Less Invasive Phenotype Found in Isocitrate Dehydrogenase-mutated Glioblastomas than in Isocitrate Dehydrogenase Wild-Type Glioblastomas: A Diffusion-Tensor Imaging Study

PURPOSE: To explore the diffusion-tensor (DT) imaging-defined invasive phenotypes of both isocitrate dehydrogenase (IDH-1)-mutated and IDH-1 wild-type glioblastomas. MATERIALS AND METHODS: Seventy patients with glioblastoma were prospectively recruited and imaged preoperatively. All patients provided signed consent, and the local research ethics committee approved the study. Patients underwent surgical resection, and tumor samples underwent immunohistochemistry for IDH-1 R132H mutations. DT imaging data were coregistered to the anatomic magnetic resonance study and reconstructed to provide the anisotropic and isotropic components of the DT. The invasive phenotype was determined by using previously published criteria and correlated with IDH-1 mutation status by using the Freeman-Halton extension of the Fisher exact probability test. RESULTS: Nine patients had an IDH-1 mutation and 61 had IDH-1 wild type. All of the patients with IDH-1 mutation had a minimally invasive DT imaging phenotype. Among the IDH-1 wild-type tumors, 42 of 61 (69%) were diffusively invasive glioblastomas, 14 of 61 (23%) were locally invasive, and five of 61 (8%) were minimally invasive (P < .001). CONCLUSION: IDH-mutated glioblastomas have a less invasive phenotype compared with IDH wild type. This finding may have implications for individualizing the extent of surgical resection and radiation therapy volumes.NIHR Clinician Scientist Fellowship (NIHR/CS/009/011); Chang Gung Medical Foundation; Chang Gung Memorial Hospital; Commonwealth Scholarship Commission; Cambridge Commonwealth Overseas Trust; NIHR Cambridge Biomedical Research Centr

Gain and Loss Learning Differentially Contribute to Life Financial Outcomes

Emerging findings imply that distinct neurobehavioral systems process gains and losses. This study investigated whether individual differences in gain learning and loss learning might contribute to different life financial outcomes (i.e., assets versus debt). In a community sample of healthy adults (n = 75), rapid learners had smaller debt-to-asset ratios overall. More specific analyses, however, revealed that those who learned rapidly about gains had more assets, while those who learned rapidly about losses had less debt. These distinct associations remained strong even after controlling for potential cognitive (e.g., intelligence, memory, and risk preferences) and socioeconomic (e.g., age, sex, ethnicity, income, education) confounds. Self-reported measures of assets and debt were additionally validated with credit report data in a subset of subjects. These findings support the notion that different gain and loss learning systems may exert a cumulative influence on distinct life financial outcomes

Multiparametric MR Imaging of Diffusion and Perfusion in Contrast-enhancing and Nonenhancing Components in Patients with Glioblastoma

Purpose To determine whether regions of low apparent diffusion coefficient (ADC) with high relative cerebral blood volume (rCBV) represented elevated choline (Cho)-to-N-acetylaspartate (NAA) ratio (hereafter, Cho/NAA ratio) and whether their volumes correlated with progression-free survival (PFS) and overall survival (OS) in patients with glioblastoma (GBM). Materials and Methods This retrospective analysis was approved by the local research ethics committee. Volumetric analysis of imaging data from 43 patients with histologically confirmed GBM was performed. Patients underwent preoperative 3-T magnetic resonance imaging with conventional, diffusion-weighted, perfusion-weighted, and spectroscopic sequences. Patients underwent subsequent surgery with adjuvant chemotherapy and radiation therapy. Overlapping low-ADC and high-rCBV regions of interest (ROIs) (hereafter, ADC-rCBV ROIs) were generated in contrast-enhancing and nonenhancing regions. Cho/NAA ratio in ADC-rCBV ROIs was compared with that in control regions by using analysis of variance. All resulting ROI volumes were correlated with patient survival by using multivariate Cox regression. Results ADC-rCBV ROIs within contrast-enhancing and nonenhancing regions showed elevated Cho/NAA ratios, which were significantly higher than those in other abnormal tumor regions (P < .001 and P = .008 for contrast-enhancing and nonenhancing regions, respectively) and in normal-appearing white matter (P < .001 for both contrast-enhancing and nonenhancing regions). After Cox regression analysis controlling for age, tumor size, resection extent, O-6-methylguanine-DNA methyltransferase-methylation, and isocitrate dehydrogenase mutation status, the proportional volume of ADC-rCBV ROIs in nonenhancing regions significantly contributed to multivariate models of OS (hazard ratio, 1.132; P = .026) and PFS (hazard ratio, 1.454; P = .017). Conclusion Volumetric analysis of ADC-rCBV ROIs in nonenhancing regions of GBM can be used to identify patients with poor survival trends after accounting for known confounders of GBM patient outcome.Supported by a Clinician Scientist Award from the National Institute for Health Research (NIHR/CS/009/011) and by the NIHR Cambridge Biomedical Research Center and Commonwealth Scholarship Commission

