Neural mechanisms of reward processing in attention-deficit/hyperactivity disorder

Contains fulltext : 148926.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 21 december 2015Promotores : Buitelaar, J.K., Cools, R. Co-promotor : Mennes, M.J.J

Establishment and characterization of the first patient-derived radiation-induced angiosarcoma xenograft model (RT-AS5).

Angiosarcomas are a heterogeneous group of rare endothelial malignancies with a complex, not completely unravelled biology. They encompass primary (sporadically occurring) angiosarcomas of several origins and secondary angiosarcomas, which often arise due to DNA damaging factors including radiotherapy or ultraviolet light exposure. The optimal treatment of metastatic angiosarcomas is unclear and the prognosis is poor. In order to discover novel treatment strategies for angiosarcomas it is important to take the heterogeneity of these tumors into account. For this reason it is also important to have preclinical models available for the different clinical subtypes. Owing to the rarity of angiosarcomas, models are scarce. So far, only five human cell lines of angiosarcomas (all of the scalp after UV exposure) are available worldwide. In this paper we describe a novel established patient-derived xenograft model of a radiotherapy-induced angiosarcoma of the breast. The tumor was characterized by a MYC amplification, CD31 and ERG immunohistochemical positivity and was further characterized by using next generation sequencing (TruSight Oncology 500) in combination with the R-package XenofilteR to separate mouse from human sequence reads

Evaluation of a Hybrid Capture-Based Pan-Cancer Panel for Analysis of Treatment Stratifying Oncogenic Aberrations and Processes

Contains fulltext : 219804.pdf (Publisher’s version ) (Open Access

Network-level assessment of reward-related activation in patients with ADHD and healthy individuals

Contains fulltext : 174503pub.pdf (Publisher’s version ) (Closed access)INTRODUCTION: Reward processing is a key aspect of cognitive control processes, putatively instantiated by mesolimbic and mesocortical brain circuits. Deficient signaling within these circuits has been associated with psychopathology. We applied a network discovery approach to assess specific functional networks associated with reward processing in participants with attention-deficit/hyperactivity disorder (ADHD). METHODS: To describe task-related processes in terms of integrated functional networks, we applied independent component analysis (ICA) to task response maps of 60 healthy participants who performed a monetary incentive delay (MID) task. The resulting components were interpreted on the basis of their similarity with group-level task responses as well as their similarity with brain networks derived from resting state fMRI analyses. ADHD-related effects on network characteristics including functional connectivity and communication between networks were examined in an independent sample comprising 150 participants with ADHD and 48 healthy controls. RESULTS: We identified 23 components to be associated with 4 large-scale functional networks: the default-mode, visual, executive control, and salience networks. The salience network showed a specific association with reward processing as well as the highest degree of within-network integration. ADHD was associated with decreased functional connectivity between the salience and executive control networks as well as with peripheral brain regions. CONCLUSIONS: Reward processing as measured with the MID task involves one reward-specific and three general functional networks. Participants with ADHD exhibited alterations in connectivity of both the salience and executive control networks and associated brain regions during task performance. Hum Brain Mapp 38:2359-2369, 2017. (c) 2017 Wiley Periodicals, Inc

The link between callous-unemotional traits and neural mechanisms of reward processing: An fMRI study

Contains fulltext : 167386pub.pdf (publisher's version ) (Closed access)Callous-unemotional (CU) traits, i.e., unconcernedness and lack of prosocial feelings, may manifest in Conduct Disorder (CD), but also in Oppositional Defiant Disorder (ODD) and Attention Deficit Hyperactivity Disorder (ADHD). These disorders have been associated with aberrant reward processing, while the influence of CU traits is unclear. Using functional Magnetic Resonance Imaging (fMRI), we examined whether CU traits affect the neural circuit for reward. A Monetary Incentive Delay (MID) task was administered to 328 adolescents and young adults with varying levels of CU traits: 40 participants with ODD/CD plus ADHD, 101 participants with ADHD only, 84 siblings of probands with ADHD and 103 typically developing (TD) individuals. During reward anticipation, CU traits related negatively to medial prefrontal cortex (mPFC) activity, independent of ADHD symptoms and ODD/CD diagnosis. Our results indicate that CU traits are a valuable dimension for assessing the neural basis of reward processing

Variation in serotonin neurotransmission genes affects neural activation during response inhibition in adolescents and young adults with ADHD and healthy controls

Contains fulltext : 152924.pdf (publisher's version ) (Closed access)OBJECTIVES: Deficits in response inhibition have been associated with attention-deficit/hyperactivity disorder (ADHD). Given the role of serotonin in ADHD and impulsivity, we postulated that genetic variants within the serotonin pathway might influence response inhibition. METHODS: We measured neural activation during stop-signal task performance in adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and healthy controls (N = 124), and investigated the relationship of two serotonin gene polymorphisms (the rs6296 SNP of the HTR1B gene and HTTLPR variants of the 5-HTT gene) with the neural correlates of response inhibition. RESULTS: The whole-brain analyses demonstrated large scale neural activation differences in the inferior and medial frontal and temporal/parietal regions of the response inhibition network between the different variants of both the HTR1B and 5HTT genes. Activation in these regions was significantly associated with stop-task performance, but not with ADHD diagnosis or severity. No associations were found between HTR1B and 5HTT variants and ADHD or ADHD-related neural activation. CONCLUSIONS: These results provide novel evidence that serotonin may play an important role in the neurobiology of response inhibition. Although response inhibition is strongly linked to ADHD, serotonin linked genetic variants associated with response inhibition and its neural correlates do not explain variance of the ADHD phenotype

Clinical Validity of Tumor-Informed Circulating Tumor DNA Analysis in Patients Undergoing Surgery of Colorectal Metastases.

