CE Regions Research Articles

Preoperative imaging of glioblastoma patients using hyperpolarized 13C pyruvate: Potential role in clinical decision making

BackgroundGlioblastoma remains incurable despite treatment with surgery, radiation therapy, and cytotoxic chemotherapy, prompting the search for a metabolic pathway unique to glioblastoma cells.13C MR spectroscopic imaging with hyperpolarized pyruvate can demonstrate alterations in pyruvate metabolism in these tumors.MethodsThree patients with diagnostic MRI suggestive of a glioblastoma were scanned at 3 T 1–2 days prior to tumor resection using a 13C/1H dual-frequency RF coil and a 13C/1H-integrated MR protocol, which consists of a series of 1H MR sequences (T2 FLAIR, arterial spin labeling and contrast-enhanced [CE] T1) and 13C spectroscopic imaging with hyperpolarized [1-13C]pyruvate. Dynamic spiral chemical shift imaging was used for 13C data acquisition. Surgical navigation was used to correlate the locations of tissue samples submitted for histology with the changes seen on the diagnostic MR scans and the 13C spectroscopic images.ResultsEach tumor was histologically confirmed to be a WHO grade IV glioblastoma with isocitrate dehydrogenase wild type. Total hyperpolarized 13C signals detected near the tumor mass reflected altered tissue perfusion near the tumor. For each tumor, a hyperintense [1-13C]lactate signal was detected both within CE and T2-FLAIR regions on the 1H diagnostic images (P = .008). [13C]bicarbonate signal was maintained or decreased in the lesion but the observation was not significant (P = .3).ConclusionsPrior to surgical resection, 13C MR spectroscopic imaging with hyperpolarized pyruvate reveals increased lactate production in regions of histologically confirmed glioblastoma.

Influence of eddies on phytoplankton composition in the Bay of Bengal

Several cyclonic (CE) and anticyclonic (ACE) eddies form in the Bay of Bengal (BoB) and they expect to contain different proportion of nutrients due to divergence and convergence of waters respectively and may have impact on phytoplankton composition. In order to test this hypothesis, one CE and two ACE (north ACE (ACEN) and south ACE (ACES)) were sampled in the BoB during spring intermonsoon. Higher concentration of dissolved inorganic nitrate and lower dissolved inorganic phosphorus was observed in the upper 25 m of water column in the CE and contrasting to that was observed in the ACE regions. Silicate concentrations were above the limiting levels for diatoms growth in the study region. High dissolved organic nitrogen (DON) and phosphorus (DOP) were observed in the upper 10 m in the CE and 80 m in the ACEs. Due to lack of nitrate in the study region DON seems to support phytoplankton growth in the BoB. The phytoplankton groups were estimated using marker pigment composition and dominant groups were evaluated using pigment ratios. Occurrence of autotrophic dinoflagellates were observed only in the ACES, which was formed in the central eastern BoB. Premnesiophytes, chrysophytes were found only in ACEN which was formed in the northeastern shelf region. In addition to this, prochlorophytes and chlorophytes were also found in both ACEN and ACES. The concentration of fucoxanthin, marker pigment for diatoms, was low and confined to the subsurface waters in the CE and ACEN regions due to unavailability of nitrate and their inability to uptake DON. This study suggested that eddies bring different composition of phytoplankton from the region of their origin to the open sea resulting in variations in their diversity. This may have impact on food web dynamics in the BoB. More than 50 eddies form each year in the BoB and their impact on the taxonomic and size composition of phytoplankton and fluxes of carbon to depth needs further studies.

