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Panitumumab, a therapeutic agent for unresectable advanced/recurrent colorectal cancer, is a human IgG2 monoclonal antibody that binds to and inhibits the activity of the epidermal growth factor receptor (EGFR). The onset of hypomagnesemia is a known side effect of anti-EGFR inhibitors, including panitumumab, and it is thought that inhibition of reabsorption of Mg in renal tubules is one of the causes. In addition, recent reports have shown that long-term administration of proton pump inhibitors (PPIs) reduces serum magnesium levels. Therefore, in this study, 102 patients who received oral PPIs treated with panitumumab were classified into a PPI combination group and a PPI non-combination group, and the effect of PPIs on the development of grade 2 or higher hypomagnesemia was investigated. The incidence of hypomagnesemia in the PPI combination group (46.9%, 15/32) was higher than that in the PPI non-combination group (25.7%, 18/70). A comparison of the backgrounds of the two groups of patients showed a significant difference in serum albumin levels. PPI administration was significantly associated with panitumumab-induced hypomagnesemia development when adjusted for known risk factors, serum albumin level, renal function, and oral magnesium oxide tablets in Cox proportional hazards regression analysis (hazard ratio 2.09; 95% confidence interval 1.03-4.22; P =0.040). These results indicate that detailed monitoring of serum magnesium levels is recommended for patients treated with panitumumab and co-administration of PPIs.
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Magnesio , Inhibidores de la Bomba de Protones , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Panitumumab/efectos adversos , Inhibidores de la Bomba de Protones/efectos adversos , Estudios Retrospectivos , Albúmina SéricaRESUMEN
The intrinsic properties of superconductors enable the direct determination of the absolute Seebeck coefficient at low temperature due to the disappearance of the Seebeck effect to obey the Meissner effect. We report a precision absolute Seebeck coefficient measurement for the fine Pt sample determined using the high-Tc YBa2Cu3O7-x (YBCO) superconductor as a reference and an analysis of the measurement uncertainty. To make a precision measurement and aid in the verification of the uncertainty components, we developed a cryostat system that enables temperature control in a stable manner. The expected performance of the reference superconductor yielded a zero value well below Tc, which was validated by a superconductor-superconductor thermocouple experiment. Uncertainty analysis shows that the main limiting factor for this measurement is the accuracy of the temperature difference measurement using the resistance temperature sensors, along with its analog noise. We obtained values of S = 5.6 ± 0.2 µV/K with a relative expanded uncertainty of 3% at 80 K and precisely compared the Pt value with that determined by the high-Tc Bi2Sr2Ca2Cu3O8+δ (Bi-2223) superconductor, which has a higher Tc. We found that there was no difference between the Seebeck coefficient values obtained from the YBCO and Bi-2223 references up to its Tc within the expanded measurement uncertainties of 0.3 µV/K (2σ). These results provide accurate validation that the high-Tc superconductor is a useful reference up to the liquid nitrogen temperature.
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We study the low-energy surface electronic structure of the transition-metal dichalcogenide superconductor PdTe_{2} by spin- and angle-resolved photoemission, scanning tunneling microscopy, and density-functional theory-based supercell calculations. Comparing PdTe_{2} with its sister compound PtSe_{2}, we demonstrate how enhanced interlayer hopping in the Te-based material drives a band inversion within the antibonding p-orbital manifold well above the Fermi level. We show how this mediates spin-polarized topological surface states which form rich multivalley Fermi surfaces with complex spin textures. Scanning tunneling spectroscopy reveals type-II superconductivity at the surface, and moreover shows no evidence for an unconventional component of its superconducting order parameter, despite the presence of topological surface states.
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Transition-metal dichalcogenides (TMDs) are renowned for their rich and varied bulk properties, while their single-layer variants have become one of the most prominent examples of two-dimensional materials beyond graphene. Their disparate ground states largely depend on transition metal d-electron-derived electronic states, on which the vast majority of attention has been concentrated to date. Here, we focus on the chalcogen-derived states. From density-functional theory calculations together with spin- and angle-resolved photoemission, we find that these generically host a co-existence of type-I and type-II three-dimensional bulk Dirac fermions as well as ladders of topological surface states and surface resonances. We demonstrate how these naturally arise within a single p-orbital manifold as a general consequence of a trigonal crystal field, and as such can be expected across a large number of compounds. Already, we demonstrate their existence in six separate TMDs, opening routes to tune, and ultimately exploit, their topological physics.
