Enhanced sensitivity of celecoxib in human glioblastoma cells: Induction of DNA damage leading to p53-dependent G1 cell cycle arrest and autophagy

Background  

Selective cyclooxygenase (COX)-2 inhibitors elicit anti-proliferative responses in various tumours, however the underlying anti-tumour mechanisms are unclear. Mutational inactivation of the tumour suppressor p53 gene is frequent in malignant gliomas. The role of p53 mutation in the anti-tumour responses of the selective COX-2 inhibitor celecoxib in human glioblastoma cells is unknown. In this study, we used human glioblastoma cells with various p53 status; U87MG (with high and low p53 functional levels), LN229 (functional p53) and U373MG (mutant p53) cells. Inhibition of p53 was achieved in U87MG cells transfected with E6 oncoprotein (U87MG-E6) and treated with pifithrin-α, a reversible inhibitor of p53 (U87MG-PFT). We investigated whether the anti-glioblastoma responses of celecoxib were p53-dependent, and whether celecoxib induced DNA damage leading to p53-dependent G₁ cell cycle arrest, followed by autophagy or apoptosis.     

CYT997 Causes apoptosis in human multiple myeloma

Multiple Myeloma (MM) is an incurable malignancy of mature plasma cells. Microtubule targeting agents (MTAs) are an established class of drug that include many conventional and some novel compounds. MTAs function by inhibiting the polymerisation or depolymerisation of microtubules (MTs) within the cell, disrupting various important cellular functions. We have investigated pre-clinically the novel tubulin polymerisation inhibitor CYT997 for the potential treatment of MM. Here we demonstrate the promising anti-myeloma activity of CYT997 as evidenced by tubulin disruption, inhibition of growth and proliferation, cell cycle arrest and most importantly apoptosis of both human myeloma cell lines (HMCLs) and primary MM cells using nanomolar drug concentrations. CYT997 also synergises with bortezomib to produce more potent anti-MM activity. These in vitro observations were validated in vivo by the ability of CYT997 to significantly prolong survival in a murine model of aggressive systemic myelomatosis. These findings provide a basis for continuing pre-clinical and clinical investigations into the anti-MM effects of CYT997.     

Human tapeworms in north Vietnam

Sixty-five Taenia samples were collected from patients in a referral hospital in Hanoi, north Vietnam, for species identification by morphological and molecular techniques. PCR-RFLP of a mitochondrial 12S rDNA fragment, developed for this study, allowed direct differentiation between all Taenia spp., overcoming the disadvantages of classical morphological examination, which failed on disintegrated samples. Taenia saginata asiatica was the most common species (55.4%) followed by T. saginata (38.5%) and T. solium (6.2%). This report demonstrates the complexity of the epidemiology of Taenia spp. in Vietnam and the need for further work to reveal transmission patterns of these species.     

Dynamic contrast-enhanced magnetic resonance imaging for characterising nasopharyngeal carcinoma: comparison of semiquantitative and quantitative parameters and correlation with tumour stage

Objectives

To evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for characterising nasopharyngeal carcinoma (NPC).

Methods

Forty-five newly diagnosed NPC patients were recruited. The initial enhancement rate (E _R ), contrast transfer rate (k _ep ), elimination rate (k _el ), maximal enhancement (MaxEn) and initial area under the curve (iAUC) were calculated from semiquantitative analysis. The K ^trans (volume transfer constant), v _e (volume fraction) and k _ep were calculated from quantitative analysis. Student’s t-test was used to evaluate the differences among tumour stages. Pearson’s correlation between the two sets of k _ep was performed.

Results

Comparing tumours of T1/2 stage (n?=?18) and T3/4 stage (n?=?27), MaxEn (P?=?0.030) and iAUC (P?=?0.039) were both significantly different; however, the iAUC was the only independent variable with 69.6 % sensitivity and 76.5 % specificity respectively; v _e was also significantly different (P?=?0.010) with 69.6 % sensitivity and 70.6 % specificity respectively. No significant difference was found among N stages. The two sets of k _ep s were highly correlated (r?=?0.809, P?<?0.001). Forty-three patients had chemoradiation, one palliative chemotherapy and one radiotherapy only. In the four patients with poor outcome, k _el, E _R, MaxEn and iAUC tended to be higher.

Conclusions

Neovasculature in higher T stage NPC exhibits some parameters of increased permeability and perfusion. Thus, DCE-MRI may be helpful as an adjunctive technique in evaluating NPC.

