gebhart/patrepeval huggingface dataset:
Probes for Narcotic Receptor-Mediated Phenomena. 21. Novel Derivatives of 3-(1,2,3,4,5,11-Hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol-6-yl)- phenols with Improved δ Opioid Receptor Selectivity (1996)

Derivatives of racemic and optically pure levorotatory 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]in dol-6-yl)phenols containing methoxy substituents in the C10', C9', and C8' positions (compounds 9-11, respectively) were synthesized and characterized by spectroscopic and X-ray methods. The binding affinities for the mu, delta and kappa 1 opioid receptors and activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD) functional bioassays were determined for these compounds. A methoxy substituent in the C8' position decreases the binding affinity for both the mu and delta receptors, while a C10' methoxy substituent has little effect on either binding affinity. Interestingly, a methoxy group at the C9' position in the levorotatory series provides compound (-)-10 which exhibits both enhanced in vitro affinity and selectivity for the delta opioid receptor relative to the unsubstituted derivative (-)-8 and is the most selective (mu/delta IC50 ratio 17.9, kappa 1/delta IC50 ratio 314) and highest affinity (IC50 3.7 nM) delta receptor ligand for this novel class of compounds. The results of the GPI and MVD bioassays are more dramatic and indicate that (-)-10 is an agonist for the delta receptor (IC50 49.0 nM) with substantial selectivity for the delta versus the mu receptor borne out by a GPI/MVD IC50 ratio of > 612.
MAPbox: Using Parameterized Behavior Classes to Confine Applications (1999)

Designing a suitable mechanism to confine commonly used applications is challenging as such a mechanism needs to satisfy conflicting requirements. The trade-off is between configurability and ease of use. In this paper, we present the design, implementation and evaluation of MAPbox, a general-purpose confinement mechanism that retains the ease of use of specialized sandboxes such as Janus and SBOX while providing significantly more configurability. The key idea is to group application behaviors into classes based on the expected functionality and the resources required to achieve that functionality. Classification of behaviors provides a set of behavior labels (class names) that can be used to concisely communicate the expected functionality of programs between the provider and the users. This is similar to the MIME-types used to concisely describe the expected format of data files. Classification of application behaviors also allows class-specific sandboxes to be built and instantiat...
Ceragenin CSA-13 induces cell cycle arrest and antiproliferative effects in wild-type and p53 null mutant HCT116 colon cancer cells (2013)

Antimicrobial peptides of the cathelicidin family play a central role in the host defense system. Our group has reported previously that cathelicidin-related or cathelicidin-modified antimicrobial peptides, such as FF/CAP-18, have antiproliferative effects on the squamous cell carcinoma cell line SAS-H1 and colon cancer-derived cell line HCT116. Ceragenin CSA-13, which mimics the hydrophobic and cationic morphology of cathelicidin-related peptides, was developed to reduce synthetic costs and resolve stability issues in the presence of proteases. In this study, we evaluated the antiproliferative effect of CSA-13 on HCT116 cells. We evaluated the effects of CSA-13 in HCT116 cells by measuring cell growth, detecting apoptosis, analyzing the cell cycle, and examining mitochondrial membrane depolarization. Treatment with CSA-13 suppressed HCT116 cell proliferation in a dose-dependent manner, increasing the incidence of apoptosis detected by the binding of Annexin V. Furthermore, cell cycle analysis showed that the cell cycle of CSA-13-treated wild-type and p53 null mutant HCT116 cells was arrested at the G1/S phase, indicating that CSA-13 affects the cell cycle by a p53-independent pathway. Our study showed that CSA-13 exerts an antiproliferative effect in cancer cells similar to that of FF/CAP-18, suggesting that membrane-permeabilizing capability is the common underlying mechanism for anticancer and antimicrobial effects of CSA-13 and anitimicrobial peptides.
Continuous particle size separation and size sorting using ultrasound in a microchannel (2006)

