Publications
46 results found
Tavana S, Shek C, Rahman T, et al., 2024, The influence of geometry on intervertebral disc stiffness, Journal of Biomechanics, Vol: 163, ISSN: 0021-9290
Geometry plays an important role in intervertebral disc (IVD) mechanics. Previous computational studies have found a link between IVD geometry and stiffness. However, few experimental studies have investigated this link, possibly due to difficulties in non-destructively quantifying internal geometric features. Recent advances in ultra-high resolution MRI provides the opportunity to visualise IVD features in unprecedented detail. This study aimed to quantify 3D human IVD geometries using 9.4 T MRIs and to investigate correlations between geometric variations and IVD stiffness. Thirty human lumbar motion segments (fourteen non-degenerate and sixteen degenerate) were scanned using a 9.4 T MRI and geometric parameters were measured. A 1kN compressive load was applied to each motion segment and stiffness was calculated. Degeneration caused a reduction (p < 0.05) in IVD height, a decreased nucleus-annulus area ratio, and a 1.6 ± 3.0 mm inward collapse of the inner annulus. The IVD height, anteroposterior (AP) width, lateral width, cross-sectional area, nucleus-annulus boundary curvature, and nucleus-annulus area ratio had a significant (p < 0.05) influence on IVD stiffness. Linear relationships (p < 0.05, r > 0.47) were observed between these geometric features and IVD compressive stiffness and a multivariate regression model was generated to enable stiffness to be predicted from features observable on clinical imaging (stiffness, N/mm = 6062 - (61.2 × AP width, mm) - (169.2 × IVD height, mm)). This study advances our understanding of disc structure-function relationships and how these change with degeneration, which can be used to both generate and validate more realistic computational models.
Chen C-N, Hajji N, Yeh F-C, et al., 2023, Restoration of Foxp31 regulatory T cells by HDAC-dependent epigenetic modulation plays a pivotal role in resolving pulmonary arterial hypertension pathology, American Journal of Respiratory and Critical Care Medicine, Vol: 208, Pages: 879-895, ISSN: 1073-449X
Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from idiopathic PAH (IPAH) patients and rodent models of pulmonary hypertension (PH): monocrotaline (MCT), Sugen5416-hypoxia (SuHx) rats and Treg-depleted mice. HDAC inhibitor Vorinostat (SAHA) was used to examine the immune modulatory effects in vivo, ex vivo and in vitro. Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased programmed cell death-1 (PD-1) signalling in PBMCs from IPAH patients. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in SuHx mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDACi is a promising approach to resolve PH pathology, highlighting the potential benefit of developing "epigenetic therapies” for PAH.
Rahman T, Tavana S, Nicoleta B, et al., 2023, Quantifying internal intervertebral disc strains to assess nucleus replacement device designs: a digital volume correlation and ultrahigh-resolution MRI study, Frontiers in Bioengineering and Biotechnology, Vol: 11, ISSN: 2296-4185
Introduction: Nucleus replacement has been proposed as a treatment to restore biomechanics and relieve pain in degenerate intervertebral discs (IVDs). Multiple nucleus replacement devices (NRDs) have been developed, however, none are currently used routinely in clinic. A better understanding of the interactions between NRDs and surrounding tissues may provide insight into the causes of implant failure and provide target properties for future NRD designs. The aim of this study was to non-invasively quantify 3D strains within the IVD through three stages of nucleus replacement surgery: intact, post-nuclectomy, and post-treatment.Methods: Digital volume correlation (DVC) combined with 9.4T MRI was used to measure strains in seven human cadaveric specimens (42 ± 18 years) when axially compressed to 1 kN. Nucleus material was removed from each specimen creating a cavity that was filled with a hydrogel-based NRD.Results: Nucleus removal led to loss of disc height (12.6 ± 4.4%, p = 0.004) which was restored post-treatment (within 5.3 ± 3.1% of the intact state, p > 0.05). Nuclectomy led to increased circumferential strains in the lateral annulus region compared to the intact state (−4.0 ± 3.4% vs. 1.7 ± 6.0%, p = 0.013), and increased maximum shear strains in the posterior annulus region (14.6 ± 1.7% vs. 19.4 ± 2.6%, p = 0.021). In both cases, the NRD was able to restore these strain values to their intact levels (p ≥ 0.192).Discussion: The ability of the NRD to restore IVD biomechanics and some strain types to intact state levels supports nucleus replacement surgery as a viable treatment option. The DVC-MRI method used in the present study could serve as a useful tool to assess future NRD designs to help improve performance in future clinical trials.
