gebhart/patrepeval huggingface dataset:
Sp1 decoy transfected to carcinoma cells suppresses the expression of vascular endothelial growth factor, transforming growth factor beta1, and tissue factor and also cell growth and invasion activities. (2000)

Vasculature development is thought to be an important aspect in the growth and metastasis of solid tumors. Among the angiogenic factors produced by tumor cells, vascular endothelial growth factor is considered to be the most potent and pathologically important. The synthesis of this growth factor has been shown to be modulated through Sp1 function following stimulation by tumor necrosis factor alpha (TNF-alpha). Oligodeoxynucleotides (ODNs) were synthesized with either the consensus sequence for Sp1 binding (Sp1 decoy ODNs) or a mutated form of this sequence (mt-Sp1 decoy ODNs). Using the hemagglutinating virus of Japan (HVJ)-liposome method, we transferred these ODNs into cultured cancer cells (A549 and U251 cells). The TNF-alpha-mediated expression of both VEGF and transforming growth factor beta1 and tissue factor (TF) by the cancer cells could be simultaneously suppressed to less than 30% by transfection of Sp1 decoy ODNs but not by mt-Sp1 decoy ODNs. In addition, in vitro invasiveness, synthesis of mRNA for urokinase-type plasminogen activator, and cell proliferation of both cell lines were also inhibited to 40% by the transfection of only Sp1 decoy ODNs. These results suggested that the Sp1 decoy strategy would be effective for regulating tumor growth by simultaneously reducing cancer cell (a) angiogenic growth factor expression, (b) proliferation, and (c) invasiveness.
Interleukin 15 protects against toxicity and potentiates antitumor activity of 5-fluorouracil alone and in combination with leucovorin in rats bearing colorectal cancer. (1998)

5-Fluorouracil (FUra) modulated by leucovorin (LV) is active in the treatment of colorectal cancer. Diarrhea and stomatitis are the most common dose-limiting toxicities. We have developed a model system in rats bearing a transplantable colon carcinoma sensitive to FUra therapy with dose-limiting toxicity profiles similar to what is observed in patients treated with either daily or weekly schedules of FUra plus LV. Interleukin 15 (IL-15), a cytokine that shares many biological activities with IL-2, was used at different doses (25, 100, and 400 microg/kg) and schedules (three doses before a single dose of FUra, FUra/LV daily x 5, or before each week of FUra/LV weekly x 4, or three doses before a single dose of FUra or FUra/LV daily x 5, then twice daily x 5 for a total of 11 doses) to evaluate its role in the modulation of the therapeutic selectivity of FUra alone and modulated by LV. IL-15 induced a dramatic decrease in chemotherapy-induced gastrointestinal toxicities, significant potentiation of antitumor activity, and an increased therapeutic index of FUra administered on single dose, daily x 5 and weekly x 4 schedules. In contrast, IL-2 (400 microg/kg) significantly potentiated the toxicity of FUra administered as a single i.v. push, with minimal potentiation of the antitumor activity. Taken together, the results clearly demonstrated the ability of IL-15, but not IL-2, to provide significant improvement of the therapeutic index of FUra alone and in combination with LV. The clinical relevance of the results obtained in this model system needs to be confirmed.
Extracellular matrix signaling from the cellular membrane skeleton to the nuclear skeleton: a model of gene regulation. (1996)

It is well established that cells must interact with their microenvironment and that such interaction is crucial for coordinated function and homeostasis. However, how cells receive and integrate external signals leading to gene regulation is far from understood. It is now appreciated that two classes of cooperative signals are implicated: a soluble class including hormones and growth factors and a class of insoluble signals emanating from the extracellular matrix (ECM) directly through contact with the cell surface. Using 3-dimensional culture systems and transgenic mice, we have been able to identify some of the elements of this ECM-signaling pathway responsible for gene regulation in rodent mammary gland differentiation and involution. Our major observations are 1) the requirement for a laminin-rich basement membrane; 2) the existence of a cooperative signaling pathway between basement membrane and the lactogenic hormone prolactin (PRL);3) the importance of beta 1-integrins and bHLH transcription factor(s) and the presence of DNA response elements (exemplified by BCE-1, located on a milk protein gene, beta-casein); and 4) the induction of mammary epithelial cell programmed cell death following degradation of basement membrane. We hypothesize that this cooperative signaling between ECM and PRL may be achieved through integrin- and laminin-directed restructuring of the cytoskeleton leading to profound changes in nuclear architecture and transcription factor localization. We postulate that the latter changes allow the prolactin signal to activate transcription of the beta-casein gene. To further understand the molecular mechanisms underlying ECM and hormonal cooperative signaling, we are currently investigating ECM regulation of a "solid-state" signaling pathway including ECM fiber proteins, plasma membrane receptors, cytoskeleton, nuclear matrix and chromatin. We further postulate that disruption of such a pathway may be implicated in cell disorders including transformation and carcinogenesis.
Modulating Retinoid X Receptor with a Series of (E)-3-[4-Hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic Acids and Their 4-Alkoxy Isomers (2009)