Impact of eddies on dissolved inorganic carbon components in the Bay of Bengal

To examine the influence of anticyclonic (ACE) and cyclonic (CE) eddies on variations in hydrographic properties and total inorganic carbon system (CT), a study was conducted in the western Bay of Bengal (BoB). The depth of seasonal thermocline, defined as depth of 20 °C isotherm (D20), shoaled (∼80 m) in the CE but deepened to ∼180 m in the ACE relative to non-eddy (NE) conditions (∼110 m) due to convergence and divergence associated with ACE and CE, respectively. Both surface and depth integrated (0–100 m) chlorophyll-a concentrations were higher in CE than in ACE and NE regions suggesting higher primary production in the CE region. Upward displacement of 2100 μM of CT and 800 μatm of pCO2 isosurfaces from a depth of 175 to 50 m was observed in the CE region resulting in an increase in mixed layer CT and pCO2 compared to that in NE region. Low CT (∼1850 μM) and high pH (∼8.15) isolines deepened to 150–175 m in ACE region. Strong positive relations were observed for CT and pCO2 with salinity whereas weak inverse correlations were found for chlorophyll-a and dissolved oxygen saturation with salinity normalized CT. This suggests that both biological and physical processes control CT in the BoB. Both biological and mixing effects contributed significantly to pCO2 variability in the CE region whereas mixing and thermal effects contributed in the ACE region. The sea-to-air fluxes of CO2 varied between −0.21 and 0.31 molC m−2 month−1. The CE and south ACE (ACEs) regions were found to act as sink for the atmospheric CO2 whereas northern ACE (ACEn) and NE regions were source. The mean CO2 flux suggests that the study region was a moderate source (0.05 ± 0.01 molC m−2 month−1) to the atmosphere. The mean sinking flux of CT to the deeper layer in ACEn and ACEs was ∼0.07 ± 0.02 molC m−2 month−1 whereas it was ∼0.02 ± 0.006 C m−2 month−1 in CE and NE regions. Assuming that the estimated flux at the eddies sampled here is applicable to all eddies in the Bay, the vertical DIC flux to the deep BoB by all eddies amounted to 3.29 ± 0.9 TgC y−1 (1 TgC = 1012 gC). Nevertheless this study suggests that ACEs transports CT to deeper waters, besides being source to the atmospheric CO2.

Role of eddies on organic matter production and f-ratios in the Bay of Bengal

In order to examine the sources of nutrients and f-ratios in the cyclonic (CE) and anticyclonic eddy (ACE), the content and isotopic composition of carbon and nitrogen in suspended particulate organic matter (POM) were analyzed in one CE and two ACEs in the western Bay of Bengal (BoB). Relatively higher concentrations of Chlorophyll-a (Chl-a) and nutrients were observed in the CE and no-eddy (NE) regions than ACE region. Higher concentrations of particulate organic carbon (POC) and nitrogen (PN) were observed in the CE and NE than ACE in the BoB. Isotope mixing model (SIAR) suggested that POM pool mainly consists of marine plankton biomass (~80%) and contribution of terrestrial organic matter is insignificant (<20%). The depth of nitracline was shallower in the CE due to divergence while it was deeper in the ACEs due to convergence of upper ocean. The isotopic composition of nitrogen in the POM varied between 2.4% and 8.5‰ and relatively lower values were associated with deeper nitracline depth in the ACE and vice versa in the CE. This suggests that upward mixing of subsurface nitrate supported primary production in the CE and regenerated nitrogen in the ACE region. The estimated f-ratios using δ15NPOM and depth of nitracline were almost double in the CE (0.31 ± 0.04) and NE (0.28 ± 0.05) than ACEs (0.19 ± 0.09) in the BoB. Though upward mixing of subsurface low DO water intensified oxygen minimum zone (OMZ) below 75 m in the CE region, enhanced phytoplankton biomass and its export may further intensify. In contrast, convergence of DO rich surface water and low f-ratios in the ACE resulted in weaker OMZ. This study suggests that eddies significantly influence primary and export productions that may lead to modifications in intensity of OMZ in the BoB. >50 eddies form every year in the BoB and its impact on primary and export production leading to intensification/weakening of OMZ should be evaluated using both observations and models.

New to total primary production ratio (f-ratio) in the Bay of Bengal using isotopic composition of suspended particulate organic carbon and nitrogen

