gebhart/patrepeval huggingface dataset:
Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase (2016)

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
Fundamentos para un arte invisible: el caso de Word$Word$Word$ de Rogelio López Cuenca (2005)

Esta investigacion propone la categoria del arte invisible, en relacion a sus modos de manifestacion y actuacion en el espacio publico. La condicion de invisibilidad como arte que podemos observar en estos comportamientos de arte publico es analizada como problematizacion del arte moderno en cuanto que distincion de sus obras respecto al resto de las cosas del mundo. Se plantea una critica y propuesta de superacion, pues, de la idea moderna de autonomia del arte (perfectamente vigente en el arte contemporaneo) desde la integracion y disolucion visual en el paisaje urbano que suponen las intervenciones de arte invisible. Para ello se realiza un recorrido por cinco vectores de fundamentacion de esta figura, en relacion, primero a las modificaciones del sujeto estetico contemporaneo al que se dirige, segundo a una critica de las tesis esencialistas y trascendentalistas que propugnan la eternidad del arte, tercero a la propia problematizacion de la condicion autonoma del arte, cuarto a la descripcion del proceso que observamos de pragmatizacion de la operacion artistica, y quinto al estudio de los nuevos territorios de manifestacion que implican estos modos del arte que se analizan. La tesis observa como caso particular la intervencion WORD$WORD$WORD$ (1994) del artista Rogelio Lopez Cuenca, e incluye una recopilacion completa de la obra publica del autor desde sus inicios hasta enero de 2005.
Effect of antioxidants on radical intensity and cytotoxic activity of eugenol. (1998)

The effect of antioxidants on the radical intensity of 2-methoxy-4-(2-propenyl)phenol (eugenol) was investigated, using ESR spectroscopy. Eugenol produced radicals in alkaline solutions, with an optimum pH of 9.5. The intensity of eugenol radical was a positive function of its concentration, reaching a plateau level at 100 mM. The eugenol radical was rapidly diminished under alkaline conditions. Water-soluble antioxidants, such as cysteine, N-acetyl-L-cysteine, glutathione and sodium ascorbate, completely scavenged the eugenol radical. Gallic acid at lower doses significantly, but not completely, scavenged the eugenol radical. Among water-insoluble antioxidants, terpenes (beta-carotene, retinol, lycopene) effectively scavenged the eugenol radical, whereas phenolic compounds (alpha-tocopherol, Trolox) were inactive. Millimolar concentrations of eugenol were cytotoxic against human salivary gland and oral squamous carcinoma cell lines. Addition of sodium ascorbate or beta-carotene reproducibly reduced the cytotoxic activity of eugenol. The applicability of the antioxidants in dentistry was discussed.
Evaluation of the therapeutic range of whole blood cyclosporin concentration in the treatment of psoriasis. (1996)

Cyclosporin (CyA) trough levels in whole blood in 17 patients receiving CyA for the treatment of severe psoriasis were measured by fluorescence polarization immunoassay (FPIA) employing a specific monoclonal antibody. Clinical success was defined as a PASI score reduction greater than or equal to 75% (group A), partial success by a PASI score reduction of 60%-74% (group B), and insufficient efficacy by a PASI score reduction of less than 60% (group C). Nine of the 17 patients given CyA (53%) exhibited an improvement rate of > or = 75% in the PASI score within 8 weeks of the initiation of treatment. At 8 weeks of treatment the values for the daily dose and whole blood trough CyA concentration were both significantly higher in group A than in group C, daily dose (3.6 +/- 1.0 vs. 2.3 +/- 0.4 mg/kg/day, respectively) and whole blood concentration (141.3 +/- 46.0 vs. 79.7 +/- 19.0 ng/ml). Throughout the study period, during an average observation period of 30 weeks, 13 of the 17 patients (76%) achieved a reduction rate of > or = 75% in the PASI score. In these 13 patients in whom psoriasis lesions cleared satisfactorily the values for the mean daily CyA dose, and whole blood trough levels were 2.4 mg/kg/day and 94.8 ng/ml, respectively. The improvement rate was significantly higher when the CyA trough level was above, rather than below, 100-140 ng/ml within the first 8 weeks, although a lower CyA dose and/or whole blood level was effective in maintaining the reduced PASI score in the subsequent phase. The most important side-effect was mild hypertension in 7 of the 17 patients (41%), however, the onset of hypertension in these patients varied from 30-100 days after the initiation of treatment. Antihypertensive drug therapy and/or dose reduction resulted in a significant decrease, from 166 +/- 17/100 +/- 7-140 +/- 6/84 +/- 10 mmHg, of the CyA-induced hypertension. The relationship between the time course of the duration of improved PASI score and the whole blood concentration of CyA was observed, which suggests that the changes in drug effects were correlated with changes in whole blood levels. During the study period we experienced recurrences in 2 patients after the tapering or withdrawal of CyA treatment. In these 2 patients the relapse may have been due, in part, to the sharp decrease in whole blood concentration secondary to partial noncompliance. Measurement of whole blood CyA trough level is the only method for assessing the patient's noncompliance. Contrary to previous reports we confirmed that the measurement of CyA concentration in whole blood was useful for monitoring the effects in patients with psoriasis.
Efficient Photosensitization by a Chlorin–Polyoxometalate Supramolecular Complex (2013)

