Extended T2-IVIM model for correction of TE dependence of pseudo-diffusion volume fraction in clinical diffusion-weighted magnetic resonance imaging.

The bi-exponential intravoxel-incoherent-motion (IVIM) model for diffusion-weighted MRI (DWI) fails to account for differential T 2 s in the model compartments, resulting in overestimation of pseudodiffusion fraction f. An extended model, T2-IVIM, allows removal of the confounding echo-time (TE) dependence of f, and provides direct compartment T 2 estimates. Two consented healthy volunteer cohorts (n  =  5, 6) underwent DWI comprising multiple TE/b-value combinations (Protocol 1: TE  =  62-102 ms, b  =  0-250 mm-2s, 30 combinations. Protocol 2: 8 b-values 0-800 mm-2s at TE  =  62 ms, with 3 additional b-values 0-50 mm-2s at TE  =  80, 100 ms; scanned twice). Data from liver ROIs were fitted with IVIM at individual TEs, and with the T2-IVIM model using all data. Repeat-measures coefficients of variation were assessed for Protocol 2. Conventional IVIM modelling at individual TEs (Protocol 1) demonstrated apparent f increasing with longer TE: 22.4  ±  7% (TE  =  62 ms) to 30.7  ±  11% (TE  =  102 ms); T2-IVIM model fitting accounted for all data variation. Fitting of Protocol 2 data using T2-IVIM yielded reduced f estimates (IVIM: 27.9  ±  6%, T2-IVIM: 18.3  ±  7%), as well as T 2  =  42.1  ±  7 ms, 77.6  ±  30 ms for true and pseudodiffusion compartments, respectively. A reduced Protocol 2 dataset yielded comparable results in a clinical time frame (11 min). The confounding dependence of IVIM f on TE can be accounted for using additional b/TE images and the extended T2-IVIM model

Characterisation of fibrosis in chemically-induced rat mammary carcinomas using multi-modal endogenous contrast MRI on a 1.5T clinical platform.

Objectives To determine the ability of multi-parametric, endogenous contrast MRI to detect and quantify fibrosis in a chemically-induced rat model of mammary carcinoma.Methods Female Sprague-Dawley rats (n=18) were administered with N-methyl-N-nitrosourea; resulting mammary carcinomas underwent nine-b-value diffusion-weighted (DWI), ultrashort-echo (UTE) and magnetisation transfer (MT) magnetic resonance imaging (MRI) on a clinical 1.5T platform, and associated quantitative MR parameters were calculated. Excised tumours were histologically assessed for degree of necrosis, collagen, hypoxia and microvessel density. Significance level adjusted for multiple comparisons was p=0.0125.Results Significant correlations were found between MT parameters and degree of picrosirius red staining (r > 0.85, p a and δ, r 1 and T1s, Pearson), indicating that MT is sensitive to collagen content in mammary carcinoma. Picrosirius red also correlated with the DWI parameter fD* (r=0.801, p=0.0004) and conventional gradient-echo T2* (r=-0.660, p=0.0055). Percentage necrosis correlated moderately with ultrashort/conventional-echo signal ratio (r=0.620, p=0.0105). Pimonidazole adduct (hypoxia) and CD31 (microvessel density) staining did not correlate with any MR parameter assessed.Conclusions Magnetisation transfer MRI successfully detects collagen content in mammary carcinoma, supporting inclusion of MT imaging to identify fibrosis, a prognostic marker, in clinical breast MRI examinations.Key points • Magnetisation transfer imaging is sensitive to collagen content in mammary carcinoma. • Magnetisation transfer imaging to detect fibrosis in mammary carcinoma fibrosis is feasible. • IVIM diffusion does not correlate with microvessel density in preclinical mammary carcinoma

Effect of Biodiversity Changes in Disease Risk: Exploring Disease Emergence in a Plant-Virus System

The effect of biodiversity on the ability of parasites to infect their host and cause disease (i.e. disease risk) is a major question in pathology, which is central to understand the emergence of infectious diseases, and to develop strategies for their management. Two hypotheses, which can be considered as extremes of a continuum, relate biodiversity to disease risk: One states that biodiversity is positively correlated with disease risk (Amplification Effect), and the second predicts a negative correlation between biodiversity and disease risk (Dilution Effect). Which of them applies better to different host-parasite systems is still a source of debate, due to limited experimental or empirical data. This is especially the case for viral diseases of plants. To address this subject, we have monitored for three years the prevalence of several viruses, and virus-associated symptoms, in populations of wild pepper (chiltepin) under different levels of human management. For each population, we also measured the habitat species diversity, host plant genetic diversity and host plant density. Results indicate that disease and infection risk increased with the level of human management, which was associated with decreased species diversity and host genetic diversity, and with increased host plant density. Importantly, species diversity of the habitat was the primary predictor of disease risk for wild chiltepin populations. This changed in managed populations where host genetic diversity was the primary predictor. Host density was generally a poorer predictor of disease and infection risk. These results support the dilution effect hypothesis, and underline the relevance of different ecological factors in determining disease/infection risk in host plant populations under different levels of anthropic influence. These results are relevant for managing plant diseases and for establishing conservation policies for endangered plant species

Repeatability of derived parameters from histograms following non-Gaussian diffusion modelling of diffusion-weighted imaging in a paediatric oncological cohort.