Continuous separation and size sorting of particles and blood cells suspended in a microchannel flow due to an acoustic force are investigated both numerically and experimentally. Good agreement in the measured particle trajectories in a microchannel flow subjected to the acoustic force with those obtained by the numerical simulations up to the fitting parameter is found. High separation efficiency, particularly in a three-stage microdevice (up to 99.975%), for particles and blood cells leads us to believe that the device can be developed into commercially useful set-up. The novel particle size sorting microdevice provides an opportunity to replace rather expensive existing devices based on specific chemical bonding with an ultrasound cell size sorter that can be considerably improved by adding many stages for multistage size sorting.
Stereochemical Analysis of Glycerophospholipids by Vibrational Circular Dichroism (2015)

The stereochemistry of glycerophospholipids (GPLs) has been of interest for its roles in the evolution of life and in their biological activity. However, because of their structural complexity, no convenient method to determine their configuration has been reported. In this work, through the first systematic application of vibrational circular dichroism (VCD) spectroscopy to various diacylated GPLs, we have revealed that their chirality can be assigned by the sign of a VCD exciton couplet generated by the interaction of two carbonyl groups. This paper also presents spectroscopic evidence for the stereochemistry of GPLs isolated from bacteria, eukaryotes, and mitochondria.
Noninvasive Prenatal Detection of Fetal Trisomy 18 by Epigenetic Allelic Ratio Analysis in Maternal Plasma: Theoretical and Empirical Considerations (2006)

Epigenetic allelic ratio analysis of maternal plasma DNA represents a promising approach for noninvasive prenatal diagnosis of fetal chromosomal aneuploidies.
Analytical Validation of a 12-Gene Molecular Test for the Prediction of Distant Recurrence in Breast Cancer (2017)

These studies demonstrate that the 12-gene molecular assay is highly robust and accurate.
A Mutational Analysis of the Binding of Two Different Proteins to the Same Antibody (1996)

The crystal structures of the complexes between the anti-hen egg white lysozyme (HEL) antibody D1.3 and HEL and between D1.3 and the anti-D1.3 antibody E5.2 have shown that D1.3 contacts these two proteins through essentially the same set of combining site residues [Fields, B. A., Goldbaum, F. A., Ysern, X., Poljak, R. J., & Mariuzza, R. A. (1995) Nature 374, 739-742]. To probe the relative contribution of individual residues to complex stabilization, single alanine substitutions were introduced in the combining site of D1.3, and their effects on affinity for HEL and for E5.2 were measured using surface plasmon resonance detection, fluorescence quench titration, or sedimentation equilibrium. The energetics of the binding to HEL are dominated by only 3 of the 13 contact residues tested (delta Gmutant-delta Gwild type > 2.5 kcal/mol): VLW92, VHD100, and VHY101. These form a patch at the center of the interface and are surrounded by residues whose apparent contributions are much less pronounced ( < 1.5 kcal/mol). This contrasts with the interaction of D1.3 with E5.2 in which most the contact residues (11 of 15) were found to play a significant role in ligand binding ( > 1.5 kcal/mol). Furthermore, even though D1.3 contacts HEL and E5.2 in very similar ways, the functionally important residues of D1.3 are different for the two interactions, with only substitutions at D1.3 positions VH100 and VH101 greatly affecting binding to both ligands. Thus, the same protein may recognize different ligands in ways that are structurally similar yet energetically distinct.
Apoptosis in the development and treatment of cancer (2004)

Our somatic cells are born by mitosis and almost all will die by apoptosis, a physiological process of cellular suicide. Cancers can occur when this balance is disturbed, either by an increase in cell proliferation or a decrease in cell death. The goal of cancer therapy is to promote the death of cancer cells without causing too much damage to normal cells. Our knowledge of the mechanisms of apoptosis has enhanced our understanding of how some cancers originate and progress. It has also revealed that existing cancer therapies can work in two ways, by induction of apoptosis as well as by direct toxicity. In some cases resistance to apoptosis may explain why cancer therapies fail. Novel treatments designed to exploit our knowledge of apoptotic mechanisms are under development to promote apoptosis of cancer cells and limit concurrent death of normal cells.
Chromatographic analysis in bacteriologic diagnostics of blood cultures, exudates, and bronchoalveolar lavages. (2005)