Variations in the content and isotopic compositions of carbon and nitrogen in the suspended particulate matter were analysed to identify sources of nutrients and compute f-ratios (ratio of new production to primary production) in the Bay of Bengal (BoB) during the post-monsoon period (November-December 2013). Remote sensing data during our observation period indicated that the study region encompassed meso-scale cyclonic (CE) and anticyclonic eddies (ACE) and was influenced by tropical cyclone Madi between 6 and 12 December 2013. Relatively higher concentrations of nitrate were observed in the CE and in the cyclone-influenced region compared to that in the ACE. Variable concentrations of nutrients controlled the size distributions of phytoplankton. Overall, the picoplankton population dominated, but the contributions of micro- and nano-plankton populations were significantly higher in the CE region because of higher concentration of nutrients. The δ13Csus, C:N molar ratios and C: Chl-a ratios suggested that suspended matter is mainly contributed by in situ processes during the study period. The δ15Nsus of suspended matter suggested that vertical supply of nutrients brought from subsurface water supported new production in the CE and cyclone-influenced regions, whereas regenerated nutrients supported phytoplankton production in the ACE. The f-ratios computed using δ15Nsus and depth of nitracline were high in the CE (0.41 ± 0.14) and cyclone-influenced region (0.54 ± 0.12) and lower in the ACE (0.27 ± 0.06). This study revealed that the meso-scale CEs are more important in enhancing exportable production in the BoB. As more than 30 CEs form annually in the BoB, their impact on basin-wide new production and export flux to the deeper ocean must be evaluated using both observations and high-resolution models.

Eutherian BetaM, a Muscle‐Specific Integral Protein of Inner Nuclear Membrane, is Implicated in Regulation of MyoD Expression

Vertebrate X‐chromosome ATP1B4 genes represent a rare instance of the orthologous gene co‐option that radically changed functions of encoded BetaM proteins during evolution. In lower vertebrates, BetaM is a subunit of Na,K‐ATPase located in the cell membrane. In placental mammals, BetaM completely lost its ancestral role and through radical changes in the structure of its N‐terminal domain gained entirely new properties as a skeletal and atrial cardiac muscle‐specific protein of the inner nuclear membrane possessing the ability to regulate gene expression. BetaM expression is strictly temporally regulated being the highest in late fetal and early postnatal myocytes. Here we show that expression of exogenous BetaM in cultured muscle cells up‐regulates expression of endogenous MyoD, a master regulator of myogenesis, both at transcriptional and translational levels. We determined that eutherian BetaM associates with nuclear transcriptional co‐regulator Ski‐interacting protein (SKIP) and both are identified by ChIP assays as components of MyoD transcriptional complex in vivo in rat neonatal skeletal muscle. Presence of BetaM was detected in the DRR but not in PRR and CE regions of the MyoD promoter. According to the results of Electrophoretic Mobility Shift Assays (EMSA) BetaM‐containing transcriptional complexes are bound to specific E‐box4 and CArG elements of the DRR region. Deletion of either E‐box4 or CArG or both in DRR luciferase reporter abolished its activation by BetaM, These findings demonstrate that BetaM is a novel eutherian‐specific transcriptional regulator which is involved in the regulation of MyoD expression during muscle development. Moreover, structural and functional alterations acquired through ATP1B4 gene co‐option and a unique pattern of expression argue that eutherian‐specific BetaM functions are essential, even might be necessary for survival of placental mammals in natural conditions, and that they provide evolutionary advantage.Support or Funding InformationSupported by Department of Physiology &amp; Pharmacology, University of Toledo College of Medicine.

Connectivity between the central nucleus of the amygdala and the bed nucleus of the stria terminalis in the non-human primate: neuronal tract tracing and developmental neuroimaging studies.

The lateral division of the bed nucleus of the stria terminalis (BSTL) and central nucleus of the amygdala (Ce) form the two poles of the 'central extended amygdala', a theorized subcortical macrostructure important in threat-related processing. Our previous work in nonhuman primates, and humans, demonstrating strong resting fMRI connectivity between the Ce and BSTL regions, provides evidence for the integrated activity of these structures. To further understand the anatomical substrates that underlie this coordinated function, and to investigate the integrity of the central extended amygdala early in life, we examined the intrinsic connectivity between the Ce and BSTL in non-human primates using ex vivo neuronal tract tracing, and in vivo diffusion-weighted imaging and resting fMRI techniques. The tracing studies revealed that BSTL receives strong input from Ce; however, the reciprocal pathway is less robust, implying that the primate Ce is a major modulator of BSTL function. The sublenticular extended amygdala (SLEAc) is strongly and reciprocally connected to both Ce and BSTL, potentially allowing the SLEAc to modulate information flow between the two structures. Longitudinal early-life structural imaging in a separate cohort of monkeys revealed that extended amygdala white matter pathways are in place as early as 3weeks of age. Interestingly, resting functional connectivity between Ce and BSTL regions increases in coherence from 3 to 7weeks of age. Taken together, these findings demonstrate a time period during which information flow between Ce and BSTL undergoes postnatal developmental changes likely via direct Ce→BSTL and/or Ce↔SLEAc↔BSTL projections.

