gebhart/patrepeval huggingface dataset:
Epithelial-Mesenchymal Plasticity of Breast Cancer Stem Cells: Implications for Metastasis and Therapeutic Resistance (2015)

Over the past several decades the traditional view of cancer being a homogeneous mass of rapid proliferating malignant cells is being replaced by a model of ever increasing complexity, which points out that cancers are complex tissues composed of multiple cell types. A large variety of immune and other host cells constitute the tumor microenvironment, which supports the growth and progression of the tumor where individual cancer cells evolve with increasing phenotypic and genetic heterogeneity. Furthermore, it has also become clear that, in addition to this cellular and genetic heterogeneity, most tumors exhibit a hierarchical organization composed of tumor cells displaying divergent lineage markers and at the apex of this hierarchy are cells capable of self-renewal. These "cancer stem cells" not only drive tumor growth, but also mediate metastasis and contribute to treatment resistance. Besides displaying remarkable genetic and phenotypic heterogeneity, cancer stem cells maintain plasticity to transition between mesenchymal-like (EMT) and epithelial-like (MET) states in a process regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in the process of tumor metastasis. In this review, we will discuss emerging knowledge regarding the plasticity of cancer stem cells and the role that this plasticity plays in tumor metastasis. We also discuss the implications of these findings for the development of cancer stem cell targeted therapeutics.
Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)→Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT3 (2008)

The C-28 methyl ester of the oleane triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) induces apoptosis of human cancer cells by disrupting redox balance and is in clinical trials. CDDO-Me contains alpha,beta-unsaturated carbonyl groups that form reversible adducts with thiol nucleophiles. The present studies show that CDDO-Me blocks interleukin-6 (IL-6)-induced and constitutive activation of the Janus-activated kinase 1 (JAK1) in cells. In support of a direct mechanism, CDDO-Me forms adducts with JAK1 at Cys(1077) in the kinase domain and inhibits JAK1 activity. In concert with these results, CDDO-Me blocked IL-6-induced and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Moreover, we show that CDDO-Me (a) binds directly to STAT3 by a mechanism dependent on the alkylation of Cys(259) and (b) inhibits the formation of STAT3 dimers. These findings indicate that CDDO-Me inhibits activation of the JAK1-->STAT3 pathway by forming adducts with both JAK1 and STAT3.
Characterization of Nonpathogenic, Live, Viral Vaccine Vectors Inducing Potent Cellular Immune Responses (2004)

Experimental vaccines based on recombinant vesicular stomatitis viruses (VSV) expressing foreign viral proteins are protective in several animal disease models. Although these attenuated viruses are nonpathogenic in nonhuman primates when given by nasal, oral, or intramuscular routes, they are pathogenic in mice when given intranasally, and further vector attenuation may be required before human trials with VSV-based vectors can begin. Mutations truncating the VSV glycoprotein (G) cytoplasmic domain from 29 to 9 or 1 amino acid (designated CT9 or CT1, respectively) were shown previously to attenuate VSV growth in cell culture and pathogenesis in mice. Here we show that VSV recombinants carrying either the CT1 or CT9 deletion and expressing the human immunodeficiency virus (HIV) Env protein are nonpathogenic in mice, even when given by the intranasal route. We then carried out a detailed analysis of the CD8+ T-cell responses, including in vivo cytotoxic T-cell activity, induced by these vectors. When given by either the intranasal or intraperitoneal route, the VSV-CT9 vector expressing HIV Env elicited primary and memory CD8+ T-cell responses to Env equivalent to those elicited by recombinant wild-type VSV expressing Env. The VSV-CT1 vector also induced potent CD8+ T-cell responses after intraperitoneal vaccination, but was less effective when given by the intranasal route. The VSV-CT1 vector was also substantially less effective than the VSV-CT9 or wild-type vector at inducing antibody to Env. The VSV-CT9 vector appears ideal because of its lack of pathogenesis, propagation to high titers in vitro, and stimulation of strong cellular and humoral immune responses.
Compact Biocompatible Quantum Dots Functionalized for Cellular Imaging (2008)

