Shallow buried SiN x layers

Copyright (2000) American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in Journal of Applied Physics 87.1 (2000): 8201-8203 and may be found at http://jap.aip.org

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 5′AMP-activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3–12 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 Economía y Competitividad BFU2016‐75352‐PInstituto de Salud Carlos III PI15/00034, PI13/ 00021, PI16/00090, PI14/01349Ministerio de Educación FPU16/05127, FPU12/01433, FPU13/01237Junta de Andalucía CTS-6264, PI-00025-2013, PI-0127-2013, PI-0198-201

A low frequency of losses in 11q chromosome Is associated with better outcome and lower rate of genomic mutations in patients with chronic lymphocytic leukemia

This is an open access article distributed under the terms of the Creative Commons Attribution License.-- et al.To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q- CLLs. In patients with ≥40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or β2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty %of CLLs with 11qshowed mutations and fewer patients with low frequencies of 11q- had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11qhad a long TFT and OS that could be associated with the presence of fewer mutated genes.This work was supported by grants from the Spanish Fondo de Investigaciones Sanitarias FIS 09/01543, PI12/00281 and PI15/01471, Instituto de Salud Carlos III (ISCIII), European Regional Development Fund (ERDF) "Una manera de hacer Europa", Proyectos de Investigación del SACYL 355/A/09, GRS/1172/A15, COST Action EuGESMA (BM0801), Fundación Manuel Solórzano, Obra Social Banca Cívica (Caja Burgos), Fundación Española de Hematología y Hemoterapia (FEHH), and by grants (RD12/0036/0069 and RD12/0036/0044) from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness and European Regional Development Fund (ERDF) "Una manera de hacer Europa" (CEI 2010-1-0010). The research leading to these results has received funding from the European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement n°306242-NGS-PTL. María Hernández-Sánchez is fully supported by an Ayuda Predoctoral de la Junta de Castilla y León from the Fondo Social Europeo (JCYL-EDU/346/2013 Ph.D. scholarship). Vera Grossmann was supported by MLL Munich and Alexander Kohlmann was supported by MLL Munich and AstraZeneca in terms of salary.Peer Reviewe

Nuevos datos geocronológicos 40Ar-39Ar en dos puntos singulares del macizo de Anaga (Tenerife): Punta Poyata e Igueste de San Andrés. Consecuencias de interés

En este trabajo se aportan nuevos datos geocronológicos Ar40-Ar39 en rocas ancaramíticas submarinas localizadas en dos puntos singulares del macizo de Anaga (NE de Tenerife): las ancaramitas submarinas hidrotermalizadas de Punta Poyata (NNW de Anaga) y las lavas submarinas ancaramíticas del Barranco de Igueste (SE de Anaga). Las muestras estudiadas pertenecen a afloramientos pertenecientes a los niveles estratigráficos más inferiores de la secuencia volcánica que conforma el edificio de Anaga. En Punta Poyata se tomaron dos especímenes que dieron edades de 12,2 ± 1,9 Ma and 13,0 ± 1,0 Ma. En el barranco de Igueste los resultados geocronológicos de las muestras tomadas dieron edades de 12,7 ± 1,6 Ma and 9,7 ± 1,0 Ma. Estos datos sugieren que el macizo de Anaga comenzó su desarrollo subaéreo antes de lo que anteriormente se creía, ajustándose dicho período inicial al Mioceno Medio en lugar de al Mioceno tardío como previamente se asumía.This work provides new Ar40-Ar39 geochronological data in submarine ankaramite rocks located in two distant points of Anaga (NE Tenerife): the submarine hydrothermally altered ankaramites of Punta Poyata area (NNW Anaga) and the ankaramitic pillow lavas at Barranco de Igueste (SE Anaga). The studied samples were collected from outcrops of the lowest stratigraphic levels throughout the volcanics that build up the Anaga massif. At Punta Poyata, two collected samples yielded an age of 12,2 ± 1,9 Ma and 13,0 ± 1,0 Ma. At Barranco de Igueste, sample results are of 12,7 ± 1,6 Ma and 9,7 ± 1,0 Ma. These data support the assumption that the Anaga massif began its subaerial growth earlier than that previously was supposed, most likely in the Mid-Miocene Instead of late Miocene as currently believed.Depto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasTRUEpu

Mutation status and immunoglobulin gene rearrangements in patients from northwest and central region of Spain with chronic lymphocytic leukemia

This is an open access article distributed under the Creative Commons Attribution License.-- et al.The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL.The study was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias 02/1041, FIS 09/01382, FIS 09/01543, and PI12/00281; RD12/0036/0069 from Red Tematica de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) “Una manera de hacer Europa”; and Caja de Burgos-Banca Cívica. A. Rodrígues was fully supported by an Ayuda Predoctoral FIS de Formación en Investigacion by the Spanish Fondo de Investigaciones Sanitarias. M. Hernandez-Sanchez was partially supported by a grant from the “Fundacion Española de Hematología y Hemoterapia.” Partially supported by grants from “Proyectos de Investigacion Biomédica del SACYL” 106/A/06.Peer Reviewe

