gebhart/patrepeval huggingface dataset:
CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC) (2008)

LBA4504 Background: Prognosis of patients (pts) with PC is dismal, even after curatively intended resection. Whereas gemcitabine-based chemotherapy is standard in advanced PC, the role of adjuvant chemotherapy is still under discussion. Methods: CONKO-001, a prospective, open, multicenter, controlled phase 3 study was designed to evaluate the efficacy and toxicity of gemcitabine in PC pts after complete (R0 or R1) resection. After stratification for R0/R1, nodal tumour involvement and tumour stage pts were randomized to receive either gemcitabine (G) (1g/m2 d 1, 8 and 15 every 4 weeks) for 6 months or observation (O). Pts in the observation group received no specific anticancer treatment. Primary study endpoint was disease free survival (DFS), secondary endpoints included OS and toxicity. The study was powered to detect a significant difference in DFS with 90% probability at a significance level of .05 on all eligible patients. Results: Between July 1998 and December 2004 368 pts were randomized and 354 were eligible for intent-to-treat-analysis. As previously discribed in JAMA 2007 first results showed that postoperative G is well tolerated and significantly delays the development of recurrent disease after complete resection of PC. By December 1st 2007 303 events (85.6%) have occurred for DFS and 293 events (82.8%) for OS. The analyses confirm the significant improvement for G in median DFS [G:13.4 months (m), O: 6.9m, p< .001]. Estimated DFS at 3 and 5 years was 23.5% and 16.0% in the G group vs. 8.5% and 6.5% in the O group, respectively. Subgroup analyses demonstrate significant increased DFS for G in all subgroups of stratification. G significantly improves median OS [G:22.8m, O: 20.2m, p=.005]. Estimated survival at 3 and 5 years was 36.5% and 21.0% for G pts vs. 19.5% and 9.0% for O pts, respectively. Conclusion: Treatment with G for 6 months for pts after complete resection of PC significantly increases DFS and OS compared with O alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Bayer, Lilly Oncology, Merck, Novartis, Pfizer, Roche, sanofi-aventis
Polarity of immunogens: implications for vaccine design (1990)

Peptide constructs have been engineered consisting of amino acid sequence determinant recognized by T cells (TD) co-linearly linked to haptenic peptides. It was found that high anti-hapten antibody titers were induced after immunization with those constructs which had the TD sequence in the N-terminal position with respect to the hapten. Low or zero titers were elicited when the TD was in C-terminal position. Also, a high anti-hapten antibody titer corresponded to a low or zero anti-TD antibody titer and vice versa. These results suggest that immunogens are polar and stress the relevance of searching the more adequate position of the TD within a peptide construct when designing immunogens or synthetic peptide vaccines.
Molecular Basis for the Inactivation of Ca2+- and Voltage-Dependent BK Channels in Adrenal Chromaffin Cells and Rat Insulinoma Tumor Cells (1999)

Large-conductance Ca2+- and voltage-dependent potassium (BK) channels exhibit functional diversity not explained by known splice variants of the single Slo alpha-subunit. Here we describe an accessory subunit (beta3) with homology to other beta-subunits of BK channels that confers inactivation when it is coexpressed with Slo. Message encoding the beta3 subunit is found in rat insulinoma tumor (RINm5f) cells and adrenal chromaffin cells, both of which express inactivating BK channels. Channels resulting from coexpression of Slo alpha and beta3 subunits exhibit properties characteristic of native inactivating BK channels. Inactivation involves multiple cytosolic, trypsin-sensitive domains. The time constant of inactivation reaches a limiting value approximately 25-30 msec at Ca2+ of 10 microM and positive activation potentials. Unlike Shaker N-terminal inactivation, but like native inactivating BK channels, a cytosolic channel blocker does not compete with the native inactivation process. Finally, the beta3 subunit confers a reduced sensitivity to charybdotoxin, as seen with native inactivating BK channels. Inactivation arises from the N terminal of the beta3 subunit. Removal of the beta3 N terminal (33 amino acids) abolishes inactivation, whereas the addition of the beta3 N terminal onto the beta1 subunit confers inactivation. The beta3 subunit shares with the beta1 subunit an ability to shift the range of voltages over which channels are activated at a given Ca2+. Thus, the beta-subunit family of BK channels regulates a number of critical aspects of BK channel phenotype, including inactivation and apparent Ca2+ sensitivity.
Low Power and High Speed Switching of Ti-doped NiO ReRAM under the Unipolar Voltage Source of less than 3 V (2007)