Objectives To examine repeatability of parameters derived from non-Gaussian diffusion models in data acquired in children with solid tumours.Methods Paediatric patients (-2 s) at 1.5 T in a prospective study. Tumour ROIs were drawn (3 slices) and all data fitted using IVIM, stretched exponential, and kurtosis models; percentage coefficients of variation (CV) calculated for each parameter at all ROI histogram centiles, including the medians.Results The values for ADC, D, DDCα, α, and DDCK gave CV 30 %) over the histogram. ADC, D, DDCα, and DDCK were strongly correlated (ρ > 0.9), DDCα and α were not correlated (ρ = 0.083).Conclusion Perfusion- and kurtosis-related parameters displayed larger, more variable CV across the histogram, indicating observed clinical changes outside of D/DDC in these models should be interpreted with caution. Centiles below 5th for all parameters show high CV and are unreliable as diffusion metrics. The stretched exponential model behaved well for both DDCα and α, making it a strong candidate for modelling multiple-b-value diffusion imaging data.Key points • ADC has good repeatability as low 5th centile of the histogram distribution. • High CV was observed for all parameters at extremes of histogram. • Parameters from the stretched exponential model showed low coefficients of variation. • The median ADC, D, DDC α , and DDC K are highly correlated and repeatable. • Perfusion/kurtosis parameters showed high CV variations across their histogram distributions

Widespread Expression of BORIS/CTCFL in Normal and Cancer Cells

BORIS (CTCFL) is the paralog of CTCF (CCCTC-binding factor; NM_006565), a ubiquitously expressed DNA-binding protein with diverse roles in gene expression and chromatin organisation. BORIS and CTCF have virtually identical zinc finger domains, yet display major differences in their respective C- and N-terminal regions. Unlike CTCF, BORIS expression has been reported only in the testis and certain malignancies, leading to its classification as a “cancer-testis” antigen. However, the expression pattern of BORIS is both a significant and unresolved question in the field of DNA binding proteins. Here, we identify BORIS in the cytoplasm and nucleus of a wide range of normal and cancer cells. We compare the localization of CTCF and BORIS in the nucleus and demonstrate enrichment of BORIS within the nucleolus, inside the nucleolin core structure and adjacent to fibrillarin in the dense fibrillar component. In contrast, CTCF is not enriched in the nucleolus. Live imaging of cells transiently transfected with GFP tagged BORIS confirmed the nucleolar accumulation of BORIS. While BORIS transcript levels are low compared to CTCF, its protein levels are readily detectable. These findings show that BORIS expression is more widespread than previously believed, and suggest a role for BORIS in nucleolar function

Detecting functional magnetic resonance imaging activation in white matter: Interhemispheric transfer across the corpus callosum

<p>Abstract</p> <p>Background</p> <p>It is generally believed that activation in functional magnetic resonance imaging (fMRI) is restricted to gray matter. Despite this, a number of studies have reported white matter activation, particularly when the corpus callosum is targeted using interhemispheric transfer tasks. These findings suggest that fMRI signals may not be neatly confined to gray matter tissue. In the current experiment, 4 T fMRI was employed to evaluate whether it is possible to detect white matter activation. We used an interhemispheric transfer task modelled after neurological studies of callosal disconnection. It was hypothesized that white matter activation could be detected using fMRI.</p> <p>Results</p> <p>Both group and individual data were considered. At liberal statistical thresholds (p < 0.005, uncorrected), group level activation was detected in the isthmus of the corpus callosum. This region connects the superior parietal cortices, which have been implicated previously in interhemispheric transfer. At the individual level, five of the 24 subjects (21%) had activation clusters that were located primarily within the corpus callosum. Consistent with the group results, the clusters of all five subjects were located in posterior callosal regions. The signal time courses for these clusters were comparable to those observed for task related gray matter activation.</p> <p>Conclusion</p> <p>The findings support the idea that, despite the inherent challenges, fMRI activation can be detected in the corpus callosum at the individual level. Future work is needed to determine whether the detection of this activation can be improved by utilizing higher spatial resolution, optimizing acquisition parameters, and analyzing the data with tissue specific models of the hemodynamic response. The ability to detect white matter fMRI activation expands the scope of basic and clinical brain mapping research, and provides a new approach for understanding brain connectivity.</p