The 4:1 supramolecular complexed ionic salt between pyridinium chlorin and polyanionic [α-SiMo12O40](4-) exhibits significantly enhanced photodynamic activity against A549 cell lines because of increased singlet oxygen photogeneration through high cellular penetration and localization of the chlorin molecules on the ionic salt into the cancer cell. Confocal laser scanning microscopy images clearly represent a higher uptake and photodynamic effect of this supramolecular complex corresponding to the lower IC50 value compared to the free chlorin.
Predicting Seizures: Are We There Yet? (2013)

Efforts to predict impending seizures before they actually occur have been the focus of extensive lines of research over decades.Successful seizure prediction would offer the possibility of immediate treatment to preempt the seizure, as well as to provide an opportunity for the patient to take precautionary measures and reduce risk.There is even evidence that simply reducing the unpredictability of seizures would significantly reduce the burden of epilepsy (1).Despite the tremendous potential benefits and years of impressive research, there are still no highly reliable, clinically useful methods available to predict and preempt impending seizures in patients with epilepsy (2).This fact underscores the complexity of epileptogenic networks, the neurophysiology of seizure generation, and preictal/peri-ictal physiology.Upon this backdrop, Cook et al. studied a "long-term implanted seizure advisory system." The system-utilizing intracranial electrodes connected to an implanted telemetry unit-was designed to predict seizure likelihood and inform the subject of this likelihood using colored advisory lights.While the primary outcome was the safety of the device, the authors developed reliable advisory algorithms for seizure occurrence, representing a significant advance in neurophysiologic seizure prediction.The term "seizure advisory" adds to a list of terms including seizure anticipation, seizure prediction or seizure detection, describing attempts to reliably identify seizures in advance of behavioral manifestations.The time period from the identification of the state of high seizure risk and actual seizure onset is considered the pre-ictal period; identification of the "preictal" Prediction of Seizure Likelihood with a Long-Term, Implanted Seizure Advisory System in Patients with Drug-Resistant Epilepsy: A First-in-Man Study.
Thermal Characterization of Absorbing Coatings for Thermal Detectors of Radiation by Photopyroelectric Method (2006)

By photothermomodulatoin method the comparative study of thermal diffusivity of absorbing coating for sensitive elements of pyroelectric detectors of radiation formed from metal dispersion layer blacks, dielectric paint blacks and carbon nanotubes paint blacks has been performed. Prospects of using carbon nanotubes based black absorbing coatings for pyroelectric and other thermal detector application are shown.
Furin-induced Cleavage and Activation of Shiga Toxin (1995)

