Barjor Gimi

In vitro and in vivo evaluation of SU-8 biocompatibility.

SU-8 negative photoresist is a high tensile strength polymer that has been used for a number of biomedical applications that include cell encapsulation and neuronal probes. Chemically, SU-8 comprises, among other components, an epoxy based monomer and antimony salts, the latter being a potential source of cytotoxicity. We report on the in vitro and in vivo evaluation of SU-8 biocompatibility based on leachates from various solvents, at varying temperatures and pH, and upon subcutaneous implantation of SU-8 substrates in mice. MTT cell viability assay did not exhibit any cytotoxic effects from the leachates. The hemolytic activity of SU-8 is comparable to that of FDA approved implant materials such as silicone elastomer, Buna-S and medical steel. In vivo histocompatibility study in mice indicates a muted immune response to subcutaneous SU-8 implants.

Imaging Characteristics of Atypical Teratoid–Rhabdoid Tumor in Children Compared with Medulloblastoma

OBJECTIVE The purpose of our study was to compare the imaging characteristics of atypical teratoid-rhabdoid tumor with medulloblastoma and seek distinguishing features that can aid in preoperative diagnosis. MATERIALS AND METHODS Preoperative MRI examinations of 55 patients (36 medulloblastomas and 19 atypical teratoid-rhabdoid tumors) were analyzed retrospectively. Imaging characteristics of atypical teratoid-rhabdoid tumor and medulloblastoma were assessed with conventional MRI and CT. Diffusion-weighted imaging (DWI) was available in 27 patients (19 medulloblastomas and eight atypical teratoid-rhabdoid tumors). Apparent diffusion coefficient (ADC) values were calculated for 14 medulloblastomas and six atypical teratoid-rhabdoid tumors. RESULTS Both atypical teratoid-rhabdoid tumors in general and infratentorial atypical teratoid-rhabdoid tumors presented at a younger age than medulloblastomas. Eleven of 19 atypical teratoid-rhabdoid tumors were infratentorial. Cerebellopontine angle (CPA) involvement was more frequent (8/11, 72.7%) in atypical teratoid-rhabdoid tumor than in medulloblastoma (4/36, 11.1%) (p < 0.001). Intratumoral hemorrhage was more common in atypical teratoid-rhabdoid tumor (9/19, 47.4%) than in medulloblastoma (2/36, 5.6%) (p < 0.0001). All atypical teratoid-rhabdoid tumors and all medulloblastomas for which DWI was available displayed increased signal intensity on DWI compared with normal brain parenchyma. The mean ADC values for tumor types were not significantly different. CONCLUSION Atypical teratoid-rhabdoid tumor presents at a younger age than medulloblastoma. Although atypical teratoid-rhabdoid tumor and medulloblastoma display similar imaging characteristics on conventional MRI, CPA involvement and intratumoral hemorrhage are more common in atypical teratoid-rhabdoid tumor. If a pediatric posterior fossa mass that displays restricted diffusion is involving the CPA, atypical teratoid-rhabdoid tumor is a more likely consideration than medulloblastoma.

Molecular and functional imaging of cancer: Advances in MRI and MRS

Publisher Summary This chapter presents an overview of the endogenous and exogenous magnetic resonance (MR) contrast mechanisms utilized in characterizing tumor vasculature. Every contrast mechanism for probing the tumor vasculature, including the use of exogenous MR contrast agents, is in some way a result of the changes in the MR signal intensity brought about by changes in tissue relaxation times. Noninvasive multinuclear magnetic resonance imaging (MRI) and MR spectroscopic imaging (MRSI) provide a wealth of spatial and temporal information on tumor vasculature, metabolism, and physiology. The most commonly used MR contrast agents (CA) are paramagnetic gadolinium chelates. These agents are tightly bound complexes of the rare earth element gadolinium and various chelating agents. A simple linear compartment model, describing uptake of the contrast agent from plasma, postulates a negligible reflux of the contrast agent from the interstitium back to the blood compartment. Blood concentrations of the CA can be approximated to be constant for the duration of the MR experiment, and under these conditions, contrast uptake is a linear function of time. The MR detection of cellular targets is also elaborated.

The Diaphragms of Fenestrated Endothelia: Gatekeepers of Vascular Permeability and Blood Composition

Fenestral and stomatal diaphragms are endothelial subcellular structures of unknown function that form on organelles implicated in vascular permeability: fenestrae, transendothelial channels, and caveolae. PV1 protein is required for diaphragm formation in vitro. Here, we report that deletion of the PV1-encoding Plvap gene in mice results in the absence of diaphragms and decreased survival. Loss of diaphragms did not affect the fenestrae and transendothelial channels formation but disrupted the barrier function of fenestrated capillaries, causing a major leak of plasma proteins. This disruption results in early death of animals due to severe noninflammatory protein-losing enteropathy. Deletion of PV1 in endothelium, but not in the hematopoietic compartment, recapitulates the phenotype of global PV1 deletion, whereas endothelial reconstitution of PV1 rescues the phenotype. Taken together, these data provide genetic evidence for the critical role of the diaphragms in fenestrated capillaries in the maintenance of blood composition.

