Flow cytometric measurement of glutathione content of human cancer biopsies.

Rice et al. (1986) have described a flow cytometric method where the non-fluorescent probe monochlorobimane (mBCl) forms a fluorescent adduct with cellular glutathione (GSH) under the action of glutathione-S-transferase. We show here that for EMT6 carcinosarcoma cells there is a close correlation between mean cell fluorescence, expressed as a ratio to that of fluorescence calibration beads, and biochemically determined GSH content over the range 0.2-2.0 fmol cell-1. Single cell suspensions from 14 human cancers were prepared by 23-gauge needle aspiration or mechanical disaggregation of surgical specimens, stained using mBCl and examined by flow cytometry. There was a wide range in individual cell fluorescence, which in contrast to EMT6 cells was not strongly correlated with Coulter volume. By comparing tumour cell fluorescence to that of calibration beads, and assuming that the relationship with GSH content for EMT6 holds for other cells, a mean GSH content of 0.95 fmol cell-1 was derived for nine carcinomas, and 0.21 fmol cell-1 for five non-Hodgkin's lymphomas. Although this semi-quantitation needs further validation, the method used here is rapid, gives an indication of heterogeneity of tumour cell GSH content, and can be applied to fine needle biopsy samples. It therefore shows promise as a means for studying prospectively the relationship of GSH content to clinical drug and radiation sensitivity, and for monitoring the effects of agents such as buthionine sulphoximine which are intended to improve treatment results through tumour cell GSH depletion

Connecting magnetic towers with Faraday rotation gradients in active galactic nuclei jets

The idea that systematic Faraday Rotation gradients across the parsec-scale jets of active galactic nuclei (AGNs) can reveal the presence of helical magnetic (B) fields has been around since the early 1990s, although the first observation of this phenomenon was about ten years later. These gradients are taken to be due to the systematic variation of the line-of-sight B field across the jet. We present here, the parsec-scale Faraday Rotation distributions for the BL Lac objects 0716+714 and 1749+701, based on polarization data obtained with the Very Long Baseline Array at two wavelengths near each of the 2 cm, 4 cm and 6 cm bands (0716+714) and at four wavelengths in the range 18-22 cm (1749+701). The Rotation Measure (RM) maps for both these sources indicate systematic gradients across their jets, as expected if these jets have helical B fields. The significance of these transverse RM gradients is >3 sigma in all cases. We present the results of Monte Carlo simulations directly demonstrating the possibility of observing such transverse RM gradients even if the intrinsic jet structure is much narrower than the observing beam. We observe an intriguing new feature in these sources, a reversal in the direction of the gradient in the jet as compared to the gradient in the core region. This provides new evidence to support models in which field lines emerging from the central region of the accretion disc and closing in the outer region of the accretion disc are both 'wound up' by the differential rotation of the disc. The net observed RM gradient will essentially be the sum effect of two regions of helical field, one nested inside the other. The direction of the net RM gradient will be determined by whether the inner or outer helix dominates the RM integrated through the jet, and RM gradient reversals will be observed if the inner and outer helical fields dominate in different regions of the jet. This potentially provides new insights about the overall configuration of the jet B fields

Retargeted adenoviruses for radiation-guided gene delivery

The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber-modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment

Characterising the types of paediatric adverse events detected by the global trigger tool - CareTrack Kids

Introduction A common method of learning about adverse events (AEs) is by reviewing medical records using the global trigger tool (GTT). However, these studies generally report rates of harm. The aim of this study is to characterise paediatric AEs detected by the GTT using descriptive and qualitative approaches. Methods Medical records of children aged 0–15 were reviewed for presence of harm using the GTT. Records from 2012–2013 were sampled from hospital inpatients, emergency departments, general practice and specialist paediatric practices in three Australian states. Nurses undertook a review of each record and if an AE was suspected a doctor performed a verification review of a summary created by the nurse. A qualitative content analysis was undertaken on the summary of verified AEs. Results A total of 232 AEs were detected from 6,689 records reviewed. Over four-fifths of the AEs (193/232, 83%) resulted in minor harm to the patient. Nearly half (112/232, 48%) related to medication/intravenous (IV) fluids. Of these, 83% (93/112) were adverse drug reactions. Problems with medical devices/equipment were the next most frequent with nearly two-thirds (32/51, 63%) of these related to intravenous devices. Problems associated with clinical processes/procedures comprise one in six AEs (38/232, 16%), of which diagnostic problems (12/38, 32%) and procedural complications (11/38, 29%) were the most frequent. Conclusion Adverse drug reactions and issues with IVs are frequently identified AEs reflecting their common use in paediatrics. The qualitative approach taken in this study allowed AE types to be characterised, which is a prerequisite for developing and prioritising improvements in practice

Proteomic profiling of high risk medulloblastoma reveals functional biology

Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in a separate cohort of medulloblastoma tissue samples to identify the most robust proteogenomic differences. Interestingly, highly expressed proteins associated with MYC-amplified tumors were significantly related to glycolytic metabolic pathways via alternative splicing of pyruvate kinase (PKM) by heterogeneous ribonucleoproteins (HNRNPs). Furthermore, when maintained under hypoxic conditions, these MYC-amplified tumors demonstrated increased viability compared to non-amplified tumors within the same subgroup. Taken together, these findings highlight the power of proteomics as an integrative platform to help prioritize genetic and molecular drivers of cancer biology and behavior

Learning difficulties : a portuguese perspective of a universal issue

In this article we present findings of a study that was conducted with the purpose of deepening the knowledge about the field of learning difficulties in Portugal. Therefore, within these findings we will discuss across several cultural boundaries, themes related with the existence of learning difficulties as a construct, the terminology, the political, social and scientific influences on the field, and the models of identification and of ongoing school support for students. While addressing the above-mentioned themes we will draw attention to the different, yet converging, international understandings of learning difficulties

Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with Autism

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato–thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto–striato–parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto–striato–cerebellar dysregulation in ASD

Strategic communication and the entrepreneurial role of the corporate communication officer

Considering the recent evolution of the communication/PR profession in large organizations both private and public, many scholars agree that a process of institutionalization is occurring. In other words, communication’s importance has been growing, reaching in recent years a strategic position as a lever for companies’ governance. A first objective of this chapter is to describe, looking at management and communication/PR literature, how and to what extent communication has become strategic. The main hypothesis is that communication has become strategic within companies’ governance in order to help each organization to develop consistently – mainly in terms of values – within its environment. A second objective is to describe, looking at the entrepreneurial organization theory and communication/PR literature, another side of the strategic evolution of communication, which is to help each organization to develop – mainly in terms of services, products and reputation – as a different, or preferably unique, entity as compared to the other organizations. The evolution of the strategic contribution of communication/PR within organizations’ decision-making has a strong impact on the role that corporate communication officers (CCOs) play in organizations both on the isomorphic and on the entrepreneurial–innovative sides of the communicational activity they carry out to support the evolution of their organizations