gebhart/patrepeval huggingface dataset:
A novel antioxidant role for hemoglobin. The comproportionation of ferrylhemoglobin with oxyhemoglobin. (1990)

Ferrylhemoglobin (X-FeIV-OH, where X denotes an amino acid residue in the globin moiety) has long been suspected as a cytotoxic agent produced by the interaction of oxyhemoglobin (X-FeIIO2) or methemoglobin (X-FeIII) with H2O2 in red blood cells. To date, however, technical difficulties have prevented the identification and quantification of X-FeIV-OH. Oxyhemoglobin exposed to a continuous flux of H2O2 (generated at a rate of 120 microM/min during the glucose oxidase-catalyzed oxidation of glucose) was oxidized to (a) X-FeIV-OH when [X-FeIIO2] less than 75 microM and (b) X-FeIII when [X-FeIIO2] greater than 75 microM (the production of X-FeIII proceeded with intermediate formation of X-FeIV-OH). The reduction of the X-FeIV-OH to X-FeIII could be explained by either of two alternative mechanisms: a O2(-)-mediated X-FeIV-OH---X-FeIII transition or a comproportionation of X-FeIV-OH and X-FeIIO2 to yield X-FeIII (a process mediated by a tyrosine moiety in the hemoprotein). The low rate of X-FeIIO2 autoxidation plus the negligible decrease in the rate of X-FeIII formation in the presence of either native or heat-denatured superoxide dismutase or apoenzyme (1 microM) suggested that O2- does not contribute to the reduction of X-FeIV-OH. Moreover, the dependence of X-FeIII formation on X-FeIIO2 concentration, together with the results of O2 uptake and H2O2 consumption measurements, provide experimental evidence to support the comproportionation reaction. Comproportionation is apparently catalyzed by intermolecular electron transfer between tyrosine residues, since the reaction did not occur when tyrosine residues were blocked by acetylation. Intact red blood cells exposed to the same flow rate of H2O2 presented a spectral profile which could be explained as a transition from X-FeIIO2 to X-FeIII. The intermediate production of X-FeIV-OH was detected by adding Na2S (2 mM), which revealed a spectral profile identical with that obtained with purified X-FeIV-OH. Measurements of concentrations and relative rate constants for the reaction of various intracellular reductants (glutathione, NAD(P)H, uric acid, ascorbic acid) with X-FeIV-OH revealed that comproportionation of X-FeIV-OH with X-FeIIO2 is the favored reaction. Our results provide (to our knowledge) the first definitive evidence for X-FeIV-OH in intact red blood cells. The rapid comproportionation reaction between X-FeIV-OH and X-FeIIO2 (to produce X-FeIII) explains why X-FeIV-OH has been elusive to date.(ABSTRACT TRUNCATED AT 400 WORDS)
TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding (2016)

<b>Purpose:</b> The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.<b>Experimental Design:</b> The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. <i>In vivo</i> antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails.<b>Results:</b> TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. <i>In vivo</i>, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.<b>Conclusions:</b> These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. <i>Clin Cancer Res; 23(4); 1068-79. ©2016 AACR</i>.
Dual IGF-I/II–Neutralizing Antibody MEDI-573 Potently Inhibits IGF Signaling and Tumor Growth (2011)

Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R-targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI-573 significantly inhibited the in vivo growth of IGF-I- or IGF-II-driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of (18)F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways.
Construction and Characterization of Novel, Recombinant Immunotoxins Targeting the Her2/neu Oncogene Product: In vitro and In vivo Studies (2009)

The goal of this study was to characterize a series of anti-Her2/neu immunotoxin constructs to identify how different antibodies and linker choices affect the specificity and cytotoxicity of these proteins. We constructed a series of immunotoxins containing either the human single-chain antibody (scFv) C6.5 or the murine scFv e23 fused to the highly toxic recombinant gelonin (rGel) molecule. Based on the flexible GGGGS linker (L), the fusion construct C6.5-L-rGel was compared with e23-L-rGel to evaluate the specific cytotoxic effects against Her2/neu-positive and Her2/neu-negative tumor cells. Both constructs retained the specificity of the original antibody as well as the biological activity of rGel toxin. The two constructs displayed similar cytotoxicity against different carcinoma cells. We additionally introduced the modified linkers TRHRQPRGWEQL (Fpe) and AGNRVRRSVG (Fdt), which contained furin cleavage sites, to determine the effect of these design changes on stability and cell killing efficiency. The introduction of furin cleavage linkers (Fpe or Fdt) into the molecules resulted in dissimilar sensitivity to protease cleavage compared with the constructs containing the L linker, but very similar intracellular rGel release, cytotoxic kinetics, and induction of autophagic cell death in vitro. Xenograft studies with SKOV3 ovarian tumors were done using various C6.5/rGel constructs. C6.5-L-rGel was more efficient in tumor inhibition than constructs containing furin linkers, attributing to a higher stability in vivo of the L version. Therefore, our studies suggest that human C6.5-L-rGel may be an effective novel clinical agent for therapy of patients with Her2/neu-overexpressing malignancies.
BRAFV600E Mutation in Melanotic Neuroectodermal Tumor of Infancy: Toward Personalized Medicine? (2015)

