Deregulated expression of LRBA facilitates cancer cell growth

LRBA expression is induced by mitogens in lymphoid and myeloid cells. The Drosophila LRBA orthologue rugose/DAKAP550 is involved in Notch, Ras and EGFR pathways. These findings suggest that LRBA could play a role in cell types that have increased proliferative and survival capacity. Here, we show by microarray and real-time PCR analyses that LRBA is overexpressed in several different cancers relative to their normal tissue controls. We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. Furthermore, inhibition of LRBA expression by RNA interference, or inhibition of its function by a dominant-negative mutant, leads to significant growth inhibition of cancer cells, demonstrating that deregulated expression of LRBA contributes to the altered growth properties of a cancer cell. Finally, we show that the phosphorylation of EGFR is affected by the dominant-negative mutant, suggesting LRBA plays a role in the mammalian EGFR pathway. These findings demonstrate that LRBA facilitates cancer cell growth and thus LRBA may represent a novel molecular target for cancer therapy.     

Rationale and design of the National Program of Cancer Registries' breast, colon, and prostate cancer patterns of care study

Background: Investigators from the Centers for Disease Control and Prevention (CDC), National Program of Cancer Registries (NPCR), are collaborating with public health professionals from seven states and the District of Columbia to conduct the Patterns of Care study to assess the quality of cancer data and to determine whether stage-specific treatments are being carried out. Methods: To assess the quality and completeness of cancer care data in the United States, trained staff from the Patterns of Care study are abstracting medical records to obtain detailed clinical data on treatment, tumor characteristics, stage at diagnosis, and demographics of representative samples of patients diagnosed with breast, colon, and prostate cancer. Altogether staff from each of the eight participating cancer registries will abstract 500 cases of breast, prostate, and colon/rectum/anus cancer for the CONCORD study and an additional 150 cases of localized breast cancer, 100 cases of stage III colon cancer, and 100 cases of localized prostate cancer for the Patterns of Care study. Chi-square tests will be used to compare routine registry data with re-abstracted data. The investigators will use logistic regression techniques to describe the characteristics of patients with localized breast and prostate cancer and stage III colon cancer. Age, race, sex, type of insurance, and comorbidity will be examined as predictors of the use of those treatments that are consistent with consensus guidelines. The investigators plan to use data from the CONCORD study to determine whether treatment factors are the reason for the reported differences between relative survival rates in the United States and Europe. Conclusions Results from the methodology used in the Patterns of Care study will provide, for the first time, detailed information about the quality and completeness of stage and treatment data that are routinely collected by states participating in the NPCR. It will add significantly to our understanding of factors that determine receipt of treatment in compliance with established guidelines. As part of the CONCORD study, it will also examine differences in survival among cancer patients with breast, prostate, and colon/rectum/anus cancers in the United States and Europe.     

Chronically stimulated microglial cells do no longer alter their immune functions in response to the phagocytosis of apoptotic cells

In an autoimmune inflammatory setting, ingestion of apoptotic T cells leads to a down-regulation of microglial immune functions. Recent studies have indicated that microglia can be matured by exposure to GM-CSF. GM-CSF stimulation led to a differentiated microglial phenotype and enhanced antigen-presenting capabilities. The secretion of TNF-alpha was significantly decreased by the uptake of apoptotic cells in unstimulated microglia, but not in GM-CSF-differentiated microglia. IL-10 secretion was unaffected. After ingestion of apoptotic cells, only previously unstimulated, but not GM-CSF-differentiated microglial cells decreased their T cell-activating potential as measured by IFN-gamma secretion in antigen-activated MBP-specific T cells. Thus, GM-CSF stimulation reduces the immunomodulatory functions of microglial cells.     

ERP old/new effects at different retention intervals in recency discrimination tasks

Recognition memory studies have suggested that event-related brain potentials (ERPs) may tap into several different memory processes. In particular, two ERP components have been hypothesized as related to familiarity (FN400 old/new effect, 300-500 ms, anterior) and recollection processes (parietal old/new effect, 400-800 ms, posterior). The functional significance of the FN400 old/new effect is uncertain because similar old/new differences have been shown to disappear at moderately long retention intervals. The present study investigated the effects of retention interval (34 min, 39 min, or 1 day) on the FN400 and parietal old/new effects in two different recency discrimination tasks. The results suggest that the FN400 old/new effect can be maintained across 1-day retention intervals, so it may index brain processes capable of contributing to long-term memory.     

Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy

The LGI4 gene is located in a region linked to benign familial infantile convulsions (BFIC) and idiopathic generalized epilepsy. Screening of the LGI4 coding region in BFIC and childhood absence epilepsy (CAE) revealed several frequent exonic polymorphisms. A genotypic association was found for the c.1914GCAT polymorphism in 42 CAE patients compared with 110 population controls (²=6.66, df=1, P=0.01), providing evidence for a so far undetected susceptibility allele for CAE in the LGI4 region.     

Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study

CONTEXT: The dopamine overactivity hypothesis of schizophrenia remains one of the most influential theories of the pathophysiology of the illness. Radiotracer brain imaging studies are now directly testing aspects of the overactivity hypothesis. OBJECTIVE: To assess presynaptic dopaminergic function in a large cohort of patients with schizophrenia by means of [18F]fluorodopa uptake and a high-sensitivity 3-dimensional positron emission tomograph. We predicted elevations in striatal [18F]fluorodopa uptake and reductions in prefrontal cortical [18F]fluorodopa uptake in patients with schizophrenia. DESIGN: Case-control study. SETTING: Research institute investigation recruiting hospital outpatients. PATIENTS: Sixteen male medicated hospital outpatients with a DSM-IV diagnosis of schizophrenia (mean age, 38 years) and 12 age-matched male volunteers free of psychiatric and neurologic illness. INTERVENTION: [18F]fluorodopa positron emission tomographic scanning. MAIN OUTDOME MEASURE: [18F]fluorodopa uptake constant Ki measured with statistical parametric mapping and region-of-interest analyses. RESULTS: Statistical parametric mapping (P<.05 corrected) and region-of-interest analyses (P<.01) showed increased [18F]fluorodopa uptake, confined primarily to the ventral striatum in patients with schizophrenia. No reductions in prefrontal cortical [18F]fluorodopa uptake Ki were seen in the statistical parametric mapping and region-of-interest analyses, although dorsal anterior cingulate [18F]fluorodopa Ki correlated with performance on the Stroop Color-Word Test in both groups. CONCLUSIONS: As in studies in unmedicated patients, presynaptic striatal dopamine dysfunction is present in medicated schizophrenic patients, adding further in vivo support for dopamine overactivity in the illness.     

Towards a common neural substrate in the immediate and effective inhibition of stuttering

Stuttering can be effectively inhibited via exogenous sensory signals (e.g., speaking in unison or using altered auditory feedback) or by using endogenous motoric strategies (e.g., singing or therapeutically implementing long vowel prolongations to reduce speech rates). We propose that these channels, which superficially appear to be diametrically opposite, centrally converge in the engagement of mirror neurons for fluent gestural productions. Sensory changes incurred via exogenous speech signals allow for direct engagement of mirror systems, while endogenous motor strategies appear to require significant departures from normal speech production (e.g., highly unnatural or droned speech) to engage mirror systems. Thus, paradoxically, stuttering is prone to resurface during attempts to impose naturalness upon therapeutic speech.     

In vivo imaging of cardiovascular endothelin receptors using the novel radiolabelled antagonist [18F]-SB209670 and positron emission tomography (microPET)

The aim of this study was to develop an F-labelled analogue of SB209670 with subnanomolar affinity for the endothelin receptor and to test whether it would have the required pharmacokinetic properties to permit binding and imaging of endothelin receptors in rat heart in vivo using small animal positron emission tomography (PET) imaging. [18F]-SB209670 could be produced in a total radiochemical yield of 14.9 +/- 3.8% in 162 +/- 7 minutes (n = 6). The radiochemical purity of the isolated radioligand was 99% and the specific activity was 100-150 GBq/micromol. In vitro characterization using ligand-binding assays demonstrated that [18F]-SB209670 bound with a single subnanomolar affinity to human heart tissue (n = 3) with a KD = 0.67 +/- 0.14 nM and a Bmax = 168.3 +/- 29.3 fmol/mg protein. The binding was time-dependent with a half-time (t(1/2)) for association of 3.8 minutes and an association rate constant (kobs) of 0.182 +/- 0.032/min. In vivo distribution in the rat was studied using microPET. Dynamic imaging revealed a fast clearance of [F]-SB209670 from the circulation by the liver, indicative of a high degree of metabolism. However, visualization of uptake in the rat heart was achievable and dynamic PET data together with the in vitro results suggest that [F]-SB209670 binds rapidly and primarily to endothelin-A receptors in the heart.