Yeh F-C, Chen C-N, Xie C-Y, et al., 2023, TLR7/8 activation induces autoimmune vasculopathy and causes severe pulmonary arterial hypertension, European Respiratory Journal, Vol: 62, ISSN: 0903-1936
Todorova VB, Baxan N, Delahaye M, et al., 2023, Drug-based mobilisation of mesenchymal stem/stromal cells improves cardiac function post myocardial infarction, Disease Models and Mechanisms, Vol: 16, Pages: 1-28, ISSN: 1754-8403
There is an unmet need for treatments that prevent the progressive cardiac dysfunction following myocardial infarction. Mesenchymal stem/stromal cells (MSCs) are under investigation for cardiac repair; however, culture expansion prior to transplantation is hindering their homing and reparative abilities. Pharmacological mobilisation could be an alternative to MSC transplantation. Here, we report that endogenous MSCs mobilise into the circulation at day 5 post myocardial infarction in male Lewis rats. This mobilisation can be significantly increased by using a combination of the FDA-approved drugs mirabegron (β3-adrenoceptor agonist) and AMD3100 (CXCR4 antagonist). Blinded cardiac magnetic resonance imaging analysis showed the treated group to have increased left ventricular ejection fraction and decreased end systolic volume at 5 weeks post myocardial infarction. The mobilised group had a significant decrease in plasma IL-6 and TNF-α levels, a decrease in interstitial fibrosis, and an increase in the border zone blood vessel density. Conditioned medium from blood-derived MSCs supported angiogenesis in vitro, as shown by tube formation and wound healing assays. Our data suggest a novel pharmacological strategy that enhances myocardial infarction-induced MSC mobilisation and improves cardiac function after myocardial infarction.
Todorova V, Baxan N, Delahaye M, et al., 2022, Mechanism of improved cardiac function after pharmacological, 24th World Congress of the International-Society-for-Heart-Research, Publisher: ELSEVIER SCI LTD, Pages: S54-S56, ISSN: 0022-2828
Rahman T, Baxan N, Murray R, et al., 2022, An in vitro comparison of three nucleus pulposus removal techniques for partial intervertebral disc replacement: An ultra-high resolution MRI study, JOR Spine, ISSN: 2572-1143
Farajzadeh Khosroshahi S, Yin X, Donat C, et al., 2021, Multiscale modelling of cerebrovascular injury reveals the role of vascular anatomy and parenchymal shear stresses, Scientific Reports, Vol: 11, ISSN: 2045-2322
Neurovascular injury is often observed in traumatic brain injury (TBI). However, the relationship between mechanical forces and vascular injury is still unclear. A key question is whether the complex anatomy of vasculature plays a role in increasing forces in cerebral vessels and producing damage. We developed a high-fidelity multiscale finite element model of the rat brain featuring a detailed definition of the angioarchitecture. Controlled cortical impacts were performed experimentally and in-silico. The model was able to predict the pattern of blood–brain barrier damage. We found strong correlation between the area of fibrinogen extravasation and the brain area where axial strain in vessels exceeds 0.14. Our results showed that adjacent vessels can sustain profoundly different axial stresses depending on their alignment with the principal direction of stress in parenchyma, with a better alignment leading to larger stresses in vessels. We also found a strong correlation between axial stress in vessels and the shearing component of the stress wave in parenchyma. Our multiscale computational approach explains the unrecognised role of the vascular anatomy and shear stresses in producing distinct distribution of large forces in vasculature. This new understanding can contribute to improving TBI diagnosis and prevention.
