Technetium-99m sestamibi single photon emission computed tomography findings correlated with P-glycoprotein expression in pituitary adenoma.

The aim of this study is to evaluate whether the technetium-99m sestamibi (99mTc-MIBI) single photon emission computed tomography (SPECT) characteristics of pituitary adenomas might be correlated with cavernous sinus invasion, proliferative potential or the multidrug-resistance (MDR-1) gene product P-glycoprotein (Pgp) expression in pituitary adenomas. Fifteen patients with pituitary adenomas, including 10 nonfunctioning adenomas, two prolactinomas, two GH producing adenomas, and one ACTH producing adenomas was investigated for this study. SPECT images with 99mTc-MIBI were acquired 15 minutes (early) and 3 hours (delayed) after injection. The tumor-to-normal brain ratio was calculated both early (ER) and delayed (DR) images. Retention index (RI) was calculated using the following formula : (DR-ER)/ER×100%. The pituitary adenomas specimens were examined by immunohistochemistry using anti-Pgp and MIB-1 monoclonal antibodies. 99mTc-MIBI SPECT findings were not related to MIB-1 labeling index or cavernous sinus invasion. 99mTc-MIBI SPECT RI (-38.55±20.77) of the Pgp-positive group was significantly lower than that (-15.78±19.40) of Pgp-negative group (p=0.0494). No siginificant difference was observed in the ER and DR of 99mTc-MIBI SPECT between Pgp-positive and negative groups. Our study suggests that although99mTc-MIBI SPECT is not useful to evaluate the proliferative potential or cavernous sinus invasion of pituitary adenomas. 99mTc-MIBI SPECT could predict anti-cancer drug resistance related to the expression of Pgp in pituitary adenomas

Reduction of expression of the multidrug resistance protein (MRP)1 in glioma cells by antisense phosphorothioate oligonucleotides

The tumor cells’ acquisition of resistance to multiple drugs due to overexpression of the multidrug resistance protein(MRP) 1gene is one of major obstacles in cancer chemotherapy. We have attempted to reverse the multidrug resistance (MDR) phenotype by treating etoposide resistant glioma cell lines (T98G-VP and Gli36-VP) with MRP1 antisense oligonucleotides. 20-mer phosphorothioate oligodeoxynucleotide (0.3μM), complementary to the coding region in the MRP cDNA sequence, could significantly inhibit the growth of multidrug resistant cell lines, T98G-VP and Gli36-VP, cultured in etoposide containing medium. No such effect was observed for the parental T98G and Gli36 cell lines. Further investigations by the reverse transcription-polymerase chain reaction and immunoblotting revealed that antisense oligomer could result in a reduction in the level of MRP1 mRNA, probably through hindering MRP1 gene transcription. This study demonstrates that the antisense oligonucleotides can increase the sensitivity of the tumor cells to the anticancer drug by decreasing the expression of the MRP gene. This strategy may be applicable to cure cancer patients with MRP mediated MDR phenotype

Matrix metalloproteinase 2 and 9 expression correlated with cavernous sinus invasion of pituitary adenomas

Object :Matrix metalloproteinase (MMP) 2 and 9 are important for tissue breakdown in the process of tumor invasion. The aim of this study is to evaluate the relationship between the expression of MMP-2, MMP-9,MIB-1 LI and cavernous sinus invasion in pituitary adenomas. Methods : Tissue samples from54 patients with pituitary adenomas were studied. Expression of MMP-2, MMP-9, and MIB-1 labeling index (LI) were evaluated by immunohistochemical method. In sixteen cases, the expression of MMP-2 and MMP-9 mRNA was also examined by RT-PCR assay. Results : Thirty-four patients were women and 20 were men, with a mean age of 49.9 years old (range 18-76 years). There were 12 cases with cavernous sinus invasion, and 42 were noninvasive cases. MMP-2 and MMP-9 score of invasive case (3.9±0.5, 4.1±0.4)were significantly higher than those (2.3±0.2 p＜0.01 2.6±0.2 p＜0.01) without invasion. The MIB-1 LI of this study presented no significantly difference between the invasive and noninvasive pituitary adenomas. The percentage of MMP-2 mRNA/β-actin mRNA and MMP-9 mRNA/β-actin mRNA were also observed significantly higher in invasive pituitary adenomas (68.2±15.3 % 59.7±12.5 %) than noninvasive pituitary adenomas (21.8±8.2 % , p＜0.05 33.3±5.4 % , p＜0.05). Conclusions : Our study suggests that the expression of MMP-2 and MMP-9 may have a value to assess the invasive pituitary adenomas, and proliferation and invasion of pituitary adenomas may present a different mechanism

Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas

<p>Abstract</p> <p>Background</p> <p>Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity <it>in vitro</it>. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas.</p> <p>Methods</p> <p>To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition <it>in vitro </it>using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m²/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).</p> <p>Results</p> <p>Doxycyline <it>in vitro </it>completely abolished MMP-9 activity at 500 μg/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.</p> <p>Conclusion</p> <p>Doxycycline can block MMP-2 and MMP-9 activities from glioma cells <it>in vitro</it>. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.</p

Correlates of reward-predictive value in learning-related hippocampal neural activity

Temporal difference learning (TD) is a popular algorithm in machine learning. Two learning signals that are derived from this algorithm, the predictive value and the prediction error, have been shown to explain changes in neural activity and behavior during learning across species. Here, the predictive value signal is used to explain the time course of learning-related changes in the activity of hippocampal neurons in monkeys performing an associative learning task. The TD algorithm serves as the centerpiece of a joint probability model for the learning-related neural activity and the behavioral responses recorded during the task. The neural component of the model consists of spiking neurons that compete and learn the reward-predictive value of task-relevant input signals. The predictive-value signaled by these neurons influences the behavioral response generated by a stochastic decision stage, which constitutes the behavioral component of the model. It is shown that the time course of the changes in neural activity and behavioral performance generated by the model exhibits key features of the experimental data. The results suggest that information about correct associations may be expressed in the hippocampus before it is detected in the behavior of a subject. In this way, the hippocampus may be among the earliest brain areas to express learning and drive the behavioral changes associated with learning. Correlates of reward-predictive value may be expressed in the hippocampus through rate remapping within spatial memory representations, they may represent reward-related aspects of a declarative or explicit relational memory representation of task contingencies, or they may correspond to reward-related components of episodic memory representations. These potential functions are discussed in connection with hippocampal cell assembly sequences and their reverse reactivation during the awake state. The results provide further support for the proposal that neural processes underlying learning may be implementing a temporal difference-like algorithm

Pattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Impairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses.</p> <p>Methods</p> <p>104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis.</p> <p>Results</p> <p>During the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls.</p> <p>Conclusions</p> <p>In summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia.</p

Immunohistochemical study of transthyretin in normal brain and brain tumors - Light and electron microscopic investigation with special reference to choroid plexus papilloma and ependymoma -

An immunohistochemical study of transthyretin (TTR), synthesized in the choroid plexus epithelia, was performed in normal brain tissue and 92 brain tumors. Glial fibrillary acidic protein (GFAP) and cytokeratin (CKER) were also examined in 11 choroid plexus papillomas (CPPs) and 19 ependymomas. A positive TTR reaction was observed diffusely in the majority of normal choroid plexus epithelia. All of the 11 cases of CPP were positive for TTR, but the other tissues and tumors (including ependymomas) were negative for TTR. GFAP -positive cells were occasionally found in five of the CPPs. The majority of the GFAP -positive cells were also positive for CKER, but not for TTR. There was an inverse relationship between the intensity of immunostaining for GFAP and for TTR in CPPs. Among the 19 cases of ependymomas, 16 were positive for GFAP, 3 for CKER, but none for TTR. TTR can be a very useful and diagnostic marker of CPP. A consective semithin-thin section microscopic method demonstrated abundant secretory granules and well-developed Golgi apparatus in TTR-positive cells. By immunoelectron microscopy using a pre-embedding method, a positive reaction for TTR was observed in the secretory granules. This result suggested that CPP cells as well as choroid plexus cells synthesize TTR de novo