Identification of the polycomb group protein SU(Z)12 as a potential molecular target for human cancer therapy

We have previously identified SU(Z)12 as an E2F target gene. Because many E2F target genes encode proteins that are critical for the control of cell proliferation, we have further characterized the regulation and expression of SU(Z)12. To understand the molecular mechanisms responsible for expression of SU(Z)12 mRNA, we have analyzed the promoter region. We found that the SU(Z)12 gene is controlled by dual promoters, one of which functions bidirectionally. In addition to the E2F binding site, we have identified two binding sites for T cell factor (TCF)/beta-catenin complexes. Using gel mobility shift assays, we demonstrated that both TCF sites can be bound by TCF4. TCF/beta-catenin complexes have been shown to be a critical regulator of gene expression in tumors of the colon, breast, and liver. Accordingly, we have used chromatin immunoprecipitation assays to confirm that TCF4/beta-catenin complexes are bound to the SU(Z)12 promoter in colon cancer cells but not in HeLa cells. We next adapted the chromatin immunoprecipitation assay for use with primary colon tumor samples, and, using matched pairs of normal and tumor tissue obtained from several different colon cancer patients, we demonstrate that levels of beta-catenin bound to the SU(Z)12 promoter are increased in colon tumors. Finally, we show that the SU(Z)12 mRNA is up-regulated in a number of different human tumors, including tumors of the colon, breast, and liver. Recent studies have found that SU(Z)12 is a component of the Drosophila ESC-E(Z) and the human EED-EZH2 Polycomb chromatin remodeling complexes. Therefore, we suggest that SU(Z)12, which may modulate the tumor phenotype by changing gene expression profiles, may be a logical target for the design of a new antitumor agent     

Early biomechanical markers of postural instability in Parkinson's disease

Current clinical assessments do not adequately detect the onset of postural instability in the early stages of Parkinson's disease (PD). The aim of this study was to identify biomechanical variables that are sensitive to the effects of early Parkinson's disease on the ability to recovery from a balance disturbance. Ten adults diagnosed with idiopathic PD and no clinically detectable postural instability, and ten healthy age-range matched controls (HC) completed the study. The first step in the response to a backwards waist pull was quantified in terms of strategy, temporal, kinematic, kinetic, and center of pressure (COP) variables. People with PD, compared to HC, tended to be less consistent in the choice of stepping limb, utilized more time for weight shift, used a modified ankle joint motion prior to liftoff, and the COP was further posterior at landing. The study results demonstrate that PD changes the response to a balance disturbance which can be quantified using biomechanical variables even before the presence of clinically detectable postural instability. Further studies are required to determine if these variables are sensitive and specific to postural instability.     

The Hospital Anxiety and Depression Scale in Greek cancer patients: psychometric analyses and applicability

Goals of work The aim of the present study was to validate the Greek version of the Hospital Anxiety and Depression Scale (HAD) in a palliative care unit.Patients and methods The scale was translated with the forward-backward procedure to Greek. It was administered twice, with a 1-week interval, to 120 patients with advanced cancer. Together with the HAD scale, the patients also completed the Spielberger State-Anxiety Scale (STAI-S).Main results Factor analyses identified a two-factor solution corresponding to the original two subscales of the HAD, which were found to be correlated. The Greek version of the HAD had Cronbachs alphas for the anxiety and depression scales of 0.887 and 0.703, respectively. Validity as performed using known-group analysis showed good results. Both anxiety and depression subscales discriminated well between subgroups of patients differing in disease severity as defined by ECOG performance status. Correlations between the HAD scale and the STAI-S was 0.681 for the anxiety subscale and 0.485 for the depression subscale.Conclusions These psychometric properties of the Greek version of the HAD scale confirm it as a valid and reliable measure when administered to patients with advanced cancer.     

Adeno-associated virus serotype 2-mediated gene transfer to the parotid glands of nonhuman primates

Salivary glands (SGs) are promising gene transfer targets with potential clinical applicability. Previous experiments in rodents using recombinant serotype 2 adeno-associated viral (rAAV2) vectors have demonstrated relatively stable transgene-encoded protein levels after SG gene transfer. In the present study, we examine direct SG administration of rAAV2 vectors encoding rhesus macaque erythropoietin (RhEPO) to the parotid glands of nonhuman primates using two different doses (n = 3 per group; 1 x 10(10) or 3 x 10(11) particles/gland, respectively). Gene transfer had no negative effects on general macaque physiology (e.g., weight, complete blood count, and serum chemistry). Macaques were euthanized 6 months after vector administration and complete necropsy and pathology assessments were performed, revealing no vector-related pathological lesions in any of the examined organs. In the high-dose group, RhEPO expression increased quickly (i.e., by week 1) and levels remained relatively stable both in serum and saliva until the end of the study. Serum-to-saliva ratios of RhEPO revealed secretion of the transgene product into the bloodstream, but not to the extent previously observed in mice. Furthermore, the kinetic results were not predicted by those observed in murine SGs. With respect to viral biodistribution, at necropsy vector was found overwhelmingly in the targeted parotid gland ( approximately 100 times more than levels in other tissues, most of which were similar to tissue levels in nontreated animals). We conclude that administration of modest doses of rAAV2 vectors to SGs for therapeutic purposes can be accomplished without significant or permanent injury to the targeted gland or to distant organs of nonhuman primates.     

Age and education adjusted normative data and discriminative validity for Rey’s Auditory Verbal Learning Test in the elderly Greek population

Rey’s Auditory Verbal Learning Test (RAVLT) is a widely used neuropsychological test to assess episodic memory. In the present study we sought to establish normative and discriminative validity data for the RAVLT in the elderly population using previously adapted learning lists for the Greek adult population. We administered the test to 258 cognitively healthy elderly participants, aged 60–89 years, and two patient groups (192 with amnestic mild cognitive impairment, aMCI, and 65 with Alzheimer’s disease, AD). From the statistical analyses, we found that age and education contributed significantly to most trials of the RAVLT, whereas the influence of gender was not significant. Younger elderly participants with higher education outperformed the older elderly with lower education levels. Moreover, both clinical groups performed significantly worse on most RAVLT trials and composite measures than matched cognitively healthy controls. Furthermore, the AD group performed more poorly than the aMCI group on most RAVLT variables. Receiver operating characteristic (ROC) analysis was used to examine the utility of the RAVLT trials to discriminate cognitively healthy controls from aMCI and AD patients. Area under the curve (AUC), an index of effect size, showed that most of the RAVLT measures (individual and composite) included in this study adequately differentiated between the performance of healthy elders and aMCI/AD patients. We also provide cutoff scores in discriminating cognitively healthy controls from aMCI and AD patients, based on the sensitivity and specificity of the prescribed scores. Moreover, we present age- and education-specific normative data for individual and composite scores for the Greek adapted RAVLT in elderly subjects aged between 60 and 89 years for use in clinical and research settings.