Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme

[EN] A novel therapeutic approach for glioblastoma multiforme (GBM) therapy has been carried out through in vitro and in vivo testing by using the prodrug camptothecin-20-O-(5-aminolevulinate) (CPT-ALA). The incorporation of ALA to CPT may promote uptake of the cytotoxic molecule by glioblastoma cells where the heme synthesis pathway is active, improving the therapeutic action and reducing the side effects over healthy tissue. The antitumor properties of CPT-ALA have been tested on different GBM cell lines (U87, U251, and C6) as well as in an orthotopic GBM model in rat, where potential toxicity in central nervous system cells was analyzed. In vitro results indicated no significant differences in the cytotoxic effect over the different GBM cell lines for CPT and CPT-ALA, albeit cell mortality induced by CPT over normal cell lines was significantly higher than CPT-ALA. Moreover, intracranial GBM in rat was significantly reduced (30% volume) with 2 weeks of CPT-ALA treatment with no significant side effects or alterations to the well-being of the animals tested. 5-ALA moiety enhances CPT diffusion into tumors due to solubility improvement and its metabolic-based targeting, increasing the CPT cytotoxic effect on malignant cells while reducing CPT diffusion to other proliferative healthy tissue. We demonstrate that CPT-ALA blocks proliferation of GBM cells, reducing the infiltrative capacity of GBM and promoting the success of surgical removal, which improves life expectancy by reducing tumor recurrence.Financial support from Spanish Ministry of Economy and Competitiveness (Projects PID2019-111436RB-C21 and SEV2016-0683) and the Generalitat Valenciana (Project PROMETEO/2017/060) is gratefully acknowledged. We thank Prof. Luis Fernandez (Group of Structural Mechanics and Materials Modellings-GEMM, University of Zaragoza, Spain) for donation of human GBM cell lines. We are grateful to Dr. Lawrence Humphreys (CIBER-BBN) for critical reading of the manuscriptCheca-Chavarria, E.; Rivero-Buceta, EM.; Sanchez Martos, MA.; Martinez Navarrete, G.; Soto-Sanchez, C.; Botella Asuncion, P.; Fernandez Jover, E. (2021). Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme. Molecular Pharmaceutics. 18(4):1558-1572. https://doi.org/10.1021/acs.molpharmaceut.0c009681558157218

Chiari Syndrome: Advances in Epidemiology and Pathogenesis: A Systematic Review

Arnold Chiari Syndrome; Hydrocephalus; ScoliosisSíndrome de Arnold Chiari; Hidrocefalia; EscoliosisSíndrome d'Arnold Chiari; Hidrocefàlia; EscoliosiArnold Chiari syndrome is a rare congenital disease of unknown prevalence and whose origin is still under study. It is encompassed within the posterior cranial malformations, showing a wide spectrum of symptomatology that can range from severe headache, dizziness, and paresthesia to complete asymptomatology. It is for this reason that early diagnosis of the disease is difficult, and it is usually diagnosed in adolescence. Treatment is based on remodeling and decompression of the malformed posterior cranial fossa, although the risk of residual symptoms after surgery is high. The aim of this review is to update all the existing information on this pathology by means of an exhaustive analysis covering all the scientific literature produced in the last 5 years. In addition, it has been carried out following the PRISMA model and registered in PROSPERO with code CRD42023394490. One of the main conclusions based on the results obtained in this review is that the origin of the syndrome could have a genetic basis and that the treatment of choice is the decompression of the posterior cerebral fossa

Comparative study of extracellular recording methods for analysis of afferent sensory information: Empirical modeling, data analysis and interpretation

Background: Physiological studies of sensorial systems often require the acquisition and processing of data extracted from their multiple components to evaluate how the neural information changes in relation to the environment changes. In this work, a comparative study about methodological aspects of two electrophysiological approaches is described. New method: Extracellular recordings from deep vibrissal nerves were obtained by using a customized microelectrode Utah array during passive mechanical stimulation of rat´s whiskers. These recordings were compared with those obtained with bipolar electrodes. We also propose here a simplified empirical model of the electrophysiological activity obtained from a bundle of myelinated nerve fibers. Results: The peripheral activity of the vibrissal system was characterized through the temporal and spectral features obtained with both recording methods. The empirical model not only allows the correlation between anatomical structures and functional features, but also allows to predict changes in the CAPs morphology when the arrangement and the geometry of the electrodes changes. Comparison with existing method(s): This study compares two extracellular recording methods based on analysis techniques, empirical modeling and data processing of vibrissal sensory information. Conclusions: This comparative study reveals a close relationship between the electrophysiological techniques and the processing methods necessary to extract sensory information. This relationship is the result of maximizing the extraction of information from recordings of sensory activity.Fil: Farfan, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Soto Sanchez, Cristina. Universidad de Miguel Hernández; España. Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina; EspañaFil: Pizá, Alvaro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Albarracin, Ana Lia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Soletta, Jorge Humberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Lucianna, Facundo Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Bioingeniería. Laboratorio de Medios e Interfases; ArgentinaFil: Fernandez, Esteve. Universidad de Miguel Hernández; España. Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina; Españ

