Michael G. Erkkinen

Temozolomide-Mediated Radiation Enhancement in Glioblastoma: A Report on Underlying Mechanisms

Purpose: In this study, we investigated the mechanisms by which temozolomide enhances radiation response in glioblastoma cells. Experimental Design: Using a panel of four primary human glioblastoma cell lines with heterogeneous O6-methylguanine-DNA methyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts, we investigated (a) the relationship of MGMT status with efficacy of temozolomide-based chemoradiation using a panel of in vitro and in vivo assays; (b) underlying mechanisms by which temozolomide enhances radiation effect in glioblastoma cells; and (c) strategies to overcome resistance to radiation + temozolomide. Results: Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA damage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest that O6-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O6-Benzylguanine was most effective when administered concurrently with radiation + temozolomide and had less of an effect when administered with temozolomide in the absence of radiation or when administered sequentially with radiation. Our in vivo data using U87 xenografts confirmed our in vitro findings. Conclusions: The present study shows that temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas by increasing the degree of radiation-induced double-strand DNA damage. In MGMT-positive glioblastomas, depletion of MGMT by the addition of O6-benzylguanine significantly enhances the antitumor effect of concurrent radiation + temozolomide. These are among the first data showing mechanisms of synergy between radiation and temozolomide and the effect of MGMT.

Neural Correlates of Lyrical Improvisation: An fMRI Study of Freestyle Rap

The neural correlates of creativity are poorly understood. Freestyle rap provides a unique opportunity to study spontaneous lyrical improvisation, a multidimensional form of creativity at the interface of music and language. Here we use functional magnetic resonance imaging to characterize this process. Task contrast analyses indicate that improvised performance is characterized by dissociated activity in medial and dorsolateral prefrontal cortices, providing a context in which stimulus-independent behaviors may unfold in the absence of conscious monitoring and volitional control. Connectivity analyses reveal widespread improvisation-related correlations between medial prefrontal, cingulate motor, perisylvian cortices and amygdala, suggesting the emergence of a network linking motivation, language, affect and movement. Lyrical improvisation appears to be characterized by altered relationships between regions coupling intention and action, in which conventional executive control may be bypassed and motor control directed by cingulate motor mechanisms. These functional reorganizations may facilitate the initial improvisatory phase of creative behavior.

Brain activity and connectivity during poetry composition: Toward a multidimensional model of the creative process

Creativity, a multifaceted construct, can be studied in various ways, for example, investigating phases of the creative process, quality of the creative product, or the impact of expertise. Previous neuroimaging studies have assessed these individually. Believing that each of these interacting features must be examined simultaneously to develop a comprehensive understanding of creative behavior, we examined poetry composition, assessing process, product, and expertise in a single experiment. Distinct activation patterns were associated with generation and revision, two major phases of the creative process. Medial prefrontal cortex (MPFC) was active during both phases, yet responses in dorsolateral prefrontal and parietal executive systems (DLPFC/IPS) were phase‐dependent, indicating that while motivation remains unchanged, cognitive control is attenuated during generation and re‐engaged during revision. Experts showed significantly stronger deactivation of DLPFC/IPS during generation, suggesting that they may more effectively suspend cognitive control. Importantly however, similar overall patterns were observed in both groups, indicating the same cognitive resources are available to experts and novices alike. Quality of poetry, assessed by an independent panel, was associated with divergent connectivity patterns in experts and novices, centered upon MPFC (for technical facility) and DLPFC/IPS (for innovation), suggesting a mechanism by which experts produce higher quality poetry. Crucially, each of these three key features can be understood in the context of a single neurocognitive model characterized by dynamic interactions between medial prefrontal areas regulating motivation, dorsolateral prefrontal, and parietal areas regulating cognitive control and the association of these regions with language, sensorimotor, limbic, and subcortical areas distributed throughout the brain. Hum Brain Mapp 36:3351–3372, 2015.

Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases

Neurodegenerative diseases are a common cause of morbidity and cognitive impairment in older adults. Most clinicians who care for the elderly are not trained to diagnose these conditions, perhaps other than typical Alzheimers disease (AD). Each of these disorders has varied epidemiology, clinical symptomatology, laboratory and neuroimaging features, neuropathology, and management. Thus, it is important that clinicians be able to differentiate and diagnose these conditions accurately. This review summarizes and highlights clinical aspects of several of the most commonly encountered neurodegenerative diseases, including AD, frontotemporal dementia (FTD) and its variants, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Parkinsons disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Huntingtons disease (HD). For each condition, we provide a brief overview of the epidemiology, defining clinical symptoms and diagnostic criteria, relevant imaging and laboratory features, genetics, pathology, treatments, and differential diagnosis.

An anomalous developmental venous anomaly

Developmental venous anomalies (DVA) are congenital variants of cerebral veins, found incidentally at autopsy in 2.6% of the population, which are most often asymptomatic.1 Symptomatic compression of a cranial nerve by the collecting vein of a DVA is extremely rare, such as tinnitus from compression of the vestibulocochlear nerve.2

Abstract 2484: Aurora B silencing attenuates radiation resistance through PARP and identification of a missense mutation in aurora B as a determinant of radiosensitization in gliomas

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Purpose: Aurora B (Aur B), a mitotic protein located on chromosome 17p13.1, is critical for proper chromosome segregation and changes in chromosome 17p are quite common in glioblastoma multiforme (GBM). Upregulation of Aur B induces multicellularity and fosters polyploidy. Aur B reaches maximum levels later in mitosis and regulates the chromosomal passenger complex progression. It has been reported that Aur B expression markedly correlates with short survival of GBM patients and may be a prognostic factor. Targeting Aur B is an ideal strategy, since it is active during mitosis and non-proliferating cells would not be adversely affected. Materials and Methods: The cell lines used for this study include both established and primary GBM cell lines. Radiation experiments were conducted using gammacell irradiator. DNA damage was estimated using comet assay. Apoptosis, cell cycle and multinucleated polyploid cells were estimated using flow cytometry. Gene silencing and overexpression were carried out using established protocols. Results and Discussion: Aur B expression increases after radiation in GBM cells and not in normal human astrocytes as determined both at transcriptional and translational levels. The radiosensitivity of cells lines was estimated by clonogenic survival assay. Through sequencing Aur B, we discovered mutations at the 885(C) and 893(T) residues in the GBM cell lines. The 885(C) was a silent mutation and 893(T) leads to an amino acid change from methionine (M) to threonine (T). This missense mutation leads to a new phospho site. The GBM cell lines tested had heterozygous and homozygous deletions. The radiosensitivity assay conducted on these cell lines shows a differential response with regards to the nature of mutation. The cell lines which had homozygous deletions on both sites 885(C) and 893(T) exhibit an increased radioresistance under in vitro conditions when compared to one of them being a heterozygote. Further, we show that Aur B silencing inhibits cytokinesis leading to 4N or 8N DNA content in p53 functional cell lines. The endoreduplicated cells due to Aur-B inhibition leads to the loss of viability in p53 mutant/null cell lines. Overexpression of Aur B increases the DNA repair enzyme PARP and scaffolding protein XRCC1 after radiation, which are critical for the activation and recruitment of Base Excision Repair. Whereas, silencing Aur B decreases the PARP expression levels. Conclusion: In GBM cell lines, we report that Aur B knockdown sensitizes cells to radiation and over expression of Aur B leads to radioresistance. Thus far, one of the prime targets in mediating this effect was found to be PARP, since silencing and forced induction of Aur B correlates with expression levels of PARP. For the first time, we have shown that the mutational status of Aur B alters the radiation sensitivity. Further in vivo studies are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2484. doi:10.1158/1538-7445.AM2011-2484