Prospective Evaluation of Virtual MR Elastography With Diffusion-Weighted Imaging in Subjects With Nonalcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is increasingly common worldwide and can lead to the development of cirrhosis, liver failure and cancer. Virtual magnetic resonance elastography (VMRE), which is based on a shifted apparent diffusion coefficient (sADC), is a potential noninvasive method to assess liver fibrosis without the specialized hardware and expertise required to implement traditional MR elastography (MRE). Although hepatic steatosis is known to confound ADC measurements, previous studies using VMRE have not corrected for hepatic fat fraction. PURPOSE: To compare VMRE, corrected for the confounding effects of unsuppressed fat signal, to MRE and biopsy in subjects with suspected NAFLD. STUDY TYPE: Prospective, cross-sectional. POPULATION: A total of 49 adult subjects with suspected NAFLD (18 male; median age 55 years, range 33-74 years) who underwent liver biopsy. FIELD STRENGTH/SEQUENCE: 3T, diffusion-weighted spin echo planar, chemical-shift encoded (IDEAL IQ) and MRE sequences. ASSESSMENT: Two observers drew regions of interest on sADC, proton density fat fraction and MRE-derived stiffness maps. Fat-corrected sADC values were used to calculate the diffusion-based shear modulus according to the VMRE method. Predicted fibrosis stage for MRE and VMRE was determined using previously published cut-off values. STATISTICAL TESTS: The relationship between VMRE and MRE was assessed with least-squares linear regression (coefficient of determination, R2 ). Agreement between MRE and VMRE-predicted fibrosis stage was evaluated with a kappa coefficient and accuracy compared using McNemar's test. A one-way ANOVA determined if the fat-corrected sADC (VMRE) and MRE differed by fibrosis stage. A P value < 0.05 was considered statistically significant. RESULTS: Least squares regression of VMRE vs. MRE revealed R2  = 0.046 and a slope that was not significantly different from zero (P = 0.14). There was no agreement between MRE and VMRE-predicted fibrosis stage (kappa = -0.01). The proportion of correctly predicted fibrosis stage was significantly higher for MRE compared to VMRE. MRE was significantly associated with fibrosis stage, but fat-corrected sADC was not (P = 0.24). DATA CONCLUSION: Fat-corrected VMRE was not associated with fibrosis stage in NAFLD. Further investigation is required if VMRE is to be considered in subjects with NAFLD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Combined Transfer Learning and Test-Time Augmentation Improves Convolutional Neural Network-Based Semantic Segmentation of Prostate Cancer from Multi-Parametric MR Images.

PURPOSE: Multiparametric MRI (mp-MRI) is a widely used tool for diagnosing and staging prostate cancer. The purpose of this study was to evaluate whether transfer learning, unsupervised pre-training and test-time augmentation significantly improved the performance of a convolutional neural network (CNN) for pixel-by-pixel prediction of cancer vs. non-cancer using mp-MRI datasets. METHODS: 154 subjects undergoing mp-MRI were prospectively recruited, 16 of whom subsequently underwent radical prostatectomy. Logistic regression, random forest and CNN models were trained on mp-MRI data using histopathology as the gold standard. Transfer learning, unsupervised pre-training and test-time augmentation were used to boost CNN performance. Models were evaluated using Dice score and area under the receiver operating curve (AUROC) with leave-one-subject-out cross validation. Permutation feature importance testing was performed to evaluate the relative value of each MR contrast to CNN model performance. Statistical significance (p<0.05) was determined using the paired Wilcoxon signed rank test with Benjamini-Hochberg correction for multiple comparisons. RESULTS: Baseline CNN outperformed logistic regression and random forest models. Transfer learning and unsupervised pre-training did not significantly improve CNN performance over baseline; however, test-time augmentation resulted in significantly higher Dice scores over both baseline CNN and CNN plus either of transfer learning or unsupervised pre-training. The best performing model was CNN with transfer learning and test-time augmentation (Dice score of 0.59 and AUROC of 0.93). The most important contrast was apparent diffusion coefficient (ADC), followed by Ktrans and T2, although each contributed significantly to classifier performance. CONCLUSIONS: The addition of transfer learning and test-time augmentation resulted in significant improvement in CNN segmentation performance in a small set of prostate cancer mp-MRI data. Results suggest that these techniques may be more broadly useful for the optimization of deep learning algorithms applied to the problem of semantic segmentation in biomedical image datasets. However, further work is needed to improve the generalizability of the specific model presented herein.