Shiga toxin has a single A subunit non-covalently associated with a pentamer of B subunits. The toxin has a trypsin-sensitive region near the COOH-terminal end of the A-chain, and upon cleavage, two disulfide bonded fragments, A1 and A2, are generated. These fragments are also formed upon incubation with cells. The disulfide loop contains the sequence (Arg-X-X-Arg), which is a consensus motif for cleavage by the membrane-anchored protease furin. We found that a soluble form of furin cleaves intact A-chain producing A1 and A2 fragments, and furin also seems to be responsible for rapid cellular cleavage of Shiga toxin. LoVo cells, which normally do not produce functional furin, cleave intact A-chain very efficiently when transfected with furin (LoVo/fur), whereas a control cell (LoVo/neo) cleaves the toxin very slowly. To investigate the role of this cleavage for intoxication of cells, we studied the ability of unnicked and furin-nicked toxin to inhibit protein synthesis in LoVo/fur and LoVo/neo cells. LoVo/fur cells were intoxicated equally well with unnicked and nicked toxin, whereas in LoVo/neo cells nicked toxin was about 20 times more active than unnicked toxin. The results suggest that cleavage of Shiga toxin is important for intoxication of cells, and they indicate that furin can cleave and thereby activate Shiga toxin in cells.
Role of RLIP76 in lung cancer doxorubicin resistance: I. The ATPase activity of RLIP76 correlates with doxorubicin and 4-hydroxynonenal resistance in lung cancer cells (2003)

RLIP76 functions as an ATP-dependent transporter of amphiphilic chemotherapeutic drugs such as doxorubicin (DOX, adriamycin), as well as of glutathione-conjugates of endogenous electrophilic toxins such as 4-hydroxynonenal (4HNE). RLIP76 couples transport and ATP-hydrolysis with a 1:1 stoichiometry, making the ATPase activity of RLIP76 an excellent surrogate for its transport activity. Present studies were performed to determine the relationship of the RLIP76 ATPase activity with DOX and 4HNE resistance in a panel of 13 native human lung cancer cell lines. RLIP76 was purified from each cell line and homogeneity demonstrated by SDS-PAGE and amino acid composition analysis. Anti-RLIP76 antibodies were shown by Ouchterlony double immunodiffusion tests to be non-cross-reactive with any other proteins including P-glycoprotein (Pgp) or multidrug resistance associated protein (MRP). These antibodies completely immunoprecipitated ATPase activity of purified RLIP76 fractions, further confirming homogeneity of purified RLIP76. RLIP76 ATPase purified from NSCLC cell lines was about 2-fold more active than that from SCLC in the absence of the stimulator dinitrophenyl S-glutathione (206+/-47, n=7 vs. 94+/-22, n=6, nmol/min/mg protein, respectively), or in its presence (340+/-60, n=7 vs. 186+/-32, n=6, nmol/min/mg; p<0.01). Partial tryptic digest revealed a 44 kDa internal fragment of RLIP76 beginning at Thr-294 in NSCLC cell lines. This fragment was absent from all SCLC, suggesting the possibility that the activity of RLIP76 in SCLC and NSCLC is differentially regulated through post-translational modifications. Taken together, these findings suggest that RLIP76 activity is a general determinant of 4HNE and DOX resistance, and that its activity contributes to the drug-resistant phenotype of NSCLC.
Reactive groups on polymer coated electrodes, 8. Novel conducting polymer interfaces produced by electrochemical copolymerization of functionalized thiophene activated esters with 3-methylthiophene (1998)

With the synthesis of two new functionalized thiophene activated esters and their electrocopolymerization with 3-methylthiophene, two types of redox active polymers have been prepared. FTIR studies of the resultant polymers reveal that both types of activated ester groups withstand the applied electrooxidative conditions and are correctly integrated into the corresponding polymers. The electrocopolymerization experiments show that the composition of the obtained polymers strongly depends on the ratio of the components in the reaction medium. With the increase of the ratios of pentafluorophenyl thiophene-3-acetate-3-methylthiophene or succinimido thiophene-3-acetate/3-methylthiophene, a higher concentration of functionalized thiophene units is incorporated into the polymer chains. The measurement of the conductivity on these polymeric films gave a value in the range of 10−3 to 10−2 S · cm−1, which is comparable to that of the unsubstituted polythiophene and consistent with the conjugation grade suggested by electrochemical and UV-vis spectroscopic data. As expected, the pendant reactive ester groups on the electrode surfaces react rapidly with different amino compounds without loss of the electroactivity of the polymers. Therefore, these novel polymeric materials can be used as electrode interfaces for further functionalizations, especially for the immobilization of amines, peptides, and enzymes.
ELISA detection of vivax malaria with recombinant multiple stage-specific antigens and its application to survey of residents in endemic areas (2003)

