gebhart/patrepeval huggingface dataset:
Combination of Tumor Site–Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses (2007)

Accumulating data indicate that tumor-infiltrating regulatory T cells (Treg) are present in human tumors and locally suppress antitumor immune cells. In this study, we found an increased Treg/CD8 ratio in human breast and cervical cancers. A similar intratumoral lymphocyte pattern was observed in a mouse model for cervical cancer (TC-1 cells). In this model, systemic Treg depletion was inefficient in controlling tumor growth. Furthermore, systemic CTL-associated antigen-4 (CTLA-4) blockade, an approach that can induce tumor immunity in other tumor models, did not result in TC-1 tumor regression but led to spontaneous development of autoimmune hepatitis. We hypothesized that continuous expression of an anti-CTLA-4 antibody localized to the tumor site could overcome Treg-mediated immunosuppression and locally activate tumor-reactive CD8+ cells, without induction of autoimmunity. To test this hypothesis, we created TC-1 cells that secrete a functional anti-CTLA-4 antibody (TC-1/alphaCTLA-4-gamma1 cells). When injected into immunocompetent mice, the growth of TC-1/alphaCTLA-4-gamma1 tumors was delayed compared with control TC-1 cells and accompanied by a reversion of the intratumoral Treg/CD8 ratio due to an increase in tumor-infiltrating IFNgamma-producing CD8+ cells. When local anti-CTLA-4 antibody production was combined with Treg inhibition, permanent TC-1 tumor regression and immunity was induced. Importantly, no signs of autoimmunity were detected in mice that received local CTLA-4 blockade alone or in combination with Treg depletion.
Development of Hyperactive Sleeping Beauty Transposon Vectors by Mutational Analysis (2004)

The Sleeping Beauty (SB) transposable element is a promising vector for transgenesis in vertebrates and is being developed as a novel, nonviral system for gene therapeutic purposes. A mutagenesis approach was undertaken to improve various aspects of the transposon, including safety and overall efficiency of gene transfer in human cells. Deletional analysis of transposon sequences within first-generation SB vectors showed that the inverted repeats of the element are necessary and sufficient to mediate high-efficiency transposition. We constructed a "sandwich" transposon, in which the DNA to be mobilized is flanked by two complete SB elements arranged in an inverted orientation. The sandwich element has superior ability to transpose >10-kb transgenes, thereby extending the cloning capacity of SB-based vectors. We derived hyperactive versions of the SB transposase by single-amino-acid substitutions. These mutations act synergistically and result in an almost fourfold enhancement of activity compared to the wild-type transposase. When combined with hyperactive transposons and transiently overexpressed HMGB1, a cellular cofactor of SB transposition, hyperactive transposases elevate transposition by almost an order of magnitude compared to the first-generation transposon system. The improved vector system should prove useful for efficient gene transfer in vertebrates.
A method for the simultaneous evaluation of the activities of seven major human drug-metabolizing cytochrome P450s using an in vitro cocktail of probe substrates and fast gradient liquid chromatography tandem mass spectrometry. (2001)

A method for the simultaneous evaluation of the activities of seven major human drug-metabolizing cytochrome P450s (CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2C19, CYP2A6, and CYP2C8) was developed. This method uses an in vitro cocktail of specific substrates (midazolam, bufuralol, diclofenac, ethoxyresorufin, S-mephenytoin, coumarin, and paclitaxel) and fast gradient liquid chromatography tandem mass spectrometry. The assay incubation time is 20 min, which is in the linear range for all of the substrates, and the analysis time is 4 min/sample. Substrate specificity was confirmed by incubating Escherichia coli-expressed enzymes with the cocktail. Potent specific inhibitors of the seven enzymes (ketoconazole, quinidine, sulfaphenazole, tranylcypromine, quercetin, furafylline, and 8-methoxypsoralen) were evaluated in cocktail and individual substrate incubations. Five of these inhibitors were further studied to determine more precise IC(50) values for inhibition of the seven enzymes. The IC(50) values obtained in both cocktail and individual incubations were in good agreement with published values. This cocktail method offers an efficient, robust way to determine the cytochrome P450 inhibition profile of large numbers of compounds. The enhanced throughput of this method greatly facilitates its use to assess CYP inhibition as a drug candidate selection criterion.
Investigating GPS Signals Indoors with Extreme High-Sensitivity Detection Techniques (2005)