Dual response of osteoblast activity and antibacterial properties of polarized strontium substituted hydroxyapatite-Barium strontium titanate composites with controlled strontium substitution.

To mimic the electrical properties of natural bone, controlled strontium substitution of both hydroxyapatite and ferroelectric barium titanate were achieved by mixing in the ratio 30:70 by weight. The composites were characterized by X-ray diffraction, Fourier transform infrared spectroscopy and scanning electron microscopy to investigate the phase composition and microstructure of the composites. Unpolarized and polarized strontium hydroxyapatite (SrHA)-barium strontium titanate (BST) composites with controlled degree of Sr substitution were examined, including 5SrHA-5BST (5% Sr substitution in both components) and 10SrHA-10BST composites. The 10SrHA-10BST composite showed a higher osteoblast activity, as observed from the cell viability studies performed using CCK-8 assay. The polarized composites showed promise against Staphylococcus aureus bacteria by minimizing the adhesion and growth of bacteria, as compared with their unpolarized counterparts. The polarized 10SrHA-10BST was found to be superior than all other composites. As a result, the approach of polarization of SrHA-BST composites has been found to be an effective bone substitute material in controlled enhancement of osteoblast growth with simultaneous reduction of bacterial infection.

Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players.

Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood-brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood-brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.

Cell density quantification with TurboSPI: R2* mapping with compensation for off-resonance fat modulation.

OBJECTIVE: Tracking the migration of superparamagnetic iron oxide (SPIO)-labeled immune cells in vivo is valuable for understanding the immunogenic response to cancer and therapies. Quantitative cell tracking using TurboSPI-based R2* mapping is a promising development to improve accuracy in longitudinal studies on immune recruitment. However, off-resonance fat signal isochromats lead to modulations in the signal time-course that can be erroneously fit as R2* signal decay, overestimating the density of labeled cells, while excluding voxels with fat-typical modulations results in underestimation of cell density in voxels with mixed content. Approaches capable of accurate R2* estimation in the presence of fat are needed. METHODS: We propose a dual-decay (separate R2f* and R2w* for fat and water) Dixon-based signal model that accounts for the presence of fat in a voxel to provide better estimates of SPIO-induced dephasing. This model was tested in silico, in phantoms with varying quantities of fat and SPIO-labeled cells, and in 5 mice injected with SPIO-labeled CD8+ T cells. RESULTS: In silico single voxel simulations illustrate how the proposed dual-decay model provides stable R2w* estimates that are invariant to fat content. The proposed model outperforms previous methods when applied to in vitro samples of SPIO-labeled cells and oil prepared with oil content ≥ 15%. Preliminary in vivo results show that, compared to previous methods, the dual-decay model improves the balance of R2* mapping in fat-dense areas, which will yield more reliable analysis in future cell tracking studies. DISCUSSION: The proposed model is a promising tool for quantitative TurboSPI R2* cell tracking, with further refinements offering the possibility of better specificity and sensitivity.

Model-free prostate cancer segmentation from dynamic contrast-enhanced MRI with recurrent convolutional networks: A feasibility study.

Dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) is a method of temporal imaging that is commonly used to aid in prostate cancer (PCa) diagnosis and staging. Typically, machine learning models designed for the segmentation and detection of PCa will use an engineered scalar image called Ktrans to summarize the information in the DCE time-series images. This work proposes a new model that amalgamates the U-net and the convGRU neural network architectures for the purpose of interpreting DCE time-series in a temporal and spatial basis for segmenting PCa in MR images. Ultimately, experiments show that the proposed model using the DCE time-series images can outperform a baseline U-net segmentation model using Ktrans. However, when other types of scalar MR images are considered by the models, no significant advantage is observed for the proposed model.