We present a family of water-soluble quantum dots (QDs) that exhibit low nonspecific binding to cells, small hydrodynamic diameter, tunable surface charge, high quantum yield, and good solution stability across a wide pH range. These QDs are amenable to covalent modification via simple carbodiimide coupling chemistry, which is achieved by functionalizing the surface of QDs with a new class of heterobifunctional ligands incorporating dihydrolipoic acid, a short poly(ethylene glycol) (PEG) spacer, and an amine or carboxylate terminus. The covalent attachment of molecules is demonstrated by appending a rhodamine dye to form a QD-dye conjugate exhibiting fluorescence resonance energy transfer (FRET). High-affinity labeling is demonstrated by covalent attachment of streptavidin, thus enabling the tracking of biotinylated epidermal growth factor (EGF) bound to EGF receptor on live cells. In addition, QDs solubilized with the heterobifunctional ligands retain their metal-affinity driven conjugation chemistry with polyhistidine-tagged proteins. This dual functionality is demonstrated by simultaneous covalent attachment of a rhodamine FRET acceptor and binding of polyhistidine-tagged streptavidin on the same nanocrystal to create a targeted QD, which exhibits dual-wavelength emission. Such emission properties could serve as the basis for ratiometric sensing of the cellular receptor's local chemical environment.
Cystatins (2003)

Chicken egg white cystatin was first described in the late 1960s. Since then, our knowledge about a superfamily of similar proteins present in mammals, birds, fish, insects, plants and some protozoa has expanded, and their properties as potent peptidase inhibitors have been firmly established. Today, 12 functional chicken cystatin relatives are known in humans, but a few evolutionarily related gene products still remain to be characterized. The type 1 cystatins (A and B) are mainly intracellular, the type 2 cystatins (C, D, E/M, F, G, S, SN and SA) are extracellular, and the type 3 cystatins (L- and H-kininogens) are intravascular proteins. All true cystatins inhibit cysteine peptidases of the papain (C1) family, and some also inhibit legumain (C13) family enzymes. These peptidases play key roles in physiological processes, such as intracellular protein degradation (cathepsins B, H and L), are pivotal in the remodelling of bone (cathepsin K), and may be important in the control of antigen presentation (cathepsin S, mammalian legumain). Moreover, the activities of such peptidases are increased in pathophysiological conditions, such as cancer metastasis and inflammation. Additionally, such peptidases are essential for several pathogenic parasites and bacteria. Thus cystatins not only have capacity to regulate normal body processes and perhaps cause disease when down-regulated, but may also participate in the defence against microbial infections. In this chapter, we have aimed to summarize our present knowledge about the human cystatins.
The conformation of neurotensin bound to its G protein-coupled receptor (2003)

G protein-coupled receptors (GPCRs) mediate the perception of smell, light, taste, and pain. They are involved in signal recognition and cell communication and are some of the most important targets for drug development. Because currently no direct structural information on high-affinity ligands bound to GPCRs is available, rational drug design is limited to computational prediction combined with mutagenesis experiments. Here, we present the conformation of a high-affinity peptide agonist (neurotensin, NT) bound to its GPCR NTS-1, determined by direct structural methods. Functional receptors were expressed in Escherichia coli, purified in milligram amounts by using optimized procedures, and subsequently reconstituted into lipid vesicles. Solid-state NMR experiments were tailored to allow for the unequivocal detection of microgram quantities of 13C,15N-labeled NT(8-13) in complex with functional NTS-1. The NMR data are consistent with a disordered state of the ligand in the absence of receptor. Upon receptor binding, the peptide undergoes a linear rearrangement, adopting a beta-strand conformation. Our results provide a viable structural template for further pharmacological investigations.
Run-length Distributions of Recursive Median Filters using Probabilistic Automata (1999)

In this paper we develop statistical models for the description of the Recursive Median (RM) filters, and for the one dimensional RM sieve, implemented as a cascade of RM filters of increasing window lengths. We are seeking analytical confirmation for the observation that the RM filter is in itself not a useful estimator of location, and should not be used in data smoothing. As the cascading element in the structure of the sieve, however, the RM filter is very efficient. Models based on finite automata, and assumptions of binary random input, allow us to predict the run length distributions of the outputs of both systems, and derive exact arguments on their statistical behaviour. 1 Introduction Median-type filters are well suited for image processing, where their non-linear effects are useful. The standard median filter, for example, removes impulsive noise and preserves sharp edges. Many median-type filters, e.g. weighted median and order statistic filters, can be thought of as speci...
Constitutive Expression of Functional 4-1BB (CD137) Ligand on Carcinoma Cells (2000)