ABSTRACT: High-sensitivity GPS and assisted GPS are being extensively researched as methods to improve positioning indoors, where weak, multipath-affected signals are often difficult or impossible to use. To improve knowledge of indoor GPS behavior, this paper presents details of a raw GPS processing technique that enables extremely long coherent integrations, thereby providing extremely high detection sensitivity for indoor signals. The technique is used to evaluate signal characteristics in a pair of datasets gathered indoors, with carrier-to-noise density ratios as much as 40 dB or more below nominal open-sky signals. Results show that weak signals such as these can be used to provide reasonably accurate positioning if a sufficient number of signals can be detected to ensure good positioning geometry. Signal degradations caused by multipath are shown to be less damaging to position than the loss of availability caused by low signal strength. In addition, the high-sensitivity techniques based on precise tracking loop control demonstrate the potential for improved high-sensitivity GPS-based technologies using ultra-tight integration with additional sensors.
A New Monoclonal Antibody Recognizing a Linear Determinant on the HLA-DRα Chain N-terminus (2009)

We report the generation of a monoclonal antibody (MAb) that reacts to the N-terminus of the denatured HLA-DRalpha chain. The 1C4.6 MAb was raised against a peptide corresponding to amino acid residues 10 to 32 of a highly conserved region within the alpha1 domain of HLA-DR. This region partially overlaps with the epitope recognized by the conformationally dependent L243 MAb. In Western blot analysis, MAb 1C4.6 reacted with denatured HLA-DRalpha chains, but failed to bind the HLA-DRbeta chain expressed individually by transfectant cells, confirming that it recognizes an epitope on the alpha-chain of HLA-DR. In addition, this antibody was found to be isotype specific to HLA-DRalpha, as it did not cross-react to HLA class II proteins HLA-DP and-HLA-DQ. The 1C4.6 MAb is a valuable addition to existing reagents used to probe the structure and function of MHC class II molecules. This anti-HLA-DRalpha1 domain MAb may prove valuable for studies of HLA class II heterodimer assembly, structure, and function, as well as for studies into the release of soluble MHC class II.
Bacterial Lipopolysaccharide Copurifies with Plasmid DNA: Implications for Animal Models and Human Gene Therapy (1995)

During the course of gene therapy experiments in rodents, using intramuscular injections of plasmid DNA derived from Escherichia coli, we noted dose-related toxicity. This observation prompted a search for possible contaminants of DNA samples. We used the highly specific and sensitive limulus amoebocyte lysate assay (LAL), to monitor endotoxin bioactivity in DNA samples, and found plasmid DNA derived from standard E. coli bacterial strains, using traditional DNA isolation protocols, to be heavily contaminated with endotoxin, or lipopolysaccharide (LPA). Standard DNA isolation procedures result in the copurification of up to 500 μg/ml of LPS. LPS is a potent inducer of cytokines and other inflammatory mediators, and may complicate the use of naked DNA in gene therapy. The copurification of endotoxin with plasmid DNA also has important implications for in vitro transfection studies and microinjection of DNA into embryos. A simple and efficient protocol to reduce LPS contamination of plasmid DNA was developed. The conversion of intact bacteria to spheroplasts prior to the isolation of plasmid DNA, incubation with lysozyme, treatment with the detergent n-octyl-β-d-thioglucopyranoside (OSPG) and polymyxin-B (PMB) chromatography, allowed the isolation of plasmid DNA containing less than 50 ng/ml LPS. This represents a 10,000-fold reduction in LPS contamination, compared to conventional methods of plasmid DNA purification, avoids potentially toxic reagents such as ethidium bromide, and produces a higher yield of plasmid DNA. Several recent experiments in gene therapy have focused on the modulation of immune responses. Bacterial lipopolysaccharide (LPS) is a potent lymphocyte mitogen and adjuvant that can confound the results of gene immunotherapy studies. Plasmid DNA prepared from E. coli by standard techniques is highly contaminated with LPS. We describe here a simple method to remove LPS from DNA by the conversion of bacteria to spheroplasts, followed by treatment with a nonionic detergent and polymyxin B chromatography. DNA prepared by this method is essentially free of LPS, and, unlike conventionally purified plasmid DNA, does not produce nonspecific immune activation following in vivo administration.
Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents (1994)