Key Points

? The correct assessment of nasopharyngeal carcinoma (NPC) is important for planning treatment. ? Neovasculature in higher T stage NPC exhibits increased permeability and perfusion. ? Correlation between quantitative and semi-quantitative analysis validates the robustness of DCE-MRI. ? DCE-MRI may be helpful as an adjunctive parameter in evaluating NPC.     

Defective deep placentation

Defective deep placentation is characterised by defective remodelling of the utero-placental arteries. Under certain conditions, it is also characterised by the presence of arterial lesions, such as acute atherosis and the persistence of endovascular trophoblast. The condition has been associated with a spectrum of complications during pregnancy, including pre-eclampsia, intrauterine growth restriction, pre-term birth, pre-term premature rupture of membranes, late sporadic miscarriage and abruptio placentae. Criteria are proposed for the classification of defective deep placentation into three types based on the degree of restriction of remodelling and the presence of obstructive lesions in the myometrial segment of the spiral arteries. Although the underlying mechanisms are not understood, evidence is emerging that the origin of defective deep placentation may not lie in primary defect of the trophoblast, but in abnormalities of the endometrium and inner myometrium before or during the early stages of placentation.     

Investigating the enhancement of template-free activation detection of event-related fMRI data using wavelet shrinkage and figures of merit

Objective

We propose a method for preprocessing event-related functional magnetic resonance imaging (fMRI) data that can lead to enhancement of template-free activation detection. The method is based on using a figure of merit to guide the wavelet shrinkage of a given fMRI data set.

Background

Several previous studies have demonstrated that in the root-mean-square error setting, wavelet shrinkage can improve the signal-to-noise ratio of fMRI time courses. However, preprocessing fMRI data in the root-mean-square error setting does not necessarily lead to enhancement of template-free activation detection. Motivated by this observation, in this paper, we move to the detection setting and investigate the possibility of using wavelet shrinkage to enhance template-free activation detection of fMRI data.

Methodology

The main ingredients of our method are (i) forward wavelet transform of the voxel time courses, (ii) shrinking the resulting wavelet coefficients as directed by an appropriate figure of merit, (iii) inverse wavelet transform of the shrunk data, and (iv) submitting these preprocessed time courses to a given activation detection algorithm. Two figures of merit are developed in the paper, and two other figures of merit adapted from the literature are described.

Results

Receiver-operating characteristic analyses with simulated fMRI data showed quantitative evidence that data preprocessing as guided by the figures of merit developed in the paper can yield improved detectability of the template-free measures. We also demonstrate the application of our methodology on an experimental fMRI data set.

Conclusions

The proposed method is useful for enhancing template-free activation detection in event-related fMRI data. It is of significant interest to extend the present framework to produce comprehensive, adaptive and fully automated preprocessing of fMRI data optimally suited for subsequent data analysis steps.     

A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia

BACKGROUND: Diffusion tensor imaging (DTI) can be used to investigate cerebral structural connectivity in never-medicated individuals with first-episode schizophrenia. METHOD: Subjects with first-episode schizophrenia according to DSM-IV-R who had never been exposed to antipsychotic medication (n=25) and healthy controls (n=26) were recruited. Groups were matched for age, gender, best parental socio-economic status and ethnicity. All subjects underwent DTI and structural magnetic resonance imaging (MRI) scans. Voxel-based analysis was performed to investigate brain regions where fractional anisotropy (FA) values differed significantly between groups. A confirmatory region-of-interest (ROI) analysis of FA scores was performed in which regions were placed blind to group membership. RESULTS: In patients, FA values significantly lower than those in healthy controls were located in the left fronto-occipital fasciculus, left inferior longitudinal fasciculus, white matter adjacent to right precuneus, splenium of corpus callosum, right posterior limb of internal capsule, white matter adjacent to right substantia nigra, and left cerebral peduncle. ROI analysis of the corpus callosum confirmed that the patient group had significantly lower mean FA values than the controls in the splenium but not in the genu. The intra-class correlation coefficient (ICC) for independent ROI measurements was 0.90 (genu) and 0.90 (splenium). There were no regions where FA values were significantly higher in the patients than in the healthy controls. CONCLUSIONS: Widespread structural dysconnectivity, including the subcortical region, is already present in neuroleptic-naive patients in their first episode of illness.