Members of the TNF superfamily, including Fas, Fas ligand, and CD40, have been shown to be expressed on tumor cells. In the studies described in this work, we report that another family member, the ligand for 4-1BB (CD137), is expressed on various human carcinoma cell lines, on cells of solid tumors derived from these cell lines, and cells obtained from human tumors. Expression of 4-1BB ligand (4-1BBL) mRNA was detected by both RT-PCR and Northern blot analysis, and expression of 4-1BBL protein was detected by Western blot analysis of whole cell lysates and by FACS analysis of tumor cells and cell lines. Incubation of tumor cells with a 4-1BB-Ig fusion protein led to the production of IL-8 by the cells, demonstrating that the 4-1BBL is functionally active and signals back into the tumor cells. Furthermore, 4-1BBL expressed on the carcinoma cells functioned as a costimulatory molecule for the production of cytokines (most notably IFN-gamma) in cocultures of T cells and tumor cells. These findings suggest that 4-1BBL expressed on carcinoma cells may significantly influence the outcome of a T cell-tumor cell interaction.
Angiotensin-(1-7): a novel vasodilator of the coronary circulation. (1998)

Angiotensin-(1-7) [Ang-(1-7)] possesses novel biological functions that are distinct from angiotensin II (Ang II). In coronary arteries, the octapeptide Ang II and the heptapeptide Ang-(1-7) exert opposing actions. Ang II elicits vasoconstriction and Ang-(1-7) is a vasodilator. Ang-(1-7) elicits vasodilation by an endothelium-dependent release of nitric oxide. Further, the vasorelaxant activity is markedly attenuated by the bradykinin (BK) B2 receptor antagonist icatibant and does not appear to be associated with the synthesis and release of prostaglandins. Ang-(1-7) vasodilation is mediated by a non-AT1/AT2 receptor, since [Sar1Thr8]-Ang II, but neither candesartan, an AT1 receptor antagonist, nor PD123319, an AT2 receptor antagonist, blocked the response. Specific and high affinity binding of 125I-Ang-(1-7) to the endothelial layer of canine coronary arteries was demonstrated using in vitro emulsion autoradiography. Binding was effectively competed for by either unlabeled Ang-(1-7) or the specific Ang-(1-7) antagonist [D-Ala7]-Ang-(1-7). Additionally, Ang-(1-7) potentiated synergistically BK-induced vasodilation. The EC50 of BK vasodilation (2.45 +/- 0.51 nmol/L vs 0.37 +/- 0.08 nmol/L) was shifted 6.6-fold left-ward in the presence of 2 mumol/L concentration of Ang-(1-7). The potentiated response was specific for BK, since Ang-(1-7) did not augment the vasodilation produced by either acetylcholine or sodium nitroprusside; further, it was specific for Ang-(1-7), since neither Ang I nor Ang II augmented the BK response. In contrast to the vasodilator actions of Ang-(1-7), the potentiated response was not blocked by candesartan, PD123319 or [Sar1Thr8]-Ang II. Novel studies from our group demonstrate that Ang-(1-7) is both a substrate and inhibitor for angiotensin converting enzyme (ACE). Ang-(1-7) was shown to retard the degradation of 125I-[Tyr0]-BK in coronary rings. These studies describe novel actions of Ang-(1-7) as a vasodilator and a local synergistic modulator of kinin-induced vasodilation in coronary arteries.
A DNS Filter and Switch for Packet-filtering Gateways (1996)

IP-transparent firewalls require access to the external Domain Name System (DNS) from protected internal hosts. Misconfigurations and misuse of this system can create internal administrative and security problems.

