gebhart/patrepeval huggingface dataset:
Biologic Basis of Sequential and Combination Therapies for Hormone-Responsive Breast Cancer (2006)

Although pharmacologic therapies that reduce or block estrogen signaling are effective treatments of estrogen receptor (ER)-positive breast cancer, acquired resistance to individual drugs can develop. Furthermore, this approach is ineffective as initial therapy for a subgroup of receptor-positive patients. The mechanisms of drug resistance are not completely understood, but the presence of alternative signaling pathways for activating ER response appears to play a significant role. Cross-talk between signaling pathways can activate ERs when conventional ER pathways are blocked or inactivated. For example, signaling via epidermal growth factor or HER-2 receptors, mitogen-activated protein kinases, phosphatidylinositol 3' kinase/protein kinase B, and vascular endothelial growth factor receptor can lead to estrogen-independent stimulation of ERs and tumor growth. The discovery that alternative pathways are involved in estrogen signaling has prompted development of newer endocrine therapies, such as aromatase inhibitors and pure estrogen antagonists, with distinct mechanisms for interrupting signal transduction. The existence of multiple pathways may explain the effectiveness of follow-up therapy with a different class of endocrine agents after failure of prior endocrine treatment. Because they do not have the partial agonist activity of tamoxifen that is enhanced by the adaptive hypersensitivity process, these alternative endocrine agents may play an increasingly important role in the treatment of ER-positive breast cancer. Although optimal sequencing of these agents has not been determined and is continuing to evolve, current evidence allows rational recommendations to be made. The multiple pathways involved in activating ERs also provide a rationale for combining endocrine and non-endocrine therapies that block different signaling pathways, which may have synergistic and overlapping interactions.
Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression (2009)

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North-South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts.
Markedly Enhanced Cytolysis by E1B-19kD -Deleted Oncolytic Adenovirus in Combination with Cisplatin (2006)

Oncolytic adenoviruses are currently being developed as novel antitumor therapeutics. To enhance their therapeutic potential, adenoviruses are being administered in combination with standard chemotherapy. Adenoviral vectors used in these clinical trials, however, can be destructive as they encode intact E1B 19-kDa protein, which can block the apoptotic pathway induced by a variety of chemotherapeutic agents. Previously, we have shown that oncolytic adenovirus Ad-DeltaE1B19/55, deleted for sequence encoding E1B 19-kDa and E1B 55-kDa proteins, exhibits marked enhancement in cytolytic and apoptotic activity [Kim, J., Cho, J.Y., Kim, J.H., Jung, K.C., and Yun, C.O. (2002). Cancer Gene Ther. 9, 725-736]. In the current study, we assess the therapeutic value of Ad- DeltaE1B55 and Ad-DeltaE1B19/55 in combination with cisplatin. A marked increase in cytotoxicity was observed for both Ad-DeltaE1B55 and Ad-DeltaE1B19/55 when combined with cisplatin. Relative to each other in all cell lines examined, the combination of the double-deleted adenovirus, Ad-DeltaE1B19/55, plus cisplatin exhibited a greater cell-killing effect than did the single-deleted adenovirus, Ad-DeltaE1B55, plus cisplatin. Propidium iodide staining and TUNEL analysis also revealed that the combination of cisplatin with Ad-DeltaE1B19/55 caused greater induction of apoptosis than that with Ad-DeltaE1B55. Similarly, in vivo, the combination of Ad-DeltaE1B55 or Ad-DeltaE1B19/55 with cisplatin also induced greater antitumor effect in a human cervical xenograft model. TUNEL staining showed that the apoptotic level was significantly higher in tumor tissue treated with Ad-DeltaE1B19/55 plus cisplatin than with any other treatment. In addition, viral presence was confirmed by immunohistological staining, with increased numbers of adenoviral particles detected in wider areas of tumors treated with Ad-DeltaE1B19/55 oncolytic adenovirus plus cisplatin. Taken together, these findings demonstrate that cisplatin in combination with E1B- 19kD-deleted oncolytic adenovirus may enhance therapeutic efficacy (via active induction of apoptosis), eliciting a greater efficacy profile than that with E1B-19kD-expressing oncolytic adenovirus.
Use of two‐dimensional gel electrophoresis proteome reference maps of dinoflagellates for species recognition of causative agents of harmful algal blooms (2004)