The melanotic neuroectodermal tumor of infancy (MNTI) is a rare neoplasm that primarily affects the maxilla of infants during their first year of life. Complete resection is the conventional treatment and recurrence rates vary from 10% to 60%. The recurrent tumors grow more aggressively and can invade other anatomic structures, such as the nasal cavity, the orbit, and the skull base. The aggressive behavior of MNTIs may require radical resection, which may not be possible in some cases because of its rapid and invading growth together with invasion of vital structures. In these situations, adjunct radiotherapy or chemotherapy has been used. However, as there are no conclusive data regarding the molecular profile of this tumor, currently there is no targeted therapy that may be used in the treatment of selected aggressive cases. On the basis of MNTI similarities with melanomas, such as derivation from the neural crest cells and presence of large melanin-containing cells, we hypothesized that MNTIs also may harbor the BRAFV600E oncogenic mutation. We show for the first time that this important pediatric tumor may harbor the oncogenic BRAFV600E mutation, providing the first insights to their personalized treatment.
Anatomy of the Left Atrium: (1999)

Anatomy of the Left Atrium. Introduction: The feasibility of treating atrial fibrillation with radiofrequency ablation has revived interest in the structure of the left atrium, a chamber that has been neglected in many textbooks of anatomy. Methods and Results: We reviewed the gross structure of the left atrium by examining the septum, the appendage, and insertions of the pulmonary veins in normal hearts. The limited extent of the true septal component is relevant to procedures using the transseptal approach. On gross examination, the musculature of the atrial wall is composed of overlapping bundles of aligned fibers that, in the majority of hearts, are arranged in characteristic patterns with only minor individual variations. Muscular sleeves extend into the walls of the pulmonary veins to varying distances. The longest sleeves are in the left upper veins. Bachmann's bundle anteriorly, and other smaller bundles superiorly and posteriorly, bridge the septal raphe to blend with musculature of the right atrium. Tongues of left atrial musculature from the posterior wall also extend into the wall of the coronary sinus. Conclusion: The left atrium is more complex than usually conceived. Understanding its structure, and the arrangement of its musculature, will help in improving strategies for linear lesions when attempting to compartmentalize the chamber, or when placing focal lesions for ablating ectopic sources.
Molecular Cloning and Characterization of the Genes Coding for the Highly Immunogenic Cluster of 90-Kilodalton Envelope Proteins from theChlamydia psittaciSubtype That Causes Abortion in Sheep (1998)

Proteins present in the outer membrane of chlamydiae that are involved in mucosal epithelial cell infection must clearly be identified and characterized if we are to understand and modify the pathogenic mechanisms utilized by these organisms. We have identified and isolated a family of four genes encoding putative outer membrane proteins (POMPs), a group of proteins of approximately 90 kDa present in the outer membrane of the subtype of Chlamydia psittaci that causes ovine enzootic abortion (strain S26/3). These proteins, although minor components, are major immunogens, as shown by the immunoblotting of chlamydial outer membrane complexes with postabortion sheep sera, and are therefore potential diagnostic and/or protective antigen candidates. Immunoblotting of the expressed amino- and carboxy-terminal halves of one of the POMPs with postabortion sheep sera showed that the major humoral immune response appeared to be directed solely against the amino-terminal half. This result, in combination with the positive immunofluorescence staining of S26/3-infected cells using POMP-specific (specific to the amino-terminal half of the proteins) monoclonal antibodies, suggests the probable surface localization of the POMPs and, more specifically, the surface exposure of the amino-terminal half of these proteins. The four pomp genes are highly homologous, sharing 82 to 100% similarity with each other (two of the genes are identical). Genes with strong and weak homologies were also detected in C. psittaci avian and feline pneumonitis strains, respectively. No pomp homologs were found in strains of C. trachomatis and C. pneumoniae, but this does not preclude their existence. The absence of homology with various subtypes of C. pecorum, which complicate the diagnosis of the ovine abortion subtype, indicates the possible suitability of the these 90-kDa proteins as serodiagnostic antigens.
Use of a macromolecular crowding agent to dissect interactions and define functions in transcriptional activation by a DNA-tracking protein: bacteriophage T4 gene 45 protein and late transcription. (1994)

