Development of a predictor for human brain tumors based on gene expression values obtained from two types of microarray technologies

Development of molecular diagnostics that can reliably differentiate amongst different subtypes of brain tumors is an important unmet clinical need in postgenomics medicine and clinical oncology. A simple linear formula derived from gene expression values of four genes (GFAP, PTPRZ1, GPM6B, and PRELP) measured from cDNA microarrays (n=35) have distinguished glioblastoma and meningioma cases in a previous study. We herein extend this work further and report that the above predictor formula showed its robustness when applied to Affymetrix microarray data acquired prospectively in our laboratory (n=80) as well as publicly available data (n=98). Importantly, GFAP and GPM6B were both retained as being significant in the predictive model upon using the Affymetrix data obtained in our laboratory, whereas the other two predictor genes were SFRP2 and SLC6A2. These results collectively indicate the importance of the expression values of GFAP and GPM6B genes sampled from the two types of microarray technologies tested. The high prediction accuracy obtained in these instances demonstrates the robustness of the predictors across microarray platforms used. This result would require further validation with a larger population of meningioma and glioblastoma cases. At any rate, this study paves the way for further application of gene signatures to more stringent biopsy discrimination challenges. © 2010, Mary Ann Liebert, Inc.This work was funded by the EU-funded grants eTUMOUR (FP6-2002-LIFESCIHEALTH503094),HealthAgents (IST-2004-27214) and the Spanish grant MEDIVO2 (SAF 2005-03650). CIBER-BNN is an initiative of ‘‘Instituto de Salud Carlos III’’ (ISCIII, Spain).Peer Reviewe

Diminished Perisomatic GABAergic Terminals on Cortical Neurons Adjacent to Amyloid Plaques

One of the main pathological hallmarks of Alzheimer's disease (AD) is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic) and perisomatic (mostly GABAergic) regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought

Development of robust discriminant equations for assessing subtypes of glioblastoma biopsies

In the preceding decade, various studies on glioblastoma (Gb) demonstrated that signatures obtained from gene expression microarrays correlate better with survival than with histopathological classification. However, there is not a universal consensus formula to predict patient survival. We developed a gene signature using the expression profile of 47 Gbs through an unsupervised procedure and two groups were obtained. Subsequent to a training procedure through leave-one-out cross-validation, we fitted a discriminant (linear discriminant analysis (LDA)) equation using the four most discriminant probesets. This was repeated for two other published signatures and the performance of LDA equations was evaluated on an independent test set, which contained status of IDH1 mutation, EGFR amplification, MGMT methylation and gene VEGF expression, among other clinical and molecular information. The unsupervised local signature was composed of 69 probesets and clearly defined two Gb groups, which would agree with primary and secondary Gbs. This hypothesis was confirmed by predicting cases from the independent data set using the equations developed by us. The high survival group predicted by equations based on our local and one of the published signatures contained a significantly higher percentage of cases displaying IDH1 mutation and non-amplification of EGFR. In contrast, only the equation based on the published signature showed in the poor survival group a significant high percentage of cases displaying a hypothesised methylation of MGMT gene promoter and overexpression of gene VEGF. We have produced a robust equation to confidently discriminate Gb subtypes based in the normalised expression level of only four genes

Characteristics and outcomes of adult patients in the PETHEMA registry with relapsed or refractory FLT3-ITD mutation-positive acute myeloid leukemia

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant.This study was supported by Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Valencia, Spain [CB16/12/00284]

C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

The GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of ALS and FTD. This mutation results in toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. A number of in vivo and in vitro models of gain and loss of function effects have suggested that both mechanisms synergize to cause the disease. However, the contribution of the loss of function mechanism remains poorly understood. We have generated C9ORF72 knockdown mice to mimic C9-FTD/ALS patients haploinsufficiency and investigate the role of this loss of function in the pathogenesis. We found that decreasing C9ORF72 leads to anomalies of the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43 and decreased synaptic density in the cortex. Knockdown mice also developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings show that C9ORF72 partial loss of function contributes to the damaging events leading to C9-FTD/ALS

Nutrición parenteral domiciliaria en España, 2019: informe del Grupo de Nutrición Artificial Domiciliaria y Ambulatoria NADYA