This article summarizes our previously achieved and published results. The method for the determination of bacterial volatile fatty acid patterns (VFA) in clinical samples was elaborated. It employs gas chromatography (GC), solvent extraction or head-space solid phase microextraction (SPME). This method was validated by analyses of reference bacterial strains. After cultivation in defined media, aerobic and facultative anaerobic bacteria provided profiles with a low or none acid content, while anaerobic bacteria provided characteristic but medium-dependent profiles with a higher acid content. This method was used for the analyses of clinical samples of total 375 blood cultures, 205 suppurative and apyogenous exudates, and 210 bronchoalveolar lavages (BALs). These analyses enabled within 30 minutes the detection of microbes, probably non-sporulating anaerobes not found by false-negative cultivation, in 11.2% of blood cultures, in 20.0% of exudates, and in 9.0 to 20.0% of BALs. Using the mass spectrometry (MS) methods, a number of other components with unclear diagnostic importance were found in BAL samples, in particular hydrogen cyanide, methanol, ethanol, hexanol, acetone, cyclohexanone, acetonitrile, formaldehyde, acetaldehyde, ethyl acetate, and other esters. Cyclohexanone, occurring mainly in BALs of patients with pneumonia, undergoing intensive care, may originate as a residual solvent from the plastic parts of the ventilation apparatus.
Development, validation, and comparison of gene analysis methods for detecting EGFR mutation from non-small cell lung cancer patients-derived circulating free DNA (2019)

The feasibility and required sensitivity of circulating free DNA (cfDNA)-based detection methods in second-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment are not well elucidated. We examined T790M and other activating mutations of <i>EGFR</i> by cfDNA to assess the clinical usability. In 45 non-small cell lung cancer (NSCLC) patients harboring activating <i>EGFR</i> mutations, cfDNAs were prepared from the plasma samples. <i>EGFR</i> mutations in cfDNA were detected using highly sensitive methods and originally developed assays and these results were compared to tissue-based definitive diagnoses. The specificity of each cfDNA-based method ranged 96-100% whereas the sensitivity ranged 56-67%, indicating its low pseudo-positive rate. In EGFR-TKI failure cohort, 41-46% samples were positive for T790M by each cfDNA-based method, which was comparable to re-biopsy tissue-based T790M positive rates in literature. The concordance of the results for each <i>EGFR</i> mutation ranged from 83-95%. In eight patients, the results of the cfDNA-based assays and re-biopsy-derived tissue-based test were compared. The observed overall agreement ranged in 50-63% in T790M, and in 63-100% in activating <i>EGFR</i> mutations. In this study, we have newly developed three types of assay which have enough sensitivity to detect cfDNA. We also detected T790M in 44% of patients who failed prior EGFR-TKI treatment, indicating that cfDNA-based assay has clinical relevance for detecting acquired mutations of <i>EGFR</i>.
Oral Tolerance Induction by Type V Collagen Downregulates Lung Allograft Rejection (2001)

Immunization with specific proteins or peptides has been used to induce immunologic tolerance to allografts other than the lung. Recently, we have reported that the immune response to lung alloantigen also involves an immune response to type V collagen [col(V)]. The purpose of the current study was to determine if oral administration of col(V) to lung allograft recipients before transplantation downregulates acute rejection episodes. The data show that, compared with controls, col(V)-fed recipients had fewer polymorphonuclear cells and lymphocytes in allograft bronchoalveolar lavage fluid, and reduced rejection pathology. Data showing that col(V)- fed allograft recipients had diminished delayed-type hypersensitivity (DTH) responses to donor alloantigens suggest that feeding col(V) prevented allograft rejection by inducing tolerance to donor antigens. Systemic production of transforming growth factor (TGF)-beta, interleukin (IL)-4, or IL-10 has been reported to be a mechanism for oral tolerance-induced suppression of immune responses. Feeding col(V) induced upregulated production of TGF-beta, but not IL-4 or IL-10 in serum. Neutralizing TGF-beta recovered the DTH response to donor antigen in tolerant allograft recipients. Collectively, these data show that oral administration of col(V) is a novel approach to induce immunologic tolerance to lung allografts, and that TGF-beta contributed to suppression of the rejection response.
The Innate Immune System in Allograft Rejection and Tolerance (2007)

