Association of Notch-1, osteopontin and stem-like cells in ENU-glioma malignant process

Notch-1 and osteopontin (OPN) mediate angiogenesis and glioma stem-like cell (GSLC) maintenance. However, the relationship between these molecules and GSLCs during the development of glioma is unknown. We investigate the expression of Notch-1, OPN and vascular endothelial growth factor (VEGF) associated to the stemness markers nestin and CD133 in three stages of murine gliomas induced by N-ethyl-N-nitrosourea (ENU). Notch-1 and OPN overexpress in the intermediate stage (II), which corresponds to the "angiogenesis switch". Nestin+ cells appear in all stages of ENU-glioma but CD133 only from stage II on. In stage III, neoplastic cells expressing nestin, CD133 and nestin/CD133 reside in spheroid-like aggregates (SAs) and in the neoangiogenic border. These aggregates show Notch-1 and VEGF+ surrounding cells and a significant size and density increase with respect to stage I (3.3 ± 1.5 to 22.4 ± 6.3 m2, n° = 0.3 ± 0.1 to 4.2 ± 0.9, from stage I to stage III, respectively). OPN expression increases in correlation to the glioma malignancy from 4.5 ± 1.8% (I) to 12.3 ± 1.2% of OPN+ cells (III). It predominates in astrocyte-like cells of the neoangiogenic border, displaying co-location with VEGF and CD133. The OPN immunopositivity distribution correlates with the CD133 distribution. In conclusion, OPN co-expressing with CD133 contributes to the identification of GSLCs in the neoangiogenic border, while Notch-1 is present around SAs in advanced stages. The ENU-glioma, mainly in stage II, is a useful tool for assessing new antitumour therapies against these molecules

Differential Exposure to N-Ethyl N-Nitrosourea During Pregnancy is Relevant to the Induction of Glioma and PNSTs in the Brain

Exposure to N-nitroso compounds (NOCs) during pregnancy has been associated with an increase in brain tumors in the progeny. This study investigated the brain tumorigenic effect of N-ethyl N-nitrosourea (ENU) after differential exposure of rats during pregnancy. Sprague Dawley rats were exposed to a single dose of ENU (80 mg/kg) in three different circumstances: 1) at first, second or third week of gestation; 2) at the 15th embryonic day (E15) in consecutive litters and 3) at E15 in three successive generations. Location and characterization of the offspring's brain tumors were performed by magnetic resonance imaging and histopathological studies. Finally, tumor incidence and latency and the animals' survival were recorded. ENU-exposure in the last two weeks of pregnancy induced intracranial tumors in over 70% of the offspring rats, these being mainly gliomas with some peripheral nerve sheath tumors (PNSTs). Tumors appeared in young adults; glioma-like small multifocal neoplasias converged on large glioblastomas in senescence and PNSTs in the sheath of the trigeminal nerve, extending to cover the brain convexity. ENU-exposure at E15 in subsequent pregnancies lead to an increase in glioma and PNST incidence. However, consecutive generational ENU-exposure (E15) decreased the animals' survival due to an early onset of both types of tumors. Moreover, PNST presented an inheritable component because progeny, which were not themselves exposed to ENU but whose progenitors were, developed PNSTs. Our results suggest that repeated exposure to ENU later in pregnancy and in successive generations favours the development of intracranial gliomas and PNSTs in the offspring.This study has been financially supported by the University of the Basque Country (UPV/EHU) (GIU 092/19 and PPG 17/51) and the Basque Government (SAN20/25

Zelulen ugalketa gliometan: PCNA eta ki-67-ren adierazpena

Garuneko tumorerik ohikoenak gliomak dira. Tumore hauek aztertzerakoan irizpide histologiko batzuk kontuan hartzen dira. Ezaugarri hauen arabera tumorearen diagnostikoa eta prognostikoa ematen da. Metodologia hau zenbait kasutan ez da oso zehatza izaten, ordea. Hau dela eta, azkeneko urteotan tumoreen hazkundea isla dezaketen beste metodo berri batzuk ikertzen ari dira, zelulen ugalketaren adierazle gisa erabiltzeko asmoz. Lan honen xedea da zelulen ugalketaren azkerketa bat egitea. Honetarako 76 glioma desberdin bildu ziren (20 I astrozitoma, 14 astrozitoma anaplasiko, 34 glioblastoma multiforme, 4 oligodendroglioma eta 4 oligoastrozitoma). Ondoren, Proliferating Cell Nuclear Antigen (PCNA) eta ki-67 antigenoen analisia burutu zen; izan ere, bi proteina hauek ugaltzen ari diren zeluletan soilik azaltzen dira. Jasotako emaitzak tumoreen histologiarekin erlazionatu ziren. Dela PCNA, dela ki-67-rekiko erreaktibotasuna glioma gaiztoenetan areagotzen zela ikusi zelarik, bi antigeno hauek zelulen ugalketaren adierazle onak direla ondorioztatu zen