This paper reports on low-power and high-speed resistive switching of a Ti-doped NiO memory, which is based on the switching mechanism of the redox reactions in a filamentary conductive path. A small reset current of less than 100 muA was achieved by controlling the gate voltage of a cell transistor, which acts as an excellent current limiter in the set operation. A fast reset time of less than 5 ns was achieved by doping the Ti into the NiO film. Ti is thought to be effective to not only stabilize the reset process by forming an oxygen reservoir, but also to suppress the abnormal set phenomenon during the reset operation due to the formation of strong Ti-O bonds. Moreover, stable pulse switching with a large resistance change ratio has been successfully demonstrated using a unipolar voltage source of less than 3 V.
The effective bioengineering method of implantation decellularized renal extracellular matrix scaffolds (2015)

End stage renal disease (ESRD) is a progressive loss of kidney function with a high rate of morbidity and mortality. Transplantable organs are hard to come by and hold a high risk of recipient immune rejection. We intended to establish a more effective and faster method to decellularize and recellularize the kidney scaffold for transplant and regeneration. We successfully produced renal scaffolds by decellularizing rat kidneys with 0.5% sodium dodecyl sulfate (SDS), while still preserving the extracellular matrix (ECM) 3D architecture, an intact vascular tree and biochemical components. We recellularized the kidney scaffolds with mouse embryonic stem (ES) cells that then populated and proliferated within the glomerular, vascular, and tubular structures. After in vivo implantation, these recellularized scaffolds were easily reperfused, tolerated blood pressure and produced urine with no blood leakage. Our methods can successfully decellularize and recellularize rat kidneys to produce functional renal ECM scaffolds. These scaffolds maintain their basic components, retain intact vasculature and show promise for kidney regeneration.
Reduction of O2 by iron-adriamycin. (1984)

Electron paramagnetic resonance studies of the Fe2+- and Fe3+-adriamycin complexes are reported which demonstrate iron-mediated reduction of O2 by adriamycin. Under anaerobic conditions, Fe2+ binds to adriamycin, giving rise to an EPR-silent Fe2+-adriamycin complex. On addition of O2, the Fe2+ is oxidized to Fe3+ and a spectrum of Fe3+-adriamycin is seen. Under anaerobic conditions, the signal of Fe3+-adriamycin decreases as a function of time as the Fe3+ bound to adriamycin is reduced to Fe2+, and a transient spectrum of iron bound to oxidized adriamycin is observed. On addition of O2, the EPR signal of Fe3+-adriamycin returns as Fe2+ is oxidized back to Fe3+ with electron transfer to O2. This cycle of iron-catalyzed O2 reduction may be the mechanism of adriamycin's antitumor potency and some of its toxic side effects.
Hacia una web independiente del dispositivo mediante CC/PP (2004)

