of unknowns in the discretized integral equation. © 1994 John Wiley &amp; Sons, Inc.
A theoretical assessment of the relative performance of spherical phased arrays for ultrasound surgery (2000)

Computer modeling of spherical-section phased arrays for ultrasound surgery (tissue ablation) is described. The influence on performance of the number of circular elements (68 to 1024), their diameter (2.5 to 10 mm), frequency (1 to 2 MHz), and degree of sparseness in the array is investigated for elements distributed randomly or in square, annular, and hexagonal patterns on a spherical shell (radius of curvature, 120 mm). Criteria for evaluating the quality of the intensity distributions obtained when focusing the arrays both on and away from their center of curvature, and in both single focus and simultaneous multiple foci modes, are proposed. Of the arrays studied, the most favorable performance, for both modes, is predicted for 256 5-mm diameter, randomly distributed elements. For the single focus mode, this performed better than regular arrays of 255 to 1024 elements and, for the case of nine simultaneous foci produced on a coplanar 3x3 grid with 4-mm spacing, better than square, hexagonal, or annular distributed arrays with a comparable number of elements. Randomization improved performance by suppressing grating lobes significantly. For single focus mode, a several-fold decrease in the number of elements could be made without degrading the quality of the intensity distribution.
A clinicopathologic analysis of adriamycin cardiotoxicity (1973)

The cardiotoxic effects of adriamycin were studied in 399 patients treated for far-advanced carcimma. Forty-five patients (11%) exhibited transient electrocardiographs changes. Eleven others developed severe congestive heart failure. Eight of these latter patients died within 3 weeks of the onset of the cardiac decompensation. The diffuse nature of this myocardiopathy was suggested by: 1. a conspicuous decrease in the QRS voltage on the electrocardiograms; 2. rapidly occurring cardiac dilatation and ventricular failure, and 3. refractoriness to inoiropic drugs and mechanical ventricular assistance. Postmortem examination of the hearts in two cases showed a striking decrease in the number of cardiac: muscle cells present, degeneration of the remaining myocardial cells, loss o contractile substance, mitochondrial swelling, and intramitochondrial dense inclusion bodies. Congestive heart failure occurred only once in the 366 patients who were treated with less than 550 mg/m2 of adriamycin (0.27%), but there were 10 cases of cardiac failure in the 33 patients who received more than 550 mg/m2 of this drug (30%). Therefore, until more direct means are established to prevent adriamycin-induced congestive heart failure, it is suggested that the total dose of adriamycin should be limited to less than 550 mg/m2 to permit safer use of this efficacious cancer chemotherapeutic agent.
Equivalence Verification of Polynomial Datapaths Using Ideal Membership Testing (2007)

This paper addresses the equivalence verification problem of register-transfer level (RTL) descriptions that implement arithmetic computations (such as add, mult) over bit vectors with finite widths. A bit vector of size represents integer values from 0 to 2 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m</sup> -1, implying that the corresponding integer values are reduced modulo 2 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m</sup> (%2 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m</sup> ). This suggests that bit-vector arithmetic can be efficiently modeled as algebra over finite integer rings, where the bit-vector size (m) dictates the cardinality of the ring (Z <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m</sup> ). This paper models the arithmetic datapath verification problem as the equivalence testing of polynomial functions from Z <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">n</sup> <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1</sub> timesZ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">n</sup> <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> times...timesZ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">n</sup> <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">d</sub> rarrZ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m</sup> . We formulate the equivalence problem into that of proving whether f-gequiv0%2 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">m</sup> . Fundamental concepts and results from ldquonumber,rdquo ldquoring,rdquo and ldquoideal theoryrdquo are subsequently employed to develop systematic complete algorithmic procedures to solve the problem. We demonstrate the application of the proposed theoretical concepts to high-level (behavioral/RTL) verification of bit-vector arithmetic within practical computer-aided design settings. Using our approach, we verify a set of arithmetic datapaths at RTL, where contemporary verification approaches prove to be infeasible.
Growth of Large Crystals of Monodispersed Spherical Colloids in Fluidic Cells Fabricated Using Non-photolithographic Methods (2001)