Rexinoids are ligands for the retinoid X receptor (RXR) that have great promise for both the prevention and treatment of cancer and metabolic diseases. In this regard, synthetic, functional, and structural investigations into the structure-activity relationships of derivatives of the potent RXR agonist (E)-3-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-hydroxyphenyl]acrylic acid (CD3254, 9) have been conducted. We recently reported on the characterization of a series of C3'-substituted alkyl ether analogues of 9 (10a-f), which display activities ranging from partial agonists to pure antagonists. The importance of the position of the alkoxy side chain for ligand activity has been further explored with the synthesis of C4'-substituted analogues (11a-f). Here we describe the synthesis of compounds 11a-f, which appear functionally different from their isomeric counterparts, as judged from transactivation assays and fluorescence anisotropy experiments. We also report on the 2.0 A resolution structure of RXR in complex with the parent compound 9, which helps understanding of the impact of the alkyl side chain location on ligand activity.
An ATF2-derived peptide sensitizes melanomas to apoptosis and inhibits their growth and metastasis (2002)

MethodsCells.SW1 and B16F10 mouse melanoma cells were maintained in DMEM supplemented with 10% FBS, L-glutamine, and antibiotics.Constructs.ATF2 peptides were cloned in frame into a hemagglutinpenetratin (HA-penetratin) pcDNA3 vector (6).ATF2 peptide, corresponding to amino acids 50-100 of human ATF2, shares 100% homology with the murine sequence (corresponding amino acids in the mouse ATF2 cDNA are 33-82).Jun2luciferase (Jun2-luc) and TRE-luc constructs were previously described (8, 10).The ATF2 50-100 peptide was
Laser-to-fiber coupling scheme by utilizing a lensed fiber integrated with a long-period fiber grating (2000)

An optical coupling scheme between a laser diode and a single-mode fiber utilizing a lensed fiber integrated with a long-period fiber grating is experimentally demonstrated and qualitatively analyzed. A long working distance of 110 μm and a coupling of 35% are obtained for a laser diode with an ellipticity of 2.5. The longitudinal and transverse tolerances at 1-dB excess loss are 26 and 2.5 μm, respectively.
An Antigenic Peptide Produced by Peptide Splicing in the Proteasome (2004)

CD8 T lymphocytes recognize peptides of 8 to 10 amino acids presented by class I molecules of the major histocompatibility complex. Here, CD8 T lymphocytes were found to recognize a nonameric peptide on melanoma cells that comprises two noncontiguous segments of melanocytic glycoprotein gp100(PMEL17). The production of this peptide involves the excision of four amino acids and splicing of the fragments. This process was reproduced in vitro by incubating a precursor peptide of 13 amino acids with highly purified proteasomes. Splicing appears to occur by transpeptidation involving an acyl-enzyme intermediate. Our results reveal an unanticipated aspect of the proteasome function of producing antigenic peptides.
Establishment of a yeast platform strain for production of p-coumaric acid through metabolic engineering of aromatic amino acid biosynthesis (2015)