Asymptotically Optimal Kinematic Design of Robots using Motion Planning.

In highly constrained settings, e.g., a tentaclelike medical robot maneuvering through narrow cavities in the body for minimally invasive surgery, it may be difficult or impossible for a robot with a generic kinematic design to reach all desirable targets while avoiding obstacles. We introduce a design optimization method to compute kinematic design parameters that enable a single robot to reach as many desirable goal regions as possible while avoiding obstacles in an environment. Our method appropriately integrates sampling based motion planning in configuration space into stochastic optimization in design space so that, over time, our evaluation of a design's ability to reach goals increases in accuracy and our selected designs approach global optimality. We prove the asymptotic optimality of our method and demonstrate performance in simulation for (i) a serial manipulator and (ii) a concentric tube robot, a tentacle-like medical robot that can bend around anatomical obstacles to safely reach clinically- relevant goal regions.

Solid-Gas Phase Photo-Catalytic Behaviour of Rutile and TiOn (1 < n < 2) Sub-Oxide Phases for Self-Cleaning Applications.

The solid-gas phase photo-catalytic activities of rutile TiO2 and TiOn (1 < n < 2) sub-oxide phases have been evaluated. Varying concentrations of Ti3+ defects were introduced into the rutile polymorph of titanium dioxide through carbo-thermal reduction at temperatures ranging from 350 °C to 1300 °C. The resulting sub-oxides formed were characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, impedance spectroscopy and UV-visible diffuse reflectance spectroscopy. The presence of Ti3+ in rutile exposed to high reduction temperatures was confirmed by X-ray diffraction. In addition, a Ti3+-Ti4+ system was demonstrated to enhance the photo-catalytic properties of rutile for the degradation of the air pollutants NO2 and CO2 under UV irradiation of wavelengths (λ) 376⁻387 nm and 381⁻392 nm. The optimum reduction temperature for photo-catalytic activity was within the range 350⁻400 °C and attributed to improved charge-separation. The materials that were subject to carbo-thermal reduction at temperatures of 350 °C and 400 °C exhibited electrical conductivities over one hundred times higher compared to the non-reduced rutile. The results highlight that sub-oxide phases form an important alternative approach to doping with other elements to improve the photo-catalytic performance of TiO2. Such materials are important for applications such as self-cleaning where particles can be incorporated into surface coatings.

Unique depot formed by an oil based vaccine facilitates active antigen uptake and provides effective tumour control.

BACKGROUND: Oil emulsions are commonly used as vaccine delivery platforms to facilitate slow release of antigen by forming a depot at the injection site. Antigen is trapped in the aqueous phase and as the emulsion degrades in vivo the antigen is passively released. DepoVax™ is a unique oil based delivery system that directly suspends the vaccine components in the oil diluent that forces immune cells to actively take up components from the formulation in the absence of passive release. The aim of this study was to use magnetic resonance imaging (MRI) with additional biological markers to evaluate and understand differences in clearance between several different delivery systems used in peptide-based cancer vaccines. METHODS: C57BL/6 mice were implanted with a cervical cancer model and vaccinated 5 days post-implant with either DepoVax (DPX), a water-in-oil emulsion (w/o), a squalene oil-in-water emulsion (squal o/w) or a saponin/liposome emulsion (sap/lip) containing iron oxide-labeled targeted antigen. MRI was then used to monitor antigen clearance, the site of injection, tumour and inguinal lymph node volumes and other gross anatomical changes. HLA-A2 transgenic mice were also vaccinated to evaluate immune responses of human directed peptides. RESULTS: We demonstrated differences in antigen clearance between DPX and w/o both in regard to how quickly the antigen was cleared and the pattern in which it was cleared. We also found differences in lymph node responses between DPX and both squal o/w and sap/lip. CONCLUSIONS: These studies underline the unique mechanism of action of this clinical stage vaccine delivery system.