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The original version of this article contained an error in Fig. 3. The calculated patterns of quasiparticle interference in the figure were incorrect due to the wrong Wannier transformation in the calculation. This correction does not affect the discussion or the conclusion of the article.
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A bulk superconductor possessing a topological surface state at the Fermi level is a promising system to realise long-sought topological superconductivity. Although several candidate materials have been proposed, experimental demonstrations concurrently exploring spin textures and superconductivity at the surface have remained elusive. Here we perform spectroscopic-imaging scanning tunnelling microscopy on the centrosymmetric superconductor ß-PdBi2 that hosts a topological surface state. By combining first-principles electronic-structure calculations and quasiparticle interference experiments, we determine the spin textures at the surface, and show not only the topological surface state but also all other surface bands exhibit spin polarisations parallel to the surface. We find that the superconducting gap fully opens in all the spin-polarised surface states. This behaviour is consistent with a possible spin-triplet order parameter expected for such in-plane spin textures, but the observed superconducting gap amplitude is comparable to that of the bulk, suggesting that the spin-singlet component is predominant in ß-PdBi2.Although several materials have been proposed as topological superconductors, spin textures and superconductivity at the surface remain elusive. Here, Iwaya et al. determine the spin textures at the surface of a superconductor ß-PdBi2 and find the superconducting gap opening in all spin-polarised surface states.
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The topological aspects of electrons in solids can emerge in real materials, as represented by topological insulators. In theory, they show a variety of new magneto-electric phenomena, and especially the ones hosting superconductivity are strongly desired as candidates for topological superconductors. While efforts have been made to develop possible topological superconductors by introducing carriers into topological insulators, those exhibiting indisputable superconductivity free from inhomogeneity are very few. Here we report on the observation of topologically protected surface states in a centrosymmetric layered superconductor, ß-PdBi2, by utilizing spin- and angle-resolved photoemission spectroscopy. Besides the bulk bands, several surface bands are clearly observed with symmetrically allowed in-plane spin polarizations, some of which crossing the Fermi level. These surface states are precisely evaluated to be topological, based on the Z2 invariant analysis in analogy to three-dimensional strong topological insulators. ß-PdBi2 may offer a solid stage to investigate the topological aspect in the superconducting condensate.
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Long-term potentiation (LTP) of synaptic transmission is considered a cellular mechanism for neural plasticity and memory formation. Previously, we showed that in the carp olfactory bulb, LTP occurs at the dendrodendritic mitral-to-granule cell synapse following tetanic electrical stimulation applied to the olfactory tract, and suggested that it is involved in the process of olfactory memory formation. As a first step towards understanding mechanisms underlying plasticity at this synapse, we examined the effects of various drugs (glutamate and GABA receptor agonists and antagonists, noradrenaline, and drugs affecting cAMP signaling) on dendrodendritic mitral-to-granule cell synaptic transmission in an in vitro preparation. Two forms of LTP are involved: a postsynaptic form (tetanus-evoked LTP) and a presynaptic form. The postsynaptic form is evoked at the granule cell dendrite following tetanic olfactory tract stimulation and is suppressed by the NMDA receptor antagonist, D-AP5, enhanced by noradrenaline, and occluded by the metabotropic glutamate receptor agonist, trans-ACPD. The presynaptic form occurs at the mitral cell dendrite following blockade of the GABA(A) receptor by picrotoxin and bicuculline, or via activation of cAMP signaling by forskolin and 8-Br-cAMP.
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Carpas/fisiología , Potenciación a Largo Plazo/fisiología , Red Nerviosa/fisiología , Bulbo Olfatorio/fisiología , Neuronas Receptoras Olfatorias/fisiología , Olfato/fisiología , Transmisión Sináptica/fisiología , Potenciales de Acción/fisiología , Animales , Plasticidad Neuronal/fisiologíaRESUMEN
Histone macroH2A1.2 (macroH2A) is an unusual histone H2A variant with a large non-histone macrodomain at its carboxyl terminal. MacroH2A1.2 is enriched in facultative heterochromatin, including inactivated X chromosomes in mammalian females and senescence-associated heterochromatin foci. We show here that a small population of macroH2A1.2 is mono-ubiquitinated in human HeLa cells. Mass spectrometry analysis revealed that the specific targeting sites for the mono-ubiquitination are Lys115 and Lys116 of the histone domain. A corresponding Lys119 conserved in histone H2A is also mono-ubiquitinated by Ring protein in the polycomb group complex. We suggest that the mono-ubiquitination of macroH2A1.2 and histone H2A has similar or synergistic implications, but that the multiple ubiquitination sites in macroH2A1.2 might confer a variety of functions upon macroH2A1.2 to modulate chromatin states.
