394 research outputs found
Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells
Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of endoplasmic reticulum (ER) stress, c-Jun-N-terminal kinase (JNK), Akt, and 5âČAMP-activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3â12 hr) ER stress characterized by an increase of Ser51P-eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185P-JNK1/2/JNK1/2, Thr172P-AMPKα, Ser413P-Foxo3a, Thr308P-AKt/AKt and Thr32P-Foxo3a/Foxo3a ratios, and reduction of Ser2481P-mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim EL, Beclin-1, Bcl-xL, Bcl-2, autophagy markers, and reduction of myeloid cell leukemia-1 (Mcl-1) expression. The progressive increase of CHOP expression, and reduction of Thr308P-AKt/AKt and Ser473P-AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim EL expression and caspase-3 activity (24 hr). Small interfering-RNA (si-RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase-3 in sorafenib-treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor-derived xenograft model. In conclusion, the early sorafenib-induced ER stress and regulation of JNK and AMPK-dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK-CHOP-dependent rise of Bim EL, which was associated with the shift from autophagy to apoptosis. The kinetic of Bim EL expression profile might also be related to the tight balance between AKt- and AMPK-related signaling leading to Foxo3a-dependent BIM EL upregulation.Ministerio de EconomĂa y Competitividad BFU2016â75352âPInstituto de Salud Carlos III PI15/00034, PI13/ 00021, PI16/00090, PI14/01349Ministerio de EducaciĂłn FPU16/05127, FPU12/01433, FPU13/01237Junta de AndalucĂa CTS-6264, PI-00025-2013, PI-0127-2013, PI-0198-201
A Great Space Weather Event in February 1730
Aims. Historical records provide evidence of extreme magnetic storms with
equatorward auroral extensions before the epoch of systematic magnetic
observations. One significant magnetic storm occurred on February 15, 1730. We
scale this magnetic storm with auroral extension and contextualise it based on
contemporary solar activity. Methods. We examined historical records in East
Asia and computed the magnetic latitude (MLAT) of observational sites to scale
magnetic storms. We also compared them with auroral records in Southern Europe.
We examined contemporary sunspot observations to reconstruct detailed solar
activity between 1729 and 1731. Results. We show 29 auroral records in East
Asian historical documents and 37 sunspot observations. Conclusions. These
records show that the auroral displays were visible at least down to 25.8{\deg}
MLAT throughout East Asia. In comparison with contemporary European records, we
show that the boundary of the auroral display closest to the equator surpassed
45.1{\deg} MLAT and possibly came down to 31.5{\deg} MLAT in its maximum phase,
with considerable brightness. Contemporary sunspot records show an active phase
in the first half of 1730 during the declining phase of the solar cycle. This
magnetic storm was at least as intense as the magnetic storm in 1989, but less
intense than the Carrington event.Comment: 30 pages, 5 figures, and 2 tables, accepted for publication in
Astronomy & Astrophysics on 25 April 2018. The figures and
transcriptions/translations of historical documents are partially omitted in
this manuscript due to the condition of reproduction. They are available in
the publisher versio
Aurorae observed by Giuseppe Toaldo in Padua (1766â1797)