RESUMEN Objetivo: comunicar los datos de nutrición parenteral domiciliaria (NPD) obtenidos del registro del grupo NADYA-SENPE (www.nadyasenpe.com) del año 2019. Material y métodos: análisis descriptivo de los datos recogidos de pacientes adultos y pediátricos con NPD en el registro NADYA-SENPE desde el 1 de enero al 31 de diciembre de 2019. Resultados: se registraron 283 pacientes (51,9 %, mujeres), 31 niños y 252 adultos procedentes de 47 hospitales españoles, lo que representa una tasa de prevalencia de 6,01 pacientes/millón de habitantes/año 2019. El diagnóstico más frecuente en los adultos fue “oncológico paliativo” y “otros” (21,0 %). En los niños fue la enfermedad de Hirschsprung junto a la enterocolitis necrotizante, las alteraciones de la motilidad intestinal y la pseudoobstrucción intestinal crónica, con 4 casos cada uno (12,9 %). El primer motivo de indicación fue el síndrome del intestino corto tanto en los niños (51,6 %) como en los adultos (37,3 %). El tipo de catéter más utilizado fue el tunelizado tanto en los niños (75,9 %) como en los adultos (40,8 %). Finalizaron 68 episodios, todos en adultos: la causa más frecuente fue el fallecimiento (54,4 %). Pasaron a la vía oral el 38,2 %. Conclusiones: el número de centros y profesionales colaboradores con el registro NADYA va incrementándose. Se mantienen estables las principales indicaciones y los motivos de finalización de la NPD

Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains

[eng] Filamentous tau pathologies are the hallmark lesions of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and corticobasal degeneration (CBD). These diseases show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. In the study, the rapid induction of tau pathology and the distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau in human mutant P301S tau transgenic (Tg) mice (line PS19) is analysed. At 1 mo post-injection of extracts obtained from brains with CBD pathology (CBD-Tau), tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of enriched tau extracts from brains with AD pathology (AD-Tau) in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 mo post-injection. With longer post-injection survival intervals of up to 6 mo, CBD-Tau and AD-Tau induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type specific pattern noted above. In conclusion, these experiments provide evidence for the prion-like hypothesis of disease spread and suggest that the tau pathology formed in vivo is dependent on the tau pathology in the preparation indicating that there are post-translational modifications or strains of tau protein that are responsible for the variation between diseases.[spa] La enfermedad de Alzheimer (AD) y la degeneración corticobasal (CBD) son enfermedades neurodegenerativas que pertenecen al grupo de las taupatías. Estas enfermedades se caracterizan por presentar agregados de proteína tau intracelulares. Cada una de estas enfermedades se manifiesta con unos síntomas clínicos propios, una determinada distribución de los agregados de tau y una afectación celular específica. Estudios recientes sugieren que la proteína tau se puede transmitir de una célula a otra por trayectos anatómicos determinados, a través de la conexión entre neuronas, de forma similar a lo que occurre con los priones. En el estudio se describe como tras la inyección de extractos enriquecidos con tau patológica obtenidos de tejido cerebral humano de donantes afectos de AD y CBD en ratones transgénicos que sobreexpresan la proteína tau con la mutación P301S (línea PS19) éstos desarrollan patología tau. Los agregados de tau aparecen rápidamente, a los 30 días posteriores a la inyección. Estos agregados presentan unas características similares a las inclusiones observadas en las enfermedades humanas correspondientes, de forma que los ratones inyectados con extractos protéicos obtenidos de casos afectos de CBD desarrollan patología predominantemente en células gliales mientras que los ratones inyectados con extractos obtenidos de casos afectos de AD desarrollan agregados en las neuronas. Asimismo, se observa un incremento de la patología tau con el aumento del tiempo transcurrido después de la inyección así como la propagación a regiones distantes a la zona de inyección que, en el caso de inyecciones con extractos de AD, se encuentran interconectadas mediante vías neuroanatómicas. En conclusión, estos experimentos proporcionan evidencia de la hipótesis de la transmisión “prion-like” de la enfermedad y sugieren que la patología tau generada in vivo depende de la patología tau en la preparación indicando que hay modificaciones postraduccionales o cepas de la proteína tau que son responsables de la variabilidad entre las enfermedades

Bancos de cerebro. Un reto para Latinoamérica.