Composite Capabilities/Preferences
Profiles (CC/PP) es el nuevo lenguaje estandar
creado por el World Wide Web Constortium (W3C)
para que la gran diversidad de dispositivos que
disponen, o dispondran, de un acceso a Internet
(movil, PDA, PC, TV ... ), sean capaces de expresar
sus capacidades y las preferencias del usuario
mediante perfiles, tal y como su nombre indica.
Para expresar estas caracteristicas, los perfiles
CC/PP emplean Resource Descripcion Framework
(RDF), otro estandar del W3C y pilar de la web
semantica, el cual, a su vez, se encuentra construido
sobre Extensible Markup Language (XML).
La especificacion User Agent Profile (UAProf)
definida por la Open Mobile Alliance (OMA), antiguo
W APForum, utiliza CC/PP para la descripcion de
los telefonos moviles. Se puede entender como el
primer gran desarrollo CC/PP y ya se encuentra
incluido en los ultimos dispositivos moviles,
implicando la existencia actual de millones de
dispositivos que usan CC/PP.Mediante CCIPP los dispositivos tienen la habilidad
de enviar la informacion CCIPP conjuntamente con
las peticiones HTTP a los servidores, de manera
que estos puedan procesar la informacion CC/PP y
realizar la adaptacion o seleccion de contenidos
adecuados a las caracteristicas del di spositivo,
consiguiendo asi una Web independiente del
dispositivo, acercandose cada vez mas a uno de las
principales metas del W3C: El Acceso Universal a
laWeb.
En este articulo se pone de manifiesto la problematica
actual de la negociacion de contenidos utilizando
HTTP/l.l y se describe la especificacion CCIPP, el
estandar propuesto por W3C para solucionar esta
carencia, justificando sus claves de diseno. Tambien
se describe el estandar de la OMA, UAProf, la primera
implementacion de CCIPP para la descripcion de los
terminales moviles que se encuentra incluido en la
nueva especificacion W AP 2.0.
Palabras clave- CC/PP, UAProJ, RDF, Adaptacion de
contenidos, movil, Web
Total acid soluble and insoluble carnitine levels in human brain tumors. (1999)

Carnitine has two main functions, i.e., transporting long-chain fatty acids into the mitochondrial matrix for beta-oxidation to provide cellular energy and modulating the rise in intramitochondrial acyl-CoA/CoA ratio, which relieves the inhibition of many intramitochondrial enzymes involving glucose and amino acid catabolism. The present study examined the acid soluble carnitine (ASCAR) acid insoluble carnitine (AICAR) and total carnitine (TCAR) concentrations of 50 human brain tumor tissues and 11 normal brain tissues. The ASCAR levels significantly higher in gliomas and meningiomas than brain, however similar to brain in metastatic adenocarcinomas. AICAR levels were lower than brain in all tumors with the exception of a medullablastoma. TCAR levels were similar to brain in all tumor types. Decreased AICAR levels may be due to increased utilization of lipids or enhanced phospholipid and cholesterol synthesis which is need for increased membrane synthesis or formation of eicosanoids. Also decreased concentrations may be a reflection of camitine and its acylesters role in preserving the physiologic membrane structure function from oxidative damage.
Transient Association of Ku with Nuclear Substrates Characterized Using Fluorescence Photobleaching (2002)

The autoantigen Ku, composed of subunits Ku70 and Ku86, is necessary for repair of DNA double-strand breaks by nonhomologous end joining. Similarly, Ku participates in repair of DNA double-strand breaks that occur during V(D)J recombination, and it is therefore required for the development of B and T lymphocytes. Although previous studies have identified the DNA-binding activities of Ku, little is known concerning its dynamics, such as the mobility of Ku in the nucleus and its rate of association with substrates. To address this question, fluorescence photobleaching experiments were performed using HeLa cells and B cells expressing a green fluorescent protein (GFP) fusion construct of either Ku70 or Ku86. The results show that Ku moves rapidly throughout the nucleus even following irradiation of the cells. However, the rate of diffusion of Ku was approximately 100-fold slower than that predicted from its size. Association of Ku-GFP with a filamentous nuclear structure was also evident, and nuclear extraction experiments suggest that this represents nuclear matrix. A central domain of Ku70 containing its DNA-binding and heterodimerization regions and its nuclear localization signal shows that this alone is sufficient for the observed mobility of Ku70-GFP and its association with nuclear matrix. These data suggest the mobility of Ku is characterized by a transient, high flux association with nuclear substrates that includes both DNA and the nuclear matrix and may represent a mechanism for repair of double-strand breaks using the nuclear matrix as a scaffold.
Brain-Derived Neurotrophic Factor Activation of NFAT (Nuclear Factor of Activated T-Cells)-Dependent Transcription: A Role for the Transcription Factor NFATc4 in Neurotrophin-Mediated Gene Expression (2003)

