Molecular Players in Hematologic Tumor Cell Trafficking

The trafficking of neoplastic cells represents a key process that contributes to progression of hematologic malignancies. Diapedesis of neoplastic cells across endothelium and perivascular cells is facilitated by adhesion molecules and chemokines, which act in concert to tightly regulate directional motility. Intravital microscopy provides spatio-temporal views of neoplastic cell trafficking, and is crucial for testing and developing therapies against hematologic cancers. Multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL) are hematologic malignancies characterized by continuous neoplastic cell trafficking during disease progression. A common feature of these neoplasias is the homing and infiltration of blood cancer cells into the bone marrow (BM), which favors growth and survival of the malignant cells. MM cells traffic between different BM niches and egress from BM at late disease stages. Besides the BM, CLL cells commonly home to lymph nodes (LNs) and spleen. Likewise, ALL cells also infiltrate extramedullary organs, such as the central nervous system, spleen, liver, and testicles. The α4β1 integrin and the chemokine receptor CXCR4 are key molecules for MM, ALL, and CLL cell trafficking into and out of the BM. In addition, the chemokine receptor CCR7 controls CLL cell homing to LNs, and CXCR4, CCR7, and CXCR3 contribute to ALL cell migration across endothelia and the blood brain barrier. Some of these receptors are used as diagnostic markers for relapse and survival in ALL patients, and their level of expression allows clinicians to choose the appropriate treatments. In CLL, elevated α4β1 expression is an established adverse prognostic marker, reinforcing its role in the disease expansion. Combining current chemotherapies with inhibitors of malignant cell trafficking could represent a useful therapy against these neoplasias. Moreover, immunotherapy using humanized antibodies, CAR-T cells, or immune check-point inhibitors together with agents targeting the migration of tumor cells could also restrict their survival. In this review, we provide a view of the molecular players that regulate the trafficking of neoplastic cells during development and progression of MM, CLL, and ALL, together with current therapies that target the malignant cells

Valoración crítica de los programas renovados de educación preescolar

Analisis de los programas renovados de educación preescolar en España y propuesta de aplicación en la Escuela Universitaria de Formación del Profesorado de E.G.B., de Badajoz.Analysis of the renewed programs of pre-school education in Spain and proposal of application in the Escuela Universitaria de Formación del Profesorado de E.G.B., Badajoz

El estudio de la ‘Desamortización de Godoy’ a través de la documentación del Archivo General de Simancas

The Archivo General de Simancas holds in the department Dirección General del Tesoro, a series of accounting control documents on the «Desamortización de Godoy», which are interesting due to their complete and unpublished nature. The function of registration and control executed by the Contaduría General de Valores on the imposition, amortisation and consolidation, within this confiscation process, characterizes the importance of the production context in Archival science. This paper aims to carry out an archival analysis of the aforementioned document, which offer important information on the location of the primary sources for the study of the confiscation carried out during the reign of Carlos IV.El Archivo General de Simancas conserva, en la sección Dirección General del Tesoro, una serie de documentos sobre la «Desamortización de Godoy», interesantes por su carácter completo e inédito. La función de asiento y control llevados a cabo por la Contaduría General de Valores sobre la imposición, amortización y consolidación, dentro de este proceso desamortizador, caracteriza la importancia del contexto de producción en Archivística. Este trabajo pretende un análisis archivístico de la mencionada documentación, que ofrece una importante información sobre la localización de las fuentes primarias para el estudio de la desamortización desarrollada durante el reinado de Carlos IV

Análisis sobre las barreras sociales y jurídicas que limitan la consolidación de las fuentes de energía no convencionales en La Guajira (Colombia)

The Mining-Energy Planning Unit of Colombia has indicated that the country must quintuple its power generation capacity over the next fifty years. In this scenario, the department of La Guajira is shown as a strategic territory for the promotion of non-conventional energies; in particular, solar and wind. However, and despite its vocation, this department has not made use of the potential. In the present research, it is identified and described the social and legal barriers that have limited the consolidation of non-conventional energy sources in La Guajira, based on the analysis of normative and doctrinal pieces, as well as studies and reports on regional development. Likert-type interviews with businessmen and semi-structured interviews with ethnic groups settled in the territory were also designed. The conclusions acknowledge the barriers and therefore offer recommendations for overcoming them.La Unidad de Planeación Minero-Energética de Colombia ha señalado que el país deberá quintuplicar su capacidad de generación de energía a los próximos cincuenta años. En dicho escenario, el departamento de La Guajira se muestra como un territorio estratégico para el fomento de las energías no convencionales; en particular, la solar y eólica. No obstante, y a pesar de su vocación, este departamento no ha hecho uso de dicho potencial. En esta investigación, se identifican y describen las barreras sociales y jurídicas que han limitado la consolidación de las fuentes de energía no convencionales en La Guajira, a partir del análisis de piezas normativas y doctrinales, así como estudios e informes sobre el desarrollo regional. Se diseñaron, además, entrevistas de tipo Likert a empresarios y entrevistas semiestructuradas a las etnias asentadas en el territorio. En las conclusiones, se reconocen las barreras y, por tanto, se ofrecen recomendaciones para su superación

Multiple particle tracking analysis in isolated nuclei reveals the mechanical phenotype of leukemia cells.