Choline kinase overexpression increases invasiveness and drug resistance of human breast cancer cells.

A direct correlation exists between increased choline kinase (Chk) expression, and the resulting increase of phosphocholine levels, and histological tumor grade. To better understand the function of Chk and choline phospholipid metabolism in breast cancer we have stably overexpressed one of the two isoforms of Chk‐α known to be upregulated in malignant cells, in non‐invasive MCF‐7 human breast cancer cells. Dynamic tracking of cell invasion and cell metabolism were studied with a magnetic resonance (MR) compatible cell perfusion assay. The MR based invasion assay demonstrated that MCF‐7 cells overexpressing Chk‐α (MCF‐7‐Chk) exhibited an increase of invasion relative to control MCF‐7 cells (0.84 vs 0.3). Proton MR spectroscopy studies showed significantly higher phosphocholine and elevated triglyceride signals in Chk overexpressing clones compared to control cells. A test of drug resistance in MCF‐7‐Chk cells revealed that these cells had an increased resistance to 5‐fluorouracil and higher expression of thymidylate synthase compared to control MCF‐7 cells. To further characterize increased drug resistance in these cells, we performed rhodamine‐123 efflux studies to evaluate drug efflux pumps. MCF‐7‐Chk cells effluxed twice as much rhodamine‐123 compared to MCF‐7 cells. Chk‐α overexpression resulted in MCF‐7 human breast cancer cells acquiring an increasingly aggressive phenotype, supporting the role of Chk‐α in mediating invasion and drug resistance, and the use of phosphocholine as a biomarker of aggressive breast cancers. Copyright

Simple Developmental Dyslexia in Children: Alterations in Diffusion-Tensor Metrics of White Matter Tracts at 3 T

PURPOSE To determine whether there are detectable differences in tensor metrics between children who read normally and children with simple developmental dyslexia and/or differences between the right and left hemispheres in these groups by using 3.0-T diffusion-tensor (DT) magnetic resonance (MR) imaging focused on the superior longitudinal fasciculus (SLF), inferior fronto-occipital and inferior longitudinal fasciculi (IFO-ILF), and posterior limb of the internal capsule (PLIC). MATERIALS AND METHODS This was a prospective, HIPAA-compliant institutional review board-approved investigation with written informed parental consent. Nineteen English-speaking, right-handed children with a normal IQ and developmental dyslexia (16 male, three female; age range, 6-16 years; mean age, 9.9 years) and 18 normal-reading, age-matched pediatric control subjects (13 male, five female; age range, 6-15 years; mean age, 10.0 years) underwent DT imaging (30 directions, three signals acquired, voxel size of 2 mm). Regions of interest were placed on the SLF, IFO-ILF, and PLIC, and tensor metrics were calculated. Statistical analyses of differences in cognitive function between the dyslexic and control groups were performed by using the two-sample t test. Differences in tensor metrics were examined by using analysis of covariance models. RESULTS In the control subjects, the fractional anisotropy (FA) of all tracts studied increased with age. In the dyslexic subjects, the age-related increases in FA in the SLF were most similar to those in the control subjects (P = .504), while mean FA values for the IFO-ILF (P = .009) and PLIC (P < .0001) were higher than those in the control subjects up to around 11 years of age, after which they were lower. Apparent diffusion coefficients consistently decreased in both groups. There was a nonsignificant increase in mean axial diffusivity in the IFO-ILF in the control group but not in the dyslexia group. Increases in axial diffusivity seen in the PLIC in the control group were not seen in the dyslexia group. There were no marked differences in tensor metrics between the left and right hemispheres within or between the two groups. CONCLUSION Findings at 3.0-T DT imaging suggest that white matter differences in dyslexic children are not limited to the portion of the brain traditionally considered to be integral to word recognition and processing.

Utility of Apparent Diffusion Coefficient Ratios in Distinguishing Common Pediatric Cerebellar Tumors

RATIONALE AND OBJECTIVES The aim of this study was to identify clinically useful tumor/normal brain apparent diffusion coefficient (ADC) ratios for distinguishing common pediatric cerebellar tumors. MATERIALS AND METHODS Review of medical records revealed 79 patients with cerebellar tumors who underwent preoperative magnetic resonance imaging, including diffusion-weighted imaging sequences, and surgery. There were 31 pilocytic astrocytomas, 27 medulloblastomas, 14 ependymomas, and seven atypical teratoid/rhabdoid tumors. ADC values were measured by placing regions of interest on the solid tumor and normal brain parenchyma by two reviewers. Tumor/normal brain ADC ratios were calculated. RESULTS Mean ADC values of the pilocytic astrocytomas were greater than those of ependymomas, whose mean ADC values were greater than those of medulloblastomas and atypical teratoid/rhabdoid tumors. Using a tumor/normal brain ADC ratio threshold of 1.70 to distinguish pilocytic astrocytomas from ependymomas, sensitivity of 92% and specificity of 79% were achieved. A tumor/normal brain ADC ratio threshold of 1.20 enabled the sorting of ependymomas from medulloblastomas with sensitivity of 93% and specificity of 88%. CONCLUSIONS Tumor/normal brain ADC ratios allow the distinguishing of common pediatric cerebellar tumors.