We have used a molecular crowding reagent to define functions in the transcriptional activation of bacteriophage T4 late genes. This activation normally requires the three T4 DNA polymerase accessory proteins encoded by T4 genes 44, 62, and 45 (the gp44/62 complex and gp45), an enhancer-like cis-acting site, an RNA polymerase-bound coactivator, and an unobstructed path along the DNA joining the promoter to the enhancer. We show that molecular crowding eliminates the requirement for the gp44/62 complex and for the enhancer, retains the requirement for gp45 and its coactivator, and generates activated promoter complexes with nearly unchanged DNase I footprints. These experiments identify gp45 as the direct activator of transcription, and the gp44/62 complex as the assembly factor for gp45. They suggest that the enhancer serves as the normal, but not invariably essential, entry site for the gp45 DNA-tracking protein.
Development of an Immunoaffinity Process forFactor IX Purification (1990)

An immunoaffinity process based on monoclonal antibody (MAb) to factor IX (FIX) has been developed. Initially, vitamin-K-dependent proteins from cryoprecipitate-poor plasma are isolated on DEAE-Sephadex. The eluate is applied to an immunoaffinity column that utilizes a divalent metal-ion-dependent MAb directed against FIX. After washing the column with high salt in the presence of magnesium ion, the FIX is eluted using a citrate- or EDTA-containing buffer. Coagulation assays and Western blots show no detectable amounts of any contaminating proteins. Purity of the FIX product is established using reduced and nonreduced Coomassie-stanined SDS-PAGE and HPLC. The N-terminal 20 amino acids of the single peak of the HPLC were shown to be identical to those reported for FIX. The process shows no detectable leakage of monoclonal antibodies (MAb), efficient utilization of MAb, and provides yields greater than 95%. The use of solvent/detergent treatment as a potential viral inactivation method is incorporated in the process. Studies with tritiated Triton X-100 indicate that the detergent can be washed out of the MAb column so that less than 1ppm (total) Triton X-100 coelutes with the FIX.
Thermal Radiation from Photonic Crystals: A Direct Calculation (2004)

A classical simulation of equilibrium thermal emissivity from dispersive, lossy photonic crystals is presented. Normal emission results consistent with those assuming Kirchoff's law are obtained; i.e., a photonic crystal does not emit more than what a blackbody does. Significant enhancement, however, can be achieved over the radiation intensity from a uniform slab, indicating the potential usefulness of photonic crystals in incandescent lighting and thermal photovoltaic applications.
Policosanol: a new treatment for cardiovascular disease? (2002)

Policosanol is a mixture of alcohols isolated and purified from sugar cane. Recently, Cuban researchers found 5-20 mg daily of policosanol to be effective at improving serum lipid profiles. Policosanol is believed to decrease total cholesterol (TC), low-density lipoprotein (LDL), and increase high-density lipoprotein (HDL) by inhibiting cholesterol synthesis and increasing LDL processing. Lipid profile improvements are seen in healthy volunteers, patients with type II hypercholesterolemia, type 2 diabetics with hypercholesterolemia, postmenopausal women with hypercholesterolemia, and patients with combined hypercholesterolemia and abnormal liver function tests. Additionally, policosanol has performed equal to or better than simvastatin, pravastatin, lovastatin, probucol, or acipimox with fewer side effects in patients with type II hypercholesterolemia. Policosanol also decreases several other risk factors of cardiovascular disease by decreasing LDL oxidation, platelet aggregation, endothelial damage, and smooth muscle cell proliferation. Furthermore, policosanol decreases progression and increases regression of cardiovascular disease assessed by thallium-labeled myocardial perfusion scintigraphy (TL-MPS) and Doppler-ultrasound, and decreases symptoms of cardiovascular disease assessed by the Specific Activity Scale. In post-marketing studies, only 0.31 percent of patients have had adverse events. Furthermore, in animal toxicity studies doses up to 1500 times normal human doses (on the basis of body weight) have shown no negative effects on carcinogenesis, reproduction, growth, and development. However, despite the positive research on policosanol on Cubans, policosanol produced in Cuba is not available in the United States, and only Cuban subjects have been studied. Further research is needed to determine if the same effects will be obtained in U.S. populations with non-Cuban produced policosanol.
Generation of Ski -knockdown mice by expressing a long double-strand RNA from an RNA polymerase II promoter (2003)

