Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism.

BackgroundPreterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury.MethodsRat pups were exposed to IH from P2 to P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20-P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed.ResultsPups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1ß at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus, and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr, and Gly/Cr; increases in TCho and GPC in the brainstem; and decreases in NAA/Cho in the hippocampus.ConclusionsWe conclude that early postnatal exposure to IH, similar in magnitude to that experienced in human preterm infants, is associated with evidence for proinflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia.

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFß, and IDO1.

Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor ß1 (TGFß1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFß1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications.

Effect of alginate microencapsulation on the catalytic efficiency and in vitro enzyme-prodrug therapeutic efficacy of cytosine deaminase and of recombinant E. coli expressing cytosine deaminase.

Cytosine deaminase (CD) catalyses the enzymatic conversion of the non-toxic prodrug 5-fluorocytosine (5-FC) to the potent chemotherapeutic form, 5-fluorouracil (5-FU). Intratumoral delivery of CD localises chemotherapy dose while reducing systemic toxicity. Encapsulation in biocompatible microcapsules immunoisolates CD and protects it from degradation. We report on the effect of alginate encapsulation on the catalytic and functional activity of isolated CD and recombinant E. coli engineered to express CD (E. coli(CD)). Alginate microcapsules containing either CD or Escherichia coli(CD) were prepared using ionotropic gelation. Conversion of 5-FC to 5-FU was quantitated in unencapsulated and encapsulated CD/E. coli(CD) using spectrophotometry, with a slower rate of conversion observed following encapsulation. Both encapsulated CD/5-FC and E. coli(CD)/5-FC resulted in cell kill and reduced proliferation of 9 L rat glioma cells, which was comparable to direct 5-FU treatment. Our results show that encapsulation preserves the therapeutic potential of CD and E. coli(CD) is equally effective for enzyme-prodrug therapy.

Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry.

Hypoxia is a critical hallmark of glioma, and significantly compromises treatment efficacy. Unfortunately, techniques for monitoring glioma pO2 to facilitate translational research are lacking. Furthermore, poor prognosis of patients with malignant glioma, in particular glioblastoma multiforme, warrant effective strategies that can inhibit hypoxia and improve treatment outcome. EPR oximetry using implantable resonators was implemented for monitoring pO2 in normal cerebral tissue and U251 glioma in mice. Breathing carbogen (95% O2 + 5% CO2 ) was tested for hyperoxia in the normal brain and glioma xenografts. A new strategy to inhibit glioma growth by rationally combining gemcitabine and MK-8776, a cell cycle checkpoint inhibitor, was also investigated. The mean pO2 of left and right hemisphere were ∼56-69 mmHg in the normal cerebral tissue of mice. The mean baseline pO2 of U251 glioma on the first and fifth day of measurement was 21.9 ± 3.7 and 14.1 ± 2.4 mmHg, respectively. The mean brain pO2 including glioma increased by at least 100% on carbogen inhalation, although the response varied between the animals over days. Treatment with gemcitabine + MK-8776 significantly increased pO2 and inhibited glioma growth assessed by MRI. In conclusion, EPR oximetry with implantable resonators can be used to monitor the efficacy of carbogen inhalation and chemotherapy on orthotopic glioma in mice. The increase in glioma pO2 of mice breathing carbogen can be used to improve treatment outcome. The treatment with gemcitabine + MK-8776 is a promising strategy that warrants further investigation.

Toward Localized In Vivo Biomarker Concentration Measurements.

We know a great deal about the biochemistry of cells because they can be isolated and studied. The biochemistry of the much more complex in vivo environment is more difficult to study because the only ways to quantitate concentrations is to sacrifice the animal or biopsy the tissue. Either method disrupts the environment profoundly and neither method allows longitudinal studies on the same individual. Methods of measuring chemical concentrations in vivo are very valuable alternatives to sacrificing groups of animals. We are developing microscopic magnetic nanoparticle (mNP) probes to measure the concentration of a selected molecule in vivo. The mNPs are targeted to bind the selected molecule and the resulting reduction in rotational freedom can be quantified remotely using magnetic spectroscopy. The mNPs must be contained in micrometer sized porous shells to keep them from migrating and to protect them from clearance by the immune system. There are two key issues in the development of the probes. First, we demonstrate the ability to measure concentrations in the porous walled alginate probes both in phosphate buffered saline and in blood, which is an excellent surrogate for the complex and challenging in vivo environment. Second, sensitivity is critical because it allows microscopic probes to measure very small concentrations very far away. We report sensitivity measurements on recently introduced technology that has allowed us to improve the sensitivity by two orders of magnitude, a factor of 200 so far.

MRI of the petromastoid canal in children.