An ELISA was developed for the diagnosis of vivax malaria using multiple stage-specific recombinant antigens of Plasmodium vivax. The DNA from the whole blood of a malaria patient was used as template to amplify the coding regions for the antigenic domains of circumsporozoite protein (CSP-1), merozoite surface protein (MSP-1), apical merozoite antigen (AMA-1), serine repeat antigen (SERA), and exported antigen (EXP-1). Each amplified DNA fragment was inserted into pQE30 plasmid to induce the expression of His-tagged protein in Escherichia coli (M15 strain) by IPTG. His-tagged proteins were purified by Ni-NTA metal-affinity chromatography and used as antigens for ELISA with patient sera that were confirmed previously by blood smear examinations. When applied to patient sera, 122 (80.3%) out of 152 vivax malaria cases reacted to at least one antigen, while no reactions were observed with 128 uninfected serum samples. We applied this ELISA to the screening of 3,262 civilian residents in endemic regions near the DMZ, which resulted in 236 positively detected (7.2%) cases. This method can be applied to serological diagnosis and mass screening in endemic regions, or can be used as a safety test for transfusion blood in endemic areas.
The shortest path from the surface to the nucleus: RBP‐Jκ/Su(H) transcription factor (1996)

Communication between cell surface receptors and nuclear transcription factors is of primary importance to multicellular organisms. Since there are numerous molecules involved in this process, their mutual interaction forms complex networks of informational regulation, which is still under extensive investigation. The RBP-J kappa transcription factor interacts directly with the Notch receptor involved in cell lineage commitment, implicating the presence of a uniquely simple communication strategy between the surface receptor and the nucleus.
Tic32, an Essential Component in Chloroplast Biogenesis (2004)

Chloroplast protein import across the inner envelope is facilitated by the translocon of the inner envelope of chloroplasts (Tic). Here we have identified Tic32 as a novel subunit of the Tic complex. Tic32 can be purified from solubilized inner envelope membranes by chromatography on Tic110 containing affinity matrix. Co-immunoprecipitation experiments using either Tic32 or Tic110 antisera indicated a tight association between these polypeptides as well as with other Tic subunits, e.g. Tic40, Tic22, or Tic62, whereas the outer envelope protein Toc75 was not found in this complex. Chemical cross-linking suggests that Tic32 is involved late in the overall translocation process, because both the precursor form as well as the mature form of Rubisco small subunit can be detected. We were unable to isolate Arabidopsis null mutants of the attic32 gene, indicating that Tic32 is essential for viability. Deletion of the attic32 gene resulted in early seed abortion because the embryo was unable to differentiate from the heart stage to the torpedo stage. The homology of Tic32 to short-chain dehydrogenases suggests a dual role of Tic32 in import, one as a regulatory component and one as an important subunit in the assembly of the entire complex.
Redox Electrolytes in Supercapacitors (2015)

Most methods for improving supercapacitor performance are based on developments of electrode materials to optimally exploit their storage mechanisms, namely electrical double layer capacitance and pseudocapacitance. In such cases, the electrolyte is supposed to be electrochemically as inert as possible so that a wide potential window can be achieved. Interestingly, in recent years, there has been a growing interest in the investigation of supercapacitors with an electrolyte that can offer redox activity. Such redox electrolytes have been shown to offer increased charge storage capacity, and possibly other benefits. There are however some confusions, for example, on the nature of contributions of the redox electrolyte to the increased storage capacity in comparison with pseudocapacitance, or by expression of the overall increased charge storage capacity as capacitance. This report intends to provide a brief but critical review on the pros and cons of the application of such redox electrolytes in supercapacitors, and to advocate development of the relevant research into a new electrochemical energy storage device in parallel with, but not the same as that of supercapacitors.
Dynamics of language reorganization after stroke (2006)