This paper describes a convenient approach to the fabrication of fluidic cells to be used for crystallizing spherical colloids into three-dimensionally periodic lattices over large areas. The major component of the fluidic cell was a rectangular gasket sandwiched between two glass substrates. Here we demonstrate that these gaskets could be simply cut out of commercial Mylar films. Three non-photolithographic methods were also demonstrated to create shadow channels between the Mylar film and two glass substrates: (i) by wiping (along one single direction) both sides of the Mylar film with a piece of soft paper (Kimwipes EX-L); (ii) by coating both surfaces of the Mylar film with polymer beads whose size was smaller than those to be packed in the cell; and (iii) by patterning the surface of the bottom glass substrate with an array of gold channels using a combination of microcontact printing and selective etching. When an aqueous dispersion of monodispersed spherical colloids was injected into this packing cell, a crystalline lattice nucleated and grew from the edge(s) of the cell as a result of solvent depletion through the channels between the Mylar film and the glass substrates. The capability and feasibility of this new approach have been demonstrated by the fabrication of uniform opaline lattices of polystyrene beads and silica colloids over areas as large as several square centimeters. Because Mylar films with thicknesses in the range 20−100 μm are commercially available in large quantities and at reasonably low costs, the present approach offers a flexible tool to those who want to explore the use of large crystals of spherical colloids but have no access to clean room facilities.
Methylation of the hMLH1 promoter in familial gastric cancer with microsatellite instability (2000)

Microsatellite instability (MSI), which is recognized as an important mechanism in tumorigenesis, has been reported in familial gastric cancers (FGC).However, genetic defects responsible for this phenotype, that is, mutations in mismatchrepair genes such as hMLH1 and hMSH2, have not been detected in most FGC cases.Earlier studies have shown that the promoter region of the hMLH1 gene was methylated in some sporadic colorectal and endometrial cancers.To determine how FGC acquire MSI, we examined the MSI status, hMLH1-protein expression and methylation status of the hMLH1-promoter region in FGC cases.Out of 9 cancers, 6 from 8 FGC kindreds showed MSI at one or more loci; no germline mutations in the hMLH1 or hMSH2 genes were detected; 4 cancers exhibiting MSI displayed aberrant hMLH1 expression: complete loss in one, decreased level in another, and partially staining pattern in the remaining 2. Methylation in the hMLH1-promoter region was found in these 4 cases.In contrast, the cancers displaying hMLH1-protein expression were not methylated in the hMLH1-promoter region.Our data show a significant association between the absence of hMLH1 expression and methylation of its promoter in FGC cases with MSI.This suggests that the mechanism of inactivation of hMLH1 is epigenetic and that there are other genes responsible for FGC.Int.
Graded-junction gate/n/sup -/ overlapped LDD MOSFET structures for high hot-carrier reliability (1991)

A newly developed gate/n/sup -/ overlapped LDD MOSFET was investigated. The MOSFET was fabricated by an oblique rotating ion implantation technique. A formula for the impurity ion profile was derived to analyze the lowering of substrate current and improvement of the degradation caused by the hot-carrier effect of the MOSFET. It was proved that the impurity ion profile near the drain edge is remarkably graded in the directions along channel and toward substrate even just after the implantation, so that the maximum lateral electric field is relaxed as compared with conventional LDD MOSFETs. Also, the maximum point of the lateral electric field at the drain edge is located apart from the main path of the channel current.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Three-dimensional location estimation of circular features for machine vision (1992)

A closed-form analytical solution to the problem of 3D estimation of circular-feature location is presented. Two different cases are considered: 3D orientation and position estimation when the radius is known and when it is not known. Extension of the method to general 3D quadratic features is also addressed. Simulated experimental results obtained for all three cases verified the analytical method. In the case of real experiments, a set of circles located on a calibration plate, whose locations were known with respect to a reference frame, were used for camera calibration as well as for the application of the method. A sequential compensation procedure was applied to the input gray-level image to compensate for distortion. These results also showed the validity of the process and the applicability of the analytical method.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer (2007)

PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser(10) is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers.
A Helmet-Mounted Pedestrian Dead Reckoning System (2006)