A member of the neurotrophin family, brain-derived neurotrophic factor (BDNF) regulates neuronal survival and differentiation during development. Within the adult brain, BDNF is also important in neuronal adaptive processes, such as the activity-dependent plasticity that underlies learning and memory. These long-term changes in synaptic strength are mediated through alterations in gene expression. However, many of the mechanisms by which BDNF is linked to transcriptional and translational regulation remain unknown. Recently, the transcription factor NFATc4 (nuclear factor of activated T-cells isoform 4) was discovered in neurons, where it is believed to play an important role in long-term changes in neuronal function. Interestingly, NFATc4 is particularly sensitive to the second messenger systems activated by BDNF. Thus, we hypothesized that NFAT-dependent transcription may be an important mediator of BDNF-induced plasticity. In cultured rat CA3-CA1 hippocampal neurons, BDNF activated NFAT-dependent transcription via TrkB receptors. Inhibition of calcineurin blocked BDNF-induced nuclear translocation of NFATc4, thus preventing transcription. Further, phospholipase C was a critical signaling intermediate between BDNF activation of TrkB and the initiation of NFAT-dependent transcription. Both inositol 1,4,5-triphosphate (IP3)-mediated release of calcium from intracellular stores and activation of protein kinase C were required for BDNF-induced NFAT-dependent transcription. Finally, increased expression of IP3 receptor 1 and BDNF after neuronal exposure to BDNF was linked to NFAT-dependent transcription. These results suggest that NFATc4 plays a crucial role in neurotrophin-mediated synaptic plasticity.
CD28‐mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: Evidence for functionally distinct forms of CD28 (1997)

JJ316 and JJ319 are rat CD28-specific monoclonal antibodies (mAb) of the gamma1 kappa isotype with identical co-stimulatory potency. At a concentration 100-1000-fold higher than that required for co-stimulation, JJ316, but not JJ319 induces massive proliferation of all T cell subsets in vitro without T cell receptor (TCR) triggering. "Direct" stimulation by JJ316 is fully blocked by JJ319, indicating that it is not due to cross-reactivity of JJ316 with the TCR complex or other activating receptors. JJ316 binds much more slowly to primary T cells than JJ319, whereas both antibodies bind with similar kinetics to CD28-transfected L-929 cells, suggesting that JJ316 binding to T cells requires redistribution or a conformational change of CD28. In vivo, JJ316 but not JJ319 induces rapid and transient proliferation of most CD4 T cells and, indirectly, of B cells. These data show that TCR engagement is not an absolute prerequisite either in vitro or in vivo for the induction of T cell proliferation through CD28 and suggest that mAb JJ316 is able to stimulate resting T cells directly by recruiting CD28 molecules from an inactive to an active form.
α-Melanocortin and Endothelin-1 Activate Antiapoptotic Pathways and Reduce DNA Damage in Human Melanocytes (2005)

UV radiation is an important etiologic factor for skin cancer, including melanoma. Constitutive pigmentation and the ability to tan are considered the main photoprotective mechanism against sun-induced carcinogenesis. Pigmentation in the skin is conferred by epidermal melanocytes that synthesize and transfer melanin to keratinocytes. Therefore, insuring the survival and genomic stability of epidermal melanocytes is critical for inhibiting photocarcinogenesis, particularly melanoma, the most deadly form of skin cancer. The paracrine factors alpha-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that alpha-melanocortin and endothelin-1 rescued human melanocytes from UV radiation-induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of alpha-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with alpha-melanocortin and/or endothelin-1 before exposure to UV radiation activated the inositol triphosphate kinase-Akt pathway and increased the phosphorylation and expression of the microphthalmia-related transcription factor. Treatment with alpha-melanocortin and/or endothelin-1 enhanced the repair of cyclobutane pyrimidine dimers and reduced the levels of hydrogen peroxide induced by UV radiation. These effects are expected to reduce genomic instability and mutagenesis.
The Contribution of Reactive Oxygen Species to the Photobleaching of Organic Fluorophores (2013)