Dnsproxy provides access to and protection from untrusted DNS services. It runs on a firewall, or on a trusted host just inside the firewall. The program receives (or intercepts) DNS queries and forwards them to an appropriate internal or external realm for processing. The responses can be checked, filtered, and modified before they are returned to the requester. The logging and consistency checks can provide information about possible DNS attacks and irregularities that are not available from most DNS implementations.
PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1: STUDIES ON STRUCTURE AND REGULATION (1987)

Human plasminogen activator inhibitor type-1 is an Mr∼54,000 protein which specifically inhibits urokinase-type (u-PA) and tissue-type (t-PA) plasminogen activators. During inhibition, u-PA and t-PA convert PAI-1 to an inactive form with Mr∼50,000. We have determined the amino-terminal amino acid sequence of native and converted PAI-1, and isolated and partly sequenced PAI-1 cDNA. The data show that the conversion of PAI-1 consists of cleavage of an Arg-Met bond 33 residues from the carboxy-terminus, thus localizing the reactive center of the inhibitor to that position, and identifying PAI-1 as an "arg-serpin". PAI-1 activity is known to be influenced by a number of agents; we have studied the mechanisms of the stimulation of PAI-1 activity by transforming growth factor-β (TGF-β) and the synthetic glucocorticoid dexame-thasone in human WI-38 lung fibroblasts and HT-1080 fibrosarcoma cells. Bytheuse of PAI-1 cDNA, TGF-β was found to course a rapid increase in PAI-1 mRNA level in WI-38 cells, reaching a maximal 50-fold enhancement after 8 hours. Dexamethasone caused a 10-fold increase in PAI-1 mRNA in HT-1080 cells, which was detectable after 4 hours and became maximal after 16 hours. In both cases, the 3.4 as well as the 2.4 Kb-PAI-1-mRNA species were increased. Quantitative studies on the effect of these agents on PAI-1 protein levels in cell extracts and culture media by ELISA gave results consistent with the effects on PAI-1 mRNA. These studies suggest that TGF-β and glucocorticoids may exert important controls over plasminogen activation-mediated extracellular proteolysis through an enhancement of PAI-1 gene transcription.
In vitro investigations of drug release and penetration--enhancing effect of ultrasound on transmembrane transport of flufenamic acid. (1998)

Although topical drugs are usually applied at a convenient site, the target for the drug interaction may be systemic. Phonophoresis is the use of ultrasound to enhance the delivery of topical applied drugs. The purposes of our study were to investigate the in vitro penetration and the in vivo transport of flufenamic acid in dependence of ultrasound. Percutaneous absorption studies are performed in various in vitro models to determine the rate of drug absorption via the skin. We designed a phonophoretic drug delivery system to investigate the influence of ultrasound on transmembrane transport of different drugs. We investigated the absorption of flufenamic acid in a buffer medium in dependence of ultrasound energy and application time. For evaluating membrane penetration of flufenamic acid, the concentration range of buffer solution was measured. Ultrasound energy was supplied for between 5 and 30 min at a range of intensities up to 1.5 W/cm2, energy levels commonly used for therapeutic purpose. The pronounced effect of ultrasound on the transmembrane absorption of the drug was observed at all ultrasound energy levels studied. The time of application was found to play an important role in delivery and transport of drug. Dependent on time, we observed a rise of temperature up to 4.5 degrees C. It appears that there was no difference between an intensity of 0.3 and 1.5 W/cm2 and the measured drug concentrations in solution. The highest penetration was observed at an intensity of 1.0 W/cm2 after 30 min. These results were not significantly different from concentration measurements after 30 min and 0.5 and 1.5 W/cm2. It seems that the arise of drug concentration is caused by effects of temperature and by variation of membrane delivery in dependence of temperature. Using this in vitro model we note it is possible to compare the transdermal penetration and absorption of commercial flufenamic ointment in volunteers.
Lethal photosensitization of periodontal pathogens by a red‐filtered Xenon lamp in vitro (2003)

The data indicate that PDT utilizing a conventional light source is at least as effective as laser-induced treatment in vitro. Furthermore, PDT achieves significant bactericidal activity in the presence of serum and blood when used with the set parameters of 10 J/cm2, 100 mW/cm2 and 12.5 micro g/ml TBO.
Migraine and Hypertension (1999)