BACKGROUND: Accurate biomarkers to monitor tumor load and response in metastatic colorectal cancer patients undergoing surgery could optimize treatment regimens. OBJECTIVE: This study aimed to explore the clinical validity of tumor-informed quantification of circulating tumor DNA in blood using ultradeep sequencing. DESIGN: Resection specimens from 53 colorectal cancer patients were analyzed for tumor-specific mutations in 15 genes. These mutations were used to measure the presence of circulating tumor DNA in preoperatively collected plasma samples using hybrid capture-based sequencing. Additional postoperative measurements were performed 1 week after surgery in 16 patients. SETTINGS: The study was conducted at the Radboud University Medical Center. PATIENTS: A total of 53 colorectal cancer patients undergoing surgery of metastases were included. MAIN OUTCOME MEASURES: The detection of circulating tumor DNA. RESULTS: At least 1 tumor-specific mutation was detected in all tumor samples. In preoperative plasma samples, circulating tumor DNA was detected in 88% (37/42) of systemic treatment-naïve patients and in 55% (6/11) of patients who received preoperative chemotherapy. More specifically, circulating tumor DNA was detected in 0% (0/3) of cases with a subtotal or partial pathologic response and in 75% (6/8) of cases without a pathologic response in the resection specimen ( p = 0.06). In postoperative plasma samples, circulating tumor DNA was detected in 80% (4/5) of patients with an incomplete resection and in 0% (0/11) of those with a complete resection ( p = 0.003). LIMITATIONS: The study was limited by the heterogeneity of the cohort and the small number of postoperative plasma samples. CONCLUSIONS: These data indicate that tumor-informed circulating tumor DNA detection in the plasma of patients undergoing surgery for metastatic colorectal cancer is feasible and may have clinical value in response monitoring and predicting residual disease. Prospective studies are needed to establish the clinical utility of circulating tumor DNA analysis to guide treatment decisions in these patients. See Video Abstract at http://links.lww.com/DCR/B990 . VALIDEZ CLNICA DEL ANLISIS DE ADN DEL TUMOR CIRCULANTE INFORMADO POR EL TUMOR EN PACIENTES SOMETIDOS A CIRUGA DE METSTASIS COLORRECTALES: ANTECEDENTES:Los biomarcadores precisos para monitorear la carga tumoral y la respuesta en pacientes con cáncer colorrectal metastásico que se someten a cirugía podrían optimizar los regímenes de tratamiento.OBJETIVO:Este estudio explora la validez clínica de la cuantificación informada por el tumor del ADN tumoral circulante en sangre mediante secuenciación ultraprofunda.DISEÑO:Se analizaron muestras de resección de 53 pacientes con cáncer colorrectal en busca de mutaciones específicas del tumor en quince genes. Estas mutaciones se usaron para medir la presencia de ADN tumoral circulante en muestras de plasma recolectadas antes de la operación usando secuenciación basada en captura híbrida. Se realizaron mediciones postoperatorias adicionales una semana después de la cirugía en dieciséis pacientes.AJUSTES:El estudio se realizó en el centro médico de la universidad de Radboud.PACIENTES:Se incluyeron un total de 53 pacientes con cáncer colorrectal sometidos a cirugía de metástasis.PRINCIPALES MEDIDAS DE RESULTADO:La detección de ADN tumoral circulante.RESULTADOS:Se detectó al menos una mutación específica de tumor en todas las muestras de tumor. En muestras de plasma preoperatorias, se detectó ADN tumoral circulante en el 88% (37/42) de los pacientes sin tratamiento sistémico previo y en el 55% (6/11) de los pacientes que recibieron quimioterapia preoperatoria. Más concretamente, en el 0% (0/3) de los casos con respuesta patológica subtotal o parcial y en el 75% (6/8) de los casos sin respuesta patológica en la pieza de resección ( p = 0,06). En muestras de plasma postoperatorio se detectó ADN tumoral circulante en el 80% (4/5) de los pacientes con una resección incompleta y en el 0% (0/11) de los que tenían resección completa ( p = 0,003).LIMITACIONES:El estudio estuvo limitado por la heterogeneidad de la cohorte y el pequeño número de muestras de plasma postoperatorias.CONCLUSIONES:Estos datos indican que la detección de ADN tumoral circulante informado por el tumor en el plasma de pacientes sometidos a cirugía por cáncer colorrectal metastásico es factible y puede tener valor clínico en el control de la respuesta y la predicción de la enfermedad residual. Se necesitan estudios prospectivos para establecer la utilidad clínica del análisis de ADN tumoral circulante para guiar las decisiones de tratamiento en estos pacientes. Consulte Video Resumen en http://links.lww.com/DCR/B990 . (Traducción-Dr. Mauricio Santamaria )