Foci of aberrant and/or hexosaminidase-negative crypts in rat colon are putative precancerous lesions that have been proposed as biomarkers for short-term bioassays for chemical carcinogens and chemopreventive agents. The ability of a substance to reduce the yield of azoxymethane (AOM)-induced foci in the colon of male Fischer 344 rats, was evaluated as a screening assay for chemopreventive agents. Twenty-eight test agents were administered continuously in the diet from the start of the experiments until the animals were killed 35 days later. AOM was s.c. administered either as 15 mg/kg body wt on days 7 and 14 or as 30 mg/kg body wt on day 7 of the experiment. Foci of aberrant crypts were evaluated in whole mounts of methylene blue-stained colons. AOM induced twice as many foci when administered between 8.40 and 11.00 a.m. than between 2.45 and 5.55 p.m. Calcium salts of carbonate, chloride and glucarate decreased the yield of AOM-induced foci while the acidic salts of lactate and phosphate did not inhibit the formation of foci. Dimethyl-fumarate, fumaric acid, genistein, piroxicam, simethicone, sodium suramin and sulindac reduced the yield of AOM-induced foci of aberrant crypts, with genistein being the most potent. Only piroxicam of this group has previously been shown to inhibit colon cancer, while the rest have yet to be evaluated. Ibuprofen did not inhibit the formation of foci, although it has been reported to inhibit AOM-induced colon cancer in rats. Piroxicam and sulindac appeared to reduce preferentially hexosaminidase-negative foci of aberrant crypts, compared with those of apparently normal morphology. The AOM-induced foci of aberrant crypts assay appears suitable for screening chemicals for chemopreventive action.
Eicosenoic acid and other fatty acids ofSapindaceae seed oils (1967)

The seed oils of 11 species ofSapindaceae were examined, and their fatty acid composition was determined.cis-11-Eicosenoic acid was identified as the major fatty acid ofKoelreuteria paniculata. It was present in nine of the 11 species in amounts from 8-60% of the total fatty acids and is evidently a common component of oils of this plant family. Arachidic acid was present in amounts up to 11%. Only three of the oils had acids of chain length greater than C-20. Seed oils of certain species ofKoelreuteria andCardiospermum are good potential sources of 11-eicosenoic acid.
PD-1 Gene Polymorphism in Children with Subacute Sclerosing Panencephalitis (2013)

Subacute sclerosing panencephalitis (SSPE) is a progressive inflammatory and degenerative disorder of the central nervous system. Several factors influence the risk of chronic brain infection with the mutant measles virus. However, to date, no pathogenic mechanism that may predispose to SSPE has been determined. Studies have indicated that specific polymorphisms in certain host genes are probably involved in impairing the ability of host immune cells to eradicate the measles virus in SSPE patients. Programmed cell death protein 1 (PD-1), a member of the CD28 family, is a negative regulator of the immune system. The purpose of our study was to investigate whether PD-1 gene polymorphisms affect susceptibility to the development of SSPE in Turkish children. In total, 109 subjects (54 SSPE patients and 55 healthy controls) were genotyped for the PD-1.9 C/T (rs2227982) single-nucleotide polymorphism (SNP). The distributions of T alleles in the PD-1.9 polymorphism in SSPE patients and healthy controls were 2.8 and 10.9%, respectively. There was a statistically significant difference between the groups; the 95% confidence interval (CI) was 0.06 to 0.85 and the odds ratio (OR) was 0.23 (χ(2) test). Thus, we identified an association between SSPE and the PD-1 rs2227982 gene polymorphism; the frequency of T alleles was higher in controls than in SSPE patients.
Rh-Catalyzed Asymmetric Hydrogenation of γ-Phthalimido-Substituted α,β-Unsaturated Carboxylic Acid Esters:  An Efficient Enantioselective Synthesis of β-Aryl-γ-amino Acids (2007)