The Interplay of the Tree and StandLevel Processes Mediate DroughtInduced Forest Dieback: Evidence from Complementary Remote Sensing and Tree-Ring Approaches

Moreno-Fernández, D., Camarero, J.J., García, M. et al. The Interplay of the Tree and Stand-Level Processes Mediate Drought-Induced Forest Dieback: Evidence from Complementary Remote Sensing and Tree-Ring Approaches. Ecosystems 25, 1738-1753 (2022).Drought-induced forest dieback can lead to a tipping point in community dominance, but the coupled response at the tree and stand-level response has not been properly addressed. New spatially and temporally integrated monitoring approaches that target different biological organization levels are needed. Here, we compared the temporal responses of dendrochronological and spectral indices from 1984 to 2020 at both tree and stand levels, respectively, of a drought-prone Mediterranean Pinus pinea forest currently suffering strong dieback. We test the influence of climate on temporal patterns of tree radial growth, greenness and wetness spectral indices; and we address the influence of major drought episodes on resilience metrics. Tree-ring data and spectral indices followed different spatio-temporal patterns over the study period (1984?2020). Combined information from tree growth and spectral trajectories suggests that a reduction in tree density during the mid-1990s could have promoted tree growth and reduced dieback risk. Additionally, over the last decade, extreme and recurrent droughts have resulted in crown defoliation greater than 40% in most plots since 2019. We found that tree growth and the greenness spectral index were positively related to annual precipitation, while the wetness index was positively related to mean annual temperature. The response to drought, however, was stronger for tree growth than for spectral indices. Our study demonstrates the value of long-term retrospective multiscale analyses including tree and stand-level scales to disentangle mechanisms triggering and driving forest dieback.Ministerio de Ciencia, Innovacion y UniversidadesUniversidad de AlcaláMinisterio de Ciencia e InnovaciónComunidad de MadridUK Research and Innovatio

La imagen y la narrativa como herramientas para el abordaje psicosocial en escenarios de violencia. Groton, Bogotá D. C, Junín, Armenia, Fusagasugá

En nuestro territorio colombiano el conflicto armado ha perpetrado actos atroces, dejando en sus víctimas secuelas físicas y emocionales, es por esta razón que psicólogos en formación de la Universidad Nacional Abierta y a Distancia (UNAD) abordan algunas historias de víctimas del conflicto, con la finalidad de brindar una propuesta para el acompañamiento psicosocial, que les permita transformar sus historias de dolor en historias positivas y significativas para su ser, mediante la promoción de recursos de afrontamiento. El método por medio del cual se desarrolla el abordaje de las diversas historias de vida es el narrativo, el cual permite analizar los relatos de las víctimas y facilitar la resignificación de los hechos traumáticos, a su vez se hace uso de las preguntas como herramienta para apoyar este proceso, aplicando preguntas estratégicas que le permitan a la víctima contemplar desde otra perspectiva su historia vivida.In our Colombian territory, the armed conflict has perpetrated atrocious acts, leaving its victims physical and emotional consequences. It is for this reason that psychologists in training at the National Open and Distance University (UNAD) address some stories of victims of the conflict, with the purpose of to provide a proposal for psychosocial accompaniment, which allows them to transform their stories of pain into positive and meaningful stories for their being, through the promotion of coping resources. The used method applied to the different situations is developed in the narrative technique which allows the analysis of the victims' stories and facilitates the traumatic events. The questions are used as a tool to support the healing process. Applying strategic questions that allow the victim to see her/his situation from another perspective

Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome

Background: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. Methods: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. Results: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. Conclusions: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.Generalitat Valenciana in Spain (AP140/08) and the Biomedical Research Foundation from the Hospital of Elche, Spain (FIBElx0902). Conselleria de Educació (Generalitat Valenciana); Fundacion Juan Peran-Pikolinos; Fundacion Carolina-BBVA and Fondo Investigación Sanitaria (FI07/00303). Instituto de Salud Carlos III (INT09/208)

Restructuring of Pancreatic Islets and Insulin Secretion in a Postnatal Critical Window

Function and structure of adult pancreatic islets are determined by early postnatal development, which in rats corresponds to the first month of life. We analyzed changes in blood glucose and hormones during this stage and their association with morphological and functional changes of alpha and beta cell populations during this period. At day 20 (d20), insulin and glucose plasma levels were two- and six-fold higher, respectively, as compared to d6. Interestingly, this period is characterized by physiological hyperglycemia and hyperinsulinemia, where peripheral insulin resistance and a high plasmatic concentration of glucagon are also observed. These functional changes were paralleled by reorganization of islet structure, cell mass and aggregate size of alpha and beta cells. Cultured beta cells from d20 secreted the same amount of insulin in 15.6 mM than in 5.6 mM glucose (basal conditions), and were characterized by a high basal insulin secretion. However, beta cells from d28 were already glucose sensitive. Understanding and establishing morphophysiological relationships in the developing endocrine pancreas may explain how events in early life are important in determining adult islet physiology and metabolism

Can serum hyaluronic acid replace simple non-invasive indexes to predict liver fibrosis in HIV/Hepatitis C coinfected patients?