We have developed a new vector, named pDECAP, to express long double-strand RNA (ds-RNA) from an RNA polymerase II (Pol II) promoter. Because the transcripts from pDECAP lack both the 5'-cap structure and the 3'-poly(A) tail that facilitate ds-RNA export to the cytoplasm, long ds-RNA from pDECAP does not induce the interferon response. Transgenic mice embryos expressing long ds-RNA for the transcriptional corepressor Ski from this vector exhibited phenotypes that were remarkably similar to those of Ski-deficient embryos, including defects of neural tube closure and eye formation. Thus, this vector provides a new tool to efficiently generate tissue-specific knockdown mice for studying gene function in whole animal systems.
<title>Spatiotemporal pattern recognition using hidden Markov models</title> (1993)

A spatio-temporal method for identifying objects contained in an image sequence is presented. The Hidden Markov Model (HMM) technique is used as the classification algorithm, making classification decisions based on a spatio-temporal sequence of observed object features. A five class problem is considered. Classification accuracies of 100% and 99.7% are obtained for sequences of images generated over two separate regions of viewing positions. HMMs trained on image sequences of the objects moving in opposite directions showed a 98.1% successful classification rate by class and direction of movement. The HMM technique proved robust to image corruption with additive correlated noise and had a higher accuracy than a single look nearest neighbor method. A real image sequence of one of the objects used was successfully recognized with the HMMs trained on synthetic data. This study shows the temporal changes that observed feature vectors undergo due to object motion hold information that can yield superior classification accuracy when compared to single frame techniques.
Regulation of ST2L expression on T helper (Th) type 2 cells (2001)

T1/ST2L, an IL-1 receptor homologue, is selectively expressed on murine Th2 cells and specific anti-ST2L antibodies can profoundly modulate the Th1/Th2 balance in vivo. Naive CD4+ T cells do not express ST2L but do so on activation with specific antigen in the presence of IL-4 or when stimulated with low doses of antigen in the absence of exogenously added IL-4. Similarly enhanced ST2L expression occurred after stimulation of Th2 cells with antigen or the mitogen ConA in the presence of APC. Restimulation of Th2 cells in the presence of IFN-gamma led to a decreased expression of ST2L to below basal levels. Conversely, Th2 cells cultured with IL-4 led to increased ST2L expression. The reduced expression of ST2L in response to high doses of antigen is also reversed by the neutralization of IFN-gamma. Using an ST2L promoter/luciferase reporter gene construct, we show that the distal but not proximal ST2L promoter is responsible for specific gene expression in Th2 cells. IL-4 enhances, whereas IFN-gamma suppresses ST2L expression via direct modulation of the distal promoter of the ST2L gene. These data provide a mechanistic explanation for the selective expression of ST2L on Th2 cells.
Segmental body composition assessed by bioelectrical impedance analysis and DEXA in humans (1996)

The present study assessed the relative contribution of each body segment to whole body fat-free mass (FFM) and impedance and explored the use of segmental bioelectrical impedance analysis to estimate segmental tissue composition. Multiple frequencies of whole body and segmental impedances were measured in 51 normal and overweight women. Segmental tissue composition was independently assessed by dual-energy X-ray absorptiometry. The sum of the segmental impedance values corresponded to the whole body value (100.5 +/- 1.9% at 50 kHz). The arms and legs contributed to 47.6 and 43.0%, respectively, of whole body impedance at 50 kHz, whereas they represented only 10.6 and 34.8% of total FFM, as determined by dual-energy X-ray absorptiometry. The trunk averaged 10.0% of total impedance but represented 48.2% of FFM. For each segment, there was an excellent correlation between the specific impedance index (length2/impedance) and FFM (r = 0.55, 0.62, and 0.64 for arm, trunk, and leg, respectively). The specific resistivity was in a similar range for the limbs (159 +/- 23 cm for the arm and 193 +/- 39 cm for the leg at 50 kHz) but was higher for the trunk (457 +/- 71 cm). This study shows the potential interest of segmental body composition by bioelectrical impedance analysis and provides specific segmental body composition equations for use in normal and overweight women.