Multimodal MRI characteristics of the glioblastoma infiltration beyond contrast enhancement

Our inability to identify the invasive margin of glioblastomas hampers attempts to achieve local control. Diffusion tensor imaging (DTI) has been implemented clinically to delineate the margin of the tumor infiltration, its derived anisotropic (q) values can extend beyond the contrast-enhanced area and correlates closely with the tumor. However, its correlation with tumor infiltration shown on multivoxel proton magnetic resonance spectroscopy1 (MRS) and perfusion magnetic resonance imaging (MRI) should be investigated. In this study, we aimed to show tissue characteristics of the q-defined peritumoral invasion on MRS and perfusion MRI. Patients with a primary glioblastoma were included (n = 51). Four regions of interest were analyzed; the contrast-enhanced lesion, peritumoral abnormal q region, peritumoral normal q region, and contralateral normal-appearing white matter. MRS, including choline (Cho)/creatinine (Cr), Cho/N-acetyl-aspartate (NAA) and NAA/Cr ratios, and the relative cerebral blood volume (rCBV) were analyzed. Our results showed an increase in the Cho/NAA (p = 0.0346) and Cho/Cr (p = 0.0219) ratios in the peritumoral abnormal q region, suggestive of tumor invasion. The rCBV was marginally elevated (p = 0.0798). Furthermore, the size of the abnormal q regions was correlated with survival; patients with larger abnormal q regions showed better progression-free survival (median 287 versus 53 days, p = 0.001) and overall survival (median 464 versus 274 days, p = 0.006) than those with smaller peritumoral abnormal q regions of interest. These results support how the DTI q abnormal area identifies tumor activity beyond the contrast-enhanced area, especially correlating with MRS

Abundant Human DNA Contamination Identified in Non-Primate Genome Databases

During routine screens of the NCBI databases using human repetitive elements we discovered an unlikely level of nucleotide identity across a broad range of phyla. To ascertain whether databases containing DNA sequences, genome assemblies and trace archive reads were contaminated with human sequences, we performed an in depth search for sequences of human origin in non-human species. Using a primate specific SINE, AluY, we screened 2,749 non-primate public databases from NCBI, Ensembl, JGI, and UCSC and have found 492 to be contaminated with human sequence. These represent species ranging from bacteria (B. cereus) to plants (Z. mays) to fish (D. rerio) with examples found from most phyla. The identification of such extensive contamination of human sequence across databases and sequence types warrants caution among the sequencing community in future sequencing efforts, such as human re-sequencing. We discuss issues this may raise as well as present data that gives insight as to how this may be occurring

Partial Depletion of Natural CD4+CD25+ Regulatory T Cells with Anti-CD25 Antibody Does Not Alter the Course of Acute Influenza A Virus Infection

Foxp3+ CD4+ regulatory T cells represent a T cell subset with well-characterized immunosuppressive effects during immune homeostasis and chronic infections, and there is emerging evidence to suggest these cells temper pulmonary inflammation in response to acute viral infection. Recent studies have demonstrated treatment with PC61 CD25-depleting antibody potentiates inflammation in a murine model of RSV infection, while paradoxically delaying recruitment of CD8+ T cells to the site of inflammation. The present study therefore sought to examine the role of these cells in a murine model of acute influenza A virus infection through the administration of PC61 CD25-depleting antibody. PC61 antibody is able to partially deplete CD25+Foxp3+ regulatory T cells to a comparable degree as seen within previous work examining RSV, however this does not alter influenza A-virus induced mortality, weight loss, viral clearance and cellularity within the lung. Collectively, these data demonstrate that partial depletion of CD4+CD25+ regulatory T cells with PC61 antibody does not alter the course of influenza A virus infection