Implantación de la Prevención de Riesgos Laborales en Empresa de Nueva Constitución, Dedicada a la Molturación y Granulación de Materias Primas

La Prevención de Riesgos Laborales presenta un déficit importante en España, sobre todo en las PYMES y micro PYMES, por la dificultad que representa muchas veces su integración en su gestión productiva y por la desorientación y falta de medios para llevar a cabo una adecuada organización de la prevención en el seno de la empresa. El trabajo realizado se refiere precisamente a la implantación de la Prevención de Riesgos Laborales en una pequeña empresa de nueva constitución con la intención primera de alcanzar los mínimos exigibles y el objetivo más general de crear una base sólida sobre la que plantear una mejora continua de la gestión preventiva de la organización. Partiendo de la Ley 31/1995 de Prevención de Riesgos Laborales y sus disposiciones de desarrollo o complementarias, y con el apoyo de la vasta documentación técnica existente, se comenzó con un chequeo de la situación inicial de la empresa, normalmente deficiente, dada su reciente creación, y se plantearon los primeros pasos sobre la implantación del Plan de Prevención de la empresa, identificación y evaluación inicial de riesgos, propuesta de medidas y planificación preventiva, de modo que se lograra alcanzar el objetivo propuesto en el trabajo, resaltando que la labor preventiva se caracteriza por ser una actividad continua, constante, que requiere de una rutina de funcionamiento y de la revisión periódica de la misma para ser mejorada y perfeccionada. La presentación de esta experiencia sirve a la propia empresa para orientarse en la implantación de la actividad preventiva, tomando ideas de ella, y puede utilizarse de referencia para el desarrollo de la prevención en empresas de características similares y/o que sean aprovechadas para el diseño de estrategias de gestión preventiv

Enriched Environment Reverts Somatostatin Interneuron Loss in MK-801 Model of Schizophrenia

Dysregulation of the inhibitory drive has been proposed to be a central mechanism to explain symptoms and pathophysiological hallmarks in schizophrenia. A number of recent neuroanatomical studies suggest that certain types of inhibitory cells are deficient in schizophrenia, including somatostatin-immunoreactive interneurons (SST+). The present study sought to use stereological methods to investigate whether the number of SST+ interneurons decreased after repeated injections of NMDA receptor antagonist MK-801 (0.5 mg/kg) and to determine the effect of limited exposure to an enriched environment (EE) in adult life on this sub-population of inhibitory cells. Considering that somatostatin expression is highly dependent on neurotrophic support, we explored the changes in the relative expression of proteins related to brain-derived neurotrophic factor—tyrosine kinase B (BDNF-TrkB) signaling between the experimental groups.We observed that early-lifeMK-801 treatment significantly decreased the number of SST+ interneurons in the medial prefrontal cortex (mPFC) and the hippocampus (HPC) of adult Long Evans rats. Contrarily, short-term exposure to EE increased the number of SST+ interneurons in MK-801-injected animals, except in the CA1 region of the hippocampus, whereas this increase was not observed in vehicle-injected rats. We also found upregulated BDNF-TrkB signaling after EE that triggered an increase in the pERK/ERK ratio in mPFC and HPC, and the pAkt/Akt ratio in HPC. Thus, the present results support the notion that SST+ interneurons are markedly affected after early-lifeNMDAR blockade and that EE promotes SST+ interneuron expression, which is partly mediated through the BDNF-TrkB signaling pathway. These results may have important implications for schizophrenia, as SST+ interneuron loss is also observed in the MK-801 pre-clinical model, and its expression can be rescued by non-pharmacological approaches.This work has been partially supported by the University of the Basque Country UPV/EHU (EHU 14/33, PPG 17/51) and by the Basque Government (GIC IT 901/16)

Short-Term Exposure to Enriched Environment in Adult Rats Restores MK-801-Induced Cognitive Deficits and GABAergic Interneuron Immunoreactivity Loss

Perinatal injections of N-methyl-D-aspartate (NMDA) receptor antagonist in rodents emulate some cognitive impairments and neurochemical alterations, such as decreased GABAergic (gamma aminobutyric acid) interneuron immunoreactivity, also found in schizophrenia. These features are pervasive, and developing neuroprotective or neurorestorative strategies is of special interest. In this work, we aimed to investigate if a short exposure to enriched environment (EE) in early adulthood (P55–P73) was an effective strategy to improve cognitive dysfunction and to restore interneuron expression in medial prefrontal cortex (mPFC) and hippocampus (HPC). For that purpose,we administered MK-801 intraperitoneally to Long Evans rats from postnatal days 10 to 20. Twenty-four hours after the last injection, MK-801 produced a transient decrease in spontaneous motor activity and exploration, but those abnormalities were absent at P24 and P55. The open field test on P73 manifested that EE reduced anxiety-like behavior. In addition, MK-801-treated rats showed cognitive impairment in novel object recognition test that was reversed by EE. We quantified different interneuron populations based on their calcium-binding protein expression (parvalbumin, calretinin, and calbindin), glutamic acid decarboxylase 67, and neuronal nuclei-positive cells by means of unbiased stereology and found that EE enhanced interneuron immunoreactivity up to normal values in MK- 801-treated rats. Our results demonstrate that a timely intervention with EE is a powerful tool to reverse long-lasting changes in cognition and neurochemical markers of interneurons in an animal model of schizophrenia.This study was supported by grants from the University of the Basque Country UPV/EHU (UFI 11/32) (EHU 14/33) and by the Government of the Basque Country (GIC IT 901/16). Murueta-Goyena A is financed by a predoctoral fellowship of the University of the Basque Country (UPV/EHU)