Using MRI cell tracking to monitor immune cell recruitment in response to a peptide-based cancer vaccine.

PURPOSE: MRI cell tracking can be used to monitor immune cells involved in the immunotherapy response, providing insight into the mechanism of action, temporal progression of tumor growth, and individual potency of therapies. To evaluate whether MRI could be used to track immune cell populations in response to immunotherapy, CD8+ cytotoxic T cells, CD4+ CD25+ FoxP3+ regulatory T cells, and myeloid-derived suppressor cells were labeled with superparamagnetic iron oxide particles. METHODS: Superparamagnetic iron oxide-labeled cells were injected into mice (one cell type/mouse) implanted with a human papillomavirus-based cervical cancer model. Half of these mice were also vaccinated with DepoVaxTM (ImmunoVaccine, Inc., Halifax, Nova Scotia, Canada), a lipid-based vaccine platform that was developed to enhance the potency of peptide-based vaccines. RESULTS: MRI visualization of CD8+ cytotoxic T cells, regulatory T cells, and myeloid-derived suppressor cells was apparent 24 h post-injection, with hypointensities due to iron-labeled cells clearing approximately 72 h post-injection. Vaccination resulted in increased recruitment of CD8+ cytotoxic T cells, and decreased recruitment of myeloid-derived suppressor cells and regulatory T cells to the tumor. We also found that myeloid-derived suppressor cell and regulatory T cell recruitment were positively correlated with final tumor volume. CONCLUSION: This type of analysis can be used to noninvasively study changes in immune cell recruitment in individual mice over time, potentially allowing improved application and combination of immunotherapies. Magn Reson Med 80:304-316, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Butyrylcholinesterase-knockout reduces fibrillar ß-amyloid and conserves 18FDG retention in 5XFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of ß-amyloid (Aß) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Aß pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Aß plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Aß than 5XFAD mice at the same age. Therefore, BChE may have a role in Aß pathogenesis. Furthermore, in AD, diminished glucose metabolism in the brain can be detected in vivo with positron emission tomography (PET) imaging following 2-deoxy-2-(18F)fluoro-D-glucose (18FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Aß burden, whole brain and regional uptake of 18FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT5XFAD and WTBChE-KO) strains at 5months. Diminished fibrillar Aß burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brain 18FDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction in 18FDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT5XFAD. Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WTBChE-KO, while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Aß, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice.

Hybrid Synthetic Receptors on MOSFET Devices for Detection of Prostate Specific Antigen in Human Plasma.

The study reports the use of extended gate field-effect transistors (FET) for the label-free and sensitive detection of prostate cancer (PCa) biomarkers in human plasma. The approach integrates for the first time hybrid synthetic receptors comprising of highly selective aptamer-lined pockets (apta-MIP) with FETs for sensitive detection of prostate specific antigen (PSA) at clinically relevant concentrations. The hybrid synthetic receptors were constructed by immobilizing an aptamer-PSA complex on gold and subjecting it to 13 cycles of dopamine electropolymerization. The polymerization resulted in the creation of highly selective polymeric cavities that retained the ability to recognize PSA post removal of the protein. The hybrid synthetic receptors were subsequently used in an extended gate FET setup for electrochemical detection of PSA. The sensor was reported to have a limit of detection of 0.1 pg/mL with a linear detection range from 0.1 pg/mL to 1 ng/mL PSA. Detection of 1-10 pg/mL PSA was also achieved in diluted human plasma. The present apta-MIP sensor developed in conjunction with FET devices demonstrates the potential for clinical application of synthetic hybrid receptors for the detection of clinically relevant biomarkers in complex samples.

Using lymph node swelling as a potential biomarker for successful vaccination.