Photoexcitation of fluorophores commonly used for biological imaging applications generates reactive oxygen species (ROS) which can cause bleaching of the fluorophore and damage to the biological system under investigation. In this study, we show that singlet oxygen contributes relatively little to Cy5 and ATTO 647N photobleaching at low concentrations in aqueous solution. We also show that Cy5 generates significantly less ROS when covalently linked to the protective agents, cyclooctatetraene (COT), nitrobenzyl alcohol (NBA) or Trolox. Such fluorophores exhibit enhanced photostability both in bulk solutions and in single-molecule fluorescence measurements. While the fluorophores ATTO 647N and ATTO 655 showed greater photostability than Cy5 and the protective-agent-linked Cy5 derivatives investigated here, both of ATTO 647N and ATTO 655 generated singlet oxygen and hydroxyl radicals at relatively rapid rates, suggesting that they may be substantially more phototoxic than Cy5 and its derivatives.
SPS-ALPHA: The First Practical Solar Power Satellite via Arbitrarily Large Phased Array (2012)

The vision of delivering solar power to Earth from platforms in space has been known for decades. However, early architectures to accomplish this vision were technically complex and unlikely to prove economically viable. Some of the issues with these earlier solar power satellite (SPS) concepts particularly involving technical feasibility were addressed by NASAs space solar power (SSP) studies and technology research in the mid-to-late 1990s. Despite that progress, ten years ago a number of key technical and economic uncertainties remained. A new SPS concept has been proposed that resolves many, if not all, of those uncertainties: SPSALPHA (Solar Power Satellite by means of Arbitrarily Large Phased Array). During 2011-2012 the NASA Innovative Advanced Concepts (NIAC) Program supported a Phase 1 SPS-ALPHA project, the goal of which was to establish the technical and economic viability of the SPS-ALPHA concept to an early TRL 3 analytical proof-of-concept and provide a framework for further study and technology development. The objectives of this project were to: (1) conduct an initial end-to-end systems analysis of the SPS-ALPHA concept in order to determine its technical feasibility; (2) identify and assess in greater detail the key technology challenges inherent in the architecture (including figures of merit for each critical technology area); (3) conduct an initial evaluation of the economic viability of the concept (as a function of key performance parameters); and, (4) define a preliminary roadmap for the further development of the SPS-ALPHA concept.\n\n\n\n
Exhuberance Over Exubera (2006)

IN BRIEF The isolation, purification, and clinical use of insulin has been enhanced many times in the past 80 years. This article outlines the development of insulin and describes the formulation, activity, and practical use of a newly approved inhaled form of insulin sold under the trade name Exubera.
Amino acid utilisation and deamination of glutamine and asparagine by Helicobacter pylori (1997)

Helicobacter pylori can utilise amino acids as the sole carbon energy source. The present study demonstrated that H. pylori grown in continuous culture in a defined medium containing glucose and amino acids utilised alanine, arginine, asparagine, aspartate, glutamine, glutamate, proline and serine. Specific asparaginase and glutaminase enzymes deaminated asparagine and glutamine respectively to aspartate and glutamate, with the production of ammonia. The glutaminase activity was inhibited by 6-diazo-5-oxo-L-norleucine. All the 13 strains of H. pylori tested produced both glutaminase and asparaginase activities. Glutamine is important in the health of the gastric and intestinal mucosa and is a primary energy source for lymphocytes. Depletion of glutamine at the site of H. pylori infection may be of significance in the pathogenesis of H. pylori-associated diseases such as peptic ulcer and gastric cancer.
Design and Synthesis of Potent, Selective Inhibitors of Endothelin-Converting Enzyme (1998)

Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The final step of posttranslational processing of this peptide is the conversion of its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP) especially at the catalytic center. A series of potent and selective arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl-2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40), showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several of these inhibitors were shown to be potent in blocking ET-1 production in vivo as demonstrated by the big ET-1-induced pressor response in rats. These potent inhibitors are the most selective for ECE-1 reported to date and are envisaged to have a variety of therapeutic applications.