PURPOSE: To characterize the MRI features of the petromastoid canal in children with sensorineural hearing loss (SNHL) and in normal infants. MATERIALS AND METHODS: High resolution MRI examinations of 564 children who were evaluated for SNHL and brain MRI examinations of 112 infants who had normal studies were studied independently by two reviewers. RESULTS: In SNHL group, visibility of the PMC decreased for right and left PMC (P < 0.001). The width of the right PMC significantly decreased as age increased (P < 0.0001). There was no relation between abnormalities of membranous labyrinth and cochlear nerve and PMC visibility in children with SNHL (p > 0.05). In the normal group, the PMC visibility decreased with increasing age (right P = 0.0001, left P = 0.001). In the normal group also, as age increased, the PMC width decreased for both PMCs (right, P = 0.0006; left, P = 0.03). CONCLUSION: The PMC is more frequently visualized in young children. Its visibility and width are not associated with abnormalities of membranous labyrinth and cochlear nerves.

Applicability of apparent diffusion coefficient ratios in preoperative diagnosis of common pediatric cerebellar tumors across two institutions.

INTRODUCTION: The purpose of our study was to test the accuracy and applicability of decision rules utilizing apparent diffusion coefficient (ADC) ratios on accurate preoperative diagnosis of common pediatric cerebellar tumors across two institutions. METHODS: In this HIPAA-compliant, IRB-approved study, performed at two institutions, 140 pediatric cerebellar tumors were included. Two separate reviewers placed regions of interest on the solid components of 140 tumors (98 at site A and 42 at site B) and normal brain on the ADC maps. The third reviewer who was blinded to the histopathological diagnoses made the same measurements on 140 patients to validate the data. Tumor to normal brain ADC ratios were calculated. Receiver operator curve (ROC) analysis was performed to generate thresholds to discriminate tumors. Utility of decision rules based on these thresholds was tested. RESULTS: While ADC values of medulloblastomas were different between the sites, there was no difference among the ADC ratios of medulloblastomas, pilocytic astrocytomas, ependymomas, and atypical teratoid rhabdoid tumors between the sites. ADC ratio of ≥1.8 correctly discriminated pilocytic astrocytomas from ependymomas with a sensitivity of 0.83 and a specificity of 0.78. ADC ratio of <1.2 correctly discriminated ependymomas from embryonal tumors with a sensitivity of 0.87 and a specificity of 0.83. The proposed decision rules correctly discriminated 120 of the 140 tumors (85.71%). Age ≥2 years criterion correctly sorted medulloblastomas in 84.48% of patients and age <2 years correctly distinguished atypical teratoid rhabdoid tumors in 90.00% of patients with embryonal tumors. CONCLUSIONS: Decision rules based on ADC ratios are applicable across two institutions in the accurate preoperative diagnosis of common pediatric cerebellar tumors.

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.

Advances in alginate gel microencapsulation of therapeutic cells.

Rapid developments in the therapeutic applications of genetically engineered cells and stem cell research have increased the possibilities of addressing some pathologies by grafting therapeutic cells. Immunoprotective encapsulation of such therapeutic cells is often essential for their survival and function. Hydrogels provide a bioteolerable matrix for cellular encapsulation and support subsequent graft survival and function. The naturally occurring marine polysaccharide, alginate, is the hydrogel of choice for most applications. However, long-term graft survival is affected by the mechanical instability of alginate and adverse immune reaction to its grafting. So, a variety of modifications have been developed to enhance the physicochemical properties and biotolerance of alginate hydrogels. We highlight the developments in alginate hydrogel microencapsulation of therapeutic cells.

Glutamine and GABA alterations in cingulate cortex may underlie alcohol drinking in a rat model of co-occurring alcohol use disorder and schizophrenia: an 1H-MRS study.

Alcohol use disorder commonly occurs in patients with schizophrenia and significantly worsens the clinical course of the disorder. The neurobiological underpinnings of alcohol drinking are not well understood. Magnetic resonance spectroscopy (MRS) has been used to assess the neurochemical substrates that may be associated with alcohol drinking in patients; however, the causal impact of these findings remains elusive, highlighting the need for studies in animal models. This study performed MRS in the neonatal ventral hippocampal lesioned (NVHL) rat model, a model of co-occurring schizophrenia and substance use disorders. NVHL lesions (or sham surgeries) were performed on post-natal day 7 and animals were given brief exposure to alcohol during adolescence (10% v/v in a 2-bottle choice design). Animals were re-exposed to alcohol during adulthood (20% v/v) until a stable drinking baseline was established, and then forced into abstinence to control for the effects of differential alcohol drinking. Animals were scanned for MRS after one month of abstinence. NVHL rats consumed significantly more alcohol than sham rats and in the cingulate cortex showed significantly higher levels of GABA and glutamine. Significantly lower GABA levels were observed in the nucleus accumbens. No differences between the NVHL and sham animals were observed in the hippocampus. Correlation analysis revealed that GABA and glutamine concentrations in the cingulate cortex significantly correlated with the rats' alcohol drinking prior to 30 days of forced abstinence. These findings suggest that a potential dysfunction in the glutamate/GABA-glutamine cycle may contribute to alcohol drinking in a rat model of schizophrenia, and this dysfunction could be targeted in future treatment-focused studies.