The nucleus is fundamentally composed by lamina and nuclear membranes that enclose the chromatin, nucleoskeletal components and suspending nucleoplasm. The functional connections of this network integrate external stimuli into cell signals, including physical forces to mechanical responses of the nucleus. Canonically, the morphological characteristics of the nucleus, as shape and size, have served for pathologists to stratify and diagnose cancer patients; however, novel biophysical techniques must exploit physical parameters to improve cancer diagnosis. By using multiple particle tracking (MPT) technique on chromatin granules, we designed a SURF (Speeded Up Robust Features)-based algorithm to study the mechanical properties of isolated nuclei and in living cells. We have determined the apparent shear stiffness, viscosity and optical density of the nucleus, and how the chromatin structure influences on these biophysical values. Moreover, we used our MPT-SURF analysis to study the apparent mechanical properties of isolated nuclei from patients of acute lymphoblastic leukemia. We found that leukemia cells exhibited mechanical differences compared to normal lymphocytes. Interestingly, isolated nuclei from high-risk leukemia cells showed increased viscosity than their counterparts from normal lymphocytes, whilst nuclei from relapsed-patient's cells presented higher density than those from normal lymphocytes or standard- and high-risk leukemia cells. Taken together, here we presented how MPT-SURF analysis of nuclear chromatin granules defines nuclear mechanical phenotypic features, which might be clinically relevant.post-print1994 K

Concurrent segregation and erosion effects in medium-energy iron beam patterning of silicon surfaces

This paper is part of: Special Issue on Surfaces Patterned by Ion SputteringWe have bombarded crystalline silicon targets with a 40 keV Fe+ ion beam at different incidence angles. The resulting surfaces have been characterized by atomic force, current-sensing and magnetic force microscopies, scanning electron microscopy, and x-ray photoelectron spectroscopy. We have found that there is a threshold angle smaller than 40 degrees for the formation of ripple patterns, which is definitely lower than those frequently reported for noble gas ion beams. We compare our observations with estimates of the value of the critical angle and of additional basic properties of the patterning process, which are based on a continuum model whose parameters are obtained from binary collision simulations. We have further studied experimentally the ripple structures and measured how the surface slopes change with the ion incidence angle. We explore in particular detail the fluence dependence of the pattern for an incidence angle value (40 degrees) close to the threshold. Initially, rimmed holes appear randomly scattered on the surface, which evolve into large, bug-like structures. Further increasing the ion fluence induces a smooth, rippled background morphology. By means of microscopy techniques, a correlation between the morphology of these structures and their metal content can be unambiguously established.This research is supported by the MINECO/FEDER (Spain/UE) grants Nos. MAT2017-85089-C2-1-R, MAT2016-80394-R, FIS2015-66020-C2-1-P, FIS2015-73337-JIN, FIS2016-78883-C2-2-P, and BIO2016-79618-R, and by Comunidad de Madrid grant NANOAVANSENS ref. S2013/MIT-3029. We want to thank C. Ballesteros and B. Galiana for their help in the SEM measurements. ARC acknowledges the Ramón y Cajal contract number RYC-2015-18047 and KL thanks FCT, Portugal, for her grant as Investigador FCT

Special issue on surfaces patterned by ion sputtering

We thank all the authors within this issue for their efforts and contributions, and the editorial staff of Journal of Physics: Condensed Matter for their efficient work. We also acknowledge funding by the MINECO/FEDER (Spain/ UE) grant Nos. MAT2017-85089-C2-1-R, MAT2016-80394-R, FIS2015-66020-C2-1-P, FIS2015-73337-JIN, FIS2016-78883-C2-2-P, BIO2016-79618-R, and CTQ2017-84309-C2-2-R, and by Comunidad de Madrid grant NANOAVANSENS ref. S2013/MIT-3029. ARC acknowledges the Ramón y Cajal contract number RYC-2015-18047