The sample preparation procedures established for Prorocentrum triestinum were adapted to cover both thecate and athecate dinoflagellates. Further, whether trichloroacetic acid (TCA) precipitation can be used to fix and preserve the harmful or nuisance species from local waters that they infest was tested. Optimized technical procedures developed were used to generate proteome reference maps for eight other local causative species of harmful algal blooms (HABs): Prorocentrum micans, Prorocentrum minimum, Prorocentrum sigmoides, Prorocentrum dentatum, Scrippsiella trochoidea, Karenia longicanalis, Karenia digitata and Karenia mikimotoi; together with one American species Karenia brevis (Florida, USA). These proteome maps were used to test their ability for species recognition in a mixed culture of dinoflagellates and whether such investigations will provide a comparative view at a global level. Comparisons of proteome profiles were made (i). between closely related species within the same family; (ii). between distantly related species belonging to different types, i.e., gymnodinioids, prorocentroids or peridinioids, or (iii). between different groups, i.e., thecate (armored) dinoflagellate cells against athecate (naked or unarmored) dinoflagellate cells. Species-specific two-dimensional electrophoresis (2-DE) protein profiles were observed in all ten species and it was possible to distinguish between even closely related species within the same family. To demonstrate the extent of reproducibility and usefulness of these 2-DE reference maps, 2-DE has been used to analyze three geographically distinct isolates of Prorocentrum dentatum, and to distinguish species composition in a mixed culture. Application of 2-D PAGE analysis to differentiate between taxonomically confused strains of a single species could be a powerful taxonomic tool.
Automatic Implantable Cardioverter‐Defibrillator Structural Characteristics (1984)

There are a number of equipment options and surgical techniques available for automatic implantable cardioverter-defibrillator implantation. The system can be successfully used even in problem cases where restrictions may be imposed because of physical build or the presence of other implanted devices. The sensing requirements and energy output of the units can be tailored to the exact needs of the particular patient. Battery life and device function are easily monitored periodically following implantation, making possible elective replacement of the pulse generator when the batteries become depleted.
Characterization and phylogenetic analysis of a novel hepatitis D virus strain discovered by restriction fragment length polymorphism analysis. (1998)

The hepatitis D virus (HDV) genotypes in 46 HDV-infected patients and 12 prostitutes were screened with Xhol restriction fragment length polymorphism (RFLP) analysis of reverse transcription PCR products of viral genomes and verified by phylogenetic analysis. The amplificates of three (6.5%) patients and two (17%) prostitutes showed a novel RFLP pattern different from those of the three known genotypes. Complete HDV genomic sequence identities between isolates with a novel RFLP and the HDV genotypes I, II and III were 72.3, 77.2 and 63.0%, respectively. Importantly, divergence was mostly seen in various regions related to replication or packaging. The novel isolates formed a monophyletic group (P < 0.05) and were most closely related to genotype II.
Staphylococcal alpha-toxin elicits hypertension in isolated rabbit lungs. Evidence for thromboxane formation and the role of extracellular calcium. (1984)