As T cells alone are both necessary and sufficient for the rejection of virtually all allogeneic tissues, much of transplantation immunology has focused on cells of the adaptive immune system. During the past decade, advances in our understanding of innate responses to pathogen-associated molecules have spurred a "rediscovery" of innate immunity. Fueled by this, an increasing body of literature has emerged in which the role of the innate immune system in allograft rejection and tolerance has been examined more closely. This review will give an overview of recent studies and emerging concepts of how the cellular components of the innate immune system participate in the immune response to solid organ transplantation. These important studies highlight the complex interplay between diverse cells of the immune response and provide the basis for optimal strategies of tolerance induction.
Targeting the Hemozoin Synthesis Pathway for New Antimalarial Drug Discovery: Technologies for In Vitro &#946;-Hematin Formation Assay (2005)

Clinical manifestations of malaria primarily result from proliferation of the parasite within the hosts' erythrocytes. During this process, hemoglobin is utilized as the predominant source of nutrition. The malaria parasite digests hemoglobin within the digestive vacuole through a sequential metabolic process involving multiple proteases. Massive degradation of hemoglobin generates large amount of toxic heme. Malaria parasite, however, has evolved a distinct mechanism for detoxification of heme through its conversion into an insoluble crystalline pigment, known as hemozoin. Hemozoin is identical to beta-hematin, which is constituted of cyclic heme dimers arranged in an ordered crystalline structure through intermolecular hydrogen bonding. The exact mechanism of biogenesis of hemozoin in malaria is still obscure and is the subject of intense debate. Hemozoin synthesis is an indispensable process for the parasite and is the target for action of several known antimalarials. The pathway has therefore attracted significant interest for new antimalarial drug discovery research. Formation of beta-hematin may be achieved in vitro under specific chemical and physiochemical conditions through a biocrystallization process. Based on these methods several experimental approaches have been described for the assay of formation of beta-hematin in vitro and screening of compounds as inhibitors of hemozoin synthesis. These assays are primarily based on differential solubility and spectral characteristics of monomeric heme and beta-hematin. Different factors viz., the malaria parasite lysate, lipids extracts, preformed beta-hematin, malarial histidine rich protein II and some unsaturated lipids have been employed for promoting beta-hematin formation in these assays. The assays based on spectrophotometric quantification of beta-hematin or incorporation of (14)C-heme yield reproducible results and have been applied to high throughput screening. Several novel antimalarial pharmacophores have been discovered through these assays.
Evidence for the Effects of a Superantigen in Rheumatoid Arthritis (1991)

While studying the αβ T cell receptor repertoire in rheumatoid arthritis (RA) patients, we found that the frequency of V β 14 + T cells was significantly higher in the synovial fluid of affected joints than in the peripheral blood. In fact, V β 14 + T cells were virtually undetectable in the peripheral blood of a majority of these RA patients. β-chain sequences indicated that one or a few clones dominated the V β 14 + population in the synovial fluid of individual RA patients, whereas oligoclonality was less marked for other Vβ's and for V β 14 in other types of inflammatory arthritis. These results implicate V β 14-bearing T cells in the pathology of RA. They also suggest that the etiology of RA may involve initial activation of V β 14 + T cells by a V β 14-specific superantigen with subsequent recruitment of a few activated autoreactive V β 14 + T cell clones to the joints while the majority of other V β 14 + T cells disappear.
Altered ErbB Receptor Signaling and Gene Expression in Cisplatin-Resistant Ovarian Cancer (2005)