OP37THREE-DIMENSIONAL MRI ASSESSMENT OF DIFFUSION AND PERFUSION STRATIFIES OVERALL SURVIVAL IN PATIENTS WITH GLIOBLASTOMA

INTRODUCTION: Imaging assessment of glioblastoma (GBM) currently involves 2-dimensional analysis of conventional T1- and T2-weighted images. This study used advanced imaging to assess 3-dimentional (3-D) patterns of diffusion and perfusion spread in GBM. METHOD: 25 patients with retrospectively-confirmed GBM underwent pre-operative MRI. Maps of apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were processed and regions of interest (ROIs) were developed using thresholds of low ADC with overlapping high rCBV. ROIs were visually assessed using interactive 3-D images. Patterns of spread within the T1- and T2-weighted abnormality (entire lesion) were qualitatively categorised and the presence or absence of ‘ROI clusters' within different tumour components was also observed. Overall survival (OS) was assessed using Kaplan-Meier statistics with significance accepted at p = 0.05 with statistical power > 95%. RESULTS: Four 3-D phenotypes were identified based on ROI pattern of spread: localised (4/25 patients, 16%), showing minimal and confined ROI spread; diffuse (19/25, 76%), shapeless ROI spread throughout the ‘entire lesion'; massive (2/25, 8%), ROI composing most of the ‘entire lesion'; and encapsulated (5/25, 20%), ROI diffusely spreading around a spherical component. The presence of ‘ROI clusters' was observed in CE (12/25, 48%) and necrotic (6/25, 24%) regions. Kaplan-Meier statistics found that an encapsulated ROI shape was associated with poor OS (p < 0.001). The presence of ‘ROI clusters' within CE was associated with improved survival patterns (p < 0.001). CONCLUSION: Qualitatively assessing 3-D patterns of ADC and rCBV spread stratifies overall survival in patients with GBM.

P16.05 * CHARACTERISING REGIONAL HETEROGENEITY OF GLIOBLASTOMA USING MULTIMODAL IMAGING: REGIONS OF AGGRESSIVE GROWTH

INTRODUCTION: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumour. Intra-tumour heterogeneity of GBM is a contributing factor to treatment failure and non-invasive methods are needed for analysis. This study aimed to identify imaging signatures of aggressive tumour belonging to different regions of GBM using multimodal imaging methods, including diffusion-weighted imaging and MR spectroscopy. METHOD: 32 Patients (mean age 57.2 years) with confirmed GBM were imaged at 3T on a Siemens Trio. Maps of apparent diffusion coefficient (ADC) were coregistered to T2-weighted images. Regions of interest (ROI) were selected: FLAIR enhancement with T1-weighted post-contrast enhancement (CE); and FLAIR enhancement without CE (FLAIR). Within these regions, an ADC cut-off value was developed using MATLAB. Metabolic maps of Cho/tNAA ratios belonging to these ADC ROIs were calculated using LCModel. Ratios from CE and FLAIR were compared to each other and to ratios of ROIs above the ADC threshold within tumour (high ADC) and normal appearing white matter (NAWM). RESULTS: Ratio values of CE and FLAIR were significantly higher than those of NAWM (0.26 ± 0.09) (0.60 ± 0.21, p < 0.001; 0.45 ± 0.22; p < 0.001 for CE and FLAIR, respectively). ROIs of high ADC had a mean ratio value (0.39± 0.16) that was significantly lower than that of CE (p < 0.01). CONCLUSION: Findings suggest that regional heterogeneity of GBM can be detected and characterised using advanced imaging. Low ADC ROIs within CE regions appear to have metabolic profiles representing aggressive tumour with higher Cho/tNAA ratios. Combining imaging modalities could potentially differentiate regions that will respond/fail to respond to treatment.