Staphylococcal alpha-toxin is known to damage mammalian cell membranes. Studies of erythrocytes indicate that the native toxin generates a discrete transmembrane channel with an effective diameter of 2-3 nm. (Füssle, R., S. Bhakdi, A. Szeigoleit, J. Tranum-Jensen, T. Kranz, and H.J. Wellensiek. 1981. J. Cell Biol. 91:83-94.) In isolated rabbit lungs, perfused with recirculating blood- and plasma-free perfusion fluid, the mediation of a toxin-provoked vascular pressor response by the triggering of the arachidonic acid cascade and its dependence on extracellular calcium were investigated. Dose-dependent pulmonary artery pressor responses were elicited by the injection of 0.5-5 micrograms staphylococcal alpha-toxin into the pulmonary artery. The pressor responses were completely abolished by preincubation of the toxin with neutralizing antibodies or by preformation of alpha-toxin hexamers in vitro. They were accompanied by the release of the arachidonic acid metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolites of thromboxane A2 and prostaglandin I2, respectively) into the perfusion fluid. They were blocked by inhibitors of thromboxane synthetase, cyclooxygenase, and phospholipase, as well as by substances that interfere with calcium-calmodulin function. alpha-Toxin induced selective release of potassium, but not lactatedehydrogenase into the medium. Calcium depletion of the intravascular space did not suppress the toxin-dependent potassium release but did abrogate the pressor response and the release of the arachidonic acid metabolites. When calcium was reintroduced into the circulation without the application of a second toxin stimulus, marked pressor responses paralleled by the release of arachidonic acid metabolites occurred. The conclusion drawn from these studies is that staphylococcal alpha-toxin provokes pulmonary vascular hypertension which is apparently mediated by thromboxane A2 formation, which surpasses the biological effect of the simultaneously formed prostaglandin I2. The triggering of the arachidonic acid cascade is strictly dependent on extracellular calcium and may be mediated by a nonphysiological calcium bypass through transmembrane toxin channels with subsequent stimulation of phospholipase activity.
Combined TLR and CD40 Triggering Induces Potent CD8+ T Cell Expansion with Variable Dependence on Type I IFN (2004)

Toll-like receptors are important in the activation of innate immunity, and CD40 is a molecule critical for many T and B cell responses. Whereas agonists for either pathway have been used as vaccine adjuvants, we show that a combination of Toll-like receptor (TLR)7 and CD40 agonists synergize to stimulate CD8+ T cell responses 10-20-fold greater than the use of either agonist alone. Antigen-specific CD8+ T cells elicited from combination CD40/TLR7 treatment demonstrated both lytic activities and interferon (IFN)gamma production and an enhanced secondary response to antigenic challenge. Agonists for TLRs 2/6, 3, 4, and 9 also synergized with CD40 stimulation, demonstrating that synergy with the CD40 pathway is a property of TLR-derived stimuli in general. The CD8+ T cell expansion induced by CD40/TLR7 triggering was independent of CD4+ T cells, IFNgamma, and IL-12 but dependent on B7-mediated costimulation and surprisingly on type I IFN. These studies provide the rational basis for the use of TLR and CD40 agonists together as essential adjuvants to optimize vaccines designed to elicit protective or therapeutic immunity.
A Short, Flexible Route toward 2‘-C-Branched Ribonucleosides (1997)

A five-step synthesis of 2‘-C-branched ribonucleosides from commercially obtained 1,3,5-tri-O-benzoyl-α-d-ribofuranose (4) is described. The free hydroxyl group of 4 was oxidized in high yield with Dess−Martin periodane reagent. The resultant 2-ketosugar was treated with MeMgBr/TiCl4, CH2CHMgBr/CeCl3, or TMSC⋮CLi/CeCl3, and in each case addition to the ketone proceeded stereoselectively to provide 2-alkylated ribofuranosides. After conversion to the corresponding tetrabenzoyl derivatives, the 2-alkylribofuranosides were coupled to nucleobases under Vorbrüggen persilylation conditions, giving the β-nucleosides with high stereoselectivity. Deprotection with methanolic ammonia provided the title compounds in 17−49% overall yields from 4.
Biological Nitrogen Fixation (1993)

The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved ...Read More
Binding of a hairpin polyamide in the minor groove of DNA: sequence-specific enthalpic discrimination. (1996)