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Histonas/metabolismo , Ubiquitina/metabolismo , Secuencia de Aminoácidos , Western Blotting , Cromatografía de Afinidad , Electroforesis en Gel de Poliacrilamida , Células HeLa , Histonas/química , Histonas/aislamiento & purificación , Humanos , Datos de Secuencia Molecular , Nucleosomas/metabolismo , Homología de Secuencia de Aminoácido , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
BACKGROUND/PURPOSE: Radiofrequency ablation (RFA) and microwave coagulation therapy (MCT) have been gaining acceptance as a standard method in the management strategy of liver cancer, for reasons of minimally invasive techniques and effective results. We present our experience of RFA and MCT in patients with liver cancer, and analyze retrospectively the advantages and disadvantages of both of the percutaneous and laparoscopic approaches. METHODS: Thirty-two consecutive patients (23 men and 9 women) with 19 hepatocellular carcinomas (HCC), 12 metastatic liver cancers, and recurrent cholangiocellular carcinoma (CCC), were enrolled in this study. Out of these 32 patients, as a prior laparotomy, 19 underwent hepatectomy, colectomy, gastrectomy or cholecystectomy, and 15 were treated with the laparoscopic approach, 17 treated with the percutaneous approach, and 2 treated with the combined approach of those two. All of these procedures were carried out under general anesthesia with ultrasound guidance. Seven and 30 days after these procedures, an assessment helical computed tomography was done. RESULTS: No sign of the residual tissues was noted in all patients except only one case. CONCLUSIONS: The percutaneous approach was thought to be a more practical and less invasive method regardless previous laparotomy. For the laparoscopic approach, tumors located at the hepatic surface or margin were preferable candidates.
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Ablación por Catéter/métodos , Laparoscopía , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Carcinoma Hepatocelular/cirugía , Colangiocarcinoma/cirugía , Femenino , Humanos , Neoplasias Hepáticas/secundario , Masculino , Microondas/uso terapéutico , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Resultado del TratamientoRESUMEN
We previously found hydroperoxide-responsive proteins (HPRPs), which are comprised of peroxiredoxin I (Prx I), Prx II, Prx III, Prx VI, HSP27, G3PDH and two unidentified proteins (HPRP-2' and HPRP-5'), in human umbilical vein endothelial cells. It was demonstrated by two-dimensional polyacrylamide gel electrophoresis (2D PAGE) that most HPRPs are converted into variants with lower pI upon exposure to hydroperoxides. In this study, we examined the HPRP response on 2D gels upon exposure of human endothelial cells (ECV304) to paraquat (PQ2+), which generates reactive oxygen species (ROS) within cells. PQ2+ exerted cytotoxic effects in a dose-(10 microM-10 mM) and time-(24-168 h) dependent manner. Two-dimensional PAGE analysis revealed that HPRP-2', and oxidized forms of Prx I, Prx II and Prx III were clearly increased upon exposure of cells to sublethal levels of PQ2+. Microsequence analysis revealed that both HPRP-2 and -2' were identical with human DJ-1. Moreover immunoblot analysis confirmed the increase of oxidized forms of Prx II, Prx III and DJ-1 in response to sublethal levels of PQ2+. PQ2+ treatment failed to increase fluorescence intensity derived from DCF, which is believed to be an indicator for intracellular levels of hydroperoxide. Although pentachlorophenol (PCP), an uncoupler of the mitochondrial respiratory chain, clearly elevated the fluorescence, PCP had no effect on HPRP response. These observations indicated that DCF-derived fluorescence is not correlated with HPRP response. We consider that the response of Prxs and DJ-1 on 2D gels could reflect endogenous production of ROS in PQ(2+)-treated cells, and might be a sensitive indicator of oxidative stress status.