Aromatic amino acids are precursors of numerous plant secondary metabolites with diverse biological functions. Many of these secondary metabolites are already being used as active pharmaceutical or nutraceutical ingredients, and there are numerous exploratory studies of other compounds with promising applications. p-Coumaric acid is derived from aromatic amino acids and, besides being a valuable chemical building block, it serves as precursor for biosynthesis of many secondary metabolites, such as polyphenols, flavonoids, and some polyketides. Here we developed a p-coumaric acid-overproducing Saccharomyces cerevisiae platform strain. First, we reduced by-product formation by knocking out phenylpyruvate decarboxylase ARO10 and pyruvate decarboxylase PDC5. Second, different versions of feedback-resistant DAHP synthase and chorismate mutase were overexpressed. Finally, we identified shikimate kinase as another important flux-controlling step in the aromatic amino acid pathway by overexpressing enzymes from Escherichia coli, homologous to the pentafunctional enzyme Aro1p and to the bifunctional chorismate synthase-flavin reductase Aro2p. The highest titer of p-coumaric acid of 1.93 ± 0.26 g L(-1) was obtained, when overexpressing tyrosine ammonia-lyase TAL from Flavobacterium johnsoniaeu, DAHP synthase ARO4(K229L), chorismate mutase ARO7(G141S) and E. coli shikimate kinase II (aroL) in Δpdc5Δaro10 strain background. To our knowledge this is the highest reported titer of an aromatic compound produced by yeast. The developed S. cerevisiae strain represents an attractive platform host for production of p-coumaric-acid derived secondary metabolites, such as flavonoids, polyphenols, and polyketides.
Effect of Primer Selection on Estimates of GB Virus C (GBV-C) Prevalence and Response to Antiretroviral Therapy for Optimal Testing for GBV-C Viremia (2006)

GB virus C (GBV-C; also called hepatitis G virus) is a common cause of infection associated with prolonged survival among HIV-infected individuals. The prevalences of GBV-C viremia vary widely in different studies, and there has been poor agreement among different laboratories performing GBV-C RNA detection in quality control studies. To determine the optimal method of measuring GBV-C RNA in clinical samples, samples obtained from 939 HIV-infected subjects were studied using reverse transcription (RT)-PCR methods amplifying four separate regions of the GBV-C genome. Primers amplifying the E2 coding region were 100% specific; however, their sensitivity was only 76.6%. In contrast, primers amplifying three additional conserved regions of the GBV-C genome (the 5' nontranslated region and the nonstructural protein-coding regions 3 and 5A) were more sensitive but produced higher rates of false-positive results. Using low-specificity primer sets influenced the significance of association between GBV-C viremia and response to antiretroviral therapy. Using a quantitative GBV-C RNA method, the GBV-C RNA concentration did not correlate with baseline or set point HIV RNA levels; however, a correlation between negative, low, and high GBV-C RNA levels and increasing reduction in HIV RNA following antiretroviral therapy was observed. Subjects with both GBV-C E2 antibody and viremia had significantly lower GBV-C RNA levels than did viremic subjects without E2 antibody. These studies demonstrate that accurate detection of GBV-C RNA by nested RT-PCR requires the use of primers representing multiple genome regions. Analyses based on testing with single primers do not lead to reliable conclusions about the association between GBV-C infection and clinical outcomes.
CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET (2015)

Asthma is characterized by airway inflammation and remodeling and CXCL8 is a CXC chemokine that drives steroid-resistant neutrophilic airway inflammation. We have shown that airway smooth muscle (ASM) cells isolated from asthmatic individuals secrete more CXCL8 than cells from nonasthmatic individuals. Here we investigated chromatin modifications at the CXCL8 promoter in ASM cells from nonasthmatic and asthmatic donors to further understand how CXCL8 is dysregulated in asthma. ASM cells from asthmatic donors had increased histone H3 acetylation, specifically histone H3K18 acetylation, and increased binding of histone acetyltransferase p300 compared with nonasthmatic donors but no differences in CXCL8 DNA methylation. The acetylation reader proteins Brd3 and Brd4 were bound to the CXCL8 promoter and Brd inhibitors inhibited CXCL8 secretion from ASM cells by disrupting Brd4 and RNA polymerase II binding to the CXCL8 promoter. Our results show a novel dysregulation of CXCL8 transcriptional regulation in asthma characterized by a promoter complex that is abnormal in ASM cells isolated from asthmatic donors and can be modulated by Brd inhibitors. Brd inhibitors may provide a new therapeutic strategy for steroid-resistant inflammation.
Can NK cells be a therapeutic target in human diseases? (2008)