BORIS, a paralogue of the transcription factor, CTCF, is aberrantly expressed in breast tumours

BORIS (for brother of the regulator of imprinted sites), a paralogue of the transcription factor, CTCF, is a novel member of the cancer-testis antigen family. The aims of the present study were as follows: (1) to investigate BORIS expression in breast cells and tumours using immunohistochemical staining, western and real-time RT–PCR analyses and (2) assess potential correlation between BORIS levels in tumours with clinical/pathological parameters. BORIS was detected in all 18 inspected breast cell lines, but not in a primary normal breast cell culture. In 70.7% (41 of 58 cases) BORIS was observed in breast tumours. High levels of BORIS correlated with high levels of progesterone receptor (PR) and oestrogen receptor (ER). The link between BORIS and PR/ER was further confirmed by the ability of BORIS to activate the promoters of the PR and ER genes in the reporter assays. Detection of BORIS in a high proportion of breast cancer patients implies potential practical applications of BORIS as a molecular biomarker of breast cancer. This may be important for diagnosis of the condition and for the therapeutic use of BORIS. The ability of BORIS to activate promoters of the RP and ER genes points towards possible involvement of BORIS in the establishment, progression and maintenance of breast tumours

The Structural Complexity of the Human BORIS Gene in Gametogenesis and Cancer

BORIS/CTCFL is a paralogue of CTCF, the major epigenetic regulator of vertebrate genomes. BORIS is normally expressed only in germ cells but is aberrantly activated in numerous cancers. While recent studies demonstrated that BORIS is a transcriptional activator of testis-specific genes, little is generally known about its biological and molecular functions.Here we show that BORIS is expressed as 23 isoforms in germline and cancer cells. The isoforms are comprised of alternative N- and C-termini combined with varying numbers of zinc fingers (ZF) in the DNA binding domain. The patterns of BORIS isoform expression are distinct in germ and cancer cells. Isoform expression is activated by downregulation of CTCF, upregulated by reduction in CpG methylation caused by inactivation of DNMT1 or DNMT3b, and repressed by activation of p53. Studies of ectopically expressed isoforms showed that all are translated and localized to the nucleus. Using the testis-specific cerebroside sulfotransferase (CST) promoter and the IGF2/H19 imprinting control region (ICR), it was shown that binding of BORIS isoforms to DNA targets in vitro is methylation-sensitive and depends on the number and specific composition of ZF. The ability to bind target DNA and the presence of a specific long amino terminus (N258) in different isoforms are necessary and sufficient to activate CST transcription. Comparative sequence analyses revealed an evolutionary burst in mammals with strong conservation of BORIS isoproteins among primates.The extensive repertoire of spliced BORIS variants in humans that confer distinct DNA binding and transcriptional activation properties, and their differential patterns of expression among germ cells and neoplastic cells suggest that the gene is involved in a range of functionally important aspects of both normal gametogenesis and cancer development. In addition, a burst in isoform diversification may be evolutionarily tied to unique aspects of primate speciation

Noninvasive Imaging of Cycling Hypoxia in Head and Neck Cancer Using Intrinsic Susceptibility MRI.

Purpose: To evaluate intrinsic susceptibility (IS) MRI for the identification of cycling hypoxia, and the assessment of its extent and spatial distribution, in head and neck squamous cell carcinoma (HNSCC) xenografts and patients.Experimental Design: Quantitation of the transverse relaxation rate, R2*, which is sensitive to paramagnetic deoxyhemoglobin, using serial IS-MRI acquisitions, was used to monitor temporal oscillations in levels of paramagnetic deoxyhemoglobin in human CALR xenografts and patients with HNSCC at 3T. Autocovariance and power spectrum analysis of variations in R2* was performed for each imaged voxel, to assess statistical significance and frequencies of cycling changes in tumor blood oxygenation. Pathologic correlates with tumor perfusion (Hoechst 33342), hypoxia (pimonidazole), and vascular density (CD31) were sought in the xenografts, and dynamic contrast-enhanced (DCE) MRI was used to assess patient tumor vascularization. The prevalence of fluctuations within patient tumors, DCE parameters, and treatment outcome were reported.Results: Spontaneous R2* fluctuations with a median periodicity of 15 minutes were detected in both xenografts and patient tumors. Spatially, these fluctuations were predominantly associated with regions of heterogeneous perfusion and hypoxia in the CALR xenografts. In patients, R2* fluctuations spatially correlated with regions of lymph nodes with low Ktrans values, typically in the vicinity of necrotic cores.Conclusions: IS-MRI can be used to monitor variations in levels of paramagnetic deoxyhemoglobin, associated with cycling hypoxia. The presence of such fluctuations may be linked with impaired tumor vasculature, the presence of which may impact treatment outcome. Clin Cancer Res; 23(15); 4233-41. ©2017 AACR