There is currently a lack of biomarkers to help properly assess novel immunotherapies at both the preclinical and clinical stages of development. Recent work done by our group indicated significant volume changes in the vaccine draining right lymph node (RLN) volumes of mice that had been vaccinated with DepoVaxTM, a lipid-based vaccine platform that was developed to enhance the potency of peptide-based vaccines. These changes in lymph node (LN) volume were unique to vaccinated mice.To better assess the potential of volumetric LN markers for multiple vaccination platforms, we evaluated 100 tumor bearing mice and assessed their response to vaccination with either a DepoVax based vaccine (DPX) or a water-in-oil emulsion (w/o), and compared them to untreated controls. MRI was used to longitudinally monitor LN and tumor volumes weekly over 4 weeks. We then evaluated changes in LN volumes occurring in response to therapy as a potential predictive biomarker for treatment success.We found that for both vaccine types, DPX and w/o, the %RLN volumetric increase over baseline and the ratio of RLN/LLN were strong predictors of successful tumor suppression (LLN is left inguinal LN). The area under the curve (AUC) was greatest, between 0.75-0.85, two (%RLN) or three (RLN/LLN) weeks post-vaccination. For optimized critical thresholds we found these biomarkers consistently had sensitivity >90% and specificity >70% indicating strong prognostic potential. Vaccination with DepoVax had a more pronounced effect on draining lymph nodes than w/o emulsion vaccines, which correlated with a higher anti-tumor activity in DPX-treated mice.

Gas sensing using porous materials for automotive applications.

Improvements in the efficiency of combustion within a vehicle can lead to reductions in the emission of harmful pollutants and increased fuel efficiency. Gas sensors have a role to play in this process, since they can provide real time feedback to vehicular fuel and emissions management systems as well as reducing the discrepancy between emissions observed in factory tests and 'real world' scenarios. In this review we survey the current state-of-the-art in using porous materials for sensing the gases relevant to automotive emissions. Two broad classes of porous material - zeolites and metal-organic frameworks (MOFs) - are introduced, and their potential for gas sensing is discussed. The adsorptive, spectroscopic and electronic techniques for sensing gases using porous materials are summarised. Examples of the use of zeolites and MOFs in the sensing of water vapour, oxygen, NOx, carbon monoxide and carbon dioxide, hydrocarbons and volatile organic compounds, ammonia, hydrogen sulfide, sulfur dioxide and hydrogen are then detailed. Both types of porous material (zeolites and MOFs) reveal great promise for the fabrication of sensors for exhaust gases and vapours due to high selectivity and sensitivity. The size and shape selectivity of the zeolite and MOF materials are controlled by variation of pore dimensions, chemical composition (hydrophilicity/hydrophobicity), crystal size and orientation, thus enabling detection and differentiation between different gases and vapours.

Using MRI to evaluate and predict therapeutic success from depot-based cancer vaccines.

In the preclinical development of immunotherapy candidates, understanding the mechanism of action and determining biomarkers that accurately characterize the induced host immune responses is critical to improving their clinical interpretation. Magnetic resonance imaging (MRI) was used to evaluate in vivo changes in lymph node size in response to a peptide-based cancer vaccine therapy, formulated using DepoVax (DPX). DPX is a novel adjuvant lipid-in-oil-based formulation that facilitates enhanced immune responses by retaining antigens at the injection site for extended latencies, promoting increased potentiation of immune cells. C57BL/6 mice were implanted with C3 (HPV) tumor cells and received either DPX or control treatments, 5 days post-implantation. Complete tumor eradication occurred in DPX-vaccinated animals and large volumetric increases were observed in the vaccine-draining right inguinal lymph node (VRILN) in DPX mice, likely corresponding to increased localized immune response to the vaccine. Upon evaluating the relative measure of vaccine-potentiated immune activation to tumor-induced immune response (VRILN/VLILN), receiver-operating characteristic (ROC) curves revealed an area under the curve (AUC) of 0.90 (±0.07), indicating high specificity and sensitivity as a predictive biomarker of vaccine efficacy. We have determined that for this tumor model, early MRI lymph node volumetric changes are predictive of depot immunotherapeutic success.

Systemic injection of CK2.3, a novel peptide acting downstream of bone morphogenetic protein receptor BMPRIa, leads to increased trabecular bone mass.