Du Y, Tavana S, Rahman T, et al., 2021, Sensitivity of intervertebral disc finite element models to internal geometric and non-geometric parameters, Frontiers in Bioengineering and Biotechnology, Vol: 9, ISSN: 2296-4185
Finite element models are useful for investigating internal intervertebral disc (IVD) behaviours without using disruptive experimental techniques. Simplified geometries are commonly used to reduce computational time or because internal geometries cannot be acquired from CT scans. This study aimed to 1) investigate the effect of altered geometries both at endplates and the nucleus-anulus boundary on model response, and 2) to investigate model sensitivity to material and geometric inputs, and different modelling approaches (graduated or consistent fibre bundle angles and glued or cohesive interlamellar contact). Six models were developed from 9.4T MRIs of bovine IVDs. Models had two variations of endplate geometry (a simple curved profile from the centre of the disc to the periphery, and precise geometry segmented from MRIs), and three variations of NP-AF boundary (linear, curved, and segmented). Models were subjected to axial compressive loading (to 0.86mm at a strain rate of 0.1/sec) and the effect on stiffness and strain distributions, and the sensitivity to modelling approaches was investigated. The model with the most complex geometry (segmented endplates, curved NP-AF boundary) was 3.1 times stiffer than the model with the simplest geometry (curved endplates, linear NP-AF boundary). Peak strains were close to the endplates at locations of high curvature in the segmented endplate models which were not captured in the curved endplate models. Differences were also seen in sensitivity to material properties, graduated fibre angles, cohesive rather than glued interlamellar contact, and NP:AF ratios. These results show that FE modellers must take care to ensure geometries are realistic so that load is distributed and passes through IVDs accurately.
Ries M, Watts H, Mota B, et al., 2021, Annexin-A1 restores cerebrovascular integrity concomitant with reduced amyloid-β and tau pathology, Brain: a journal of neurology, Vol: 144, Pages: 1526-1541, ISSN: 0006-8950
Alzheimer’s disease (AD), characterized by brain deposits of amyloid-β(Aβ) plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood-brain barrier (BBB) breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in AD. Annexin A1 (ANXA1) is a mediator of glucocorticoids anti-inflammatory action that can suppress microglial activation and reduce BBB leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) 2reduced Aβ levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient BBB function and decreasing Aβ and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated BBB permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain A load, due to increased clearance and degradation of Aβ by the insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5XFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that the BBB breakdown early in AD can be restored by hrANXA1 as a potential therapeutic approach.
Handa B, Li X, Baxan N, et al., 2021, Ventricular fibrillation mechanism and global fibrillatory organisation are determined by gap junction coupling and fibrosis pattern, Cardiovascular Research, Vol: 117, Pages: 1078-1090, ISSN: 0008-6363
AimsConflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganised multiple-wavelet activation to organised rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism.Methods and ResultsOptical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact (CF), diffuse (DiF) and patchy (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum.Enhanced GJ coupling with rotigaptide (n = 10) progressively organised fibrillation in a concentration-dependent manner; increasing FDI (0nM: 0.53±0.04, 80nM: 0.78±0.03, p < 0.001), increasing RA sustained VF time (0nM:44±6%, 80nM: 94±2%, p < 0.001) and stabilised RAs (maximum rotations for a RA; 0nM:5.4±0.5, 80nM: 48.2±12.3, p < 0.001). GJ uncoupling with carbenoxolone progressively disorganised VF; the FDI decreased (0µM: 0.60±0.05, 50µM: 0.17±0.03, p < 0.001) and RA-sustained VF time decreased (0µM: 61±9%, 50µM: 3±2%, p < 0.001).In CF, VF activity was disorganised and the RA-sustained VF time was the lowest (CF: 27±7% versus PF: 75±5%, p < 0.001). Global fibrillatory organisation measured by FDI was highest in PF (PF: 0.67±0.05 versus CF: 0.33±0.03, p < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411&plusm