Abstract. Since most persons in emergency service wear some sort of headgear, we investigate how basic navigation sensors could be incorporated into a safety helmet and thereby be made truly wearable. It is well known that the key to solving the generic ubiquitous localization problem is the combination of different positioning techniques and sensor modalities. In this paper, a combined approach of pedestrian dead reckoning (PDR) and GPS positioning is followed. An novel combination of neural-network step length predictions and helmet-mounted sensors is presented. The experimental system shows low accumulated error over an extended walk and indoor/outdoor navigation is demonstrated. 1
The nutrient status of algal cells in continuous culture (1974)

Chemostats were used to study the relation between growth rate, the rate of nutrient uptake and internal and external nutrient concentrations of two nutrients simultaneously. ( Monochrysis lutheri : phosphorus and vitamin B 12 .) Growth rate and internal concentrations of both limiting and excess nutrients are related by simple rectangular hyperbolas. Control was shown to follow a threshold rather than multiplicative pattern; that is, non-limiting nutrients exert no control at all over the pattern of growth. The limiting nutrient was the one that showed the smallest cell quota: subsistence quota ratio. Monochrysis populations exhibited two modes of growth. ‘Slow adapted cells’ differed from ‘fast adapted cells’ in the values of the constants for the above relation. Uptake of both limiting and non-limiting nutrients was found to be controlled by internal as well as external substrate concentrations. There was thus a limit to luxury consumption of one nutrient when growth was limited by another. The mathematical model formulated for growth in a chemostat (equations (23)–(29)) allowed prediction of external and internal substrate concentrations and rates of uptake of two nutrients and of biomass, given only the input concentrations of the two nutrients and the dilution rate. This model should apply equally well to growth in batch cultures; its possible application to natural populations was discussed.
Pathophysiology of Pain (2002)

Pain is a sensation induced by activation of the peripheral nociceptors when tissue is damaged by direct stimuli or has a possibility of damage. There exist nociceptors for detecting the noxious stimuli in periphery, and the nociceptive informations were transmitted via A - or C-fibers. Acute pain is caused by direct noxious stimuli, and chronic pains are produced by inflammation or nerve damage. The mechanisms of chronic pains are associated with the changes of central nervous system (CNS) as well as those in peripheral nocicpetors. Immune cells and neurotrophins are also involved in the mechanisms of chronic pain. Recently, there has been a tendency among pain researchers that chronic pain might be explained the plastic changes in the nociceptive synaptic transmission through the spinal cord. These are associated with changes in intracellular concentration, subsequent intracellular signal transduction pathways, which result in changes in AMPA receptor dynamics. This sequential changes may induce allodynia and hyperalgesia observed in chronic pain patients. This review suggests new interpretation for pain mechanism and new approach for chronic pain.
Beta-glucan, a "specific" biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18). (1999)

beta-Glucans were identified 36 years ago as a biologic response modifier that stimulated tumor rejection. In vitro studies have shown that beta-glucans bind to a lectin domain within complement receptor type 3 (CR3; known also as Mac-1, CD11b/CD18, or alphaMbeta2-integrin, that functions as an adhesion molecule and a receptor for factor I-cleaved C3b, i.e., iC3b) resulting in the priming of this iC3b receptor for cytotoxicity of iC3b-opsonized target cells. This investigation explored mechanisms of tumor therapy with soluble beta-glucan in mice. Normal mouse sera were shown to contain low levels of Abs reactive with syngeneic or allogeneic tumor lines that activated complement, depositing C3 onto tumors. Implanted tumors became coated with IgM, IgG, and C3, and the absent C3 deposition on tumors in SCID mice was reconstituted with IgM or IgG isolated from normal sera. Therapy of mice with glucan- or mannan-rich soluble polysaccharides exhibiting high affinity for CR3 caused a 57-90% reduction in tumor weight. In young mice with lower levels of tumor-reactive Abs, the effectiveness of beta-glucan was enhanced by administration of a tumor-specific mAb, and in SCID mice, an absent response to beta-glucan was reconstituted with normal IgM or IgG. The requirement for C3 on tumors and CR3 on leukocytes was highlighted by therapy failures in C3- or CR3-deficient mice. Thus, the tumoricidal function of CR3-binding polysaccharides such as beta-glucan in vivo is defined by natural and elicited Abs that direct iC3b deposition onto neoplastic cells, making them targets for circulating leukocytes bearing polysaccharide-primed CR3. Therapy fails when tumors lack iC3b, but can be restored by tumor-specific Abs that deposit iC3b onto the tumors.