A specific case in the classification of woods by FTIR and chemometric: discrimination of Fagales from Malpighiales

Fourier transform infrared (FTIR) spectroscopic data was used to classify wood samples from nine species within the Fagales and Malpighiales using a range of multivariate statistical methods. Taxonomic classification of the family Fagaceae and Betulaceae from Angiosperm Phylogenetic System Classification (APG II System) was successfully performed using supervised pattern recognition techniques. A methodology for wood sample discrimination was developed using both sapwood and heartwood samples. Ten and eight biomarkers emerged from the dataset to discriminate order and family, respectively. In the species studied FTIR in combination with multivariate analysis highlighted significant chemical differences in hemicelluloses, cellulose and guaiacyl (lignin) and shows promise as a suitable approach for wood sample classification

Species-specific differences in the Pro-Ala rich region of cardiac myosin binding protein-C

Cardiac myosin binding protein-C (cMyBP-C) is an accessory protein found in the A-bands of vertebrate sarcomeres and mutations in the cMyBP-C gene are a leading cause of familial hypertrophic cardiomyopathy. The regulatory functions of cMyBP-C have been attributed to the N-terminus of the protein, which is composed of tandem immunoglobulin (Ig)-like domains (C0, C1, and C2), a region rich in proline and alanine residues (the Pro-Ala rich region) that links C0 and C1, and a unique sequence referred to as the MyBP-C motif, or M-domain, that links C1 and C2. Recombinant proteins that contain various combinations of the N-terminal domains of cMyBP-C can activate actomyosin interactions in the absence of Ca2+, but the specific sequences required for these effects differ between species; the Pro-Ala region has been implicated in human cMyBP-C whereas the C1 and M-domains appear important in mouse cMyBP-C. To investigate whether species-specific differences in sequence can account for the observed differences in function, we compared sequences of the Pro-Ala rich region in cMyBP-C isoforms from different species. Here we report that the number of proline and alanine residues in the Pro-Ala rich region varies significantly between different species and that the number correlates directly with mammalian body size and inversely with heart rate. Thus, systematic sequence differences in the Pro-Ala rich region of cMyBP-C may contribute to observed functional differences in human versus mouse cMyBP-C isoforms and suggest that the Pro-Ala region may be important in matching contractile speed to cardiac function across species

Different atmospheric moisture divergence responses to extreme and moderate El Niños

On seasonal and inter-annual time scales, vertically integrated moisture divergence provides a useful measure of the tropical atmospheric hydrological cycle. It reflects the combined dynamical and thermodynamical effects, and is not subject to the limitations that afflict observations of evaporation minus precipitation. An empirical orthogonal function (EOF) analysis of the tropical Pacific moisture divergence fields calculated from the ERA-Interim reanalysis reveals the dominant effects of the El Niño-Southern Oscillation (ENSO) on inter-annual time scales. Two EOFs are necessary to capture the ENSO signature, and regression relationships between their Principal Components and indices of equatorial Pacific sea surface temperature (SST) demonstrate that the transition from strong La Niña through to extreme El Niño events is not a linear one. The largest deviation from linearity is for the strongest El Niños, and we interpret that this arises at least partly because the EOF analysis cannot easily separate different patterns of responses that are not orthogonal to each other. To overcome the orthogonality constraints, a self-organizing map (SOM) analysis of the same moisture divergence fields was performed. The SOM analysis captures the range of responses to ENSO, including the distinction between the moderate and strong El Niños identified by the EOF analysis. The work demonstrates the potential for the application of SOM to large scale climatic analysis, by virtue of its easier interpretation, relaxation of orthogonality constraints and its versatility for serving as an alternative classification method. Both the EOF and SOM analyses suggest a classification of “moderate” and “extreme” El Niños by their differences in the magnitudes of the hydrological cycle responses, spatial patterns and evolutionary paths. Classification from the moisture divergence point of view shows consistency with results based on other physical variables such as SST