Se presenta un registro de las observaciones de auroras hechas por Giuseppe Toaldo y su asistente Vincenzo Chiminello en Padua, Italia, en la segunda mitad del siglo XVIII. Las fuentes histĂłricas consultadas incluyen los manuscritos originales que contienen los registros meteorolĂłgicos realizados por esos dos observadores. Se construye un pequeño catĂĄlogo con las 148 observaciones aurorales. Las caracterĂsticas de estas observaciones son analizadas. La principal caracterĂstica de este conjunto de datos es que el nĂșmero anual de observaciones aurorales presenta un pico intenso alrededor de 1779 y una disminuciĂłn abrupta alrededor de 1790.A record is presented of the auroral observations made by Giuseppe Toaldo and his assistant Vincenzo Chiminello in Padua, Italy, in the second half of the 18th century. The historical sources consulted include the original manuscripts containing the meteorological records made by those two observers. A small catalogue is constructed with the 148 auroral observations. The characteristics of these observations are analysed. The main feature of this data set is that the annual number of auroral observations presents an intense peak at around 1779 and an abrupt decline at around 1790.âą Ministerio de Ciencia e InnovaciĂłn. Proyectos AYA2008-04864/AYA y AYA2014-57556-P
âą Junta de Extremadura. Ayuda para Grupos de InvestigaciĂłn GR15137
âą Universidad de las Fuerzas Armadas of Ecuador (ESPE). Proyecto 2015-PIC-014
âą Gobierno de Ecuador. SecretarĂa de EducaciĂłn Superior, Ciencia, TecnologĂa e InnovaciĂłn. Proyecto PROMETEO, para Fernando DomĂnguez CastropeerReviewe
Dihydrocapsiate does not increase energy expenditure nor fat oxidation during aerobic exercise in men with overweight/ obesity: a randomized, triple-blinded, placebo-controlled, crossover trial
Background: Prior evidence suggests that capsinoids ingestion may
increase resting energy expenditure (EE) and fat oxidation (FATox), yet
whether they can modulate those parameters during exercise conditions
remains poorly understood. We hypothesized that dihydrocapsiate
(DHC) ingestion would increase EE and specifically FATox during an
acute bout of aerobic exercise at FATmax intensity (the intensity that
elicits maximal fat oxidation during exercise [MFO]) in men with overweight/
obesity. Since FATmax and MFO during aerobic exercise
appear to be indicators of metabolic flexibility, whether DHC has an
impact on FATox in this type of population is of clinical interest.
Methods: A total of 24 sedentary men (age = 40.2 ± 9.2 years-old;
body mass index = 31.6 ± 4.5 kg/m2 [n = 11 overweight, n = 13
obese]) participated in this randomized, triple-blinded, placebocontrolled,
crossover trial (registered under ClinicalTrials.gov
Identifier no. NCT05156697). On the first day, participants underwent
a submaximal exercise test on a cycle ergometer to determine their MFO and FATmax intensity during exercise. After 72 hours had
elapsed, the participants returned on 2 further days (â„ 72 hours
apart) and performed a 60 min steady-state exercise bout (i.e. cycling
at their FATmax, constant intensity) after ingesting either 12 mg of
DHC or placebo; these conditions were randomized. Respiratory gas
exchange was monitored by indirect calorimetry. Serum marker
concentrations (i.e. glucose, triglycerides, non-esterified fatty acids
(NEFAs), skin temperature, thermal perception, heart rate, and perceived
fatigue) were assessed.
Results: There were no significant differences (P > 0.05) between
DHC and placebo conditions in the EE and FATox during exercise.
Similarly, no significant changes were observed in glucose, triglycerides,
or NEFAs serum levels, neither in the skin temperature nor
thermal perception across conditions. Heart rate and perceived
fatigue did not differ between conditions.
Conclusions: DHC supplementation does not affect energy metabolism
during exercise in men with overweight/obesity.Spanish Junta de Andalucia via Consejeria de Conocimiento, Investigacion y Universidades, Proyectos I+D+i del Programa Operativo del Fondo Europeo de Desarrollo Regional (FEDER 2018) B.CTS.377.UGR18Spanish Government PTA 12264-I
FPU16/02828
FPU16/0515
Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer
Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages.