Ingurune aberastuaren eragina eskizofrenian

Eskizofrenia gure giza11eari eragiten dioten patologia psikiatriko ohikoen eta minusbaliagarrienetakoa da. Besteak beste, ikasteko zailtasunak eta oroimenaren hutsegiteak dira zailtasun garrantzitsuak gizarte-integrazioari begira. Eskizofrenia, degeneraziozko gaixotasun kronikoa da eta denboran zehar lanitzen doa, baina gaur egungo ikerketa desberdinek erakusten dute terapia-estrategia egoki batek posible egin dezakeela gaixotasuna pairatzen duten kideen integrazioa hobetzea egungo gizartean. Nahiz eta eragin handiko patologia izan , bere jatorri etiopatogenikoa ez da guztiz ezaguna, bere sorreran parte bar baitezakete hainbat eta hainbat faktore desberdinek, hala nola intlamazioak, substantzia psikoaktiboak eta batik bat neurona-zirkuitu kitzikatzaileen eta inhibitzaileen arteko desorekak garapenean zehar. Nerbio Sistema Zentralaren jaio ondorengo garapenean oso funtsezkoa da neurona kitzikatzaileek sortzen dituzten se inale aferenteen eta in terneurona GABAergikoek bideratutako zirkuitu inhibitzaileen arteko oreka. Bizimoduaren eta eskizofreniaren larritasun mailen arteko korrelazio zuzena dago, eta ikusi da sedentarismoak sintomatologia areagotzen duela. Patologia neurologikoak eta neuropsikiatrikoak aztertzeko erabiltzen diren animali modeloetan, ikusi izan da ingurune aberastua dela efektuak murri zteko ahalmena duen tresnetako bat. Ingurune aberastuak, zentzumenen erabi lera, ariketa fisikoa eta gizarte-elkarrekintza areagotzen ditu. lngurunea aberasteak ikas ahalmenen eta oroimena areagotzea eragiten ditu, bai baldintza patologikoetan, baita baldintza arruntetan ere. Halaber, aberastutako ingurunean hazitako animaliek neurogenesia, gliogenesia eta dendriten adarkatze handiago bat erakutsi dute eta horrek lagun dezake hainbat neurodegenerazio gaixotasunen efektuei aurka egiten.Eskizofreniaren ezaugarri etiopatogenikoen alderdian, garrantzi handia hartzen dute sistema sentsorialen garapenean inhibizio-zirkuituei gertatzen zaizkien eraldaketek. Hori dela eta, ingurune aberastuak eskizofreniako animali modeloetan duen eragin positiboa aztertuko dugu

Gliometako zelula nestina-positiboen banaketa

Zelula ama tumoralak (ZAT), ze lula amen ezaugarriak dituzten eta tumore bat birsortzeko gaitasuna duten tumore-ze1ulak dira. Bai anima1ietan eta bai gizakietan ere , multzoka agertzen dira eremu peribaskularrean, askotan egitura berezietan multzokatuta. Azken urteotan , ZATak kimio-erradio terapiekiko erresistenteak direla ikusi da, baita berreritzearen eragileak direla ere. Nerbio Sistema Zentraleko glioma tumoreetan, ehuna infiltratzeko eta angiogenesia pizteko gai dira zelula hauek. Lan honen helburua, gliomaren garapenaren zeharreko tumore-ama zelulen agerpena eta banaketa aztertzea da, batez ere multzoka agertzen direnenen kasuan.Horretarako, etilnitrosourearen (ENU) bitartez arratoiei glioma tumoreak induzitzen zaizkie eta nestinaren markaketaren bidez bertako zelula amak izan daitezkeen zelulak identifikatzen ditugu. Datuen arabera. nestina-positibo diren zelula multzoen tamaina eta kantitatea gliomaren garapenarekin batera handitzen doa. Taldekatze hauek, eremu peribaskularrean eta baita tumore barruan ere agertzen dira eta in vitro agertzen diren neurosferen antzeko morfologia erakutsi dute. Multzoek eta neurosferek in vitro azaltzen dituzten parekotasun hauek, in vivo agertzen dituztenen seinale izan daitezke. Egitura berezi hauek, kontra duten mikroingurune batetik ihes egiteko ZATek sortzen duten gordailua izatea proposatu da