Association between mild to moderate hypertension and headache is probably coincidental. Severe sustained hypertension, malignant hypertension and paroxysmal hypertension (sudden rise) are associated with severe headache. Transient hypertension can occur during an attack of migraine or cluster headache. Hypertension may increase the frequency and severity of migraine in migraineurs and may transform an episodic migraine into chronic daily headache. Concomitant treatment of hypertension is important in these patients.
Biochemical characterization of the 2-ketoacid reductases encoded by ycdW and yiaE genes in Escherichia coli (2001)

Glyoxylate is an important intermediate of the central microbial metabolism formed from acetate, allantoin or glycolate. Depending on the physiological conditions, glyoxylate is incorporated into the central metabolism by the combined actions of the activity of malate synthase and the D-glycerate pathway, or alternatively it can be reduced to glycolate by constitutive glyoxylate reductase activity. At present no information is available on this latter enzyme in Escherichia coli, although similar enzymes, classified as 2-hydroxyacid dehydrogenases, have been characterized in other organisms. A BLAST search using as the query sequence the hydroxypyruvate/glyoxylate reductase from Cucumis sativus identified as an orthologue the yiaE gene of E. coli encoding a ketoaldonate reductase. Use of this sequence in a subsequent BLAST search yielded the ycdW gene as a good candidate to encode glyoxylate reductase in this bacterium. Cloning and overexpression of the ycdW gene showed that its product displayed a high NADPH-linked glyoxylate reductase activity, and also catalysed the reduction of hydroxypyruvate with a lower efficiency. Disruption of the ycdW gene by a chloramphenicol acetyltransferase ('CAT') cassette did not totally abolish the glyoxylate reductase activity, indicating that another enzyme accomplished this function. The similarity with YiaE led us to test whether this protein was responsible for the remaining glyoxylate reductase activity. Purification of YcdW and YiaE proteins permitted their kinetic characterization and comparison. Analysis of the catalytic power (k(cat)/K(m)) disclosed a higher ratio of YcdW for glyoxylate and of YiaE for hydroxypyruvate.
Precursor cell types in the germinal zone of the cerebral cortex (1995)

Retroviral lineage tracing experiments suggest that the cortical ventricular zone is composed of a mixture of precursor cell types. The majority generate a single cell type (neurones, astrocytes or oligodendrocytes) and the remainder generate neurones and a single type of glial cell. Pluripotential precursor cells, that have the ability to generate all three cell types, are not observed. A recent paper, however, reports that when single ventricular zone cells are cultured in isolation, a small percentage of these cells are pluripotential. This review will discuss what this knowledge tells us about cortical development.
Prevalence and Significance of HER-2/neuAmplification in Epithelial Ovarian Cancer (1995)

Amplification of the HER-2/neu oncogene was assessed in 80 cases of epithelial ovarian tumors using differential polymerase chain reaction. HER-2/neu gene was amplified in 22 of 46 invasive cancers (48%) and in 5 of 34 borderline cancers (15%), but none of the 20 specimens of normal ovaries showed amplification. THis difference is statistically significant (p = 0.00004). The incidence of HER-2/neu amplification in late stage (III-IV, 77%) was significantly higher than that in early stage (I-II, 21%) in invasive epithelial carcinoma (p = 0.0004). There was no correlation between HER-2/neu amplification and cell type or grade of tumor. In cases of ovarian tumors of borderline malignant potential, the amplification of HER-2/neu was not correlated with clinicopathologic features. Follow-up with a mean of 22 months (6-50 months) was available for 39 cases of invasive ovarian cancers and all 34 borderline ovarian cancers. The incidence of HER-2/neu amplification in the invasive cancer and borderline cancer patients who were alive with disease was 50 and 50%, and is not statistically different from that in the patients who were alive with no evidence of disease (p = 0.662 and 0.345, respectively). The incidence of amplification in the invasive cancers of patients who died of the disease (86%) was higher than that in the patients who were still alive (44%), but the difference is not statistically significant (p = 0.175). This study supports the association of HER-2/neu amplification with progression of invasive ovarian cancer. It also suggests that HER-2/neu amplification may be an adjunctive prognostic factor of invasive epithelial ovarian cancer, shown to be associated with an unfavorable clinical course. In addition, HER-2/neu amplification occurs relatively infrequently in early invasive and borderline ovarian cancers, making it unlikely that such amplification is a general early event in ovarian carcinogenesis.