Bone Morphogenetic Protein 2 (BMP2) regulates bone integrity by driving both osteogenesis and osteoclastogenesis. However, BMP2 as a therapeutic has significant drawbacks. We have designed a novel peptide CK2.3 that blocks the interaction of Casein Kinase 2 (CK2) with Bone Morphogenetic Protein Receptor type Ia (BMPRIa), thereby activating BMP signaling pathways in the absence of ligand. Here, we show that CK2.3 induced mineralization in primary osteoblast cultures isolated from calvaria and bone marrow stromal cells (BMSCs) of 8 week old mice. Further, systemic tail vein injections of CK2.3 in 8 week old mice resulted in increased bone mineral density (BMD) and mineral apposition rate (MAR). In situ immunohistochemistry of the femur found that CK2.3 injection induced phosphorylation of extracellular signal-related kinase (ERK), but not Smad in osteocytes and osteoblasts, suggesting that CK2.3 signaling occurred through Smad independent pathway. Finally mice injected with CK2.3 exhibited decreased osteoclast differentiation and osteoclast activity. These data indicate that the novel mimetic peptide CK2.3 activated BMPRIa downstream signaling to enhance bone formation without the increase in osteoclast activity that accompanies BMP 2 stimulation.

Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss.

Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1-/-NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1-/-NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers.

Clearance of depot vaccine SPIO-labeled antigen and substrate visualized using MRI.

Immunotherapies, including peptide-based vaccines, are a growing area of cancer research, and understanding their mechanism of action is crucial for their continued development and clinical application. Exploring the biodistribution of vaccine components may be key to understanding this action. This work used magnetic resonance imaging (MRI) to characterize the in vivo biodistribution of the antigen and oil substrate of the vaccine delivery system known as DepoVax(TM). DepoVax uses a novel adjuvanted lipid-in-oil based formulation to solubilise antigens and promote a depot effect. In this study, antigen or oil were tagged with superparamagnetic iron oxide (SPIO), making them visible on MR images. This enables tracking of individual vaccine components to determine changes in biodistribution. Mice were injected with SPIO-labeled antigen or SPIO-labeled oil, and imaged to examine clearance of labeled components from the vaccine site. The SPIO-antigen was steadily cleared, with nearly half cleared within two months post-vaccination. In contrast, the SPIO-oil remained relatively unchanged. The biodistribution of the SPIO-antigen component within the vaccine site was heterogeneous, indicating the presence of active clearance mechanisms, rather than passive diffusion or drainage. Mice injected with SPIO-antigen also showed MRI contrast for several weeks post-vaccination in the draining inguinal lymph node. These results indicate that MRI can visualize the in vivo longitudinal biodistribution of vaccine components. The sustained clearance is consistent with antigen up-take and trafficking by immune cells, leading to accumulation in the draining lymph node, which corresponds to the sustained immune responses and reduced tumor burden observed in vaccinated mice.

Study of solid/gas phase photocatalytic reactions by electron ionization mass spectrometry.

This paper describes a novel methodology for the real-time study of solid-gas phase photocatalytic reactions in situ. A novel reaction chamber has been designed and developed to facilitate the investigation of photoactive materials under different gas compositions. UV irradiation in the wavelength of ranges 376-387 and 381-392 nm was provided using specially designed high efficiency light emitting diode arrays. The experiments used air containing 190 ppm NO2 in a moist environment with a relative humidity of 0.1%. Photocatalytic samples consisting of pressed pellets of rutile and anatase crystalline forms of TiO2 were monitored over a period of 150 min. An ultra-high vacuum right angled bleed valve allowed a controlled flow of gas from the main reaction chamber at atmospheric pressure to a residual gas analyser operating at a vacuum of 10(-5) mbar. The apparatus and methodology have been demonstrated to provide high sensitivity (ppb). The rate of degradation of NO2 attributed to reaction at the TiO2 surface was sensitive to both crystal structures (anatase or rutile) and wavelength of irradiation.