The majority of ovarian cancer patients are treated with platinum-based chemotherapy, but the emergence of resistance to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this treatment can modify cell signaling responses in a model system wherein cisplatin treatment has altered cell responsiveness to ligands of the erbB receptor family. A cisplatin-resistant ovarian carcinoma cell line PE01CDDP was derived from the parent PE01 line by exposure to increasing concentrations of cisplatin, eventually obtaining a 20-fold level of resistance. Whereas PE01 cells were growth stimulated by the erbB receptor-activating ligands, such as transforming growth factor-alpha (TGFalpha), NRG1alpha, and NRG1beta, the PE01CDDP line was growth inhibited by TGFalpha and NRG1beta but unaffected by NRG1alpha. TGFalpha increased apoptosis in PE01CDDP cells but decreased apoptosis in PE01 cells. Differences in extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling were also found, which may be implicated in the altered cell response to ligands. Microarray analysis revealed 51 genes whose mRNA increased by at least 2-fold in PE01CDDP cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, TRAP1, and FANCG), whereas 36 genes (including IGFBP3, TRAM1, and KRT4 and KRT19) decreased by a similar amount. Differential display reverse transcriptase-PCR identified altered mRNA expression for TCP1, SLP1, proliferating cell nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1, and MCM2 expression was associated with reduced growth and FRA1 inhibition with enhanced cisplatin sensitivity. Altered expression of these genes by cytotoxic exposure may provide survival advantages to cells including deregulation of signaling pathways, which may be critical in the development of drug resistance.
Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion (2000)

Abstract Sickle cell anemia is characterized by painful vaso-occlusive crises. It is hypothesized that monocytes are activated in sickle cell disease and can enhance vaso-occlusion by activating endothelium. To test this hypothesis, human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (MVEC) with sickle and normal mononuclear leukocytes were incubated, and endothelial activation was measured. Endothelial cells incubated with sickle mononuclear leukocytes were more activated than those incubated with normal mononuclear leukocytes, as judged by the increased endothelial expression of adhesion molecules and tissue factor and the adhesion of polymorphonuclear leukocytes (PMNL). Monocytes, not lymphocytes or platelets, were the mononuclear cells responsible for activating endothelial cells. Sickle monocytes triggered endothelial nuclear factor-kappa B (NF-κB) nuclear translocation. Cell-to-cell contact of monocytes and endothelium enhanced, but was not required for, activation. Antibodies to tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) blocked activation of the endothelium by monocytes. Peripheral blood monocytes from patients with sickle cell disease had 34% more IL-1β (P = .002) and 139% more TNF-α (P = .002) per cell than normal monocytes. Sixty percent of sickle monocytes expressed the adhesion molecule ligand CD11b on their surfaces compared with only 20% of normal monocytes (P = .002). Serum C-reactive protein, a marker of systemic inflammation, was increased 12-fold in sickle serum than in normal serum (P = .003). These results demonstrate that sickle monocytes are activated and can, in turn, activate endothelial cells. It is speculated that vascular inflammation, marked by activated monocytes and endothelium, plays a significant role in the pathophysiology of vaso-occlusion in sickle cell anemia.
An integrated photocatalytic/enzymatic system for the reduction of CO2 to methanol in bioglycerol–water (2014)

A hybrid enzymatic/photocatalytic approach for the conversion of CO2 into methanol is described. For the approach discussed here, the production of one mol of CH3OH from CO2 requires three enzymes and the consumption of three mol of NADH. Regeneration of the cofactor NADH from NAD(+) was achieved by using visible-light-active, heterogeneous, TiO2-based photocatalysts. The efficiency of the regeneration process is enhanced by using a Rh(III)-complex for facilitating the electron and hydride transfer from the H-donor (water or a water-glycerol solution) to NAD(+). This resulted in the production of 100 to 1000 mol of CH3OH from one mol of NADH, providing the possibility for practical application.