Dysregulation of heat shock protein 27 expression in oral tongue squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Recent proteomic studies identified Hsp27 as a highly over-expressed protein in oral squamous cell carcinoma (OSCC). Clinical studies that attempted to evaluate the prognostic values of Hsp27 yielded inconsistent results, which may be due to inclusion of OSCC cases from multiple anatomic sites. In this study, to determine the utility of Hsp27 for prognosis, we focused on oral tongue SCC (OTSCC), one of the most aggressive forms of OSCC.</p> <p>Methods</p> <p>Archival clinical samples of 15 normal oral tongue mucosa, 31 dysplastic lesions, 80 primary OTSCC, and 32 lymph node metastases were examined for Hsp27 expression by immunohistochemistry (IHC). Statistical analyses were carried out to assess the prognostic value of Hsp27 expression for patients with this disease.</p> <p>Results</p> <p>Dysregulation of Hsp27 expression was observed in dysplastic lesions, primary OTSCC, and lymph node metastases, and appears to be associated with disease progression. Statistical analysis revealed that the reduced Hsp27 expression in primary tumor tissue was associated with poor differentiation. Furthermore, the higher expression of Hsp27 was correlated with better overall survival.</p> <p>Conclusion</p> <p>Our study confirmed that the dysregulation of Hsp27 expression is a frequent event during the progression of OTSCC. The expression of Hsp27 appears to be an independent prognostic marker for patients with this disease.</p

ANO1 amplification and expression in HNSCC with a high propensity for future distant metastasis and its functions in HNSCC cell lines

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is associated with poor survival. To identify prognostic and diagnostic markers and therapeutic targets, we studied ANO1, a recently identified calcium-activated chloride channel (CaCC). METHODS: High-resolution genomic and transcriptomic microarray analysis and functional studies using HNSCC cell line and CaCC inhibitors. RESULTS: Amplification and overexpression of genes within the 11q13 amplicon are associated with the propensity for future distance metastasis of HPV-negative HNSCC. ANO1 was selected for functional studies based on high correlations, cell surface expression and CaCC activity. ANO1 overexpression in cells that express low endogenous levels stimulates cell movement, whereas downregulation in cells with high endogenous levels has the opposite effect. ANO1 overexpression also stimulates attachment, spreading, detachment and invasion, which could account for its effects on migration. CaCC inhibitors decrease movement, suggesting that channel activity is required for the effects of ANO1. In contrast, ANO1 overexpression does not affect cell proliferation. INTERPRETATION: ANO1 amplification and expression could be markers for distant metastasis in HNSCC. ANO1 overexpression affects cell properties linked to metastasis. Inhibitors of CaCCs could be used to inhibit the tumourigenic properties of ANO1, whereas activators developed to increase CaCC activity could have adverse effects

The Role of Additive Neurogenesis and Synaptic Plasticity in a Hippocampal Memory Model with Grid-Cell Like Input

Recently, we presented a study of adult neurogenesis in a simplified hippocampal memory model. The network was required to encode and decode memory patterns despite changing input statistics. We showed that additive neurogenesis was a more effective adaptation strategy compared to neuronal turnover and conventional synaptic plasticity as it allowed the network to respond to changes in the input statistics while preserving representations of earlier environments. Here we extend our model to include realistic, spatially driven input firing patterns in the form of grid cells in the entorhinal cortex. We compare network performance across a sequence of spatial environments using three distinct adaptation strategies: conventional synaptic plasticity, where the network is of fixed size but the connectivity is plastic; neuronal turnover, where the network is of fixed size but units in the network may die and be replaced; and additive neurogenesis, where the network starts out with fewer initial units but grows over time. We confirm that additive neurogenesis is a superior adaptation strategy when using realistic, spatially structured input patterns. We then show that a more biologically plausible neurogenesis rule that incorporates cell death and enhanced plasticity of new granule cells has an overall performance significantly better than any one of the three individual strategies operating alone. This adaptation rule can be tailored to maximise performance of the network when operating as either a short- or long-term memory store. We also examine the time course of adult neurogenesis over the lifetime of an animal raised under different hypothetical rearing conditions. These growth profiles have several distinct features that form a theoretical prediction that could be tested experimentally. Finally, we show that place cells can emerge and refine in a realistic manner in our model as a direct result of the sparsification performed by the dentate gyrus layer

Synergetic Effects of Granulocyte-Colony Stimulating Factor and Cognitive Training on Spatial Learning and Survival of Newborn Hippocampal Neurons

Granulocyte-Colony Stimulating Factor (G-CSF) is an endogenous hematopoietic growth factor known for its role in the proliferation and differentiation of cells of the myeloic lineage. Only recently its significance in the CNS has been uncovered. G-CSF attenuates apoptosis and controls proliferation and differentiation of neural stem cells. G-CSF activates upstream kinases of the cAMP response element binding protein (CREB), which is thought to facilitate the survival of neuronal precursors and to recruit new neurons into the dentate gyrus. CREB is also essential for spatial long-term memory formation. To assess the role and the potential of this factor on learning and memory-formation we systemically administered G-CSF in rats engaged in spatial learning in an eight-arm radial maze. G-CSF significantly improved spatial learning and increased in combination with cognitive training the survival of newborn neurons in the hippocampus as measured by bromodeoxyuridine and doublecortin immunohistochemistry. Additionally, G-CSF improved re-acquisition of spatial information after 26 days. These findings support the hypothesis that G-CSF can enhance learning and memory formation. Due to its easy applicability and its history as a well-tolerated hematological drug, the use of G-CSF opens up new neurological treatment opportunities in conditions where learning and memory-formation deficits occur

Hippocampal lesions impair performance on a conditional delayed matching and non-matching to position task in the rat

The hippocampus is thought to be involved in a range of cognitive processes, from the ability to acquire new memories, to the ability to learn about spatial relationships. Humans and monkeys with damage to the hippocampus are typically impaired on delayed matching to sample tasks, of which the operant delayed matching to position task (DMTP) is a rat analogue. The reported effects of hippocampal damage on DMTP vary, ranging from delay-dependent deficits to no deficit whatsoever. The present study investigates a novel memory task; the conditional delayed matching/non-matching to position task (CDM/NMTP) in the Skinner box. CDM/NMTP uses the presence of specific stimulus cues to signify whether a particular trial is matching or non-matching in nature. Thus, it incorporates both the task contingencies within one session, and supplements the requirement for remembering the side of the lever in the sample phase with attending to the stimulus and remembering the conditional discrimination for the rule. Rats were trained preoperatively and the effects of bilateral excitotoxic lesions of the hippocampus were examined on postoperative retention of the task. Rats with lesions of the hippocampus incurred a significant impairment on the task that was manifest at all delays intervals. Despite a bias towards matching during training, trials of either type were performed with equivalent accuracy and neither rule was affected differentially by the lesion. This task may prove useful in determining the cognitive roles of a range of brain areas