Previous functional imaging studies of chronic stroke patients with aphasia suggest that recovery of language occurs in a pre-existing, bilateral network with an upregulation of undamaged areas and a recruitment of perilesional tissue and homologue right language areas. The present study aimed at identifying the dynamics of reorganization in the language system by repeated functional MRI (fMRI) examinations with parallel language testing from the acute to the chronic stage. We examined 14 patients with aphasia due to an infarction of the left middle cerebral artery territory and an age-matched control group with an auditory comprehension task in an event-related design. Control subjects were scanned once, whereas patients were scanned repeatedly at three consecutive dates. All patients recovered clinically as shown by a set of aphasia tests. In the acute phase [mean: 1.8 days post-stroke (dps)], patients' group analysis showed little early activation of non-infarcted left-hemispheric language structures, while in the subacute phase (mean: 12.1 dps) a large increase of activation in the bilateral language network with peak activation in the right Broca-homologue (BHo) was observed. A direct comparison of both examinations revealed the strongest increase of activation in the right BHo and supplementary motor area (SMA). These upregulated areas also showed the strongest correlation between improved language function and increased activation (r(BHo) = 0.88, r(SMA) = 0.92). In the chronic phase (mean: 321 dps), a normalization of activation with a re-shift of peak activation to left-hemispheric language areas was observed, associated with further language improvement. The data suggest that brain reorganization during language recovery proceeds in three phases: a strongly reduced activation of remaining left language areas in the acute phase is followed by an upregulation with recruitment of homologue language zones, which correlates with language improvement. Thereafter, a normalization of activation is observed, possibly reflecting consolidation in the language system.
Monomeric G-Protein-Coupled Receptor as a Functional Unit (2005)

Rhodopsin, the first purified G-protein-coupled receptor (GPCR), was characterized as a functional monomer 30 year ago, but dimerization of GPCRs recently became the new paradigm of signal transduction. It has even been claimed, on the basis of recent biophysical and biochemical studies, that this new concept could be extended to higher-order oligomerization. Here this view is challenged. The new studies of rhodopsin and other simple (class 1a) GPCRs solubilized in detergent are re-assessed and are compared to the earlier classical studies of rhodopsin and other membrane proteins solubilized in detergent. The new studies are found to strengthen rather than invalidate the conclusions of the early ones and to support a monomeric model for rhodopsin and other class 1a GPCRs. A molecular model is proposed for the functional coupling of a rhodopsin monomeric unit with a G-protein heterotrimer. This model should be valid even for GPCRs that exist as structural dimers.
Single Adult Human CD34+/Lin−/CD38− Progenitors Give Rise to Natural Killer Cells, B-Lineage Cells, Dendritic Cells, and Myeloid Cells (1999)

Abstract Marrow stromal cultures support adult CD34+/Lin−/HLA-DR− or CD34+/Lin−/CD38− cell differentiation into natural killer (NK) or myeloid cells, but unlike committed lymphoid progenitors (CD34+/Lin−/CD45RA+/CD10+), no B cells are generated. We tested whether different microenvironments could establish a developmental link between the NK and B-cell lineages. Progenitors were cultured in limiting dilutions with interleukin-7 (IL-7), flt3 ligand (FL), c-kit ligand (KL), IL-3, IL-2, and AFT024, a murine fetal liver line, which supports culture of transplantable murine stem cells. NK cells, CD10+/CD19+ B-lineage cells and dendritic cells (DC) developed from the same starting population and IL-7, FL, and KL were required in this process. Single cell deposition of 3,872 CD34+/Lin−/CD38− cells onto AFT024 with IL-7, FL, KL, IL-2, and IL-3 showed that a one time addition of IL-3 at culture initiation was essential for multilineage differentiation from single cells. Single and double lineage progeny were frequently detected, but more importantly, 2% of single cells could give rise to at least three lineages (NK cells, B-lineage cells, and DC or myeloid cells) providing direct evidence that NK and B-lineage differentiation derive from a common lymphomyeloid hematopoietic progenitor under the same conditions. This study provides new insights into the role of the microenvironment niche, which governs the earliest events in lymphoid development.