Self-organized nanopattrening of silicon surfaces by ion beam sputtering

In recent years Ion Beam Sputtering (IBS) has revealed itself as a powerful technique to induce surface nanopatterns with a large number of potential applications. These structures are produced in rather short processing times and over relatively large areas, for a wide range of materials, such as metals, insulators, and semiconductors. In particular, silicon has become a paradigmatic system due to its technological relevance, as well as to its mono-elemental nature, wide availability, and production with extreme flatness. Thus, this review focuses on the IBS nanopatterning of silicon surfaces from the experimental and the theoretical points of view. First, the main experimental results and applications are described under the light of the recently established evidence on the key role played by simultaneous impurity incorporation during irradiation, which has opened a new scenario for an improved understanding of the phenomenon. Second, the progress and state-of-art of the theoretical descriptions of the IBS nanopatterning process for this type of targets are discussed. We summarize the historical approach to IBS through simulation techniques, with an emphasis on recent information from Molecular Dynamics methods, and provide a brief overview of the earlier and most recent continuum models for pure and compound systems.This work has been partially supported by the Spanish Ministries of Science and Innovation (grants Nos. FIS2009-12964-C05-01, FIS2009-12964-C05-03, FIS2009-12964-C05-04, and BES-2010-036179) and of Economy and Competitiveness (grants Nos. FIS2012-38866-C05-01 and FIS2012-38866-C05-05, FIS2012-32349 and FIS2013-47949-C2-2). A.R.C. also acknowledges funding from SFRH/BPD/74095/2010 (Portugal) and from Juan de la Cierva program (Spain) under contract No. JCI-2012-14509.Publicad

Nonuniversality due to inhomogeneous stress in semiconductor surface nanopatterning by low-energy ion-beam irradiation

A lack of universality with respect to ion species has been recently established in nanostructuring of semiconductor surfaces by low-energy ion-beam bombardment. This variability affects basic properties of the pattern formation process, like the critical incidence angle for pattern formation, and has remained unaccounted for. Here, we show that nonuniform generation of stress across the damaged amorphous layer induced by the irradiation is a key factor behind the range of experimental observations, as the form of the stress field is controlled by the ion/target combination. This effect acts in synergy with the nontrivial evolution of the amorphous-crystalline interface. We reach these conclusions by contrasting a multiscale theoretical approach, which combines molecular dynamics and a continuum viscous flow model, with experiments using Xe+ and Ar+ ions on a Si(100) target. Our general approach can apply to a variety of semiconductor systems and conditions.This work has been partially supported by MICINN (Spain) Grant MAT2011-13333-E, and MINECO (Spain) Grants FIS2012-38866-C05-01, FIS2012-38866-C05-05, FIS2013-47949-C2-2-P and FIS2012-32349. TEM work has been conducted at LABMET laboratory, associated with Red de Laboratorios of CAM, Spain. A.M.-B. acknowledges support from MINECO, through FPI scolarship BES-2010-036179. A.R.C. acknowledges funding from Juan de la Cierva program (Spain) under Contract No. JCI-2012-14509.Publicad

Sphingosine-1-phosphate activates chemokine-promoted myeloma cell adhesion and migration involving α4β1 integrin function

51 p.-7 fig.-1 tab.-2 fig.supl.Myeloma cell adhesion dependent on α4β1 integrin is crucial for the progression of multiple myeloma (MM). The α4β1-dependent myeloma cell adhesion is up-regulated by the chemokine CXCL12, and pharmacological blockade of the CXCL12 receptor CXCR4 leads to defective myeloma cell homing to bone marrow (BM). Sphingosine-1-phosphate (S1P) regulates immune cell trafficking upon binding to G-protein-coupled receptors. Here we show that myeloma cells express S1P1, a receptor for S1P. We found that S1P up-regulated the α4β1-mediated myeloma cell adhesion and transendothelial migration stimulated by CXCL12. S1P promoted generation of high-affinity α4β1 that efficiently bound the α4β1 ligand VCAM-1, a finding that was associated with S1P-triggered increase in talin-β1 integrin association. Furthermore, S1P cooperated with CXCL12 for enhancement of α4β1-dependent adhesion strengthening and spreading. CXCL12 and S1P activated the DOCK2-Rac1 pathway, which was required for stimulation of myeloma cell adhesion involving α4β1. Moreover, in vivo analyses indicated that S1P contributes to optimizing the interactions of MM cells with the BM microvasculture and for their lodging inside the bone marrow. The regulation of α4β1-dependent adhesion and migration of myeloma cells by CXCL12-S1P combined activities might have important consequences for myeloma disease progressionThis study was supported by the Ministerio de Ciencia e Innovación (Grant Nos SAF2011-24022 to JT, SAF2009-07035 to AGP, SAF2009-11037 to AH, RD06/0020/0011 to JT and AGP, RD06/0020/0006 to NCG and MG and PI081825 to MG), the Comunidad de Madrid (Grant No. P2010/BMD-2314 to AGP, JT and AH) and the Fundación de Investigación Médica Mutua Madrileña (to AGP and MG). AH was also funded by the FP7-People-2009-RG (Grant No. 246655), a Ramón y Cajal Fellowship (Grant No. RYC-2007-00697) and the Pro-CNIC Foundation.Peer reviewe