A series of chiral beta-aryl-gamma-amino acid ester derivatives were synthesized in high enantioselectivities (93-97% ee) via the Rh-catalyzed asymmetric hydrogenation of gamma-phthalimido-alpha,beta-unsaturated carboxylic acid esters using highly modular chiral BoPhoz-type phosphine-aminophosphine ligands. The method has been applied successfully to the synthesis of several chiral pharmaceuticals including (R)-baclofen and (R)-rolipram with high enantioselectivities.
Endothelial Progenitor Cells and a Stromal Cell–derived Factor-1α Analogue Synergistically Improve Survival in Sepsis (2014)

EPCs and CTCE represent important potential therapeutic strategies in sepsis.
Improved Glucose Excursions Using an Implantable Real-Time Continuous Glucose Sensor in Adults With Type 1 Diabetes (2004)

The availability of real-time continuous glucose values may help patients reduce their hyperglycemic excursions and lower the risk of hypoglycemia.
Novel mechanism for carbamoyl-phosphate synthetase: A nucleotide switch for functionally equivalent domains (1997)

Carbamoyl-phosphate synthetases (CPSs) utilize two molecules of ATP at two internally duplicated domains, B and C. Domains B and C have recently been shown to be structurally [Thoden, J. B., Holden, H. M., Wesenberg, G., Raushel, F. M. & Rayment, I. (1997) Biochemistry 36, 6305-6316] and functionally [Guy, H. I. & Evans, D. R. (1996) J. Biol. Chem. 271, 13762-13769] equivalent. We have carried out a site-directed mutagenic analysis that is consistent with ATP binding to a palmate motif rather than to a Walker A/B motif in domains B and C. To accommodate our present findings, as well as the other recent findings of structural and functional equivalence, we are proposing a novel mechanism for CPS. In this mechanism utilization of ATP bound to domain C is coupled to carbamoyl-phosphate synthesis at domain B via a nucleotide switch, with the energy of ATP hydrolysis at domain C allowing domain B to cycle between two alternative conformations.
Delivery of therapeutic doses of radioiodine using bispecific antibody-targeted bivalent haptens. (1998)

Two-step pretargeting strategies have been designed to deliver radioisotopes to tumors more selectively than directly labeled antibodies or fragments. In this article, we compare quantitatively the potential of these strategies for the radioimmunotherapy of solid tumors.Direct targeting was performed using iodine-labeled IgG and F(ab')2. As two-step strategies, we used the sequential injection of anti-CEA x anti-DTPA-In bispecific F(ab')2 (BsF(ab')2) and monovalent and bivalent DTPA derivatives labeled with iodine. The biodistribution of iodine in nude mice grafted with the LS174T human colorectal carcinoma was monitored in time and used for calculating radiation doses.In agreement with earlier studies, the IgG was more effective for delivering a radiation dose to the tumor than the F(ab')2 (7.8 versus 0.76 Gy/MBq, respectively) and both were moderately selective with respect to normal tissues (tumor:blood of 2.9 and 1.7, respectively). At their MTD, they should deliver 86 and 34 Gy, respectively, to the tumor. Using a nM-affinity DTPA-In bivalent hapten, the two-step protocol was optimized by varying the dosage of the BsF(ab')2, the stoichiometry of the reagents and the pretargeting time. The saturation of the tumor was obtained by injecting 5 nmol (500 microg) of BsF(ab')2. The pretargeted BsF(ab')2 was saturated by the injection of 0.5 mol of bivalent hapten per mole of antibody. With a 48-hr pretargeting time, the selectivity of the irradiation of the tumor was optimized (tumor:blood of 7.8) but only at the price of a lower efficiency (0.35 versus 0.86 Gy/MBq, 48-hr and 20-hr pretargeting time, respectively). Attempts to increase selectivity by using a microM-affinity DTPA-Y bivalent hapten or by chasing excess circulating radiolabeled hapten with an excess of unlabeled hapten also reduced tumor exposure. The use of a monovalent hapten resulted in both lower efficiency and selectivity. However, the two-step pretargeting of high-affinity bivalent hapten (Affinity Enhancement System, AES) should deliver 30-60 Gy to the tumor with less than 9 Gy to the blood in tumor-bearing mice.Radioimmunotherapy with AES is predicted to be as efficient and with lower hematological toxicity than direct targeting.
Expression of a foreign gene linked to either a plant-virus or a Drosophila promoter, after electroporation of protoplasts of rice, wheat, and sorghum (1986)