There are important interrelationships between cell stress, redox status, mitochondrial function, metabolism and cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrest widely related to the antitumoral properties of TKIs result from tightly controlled events involving different cellular compartments and signaling pathways. The aim of the present review is to update the most relevant studies dealing with the impact of TKI treatment on cell function. The induction of endoplasmic reticulum (ER) stress and Ca2+ disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will be covered. Emphasis will be given to studies that identify key components of the integrated molecular pattern including receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events that appear to be involved in the resistance of cancer cells to TKI treatments.This study was funded by Institute of Health Carlos III (ISCiii) (PI16/00090, PI19/00838 and PI19/01266), Spanish Ministry of Economy and Competitiveness (BFU2016-80006-P), Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-6264), Andalusian Ministry of Equality, Health and Social Policies (PI-0198-2016) and Valencian Ministry of Education, Culture and Sports (PROMETEO/2019/027). P de la C-O was supported by FPU predoctoral fellowship (FPU17/00026) from Spanish Ministry of Education, Culture and Sports. E N-V was supported by the the predoctoral i-PFIS IIS-enterprise contract in science and technologies in health (IFI18/00014) from ISCiii. We thank the Biomedical Research Network Center for Cardiovascular Diseases (CIBERcv), and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCiii and co-financed by European Regional Development Fund (ERDF) "A way to achieve Europe" for their financial support
Randomized crossover pharmacokinetic evaluation of subcutaneous versus intravenous granisetron in cancer patients treated with platinum-based chemotherapy
BACKGROUND:
5-HT3-receptor antagonists are one of the mainstays of antiemetic treatment, and they are administered either i.v. or orally. Nevertheless, sometimes neither administration route is feasible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to evaluate the bioavailability of s.c. granisetron.
PATIENTS AND METHODS:
Patients receiving platinum-based chemotherapy were randomized to receive 3 mg of granisetron either s.c. or i.v. in a crossover manner during two cycles. Blood and urine samples were collected after each cycle. Pharmacokinetic parameters observed with each administration route were compared by analysis of variance.
RESULTS:
From May to November 2005, 31 patients were included and 25 were evaluable. Subcutaneous granisetron resulted in a 27% higher area under the concentration-time curve for 0-12 hours (AUC(0-12h)) and higher levels at 12 hours, with similar values for AUC(0-24h). The maximum concentration was lower with the s.c. than with the i.v. route and was observed 30 minutes following s.c. administration.
CONCLUSION:
Granisetron administered s.c. achieves complete bioavailability. This is the first study that shows that s.c. granisetron might be a valid alternative to i.v. delivery. Further trials to confirm clinical equivalence are warranted. This new route of administration might be especially relevant for outpatient management of emesis in cancer patients
The Rise and Fall of "Respectable" Spanish Liberalism, 1808-1923: An Explanatory Framework
The article focuses on the reasons behind both the consolidation of what I have termed ârespectableâ liberalism between the 1830s and the 1840s and its subsequent decline and fall between 1900 and 1923. In understanding both processes I study the links established between ârespectableâ liberals and propertied elites, the monarchy, and the Church. In the first phase these links served to consolidate the liberal polity. However, they also meant that many tenets of liberal ideology were compromised. Free elections were undermined by the operation of caciquismo, monarchs established a powerful position, and despite the Church hierarchy working with liberalism, the doctrine espoused by much of the Church was still shaped by the Counter-Reformation. Hence, ârespectableâ liberalism failed to achieve a popular social base. And the liberal order was increasingly denigrated as part of the corrupt âoligarchyâ that ruled Spain. Worse still, between 1916 and 1923 the Church, monarch, and the propertied elite increasingly abandoned the liberal Monarchist Restoration. Hence when General Primo de Rivera launched his coup the rug was pulled from under the liberalsâ feet and there was no one to cushion the fall
Standalone vertex ïŹnding in the ATLAS muon spectrometer
A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at âs = 7 TeV collected with the ATLAS detector at the LHC during 2011
Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC
Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H âÎł Îł, H â Z Zâ â4l and H âW Wâ âlÎœlÎœ. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of âs = 7 TeV and âs = 8 TeV, corresponding to an integrated luminosity of about 25 fbâ1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined ïŹts probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson
- âŠ