Biomechanical behavior of customized scaffolds: A three-dimensional finite element analysis

Teeth loss due to periodontal diseases, trauma, or infections often causes dimensional loss in the affected maxillary. In patients with reduced maxillary size, restoration of chewing function and esthetics with endosseous dental implants may fail. The aim of this work was to simulate the biomechanical behavior, using the finite element method, of customized scaffolds fixed by a dental implant on a partially edentulous jaw. Porous scaffolds were designed from medical images of a partially edentulous jaw with type IV bone quality. The influence of the diameter of the hole and the porosity of the scaffold on the maximum levels of stress and strain in the peri-implant bone was evaluated. The highest stress values in the scaffolds, dental implant, and crown were lower than the yield strength of their respective materials. The customized scaffolds allow to recover the dimensions of the evaluated jaw. A significant decrease in stress and strain values was observed in the peri-implant cortical bone. Furthermore, it was found that the evaluated parameters did not have a significant influence on the maximum von Mises equivalent stress and maximum strain values in the peri-implant bone.MCIN/ AEI/10.13039/501100011033 PID2019-109371 GB-I0

Variación espacial y temporal del índice gonadal de Diadema antillarum (Echinodermata: Echinoidea) en las Islas Canarias

Diadema antillarum Philippi occurs in high density populations in the Canary Islands, creating extensive barren areas. During one year we determined seasonal changes in the algal abundance and population densities, test diameter, gut contents and gonad index of sea urchins in two localities (Abades and Boca Cangrejo). Boca Cangrejo shows higher algae cover and species richness than Abades. The sea urchin population at Abades had a higher density and smaller urchins than Boca Cangrejo. Boca Cangrejo sea urchins showed higher specific richness in gut contents than Abades urchins. The sea urchin population at Abades did not have a clearer reproductive periodicity or higher gonad index than the Boca Cangrejo population. Temporal and spatial changes in gonad periodicity of Diadema antillarum are attributed, at least in part, to benthic food availability (algal cover and algal species number) and intra-specific competition.Diadema antillarum Philippi presenta unas densidades altísimas en las islas Canarias, eliminando casi por completo la cubierta vegetal de los fondos rocosos litorales. Durante un año, hemos muestreado estacionalmente los cambios en la abundancia de algas y las densidades poblacionales, diámetros de caparazón, contenidos intestinales e índice gonadal de los erizos en dos localidades (Abades y Boca Cangrejo). Boca Cangrejo presenta mayores coberturas y riqueza algal que Abades. La población de erizos en Abades es más densa y esta formada por erizos de menor tamaño que en Boca Cangrejo. La riqueza algal en los contenidos estomacales es mayor en los erizos de Boca Cangrejo que la de los de Abades. Los erizos de Boca Cangrejo presentan una clara periodicidad reproductiva e índices gonadales superiores a los erizos de Abades. Las variaciones espaciales y estacionales en la periodicidad gonadal de Diadema antillarum pueden ser atribuidas, al menos en parte, a la disponibilidad bentónica de alimento (recubrimiento y número de especies de algas) y a la competencia intraespecífica.

Interplay Among Different Fosfomycin Resistance Mechanisms in Klebsiella Pneumoniae

The objectives of this study were to characterize the role of the uhpT, glpT, and fosA genes in fosfomycin resistance in Klebsiella pneumoniae and evaluate the use of sodium phosphonoformate (PPF) in combination with fosfomycin. Seven clinical isolates of K. pneumoniae and the reference strain (ATCC 700721) were used, and their genomes were sequenced. DuhpT, DglpT, and DfosA mutants were constructed from two isolates and K. pneumoniae ATCC 700721. Fosfomycin susceptibility testing was done by the gradient strip method. Synergy between fosfomycin and PPF was studied by checkerboard assay and analyzed using SynergyFinder. Spontaneous fosfomycin mutant frequencies at 64 and 512mg/liter, in vitro activity using growth curves with fosfomycin gradient concentrations (0 to 256mg/liter), and time-kill assays at 64 and 307mg/liter were evaluated with and without PPF (0.623mM). The MICs of fosfomycin against the clinical isolates ranged from 16 to ≥1,024mg/liter. The addition of 0.623mM PPF reduced fosfomycin MIC between 2- and 8-fold. Deletion of fosA led to a 32-fold decrease. Synergistic activities were observed with the combination of fosfomycin and PPF (most synergistic area at 0.623mM). The lowest fosfomycin-resistant mutant frequencies were found in ΔfosA mutants, with decreases in frequency from 1.69×10-1 to 1.60×10-5 for 64mg/liter of fosfomycin. In the final growth monitoring and time-kill assays, fosfomycin showed a bactericidal effect only with the deletion of fosA and not with the addition of PPF. We conclude that fosA gene inactivation leads to a decrease in fosfomycin resistance in K. pneumoniae. The pharmacological approach using PPF did not achieve enough activity, and the effect decreased with the presence of fosfomycin-resistant mutations.Ministerio de Economía y Competitividad PI16/01824, REIPI RD12/0015/0010, EIPI RD16/0016/0001Junta de Andalucía PI-0044Innovative Medicines Initiative 115523, 115620, 11573