Hairpin polyamides are synthetic ligands for sequence-specific recognition in the minor groove of double-helical DNA. A thermodynamic characterization of the DNA-binding properties exhibited by a six-ring hairpin polyamide, ImPyPy-gamma-PyPyPy-beta-Dp (where Im = imidazole, Py = pyrrole, gamma = gamma-aminobutyric acid, beta = beta-alanine, and Dp = dimethylaminopropylamide), reveals an approximately 1-2 kcal/mol greater affinity for the designated match site, 5'-TGTTA-3', relative to the single base pair mismatch sites, 5'-TGGTA-3' and 5'-TATTA-3'. The enthalpy and entropy data at 20 degrees C reveal this sequence specificity to be entirely enthalpic in origin. Correlations between the thermodynamic driving forces underlying the sequence specificity exhibited by ImPyPy-gamma-PyPyPy-beta-Dp and the structural properties of the heterodimeric complex of PyPyPy and ImPyPy bound to the minor groove of DNA provide insight into the molecular forces that govern the affinity and specificity of pyrrole-imidazole polyamides.
Hydrothermal preparation and optical properties of orientation-controlled WO3nanorod arrays on ITO substrates (2012)

The orientation controlled synthesis of h-WO3 nanostructures on ITO substrates has been successfully realized in large scale via a simple hydrothermal method. The influences of pH value and growth time on the orientation and morphology of WO3 nanostructures were investigated by scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). The nanorod bundles parallel to ITO substrate and nanorod arrays vertical to ITO substrate can be selectively prepared by adjusting the final pH value just to 2.0 and 2.4, respectively. The morphology evolution and the growth mechanism of well aligned WO3 nanorod arrays were intensively studied. Moreover, the optical properties of the WO3 with different oriented alignment were also examined.
Isolation and structure determination of diazonamides A and B, unusual cytotoxic metabolites from the marine ascidian Diazona chinensis (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIsolation and structure determination of diazonamides A and B, unusual cytotoxic metabolites from the marine ascidian Diazona chinensisNiels Lindquist, William Fenical, Gregory D. Van Duyne, and Jon ClardyCite this: J. Am. Chem. Soc. 1991, 113, 6, 2303–2304Publication Date (Print):March 1, 1991Publication History Published online1 May 2002Published inissue 1 March 1991https://pubs.acs.org/doi/10.1021/ja00006a060https://doi.org/10.1021/ja00006a060research-articleACS PublicationsRequest reuse permissionsArticle Views1456Altmetric-Citations312LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Distribution and lateral mobility of GABA/benzodiazepine receptors on nerve cells (1989)

The distribution and mobility of GABA/benzodiazepine receptors has been examined on living nerve cells by fluorescence digital imaging and fluorescence photobleach recovery with 2 novel fluorescent derivatives of the benzodiazepines Ro7-1986 and 1012S. These fluorescent derivatives retain their high affinity for the GABA/benzodiazepine receptor complex with Ks of 79 and 85 nM, respectively. Digital fluorescence imaging of GABA/benzodiazepine receptors on rat spinal cord neurons maintained in culture reveal that, even in the absence of observable synaptic contact, GABA/benzodiazepine receptors are localized on the cell body in clusters of very high density. Receptor density on processes is lower than on cell bodies, although occasional areas of intense fluorescence were observed. Fluorescence photobleach recovery measurements show that 70% of the GABA/benzodiazepine receptors on the cell body and greater than 85% on the processes of rat spinal cord neurons are immobile. In comparison, voltage-gated sodium channels are diffusely distributed and very mobile on the cell body (D = 10(-9) cm2/sec). The results suggest that even in the absence of nerve-nerve cell contact, there are specific mechanisms that segregate GABA/benzodiazepine receptors to the neuronal cell body and control their lateral mobility.
Adenine nucleotide and lysine transport in Chlamydia psittaci (1982)