Identification of serum markers of glioblastoma multiforme patients using image-guided genomic and proteomic analysis

20008 Background: Biomarkers in serum has been demonstrated to play a critical role in caner diagnostics. Glioblastoma multiforme (GBM) is a primary brain tumor with poor prognosis and low survival rate, which often has significant heterogeneity in morphology and increased vascular permeability and vessel density. In this study we identified molecules related to angiogenesis and vasculature development for GBM using a combination of contrast enhanced MR imaging, genomic and proteomic analysis, and enzyme immunoassay (ELISA). Methods: GBM patient without any prior procedures were scanned on a GE 1.5T MRI scanner using standard T1- and T2-weighted pulse sequences and gadopentetate dimeglumine as contrast agent. Samples from regions with contrast agent accumulation (contrast-enhancing, CE) and no uptake (non-enhancing, NE) were collected for microarray, Mass spectroscopic analysis and immunochemical staining. Patient serum samples were collected for protein expression quantification using ELISA assay. Results: Tissue samples from the CE and NE regions of 13 patients reveal significantly distinct gene expression patterns. Mass spectroscopy using MALDI system will also be examined. Growth factors such as laminin receptor, IGFBP-2, IGFBP-3, IGFBP-5, aFGF were all up-regulated in the CE regions, and immunohistochemical staining confirmed their protein expression. The presence of proteins with MW &lt; 30 kD in the serum were examined using ELISA. IGFBP-2 showed to have a higher mean value (86.1 ± 29.1 ng/ml) in GBM serum as compared to healthy individuals (55.7 ± 9.9 ng/ml). Other potential markers such as IGFBP-3 and aFGF do not exhibit significant difference. Conclusions: CE-MRI using the clinical MRI agent Gd(DTPA) can reveal imaging features associated with increased vascular permeability and vessel density, and areas of fluid accumulation and necrosis. We have observed that differences in spatial resolution in the tumor correlate to changes in gene expression profiles, resulting in potential molecules that have high gene and protein expression levels in tumor area with high vascular activity and in serum. These targets can be used for diagnostic and clinical monitoring of the patient before and after therapeutic intervention. No significant financial relationships to disclose.

Neutron-diffraction study of magnetization avalanches in Pr0.50Ca0.50Mn1−xNixO3

The magnetization avalanches under field have been investigated at low temperature in Pr0.50Ca0.50Mn1−xNixO3 (x=0.05). In zero field, a 5% of Ni at the Mn site provokes the coexistence of three types of magnetic∕structural mesoscopic domains at low temperature: ferromagnetic metallic (majority phase), pseudo-CE and CE-type (minority phase). The ultrasharp steps observed in the low-temperature isothermal magnetization and resistivity curves were investigated by neutron powder diffraction in magnetic fields up to 5T. At 3T an abrupt growth of ferromagnetic microclusters occurs at the expenses of the two types of antiferromagnetic orbital-ordered domains (CE and pseudo-CE regions).

Regional density functions and growth patterns in major plains of China, 1982–1990

This research analyzes the spatial patterns of regional development in China through the change of population density functions from 1982 to 1990, using several online digital data sets. To minimize the influence of physical environment on population densities, the study areas are limited to four major plains of China: the Northeast (Dongbei), North China (Huabei) and Hubei-Hunan (Lianghu) Plains, and the Sichuan Basin. A gravity-based delineation approach is used to delineate the influen ce regions of 17 cities. Regional densities in China decline with distance from a city, similar to western countries. In addition, areas close to central cities grew faster than remote areas, described as a trend of centralization. However, regions with strong core growth are generally associated with stagnant hinterlands (‘core growth-hinterland stagnation’); and regions with moderate core growth are usually matched by similar growth rates in the hinterlands (‘spread through growth’ ).

Regional density functions and growth patterns in major plains of China, 1982–1990

Abstract. This research analyzes the spatial patterns of regional development in China through the change of population density functions from 1982 to 1990, using several online digital data sets. To minimize the influence of physical environment on population densities, the study areas are limited to four major plains of China: the Northeast (Dongbei), North China (Huabei) and Hubei‐Hunan (Lianghu) Plains, and the Sichuan Basin. A gravity‐based delineation approach is used to delineate the influence regions of 17 cities. Regional densities in China decline with distance from a city, similar to western countries. In addition, areas close to central cities grew faster than remote areas, described as a trend of centralization. However, regions with strong core growth are generally associated with stagnant hinterlands ('core growth‐hinterland stagnation'); and regions with moderate core growth are usually matched by similar growth rates in the hinterlands ('spread through growth').