Our current knowledge of NK-cell recognition and effector function suggests that it will be possible to design various new NK-cell-based immunotherapies against human cancer. The application of NK cells is already showing promise using HLA-mismatched haematopoietic stem cell transplantation for treatment of haematological malignancies. A better understanding of NK-cell heterogeneity and function will only broaden the applications for human cancer. Here we review the key developments that will propel this field.
Learning to advertise (2006)

Content-targeted advertising, the task of automatically associating ads to a Web page, constitutes a key Web monetization strategy nowadays. Further, it introduces new challenging technical problems and raises interesting questions. For instance, how to design ranking functions able to satisfy conflicting goals such as selecting advertisements (ads) that are relevant to the users and suitable and profitable to the publishers and advertisers? In this paper we propose a new framework for associating ads with web pages based on Genetic Programming (GP). Our GP method aims at learning functions that select the most appropriate ads, given the contents of a Web page. These ranking functions are designed to optimize overall precision and minimize the number of misplacements. By using a real ad collection and web pages from a newspaper, we obtained a gain over a state-of-the-art baseline method of 61.7% in average precision. Further, by evolving individuals to provide good ranking estimations, GP was able to discover ranking functions that are very effective in placing ads in web pages while avoiding irrelevant ones.
Np95 is regulated by E1A during mitotic reactivation of terminally differentiated cells and is essential for S phase entry (2002)

Terminal differentiation exerts a remarkably tight control on cell proliferation. However, the oncogenic products of DNA tumor viruses, such as adenovirus E1A, can force postmitotic cells to proliferate, thus representing a powerful tool to study progression into S phase. In this study, we identified the gene encoding Np95, a murine nuclear phosphoprotein, as an early target of E1A-induced transcriptional events. In terminally differentiated (TD) cells, the activation of Np95 was specifically induced by E1A, but not by overexpression of E2F-1 or of the cyclin E (cycE)–cyclin-dependent kinase 2 (cdk2) complex. In addition, the concomitant expression of Np95 and of cycE–cdk2 was alone sufficient to induce S phase in TD cells. In NIH-3T3 cells, the expression of Np95 was tightly regulated during the cell cycle, and its functional ablation resulted in abrogation of DNA synthesis. Thus, expression of Np95 is essential for S phase entry. Previous evidence suggested that E1A, in addition to its well characterized effects on the pRb/E2F-1 pathway, activates a parallel and complementary pathway that is also required for the reentry in S phase of TD cells (Tiainen, M., D. Spitkousky, P. Jansen-Dürr, A. Sacchi, and M. Crescenzi. 1996. Mol. Cell. Biol. 16:5302–5312). From our results, Np95 appears to possess all the characteristics to represent the first molecular determinant identified in this pathway.
Observation of a disordered vortex state inBi2Sr2CaCu2O8+xsingle crystals containing columnar defects (1993)

We report on the visualization of vortex patterns by means of the high-resolution Bitter-decoration technique in ${\mathrm{Bi}}_{2}$${\mathrm{Sr}}_{2}$${\mathrm{CaCu}}_{2}$${\mathrm{O}}_{8+\mathit{x}}$ single crystals containing columnar defects generated via high-energy heavy-ion irradiation. By irradiating only a part of each sample, a simultaneous decoration of irradiated and nonirradiated parts was possible. The columnar defects lead to a complete destruction of translational order, whereas the vortex lattice in the nonirradiated parts exhibits hexagonal ordering. Analyses of the decoration images yield translational correlation lengths of 1.5 to 2 flux spacings in the nonirradiated areas and about 0.5 flux spacings in the irradiated areas.
Controlled In Vivo Swimming of a Swarm of Bacteria‐Like Microrobotic Flagella (2015)

In vivo imaging and actuation of a swarm of magnetic helical microswimmers by external magnetic fields (less than 10 mT) in deep tissue is demonstrated for the first time. This constitutes a major milestone in the field, yielding a generation of micrometer-scale transporters with numerous applications in biomedicine including synthetic biology, assisted fertilization, and drug/gene delivery.
High-speed digital-image correlation method (2009)