Encapsulated cell grafts to treat cellular deficiencies and dysfunction.

Cell transplantation provides a therapeutic alternative to whole organ transplantation in the management of diseases arising from the absence or failure of specialized cells. Though allogenic transplantation is favorable in terms of graft acceptance, xenotransplantation can provide a potentially unlimited source of cells and can overcome shortage of human donors. Effective immunoisolation of the xenografts is critical for their long term survival and function. Encapsulation of cells in polymeric matrices, organic or inorganic, provides a physical selectively permeable barrier between the host and the graft, thereby immunoisolating the graft. Microencapsulation of cells in alginate hydrogels has been pervasive, but this approach does not provide precise control over porosity, whereas micro- and nano-fabrication technologies can provide precise and reproducible control over porosity. We highlight both encapsulation approaches in this review, with their relative advantages and challenges. We also highlight the therapeutic potential of encapsulated cells for treating a variety of diseases, detailing the xenotransplantation of pancreatic islets in diabetes therapy as well as the grafting of engineered cells that facilitate localized enzyme-prodrug therapy of pancreatic cancer.

Biofriendly bonding processes for nanoporous implantable SU-8 microcapsules for encapsulated cell therapy.

Mechanically robust, cell encapsulating microdevices fabricated using photolithographic methods can lead to more efficient immunoisolation in comparison to cell encapsulating hydrogels. There is a need to develop adhesive bonding methods which can seal such microdevices under physiologically friendly conditions. We report the bonding of SU-8 based substrates through (i) magnetic self assembly, (ii) using medical grade photocured adhesive and (iii) moisture and photochemical cured polymerization. Magnetic self-assembly, carried out in biofriendly aqueous buffers, provides weak bonding not suitable for long term applications. Moisture cured bonding of covalently modified SU-8 substrates, based on silanol condensation, resulted in weak and inconsistent bonding. Photocured bonding using a medical grade adhesive and of acrylate modified substrates provided stable bonding. Of the methods evaluated, photocured adhesion provided the strongest and most stable adhesion.

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-alpha 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-alpha (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-alpha overexpression resulted in MCF-7 human breast cancer cells acquiring an increasingly aggressive phenotype, supporting the role of Chk-alpha in mediating invasion and drug resistance, and the use of phosphocholine as a biomarker of aggressive breast cancers.

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.

Cell encapsulation and oxygenation in nanoporous microcontainers.

With strides in stem cell biology, cell engineering and molecular therapy, the transplantation of cells to produce therapeutic molecules endogenously is an attractive and achievable alternative to the use of exogenous drugs. The encapsulation of such cell transplants in semi-permeable, nanoporous constructs is often required to protect them from immune attack and to prevent their proliferation in the host. However, effective graft immunoisolation has been mostly elusive owing to the absence of a high-throughput method to create precisely controlled, high-aspect-ratio nanopores. To address the clinical need for effective cell encapsulation and immunoisolation, we devised a biocompatible cell-encapsulating microcontainer and a method to create highly anisotropic nanopores in the microcontainer's surface. To evaluate the efficacy of these nanopores in oxygenating the encapsulated cells, we engineered 9L rat glioma cells to bioluminesce under hypoxic conditions. The methods described above should aid in evaluating the long term survival and efficacy of cellular grafts.

An immunotolerant HER-2/neu transgenic mouse model of metastatic breast cancer.

PURPOSE: Animal models of breast cancer metastases that recapitulate the pattern of metastatic progression seen in patients are lacking; metastatic breast cancer models do not currently exist for evaluation of immune-mediated therapies. We have developed and characterized a preclinical model for the evaluation of immune-mediated metastatic breast cancer therapies. EXPERIMENTAL DESIGN: The NT2.5 mammary tumor cell line was injected into the left cardiac ventricle of immunotolerant transgenic neu-N mice and athymic nu/nu mice. Metastatic progression was monitored by bioluminescent, small-animal magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography/computed tomography imaging, and also by histopathology. Antigen expression in normal organs and tumor metastases was evaluated by Western blot analysis and flow cytometry. RESULTS: Left cardiac ventricle injection of NT2.5 cells yielded widespread metastases in bones, liver, and spleen. Three to four weeks after injection, mice exhibited hind limb paralysis and occasional abdominal enlargement. Bioluminescence imaging of metastatic progression was successful in nude mice but the bioluminescent cells were rejected in immunocompetent mice. Other imaging modalities allowed successful imaging of nonbioluminescent cells. Small-animal positron emission tomography imaging allowed visualization of disease, in vivo, in the bones and liver. Magnetic resonance imaging revealed initial dissemination of the tumor cells to the bone marrow. Small-animal single-photon emission computed tomography/computed tomography imaging identified metastatic bone lesions targeted by a radiolabeled antibody. CONCLUSION: The model closely recapitulates the pattern of metastatic spread in breast cancer. This immunotolerant metastatic model is a novel addition to existing breast cancer models and coupling the model with in vivo imaging greatly facilitates the evaluation of targeted immunotherapies of metastasis.