International audienceMany of the latest findings to understand the pathogenesis of common and rare disorders of the nervous system have been produced by the use of post-mortem human brain tissue. Brain banks have played a crucial role in this process, rare and invaluable material. The function of a modern brain bank is the collection of post-mortem material or biopsy of clinically and pathologically well-characterized cases in a continuous and systematic manner, considering safety and ethical issues surrounding the use of human tissue for medical research. This review give importance of brain banks in the collection and storage of post-mortem material to satisfy the needs of specific research projects, the technical, ethical and legal aspects related to donation and manipulation of biological material, as well as proposing the development of a network in Latin America of brain banks that allows us to have material for the study of various diseases in our population.Muchos de los progresos recientes en la comprensión de la patogénesis de trastornos comunes y raros del sistema nervioso se han producido mediante el uso de tejido cerebral humano post-mortem. Los bancos de cerebros han tenido un papel crucial en este proceso, proporcionando material raro e invaluable. La función de un banco de cerebro moderno es recolectar material post-mortem o de biopsia de casos clínicamente y patológicamente bien caracterizados de manera continua y sistemática, considerando cuestiones de seguridad y éticas que rodean el uso de tejido humano donado para investigación médica. El presente artículo llama la atención sobre la importancia de los bancos de cerebro, en la recolección y almacenamiento de material post-mortem para satisfacer las necesidades de proyectos de investigación específicos, los aspectos tanto técnicos como éticos y legales, relacionados a la donación y manipulación de material biológico, así como proponer el desarrollo de una red en América Latina de bancos de cerebro que permita contar con material de estudio de diversos padecimientos en nuestra población

'Keeping the plates spinning': a qualitative study of the complexity, barriers, and facilitators to caregiving in heart failure with preserved ejection fraction

AimsHeart failure with preserved ejection fraction (HFpEF) accounts for 50% of all heart failure cases; yet remains poorly understood, diagnosed, and managed, which adds complexity to the carer role. No study to date has investigated the experiences of informal carers of people with HFpEF. The aim of this study was to explore the role and experiences of informal carers of people with HFpEF.Methods and resultsA qualitative study using semi-structured interviews involving carers alone, patients alone, or carer/patient dyads. The interviews were part of a larger programme of research in HFpEF. Participants were recruited from three regions of England. Interviews were recorded, transcribed verbatim, and analysed thematically. Twenty-two interviews were conducted with 38 participants, 17 were informal carers. Three inter-related themes were identified: Theme 1, the complex nature of informal caregiving ('spinning plates'); Theme 2, the barriers to caregiving ('the spinning falters'); and Theme 3, the facilitators of caregiving ('keeping the plates spinning').ConclusionsInformal carers play an important role in supporting people with HFpEF. The experience of caregiving in HFpEF is similar to that described for Heart Failure with reduced Ejection Fraction, but complicated by challenges of limited information and support specific to HFpEF, and high burden of multi-morbidity. Healthcare providers should assess the needs of informal carers as part of patient care in HFpEF. Carers and patients would benefit from improved information and co-ordinated management of HFpEF and multi-morbidities. Helping carers 'keep the plates spinning' will require innovative approaches and co-ordination across the care continuum

Visual deep learning-based explanation for neuritic plaques segmentation in Alzheimer's Disease using weakly annotated whole slide histopathological images

International audienceQuantifying the distribution and morphology of tau protein structures in brain tissues is key to diagnosing Alzheimer's Disease (AD) and its subtypes. Recently, deep learning (DL) models such as UNet have been successfully used for automatic segmentation of histopathological whole slide images (WSI) of biological tissues. In this study, we propose a DL-based methodology for semantic segmentation of tau lesions (i.e., neuritic plaques) in WSI of postmortem patients with AD. The state of the art in semantic segmentation of neuritic plaques in human WSI is very limited. Our study proposes a baseline able to generate a significant advantage for morphological analysis of these tauopathies for further stratification of AD patients. Essential discussions concerning biomarkers (ALZ50 versus AT8 tau antibodies), the imaging modality (different slide scanner resolutions), and the challenge of weak annotations are addressed within this seminal study. The analysis of the impact of context in plaque segmentation is important to understand the role of the micro-environment for reliable tau protein segmentation. In addition, by integrating visual interpretability, we are able to explain how the network focuses on a region of interest (ROI), giving additional insights to pathologists. Finally, the release of a new expert-annotated database and the code (https://github.com/aramis-lab/miccai2022-stratifiad.git) will be helpful for the scientific community to accelerate the development of new pipelines for human WSI processing in AD