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Antioxidantes/metabolismo , Endotelio Vascular/efectos de los fármacos , Proteínas de Choque Térmico , Herbicidas/toxicidad , Proteínas Oncogénicas/metabolismo , Paraquat/toxicidad , Peroxidasas/metabolismo , Animales , Línea Celular , Electroforesis en Gel Bidimensional , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Expresión Génica , Gliceraldehído-3-Fosfato Deshidrogenasas/química , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Proteínas de Choque Térmico HSP27 , Humanos , Peróxido de Hidrógeno/farmacología , Immunoblotting , Péptidos y Proteínas de Señalización Intracelular , Punto Isoeléctrico , Chaperonas Moleculares , Peso Molecular , Proteínas de Neoplasias/metabolismo , Peroxiredoxina VI , Peroxirredoxinas , Fosforilación , Proteína Desglicasa DJ-1 , Conejos , Especies Reactivas de Oxígeno/metabolismoAsunto(s)
Embolización Terapéutica/métodos , Várices Esofágicas y Gástricas/terapia , Fallo Renal Crónico/complicaciones , Diálisis Renal/efectos adversos , Anciano , Oclusión con Balón , Humanos , Fallo Renal Crónico/terapia , Masculino , Ácidos Oléicos/administración & dosificación , Soluciones Esclerosantes/administración & dosificaciónRESUMEN
We examined patterns of the proteins that were expressed in human umbilical vein endothelial cells (HUVEC) in response to oxidative stress by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). When HUVEC were exposed to H2O2 at 100 microM for 60 min, the intensities of eight spots increased and those of eight spots decreased on 2D gels, as compared with control gels, after staining with silver. These changes were also observed after exposure of cells to hydroperoxides such as cumene hydroperoxide and tert-butyl hydroperoxide, but not after exposure to other reagents that induce oxidative stress such as S-alkylating compounds, nitric oxide, and salts of heavy metals. Therefore, these proteins were designated hydroperoxide responsive proteins (HPRPs). Microsequencing analysis revealed that these HPRPs corresponded to at least six pairs of proteins. Of these, four pairs of HPRPs were thioredoxin peroxidase I (TPx I), TPx II, TPx III, and the product of human ORF06, all of which belong to the peroxiredoxin (Prx) family and all of which are involved in the elimination of hydroperoxides. The other two pairs corresponded to heat shock protein 27 (HSP27) and glyceraldehyde-3-phosphate dehydrogenase (G3PDH), respectively. The variants that appeared in response to hydroperoxides had molecular masses similar to the respective native forms, but their pI values were lower by 0.2-0.3 pH units than those of the corresponding native proteins. These variants were detected on 2D gels after cells had been exposed to hydroperoxides in the presence of an inhibitor of protein synthesis. All variants were generated within 30 min of exposure to 100 microM H2O2. The variants of TPx I and TPx II appeared within 2 min of the addition of H2O2 to the culture medium. The HPRPs returned to their respective native forms after the removal of stress. Our results indicated that at least six proteins were structurally modified in response to hydroperoxides. Analysis by 2D-PAGE of 32P-labeled proteins revealed that the variant of HSP27 was its phosphorylated form while the other HPRPs were not modified by phosphorylation. Taken together, the results suggest that 2D-PAGE can reveal initial responses to hydroperoxide stress at the level of protein modification. Moreover, it is possible that the variants of four types of Prx might reflect intermediate states in the process of hydroperoxide elimination.