SU-8-based immunoisolative microcontainer with nanoslots defined by nanoimprint lithography.

Cells can secrete biotherapeutic molecules that can replace or restore host function. The transplantation of such cells is a promising therapeutic modality for the treatment of several diseases including type 1 diabetes mellitus. These cellular grafts are encapsulated in semipermeable and immunoisolative membranes to protect them from the host immune system, while allowing the transport of nutrients and small molecules that are required for cell survival and function. The authors report on SU-8-based biocompatible immunoisolative cuboid microcontainers for cell transplantation. Each microcontainer comprises a 300×300×250 or a 1100×1100×250 µm(3) SU-8 hollowed cuboid base that houses the cells and an optically transparent SU-8-based nanoporous lid that closes the device. The hollowed cuboid base was formed by conventional optical lithography to have 8 nl (200×200×200 µm(3)) encapsulation volume for cellular payload. The lid comprises a thick SU-8 slab with an array of cylindrical wells, whose bottom surface is sealed with a thin nanoporous SU-8 membrane. The nanoporous membrane was created from a 100 nm grating (width and spacing) initial silicon mold subjected to a repeated cycle of oxidation and wet etching to achieve a 20 nm wide and 200 nm pitch nano silicon grating. Nanoimprinting and oblique-angle metal deposition, followed by inductively coupled plasma etching were utilized to create 15 nm wide and 350-450 nm deep nanoslots in the thin SU-8 membrane. Isolated mouse islets were encapsulated in the hollowed cuboid base and the nanoporous lid was assembled on top. The penetration of large and small molecules into the microcontainer was observed with fluorescence.

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.

Cell viability and noninvasive in vivo MRI tracking of 3D cell encapsulating self-assembled microcontainers.

Several molecular therapies require the implantation of cells that secrete biotherapeutic molecules and imaging the location and microenvironment of the cellular implant to ascertain its function. We demonstrate noninvasive in vivo magnetic resonance imaging (MRI) of self-assembled microcontainers that are capable of cell encapsulation. Negative contrast was obtained to discern the microcontainer with MRI; positive contrast was obtained in the complete absence of background signal. MRI on a clinical scanner highlights the translational nature of this research. The microcontainers were loaded with cells that were dispersed in an extracellular matrix, and implanted both subcutaneously and in human tumor xenografts in SCID mice. MRI was performed on the implants, and microcontainers retrieved postimplantation showed cell viability both within and proximal to the implant. The microcontainers are characterized by their small size, three dimensionality, controlled porosity, ease of parallel fabrication, chemical and mechanical stability, and noninvasive traceability in vivo.

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice.

Inhibition of the aryl hydrocarbon receptor (AHR) prevents Western diet-induced obesity and fatty liver in C57Bl/6J (B6) male mice. The AHR is a ligand-activated nuclear receptor that regulates genes involved in xenobiotic metabolism and T-cell differentiation. Here, we tested the hypothesis that AHR antagonism would also prevent obesity and fatty liver in female mice and that B6 mice (higher-affinity AHR) and congenic B6.D2 mice (lower-affinity AHR) would differentially respond to AHR inhibition. Female and male adult B6 and B6.D2 mice were fed control and Western diets with and without α-naphthoflavone (NF), an AHR inhibitor. A nonlinear mixed-model analysis was developed to project asymptote body mass. We found that obesity, adiposity, and liver steatosis were reduced to near control levels in all female and male B6 and B6.D2 experimental groups fed Western diet with NF. However, differences were noted in that female B6.D2 vs B6 mice on Western diet became more obese; and in general, female mice compared with male mice had a greater fat mass to body mass ratio, were less responsive to NF, and had reduced liver steatosis and hepatomegaly. We report that male mice fed Western diet containing NF or CH-223191, another AHR inhibitor, caused reduced mRNA levels of several liver genes involved in metabolism, including Cyp1b1 and Scd1, offering evidence for a possible mechanism by which the AHR regulates obesity. In conclusion, although there are some sex- and Ahr allelic-dependent differences, AHR inhibition prevents obesity and liver steatosis in both males and females regardless of the ligand-binding capacity of the AHR. We also present evidence consistent with the notion that an AHR-CYP1B1-SCD1 axis is involved in obesity, providing potentially convenient and effective targets for treatment.