Isolated reticulate bodies of Chlamydia psittaci were found to transport ATP and ADP by an ATP-ADP exchange mechanism. ATP uptake activity was not detected in elementary bodies. The apparent Km of transport for both ATP and ADP was approximately 5 microM, and the calculated Vmax for both was about 1 nmol of nucleotide transported per min per mg of protein. ADP competitively inhibited ATP transport with a Ki of 4.5 microM. Other nucleotides tested had no effect on the uptake of ATP. A magnesium-dependent, oligomycin-sensitive ATPase (ATP phosphohydrolase, EC 3.6.1.3) was associated with reticulate bodies, and most of the transported ATP was hydrolyzed to ADP, which was exchanged for additional, extracellular nucleotide. Some ADP was hydrolyzed to AMP, which exited the cells slowly. Lysine was transported against the electrochemical gradient by reticulate bodies in the presence of ATP. Oligomycin and carbonyl cyanide p-trifluoromethoxyphenylhydrazone inhibited ATP-dependent lysine transport. Lysine exited reticulate bodies when the reticulate bodies were incubated in the presence of ADP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, or a reduced concentration of ATP. The results support the concept that chlamydiae are energy parasites which are capable of drawing upon the adenine nucleotides of their hosts, hydrolyzing ATP, and establishing an energized membrane.
Effects of intramyocardial injection of platelet-rich plasma on the healing process after myocardial infarction (2008)

Injection of thrombin-activated PRP could modulate favorably the postinfarction remodeling process. Platelet-released VEGF may participate in this protective effect.
The sources of external work in level walking and running. (1976)

The work done at each step during level walking and running to lift the centre of mass of the body, Wv, and to increase its forward speed, Wf, and the total mechanical energy involved (potential + kinetic) Wext, have been measured at various 'constant' speeds (2-32 km/hr) with the technique described by Cavagna (1975). 2. At intermediate speeds of walking (about 4 km/hr) Wv = Wf and Wext/km is at a minimum, as is the energy cost. At lower speeds Wv greater than Wf whereas at higher speeds Wf greather than Wv: in both cases Wext/km increases. 3. The recovery of mechanical energy, through the pendular motion characteristic of walking, was measured as (/Wv/ + /Wf/ - Wext)/(/Wv/ + /Wf/): it attains a maximum (about 65%) at intermediate speeds. 4. A simple model, assuming that in walking the body rotates as an inverted pendulum over the foot in contact with the ground, fits the experimental data better at intermediate speeds but is no longer tenable above 7 km/hr. 5. In running the recovery defined above is minimal (0-4% independent of speed), i.e. Wext congruent to /Wv/ + /Wf/: potential and kinetic energy of the body do not interchange but are simultaneously taken up and released by the muscles with a rate increasing markedly with the speed (from about 1 to 4 h.p.). 6. Wext increases linearly with the running speed Vf from a positive y intercept owing to the fact that Wv is practically constant independent of Vf. On the contrary, Wf = aVf2/(1 + bVf), where b is the ratio between the time spent in the air and the forward distance covered while on the ground during each step.
Structural and enzymic properties of adenine 1-oxide nucleotides (1975)

We decribed the preparation of adenine 1-oxide nucleotides by oxidation of the natural compounds with monopermaleic acid in aqueous solutions at neutral pH, with an overall yield after chromatographic purification between 75 and 80%. If irradiated, the adenine 1-oxide nucleotides undergo a photochemical rearrangement reaction, the main photoproducts in aqueous solution at alkaline pH being the corresponding isoguanine nucleotides. The modified ring vibration pattern of the 1-oxide analogues as well as the 13C chemical shift indicate a loss of aromaticity as compared to the natural compounds. Coupling constant measurements show that the dihedral angle between the 31POC and OC13C planes is around 180degree, i.e., trans, as in the natural adenine nucleotides. The modified adenine nucleotides were tested as potential substrates and/or inhibitors of mitochondrial processes, as substrates of varous phosphotransferases from mitochondria or cytosol, and as allosteric effectors in the reactions catalyzed by glutamate dehydrogenase and phosphofructokinase. Although the adenine 1-oxide nucleotides are not recognized by the translocase system of the inner mitochondrial membrane, they are good substrates for mitochondrial phosphotransferases located in the intermembrane space. Similarly, they participate in the phosphoryl group transfer reactions catalyzed by pyruvate kinase, phosphofructokinase, and hexokinase. As allosteric effectors, the modified nucleotides are less active than the natural compounds, probably because of a lower binding capacity to the allosteric sites of the regulatory enzymes.