<p>Abstract</p> <p>Background</p> <p>Hyaluronic acid (HA) serum levels correlate with the histological stages of liver fibrosis in hepatitis C virus (HCV) monoinfected patients, and HA alone has shown very good diagnostic accuracy as a non-invasive assessment of fibrosis and cirrhosis. The aim of this study was to evaluate serum HA levels as a simple non-invasive diagnostic test to predict hepatic fibrosis in HIV/HCV-coinfected patients and to compare its diagnostic performance with other previously published simple non-invasive indexes consisting of routine parameters (HGM-1, HGM-2, Forns, APRI, and FIB-4).</p> <p>Methods</p> <p>We carried out a cross-sectional study on 201 patients who all underwent liver biopsies and had not previously received interferon therapy. Liver fibrosis was determined via METAVIR score. The diagnostic accuracy of HA was assessed by area under the receiver operating characteristic curves (AUROCs).</p> <p>Results</p> <p>The distribution of liver fibrosis in our cohort was 58.2% with significant fibrosis (F≥2), 31.8% with advanced fibrosis (F≥3), and 11.4% with cirrhosis (F4). Values for the AUROC of HA levels corresponding to significant fibrosis (F≥2), advanced fibrosis (F≥3) and cirrhosis (F4) were 0.676, 0.772, and 0.863, respectively. The AUROC values for HA were similar to those for HGM-1, HGM-2, FIB-4, APRI, and Forns indexes. The best diagnostic accuracy of HA was found for the diagnosis of cirrhosis (F4): the value of HA at the low cut-off (1182 ng/mL) excluded cirrhosis (F4) with a negative predictive value of 99% and at the high cut-off (2400 ng/mL) confirmed cirrhosis (F4) with a positive predictive value of 55%. By utilizing these low and high cut-off points for cirrhosis, biopsies could have theoretically been avoided in 52.2% (111/201) of the patients.</p> <p>Conclusions</p> <p>The diagnostic accuracy of serum HA levels increases gradually with the hepatic fibrosis stage. However, HA is better than other simple non-invasive indexes using parameters easily available in routine clinical practice only for the diagnosing of cirrhosis.</p

Científicas españolas: un mundo por descubrir

Objetivos: La Unión Europea sugiere, entre otros puntos, que la formación universitaria sea complementada con los avances que se vayan produciendo en la investigación científica y, además, pone un especial énfasis en la digitalización de contenidos y en la difusión a través de internet en la Educación Superior. Por ello, el objetivo del proyecto llevado a cabo fue realizar una actividad en la que los alumnos entrevistaran a una mujer científica española que trabajara en alguno de los temas estudiados en clases e ir creando un blog, vinculado a Facebook, con las entrevistas realizadas. De esta forma, además de dar visibilidad a las científicas de nuestro país, ya que en muchos casos la mujer está infravalorada por la sociedad en el ámbito científico, se pretendía conseguir la participación activa del alumnado y favorecer y fomentar su aprendizaje activo, desarrollar la capacidad del alumno de profundizar en un tema de investigación y de plantearse y de que tomaran conciencia del relevante nivel científico que existe en nuestro país y, en concreto, de la importancia que tienen las mujeres. Metodología: Se propuso la actividad a alumnos de 5 Grados diferentes (Farmacia, Doble Grado de Nutrición y Dietética, Ciencia y Tecnología de los Alimentos, Terapia Ocupacional y Óptica y Optometría). Los alumnos interesados en participar formaron grupos de trabajo y eligieron el tema sobre el que querían trabajar del listado propuesto por los profesores. Buscaron una mujer científica española de reconocido prestigio que trabajara en el tema elegido y, después de comunicárselo al profesor, se pusieron en contacto con ella para solicitarles la realización de la entrevista. Una vez que esta accedía a su realización, los alumnos prepararon un dossier de preguntas basándose en los trabajos publicados de la misma, y, tras ser supervisado y corregido por el profesor, eran formuladas a la científica elegida. Una vez realizada la entrevista, los alumnos redactaron un artículo y tras su revisión por el profesor, se hacía público en el blog. Para dar mayor visibilidad al blog, se creó una cuenta abierta de Facebook en la que se iba vinculando el mismo. Al final de todo el proceso se realizó una valoración de la actividad global por parte de los alumnos mediante una encuesta de opinión tipo Likert. Resultados: Se ofertó la actividad a 581 alumnos y participaron 195 (33,6%). Con la actividad propuesta se ha conseguido la participación activa de un porcentaje considerable del alumnado, destacando en los Grados de CYTA (78,4%), Doble Grado de Farmacia y Nutrición (72,3%) y Farmacia (24,1%). Dentro de los que participaron en la actividad, el porcentaje de aprobados fue mayor que el de suspensos (78 vs. 22%; p<0,05, respectivamente). Por otra parte, la valoración otorgada a la actividad fue bastante buena (3,8 sobre 5 puntos), aunque muchos estudiantes manifestaron que les llevó bastante tiempo su realización. Por último, según los alumnos, la actividad les hizo tomar conciencia del alto nivel científico de muchas científicas españolas (4,5 puntos sobre 5)