Molecular sensing with magnetic nanoparticles using magnetic spectroscopy of nanoparticle Brownian motion.

Functionalized magnetic nanoparticles (mNPs) have shown promise in biosensing and other biomedical applications. Here we use functionalized mNPs to develop a highly sensitive, versatile sensing strategy required in practical biological assays and potentially in vivo analysis. We demonstrate a new sensing scheme based on magnetic spectroscopy of nanoparticle Brownian motion (MSB) to quantitatively detect molecular targets. MSB uses the harmonics of oscillating mNPs as a metric for the freedom of rotational motion, thus reflecting the bound state of the mNP. The harmonics can be detected in vivo from nanogram quantities of iron within 5s. Using a streptavidin-biotin binding system, we show that the detection limit of the current MSB technique is lower than 150 pM (0.075 pmole), which is much more sensitive than previously reported techniques based on mNP detection. Using mNPs conjugated with two anti-thrombin DNA aptamers, we show that thrombin can be detected with high sensitivity (4 nM or 2 pmole). A DNA-DNA interaction was also investigated. The results demonstrated that sequence selective DNA detection can be achieved with 100 pM (0.05 pmole) sensitivity. The results of using MSB to sense these interactions, show that the MSB based sensing technique can achieve rapid measurement (within 10s), and is suitable for detecting and quantifying a wide range of biomarkers or analytes. It has the potential to be applied in variety of biomedical applications or diagnostic analyses.

Diffusion-weighted and macromolecular contrast enhanced MRI of tumor response to antivascular therapy with ZD6126

The effects of the anti-vascular agent ZD6126 were studied in volume matched subcutaneous DU-145 human prostate cancer xenografts in SCID mice using two different MRI techniques, diffusion and vascular imaging. Diffusion weighted MRI was performed before and at 24 h, 48 h, and 72 h following a single dose of 200 mg/kg. Tumor vascular volume and permeability surface area product (PSP) were determined 24 h post antivascular therapy following an identical dose using dynamic contrast enhanced MRI of the macromolecular contrast agent albumin-gadolinium diethylenetriaminepentaacetate (albumin-GdDTPA). Consistent with the mechanism of action of ZD6126, significantly lower vascular volume was detected at 24 h whereas diffusion changes were evident at 48 h. Diffusion MRI findings correlated well with histological determination of the necrotic fraction in the tumors by 48 h. Both diffusion and vascular imaging are useful noninvasive techniques to detect response of tumors to antivascular therapy with ZD6126 in the DU-145 human prostate cancer xenograft model.

Common Pediatric Cerebellar Tumors: Correlation between Cell Densities and Apparent Diffusion Coefficient Metrics

PURPOSE To test whether there is correlation between cell densities and apparent diffusion coefficient (ADC) metrics of common pediatric cerebellar tumors. MATERIALS AND METHODS This study was reviewed for issues of patient safety and confidentiality and was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center and was compliant with HIPAA. The need for informed consent was waived. Ninety-five patients who had preoperative magnetic resonance imaging and surgical pathologic findings available between January 2003 and June 2011 were included. There were 37 pilocytic astrocytomas, 34 medulloblastomas (23 classic, eight desmoplastic-nodular, two large cell, one anaplastic), 17 ependymomas (13 World Health Organization [WHO] grade II, four WHO grade III), and seven atypical teratoid rhabdoid tumors. ADCs of solid tumor components and normal cerebellum were measured. Tumor-to-normal brain ADC ratios (hereafter, ADC ratio) were calculated. The medulloblastomas and ependymomas were subcategorized according to the latest WHO classification, and tumor cellularity was calculated. Correlation was sought between cell densities and mean tumor ADCs, minimum tumor ADCs, and ADC ratio. RESULTS When all tumors were considered together, negative correlation was found between cellularity and mean tumor ADCs (ρ = -0.737, P < .05) and minimum tumor ADCs (ρ = -0.736, P < .05) of common pediatric cerebellar tumors. There was no correlation between cellularity and ADC ratio. Negative correlation was found between cellularity and minimum tumor ADC in atypical teratoid rhabdoid tumors (ρ = -0.786, P < .05). In atypical teratoid rhabdoid tumors, no correlation was found between cellularity and mean tumor ADC and ADC ratio. There was no correlation between the ADC metrics and cellularity of the pilocytic astrocytomas, medulloblastomas, and ependymomas. CONCLUSION Negative correlation was found between cellularity and ADC metrics of common pediatric cerebellar tumors. Although ADC metrics are useful in the preoperative diagnosis of common pediatric cerebellar tumors and this utility is generally attributed to differences in cellularity of tumors, tumor cellularity may not be the sole determinant of the differences in diffusivity.