Provided that the software and hardware equipment in a digital-image correlation method is unchanged, the only major factor affecting integer-pixel correlation computation precision and the integer-pixel processing time is the size of the computing window. The bigger the size of the computing window is, the more reliable the computation result is. However, a bigger computing window means longer processing time. For reduction of the integer-pixel processing time without affecting the reliability of the result, a two-step correlation computation method (which uses a small window and a big window in the correlation computation) is proposed. The experiment results confirm the validity of the new method, and the total processing time of this method can be approximately reduced to a twentieth of that of the traditional method.
Continuous Cell Substrate Considerations (2018)

The debate over the potential risk of tumorigenicity attributable to the use of CCL substrates for biologicals production has continued for over 30 years and may continue for some time to come. Manufacturers and regulatory agencies are developing scientifically based guidelines for such products. It is currently possible to follow these guidelines to prepare recombinant biologicals and monoclonal antibodies in CCLs which do not pose unreasonable risks. This chapter has attempted to describe the scientific tools available to evaluate the putative risk of tumorigenicity due to potential virus DNA and protein contaminants. No theoretical or experimental basis exists to hypothesize that residual cellular protein might present a significant risk of tumorigenicity. The tools are certainly adequate for characterization of putative risks due to viruses and DNA but are not sufficiently powerful by themselves to assure product safety. The subsequent chapter on process validation describes how adequate assurances of safety ultimately can be obtained for products of CCLs against theoretical risks of tumorigenicity due to putative viruses and DNA. In addition to these safeguards, no evidence of tumorigenicity has been found in human or livestock animal recipients of the products prepared in CCL substrates. Many patients have received inoculations of tissue plasminogen activator, erythropoeitin, factor VIII, soluble CD4, GM-CSF, hepatitis B surface antigen vaccine, and various monoclonal antibodies and other recombinant products of continuous cell lines in clinical trials. For tissue plasminogen activator, large doses of 100 mg per patient or more have been used. At the time of writing over 10 kg of CHO-derived tissue plasminogen activator has been sold since late 1987 for administration to over 100,000 human patients. For recombinant factor VIII, erythropoeitin, and soluble CD4 proteins, chronic administration has been employed. Millions have received polio and rabies vaccines prepared in continuous Vero cells. In addition to this human experience, livestock animals have received annual inoculations of foot-and-mouth virus vaccine prepared in BHK-21 (a highly tumorigenic CCL) for up to 14 years without effect (69). No effects have been reported which might be attributed to oncogenic factors. Thus, scientific tools of characterization and principles of process validation are available to protect patients from putative risks of tumorigenicity associated with products prepared in CCLs. Increasing clinical experience also supports this conclusion.
One-Year Cardiovascular Event Rates in Outpatients With Atherothrombosis (2007)

In this large, contemporary, international study, outpatients with established atherosclerotic arterial disease, or at risk of atherothrombosis, experienced relatively high annual CV event rates. Multiple disease locations increased the 1-year risk of CV events.
Reflections on the "Republican Revival": Interdisciplinary Scholarship in the Legal Academy (1994)

In a recent article in the Journal of American History, Daniel Rodgers attempts to sketch out the "career" of republicanism as an organizing historiographical concept. Rodgers is principally interested in establishing republicanist historiography as a "paradigm," a status comparable to that conventionally assigned to two other significant twentieth-century historiographical concepts, which he labels "Beardian" and "Hartzian," and which many other scholars have characterized as "progressive" and "liberal," or "conflict"-focused and "consensus"-focused.\nAccording to Rodgers's historiographical chronology, the twentieth century has witnessed three conceptual paradigms: the "Beardian"/ "progressive" paradigm, dominant throughout the 1940s, which portrayed history as an unending series of conflicts among antagonistic "classes," "groups," and "interests"; the "Hartzian"/"liberal" paradigm, emphasizing the consensual values that defined America as a civilization and profoundly limited the course and pace of cultural change, predominating from the early 1950s through the late 1960s; and the "republican" paradigm, which Rodgers seeks to characterize in far greater detail, emerging in the late sixties and "perceptibly thinning out" by 1990.\nMy purpose here is not to critique Rodgers's historiographical synthesis, which I believe most historians would find useful and even illuminating. It is rather to explore, in more detail, a tiny episode in Rodgers's narrative. In that episode, as Rodgers describes it, "legal philosophers discovered the terminology" of the republican historiographical paradigm in the late 1980s.