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Antioxidantes/metabolismo , Proteínas de Choque Térmico , Peróxido de Hidrógeno/farmacología , Oxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Peroxidasas/metabolismo , Secuencia de Aminoácidos , Antioxidantes/química , Electroforesis en Gel Bidimensional , Endotelio/citología , Endotelio/efectos de los fármacos , Endotelio/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Gliceraldehído-3-Fosfato Deshidrogenasas/química , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Proteínas de Choque Térmico HSP27 , Humanos , Punto Isoeléctrico , Chaperonas Moleculares , Peso Molecular , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Peroxidasas/química , Peroxiredoxina III , Peroxirredoxinas , Fosforilación/efectos de los fármacos , Análisis de Secuencia de Proteína , Venas Umbilicales/citología , Venas Umbilicales/efectos de los fármacos , Venas Umbilicales/metabolismoRESUMEN
Paxillin acts as an adaptor protein in integrin signaling. We have shown that paxillin exists in a relatively large cytoplasmic pool, including perinuclear areas, in addition to focal complexes formed at the cell periphery and focal adhesions formed underneath the cell. Several ADP-ribosylation factor (ARF) GTPase-activating proteins (GAPs; ARFGAPs) have been shown to associate with paxillin. We report here that Git2-short/KIAA0148 exhibits properties of a paxillin-associated ARFGAP and appears to be colocalized with paxillin, primarily at perinuclear areas. A fraction of Git2-short was also localized to actin-rich structures at the cell periphery. Unlike paxillin, however, Git2-short did not accumulate at focal adhesions underneath the cell. Git2-short is a short isoform of Git2, which is highly homologous to p95PKL, another paxillin-binding protein, and showed a weaker binding affinity toward paxillin than that of Git2. The ARFGAP activities of Git2 and Git2-short have been previously demonstrated in vitro, and we provided evidence that at least one ARF isoform, ARF1, is an intracellular substrate for the GAP activity of Git2-short. We also showed that Git2-short could antagonize several known ARF1-mediated phenotypes: overexpression of Git2-short, but not its GAP-inactive mutant, caused the redistribution of Golgi protein beta-COP and reduced the amounts of paxillin-containing focal adhesions and actin stress fibers. Perinuclear localization of paxillin, which was sensitive to ARF inactivation, was also affected by Git2-short overexpression. On the other hand, paxillin localization to focal complexes at the cell periphery was unaffected or even augmented by Git2-short overexpression. Therefore, an ARFGAP protein weakly interacting with paxillin, Git2-short, exhibits pleiotropic functions involving the regulation of Golgi organization, actin cytoskeletal organization, and subcellular localization of paxillin, all of which need to be coordinately regulated during integrin-mediated cell adhesion and intracellular signaling.
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Factores de Ribosilacion-ADP/metabolismo , Actinas/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Fosfoproteínas/metabolismo , Factor 1 de Ribosilacion-ADP/metabolismo , Factores de Ribosilacion-ADP/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células COS , Proteínas Portadoras/genética , Línea Celular , Citoesqueleto/metabolismo , Cartilla de ADN/genética , Proteínas Activadoras de GTPasa/genética , Células HeLa , Humanos , Microscopía Fluorescente , Microscopía Inmunoelectrónica , Datos de Secuencia Molecular , Paxillin , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Fracciones Subcelulares/metabolismoRESUMEN
Isoamyl alcohol is an important flavor component of yeast-fermented alcoholic beverages. To identify the enzyme and gene involved in the decarboxylation of alpha-ketoisocaproate (alpha-KIC) for isoamyl alcohol formation, the enzyme was partially purified and analyzed by mass spectrometry. The pyruvate decarboxylase encoded by the PDC1 gene was considered a likely candidate enzyme. Genetic analysis showed that the activity of alpha-KIC decarboxylase and production of isoamyl alcohol partially decreased in a pdc1 null mutant and increased in a transformant with a multi-copy plasmid carrying the PDC1 gene. These results indicate that pyruvate decarboxylase encoded by the PDC1 gene contributes, at least partially, to the decarboxylation of alpha-KIC for isoamyl alcohol formation.
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We previously found that glyoxalase I (Glo I) is inactivated upon exposure of human endothelial cells to extracellular nitric oxide (NO), and this event correlates with an increase in its pI on two-dimensional gels. In this study, we demonstrate that NO can modulate Glo I activity in cooperation with cellular glutathione (GSH). Severe depletion of intracellular GSH prevents the inactivation of Glo I in response to NO, although such depletion enhances the inactivation of glyceraldehyde-3-phosphate dehydrogenase (G3PDH), a well-known enzyme susceptible to NO-induced oxidation. S-Nitrosoglutathione (GSNO), an adduct of GSH and NO, lowers the activity of purified human Glo I, while S-nitrosocysteine (CysNO) inactivates the enzyme only in the presence of GSH. This indicates that a dysfunction in Glo I would require the formation of GSNO in situ. Competitive inhibitors of Glo I, S-(4-bromobenzyl)glutathione and its membrane-permeating form, completely abolish the NO action in vitro and inside cells, respectively. Taken together, these results reveal that Glo I can interact directly with GSNO, and that the interaction converts Glo I into an inactive form. Moreover, the data suggest that the substrate recognition site of Glo I might be involved in the interaction with GSNO.