The bacterial chloramphenicol acetyltransferase (CAT) gene was expressed in protoplasts of three important graminaceous plant species after introduction of the gene by electroporation. Gene transfer occurred when high-voltage electric pulses were applied either directly or indirectly (without anode contact) to a solution containing plasmid DNA and protoplasts of rice, wheat, or sorghum. The indirect method was more rapid, resulted in higher protoplast viability, and was less subject to contamination than the direct-contact method. Gene expression of approximately equal magnitude resulted when the CAT gene was fused to either the 35S promoter of cauliflower mosaic virus or the copia long terminal repeat promoter of Drosophila. Together with recent advances in regeneration of callus and whole plants from protoplasts, this system makes it possible to study inheritance and expression of genes introduced into graminaceous monocotyledonous plants.
The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells (2001)

Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.
Single-Element Focused Ultrasound Transducer Method for Harmonic Motion Imaging (2006)

The harmonic motion imaging (HMI) technique for simultaneous monitoring and generation of ultrasound therapy using two separate focused ultrasound transducer elements was previously demonstrated. In this study, a new HMI technique is described that images tissue displacement induced by a harmonic radiation force using a single focused-ultrasound element. A wave propagation simulation model first indicated that, unlike in the two-beam configuration, the amplitude-modulated beam produced a stable focal zone for the applied harmonic radiation force. The AM beam thus offered the unique advantage of sustaining the application of the spatially-invariant radiation force. Experiments were performed on gelatin phantoms and ex vivo tissues. The radiation force was generated by a 4.68 MHz focused ultrasound (FUS) transducer using a 50 Hz amplitude-modulated wave. A 7.5 MHz pulse-echo transducer was used to acquire rf echoes during the application of the harmonic radiation force. Consecutive rf echoes were acquired with a pulse repetition frequency (PRF) of 6.5 kHz and 1D cross-correlation was performed to estimate the resulting axial tissue displacement. The HMI technique was shown capable of estimating stiffness-dependent displacement amplitudes. Finally, taking advantage of the real-time capability of the HMI technique, temperature-dependent measurements enabled monitoring ofHIFU sonication in ex vivo tissues. The new HMI method may thus enable a highly-localized force and stiffness-dependent measurements as well as real-time and low-cost HIFU monitoring.
A Prospective Randomized Trial of Lidocaine 30 mg Versus 45 mg for Epidural Test Dose for Intrathecal Injection in the Obstetric Population (2012)

Our results suggest that there is unlikely to be a large difference in the ability of these doses to detect unintentional intrathecal catheter placement. While the negative predictive value for intrathecal injection is very high for both doses, the 95% CI for the sensitivity of either dose is too wide to demonstrate clinical safety to identify all intrathecal catheters. A much larger study is warranted to assess whether there is a lower sensitivity with the 30-mg dose, or a propensity toward high cephalad motor block levels with the 45-mg dose.