Tavana S, Masouros S, Baxan N, et al., 2021, The Effect of Degeneration on Internal Strains and the Mechanism of Failure in Human Intervertebral Discs Analyzed Using Digital Volume Correlation (DVC) and Ultra-High Field MRI, Frontiers in Bioengineering and Biotechnology, Vol: 8, ISSN: 2296-4185
The intervertebral disc (IVD) plays a main role in absorbing and transmitting loads within the spinal column. Degeneration alters the structural integrity of the IVDs and causes pain, especially in the lumbar region. The objective of this study was to investigate non-invasively the effect of degeneration on human 3D lumbar IVD strains (n = 8) and the mechanism of spinal failure (n = 10) under pure axial compression using digital volume correlation (DVC) and 9.4 Tesla magnetic resonance imaging (MRI). Degenerate IVDs had higher (p < 0.05) axial strains (58% higher), maximum 3D compressive strains (43% higher), and maximum 3D shear strains (41% higher), in comparison to the non-degenerate IVDs, particularly in the lateral and posterior annulus. In both degenerate and non-degenerate IVDs, peak tensile and shear strains were observed close to the endplates. Inward bulging of the inner annulus was observed in all degenerate IVDs causing an increase in the AF compressive, tensile, and shear strains at the site of inward bulge, which may predispose it to circumferential tears (delamination). The endplate is the spine's “weak link” in pure axial compression, and the mechanism of human vertebral fracture is associated with disc degeneration. In non-degenerate IVDs the locations of failure were close to the endplate centroid, whereas in degenerate IVDs they were in peripheral regions. These findings advance the state of knowledge on mechanical changes during degeneration of the IVD, which help reduce the risk of injury, optimize treatments, and improve spinal implant designs. Additionally, these new data can be used to validate computational models.
Forte E, Panahi M, Baxan N, et al., 2021, Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart., J Cell Mol Med, Vol: 25, Pages: 229-243
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
Donat C, Yanez Lopez M, Sastre M, et al., 2021, From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury., Brain: a journal of neurology, Vol: 144, Pages: 70-91, ISSN: 0006-8950
The relationship between biomechanical forces and neuropathology is key to understanding traumatic brain injury. White matter tracts are damaged by high shear forces during impact, resulting in axonal injury, a key determinant of long-term clinical outcomes. However, the relationship between biomechanical forces and patterns of white matter injuries, associated with persistent diffusion MRI abnormalities, is poorly understood. This limits the ability to predict the severity of head injuries and the design of appropriate protection. Our previously developed human finite element model of head injury predicted the location of post-traumatic neurodegeneration. A similar rat model now allows us to experimentally test whether strain patterns calculated by the model predicts in vivo MRI and histology changes. Using a Controlled Cortical Impact, mild and moderate injuries(1 and 2 mm) were performed. Focal and axonal injuries were quantified withvolumetric and diffusion 9.4T MRI two weeks post injury. Detailed analysis of the corpus callosum was conducted using multi-shell diffusion MRI and histopathology. Microglia and astrocyte density, including process parameters,along with white matter structural integrity and neurofilament expression were determined by quantitative immunohistochemistry. Linear mixed effects regression analyses for strain and strain rate with the employed outcome measures were used to ascertain how well immediate biomechanics could explain MRI and histology changes.The spatial pattern of mechanical strain and strain rate in the injured cortex shows good agreement with the probability maps of focal lesions derived from volumetric MRI. Diffusion metrics showed abnormalities in segments of the corpus callosum predicted to have a high strain, indicating white matter changes. The same segments also exhibited a severity-dependent increase in glia cell density, white matter thinning
Franke J, Baxan N, Lehr H, et al., 2020, Hybrid MPI-MRI System for Dual-Modal In Situ Cardiovascular Assessments of Real-Time 3D Blood Flow Quantification-A Pre-Clinical In Vivo Feasibility Investigation., IEEE Trans Med Imaging, Vol: 39, Pages: 4335-4345
Non-invasive quantification of functional parameters of the cardiovascular system, in particular the heart, remains very challenging with current imaging techniques. This aspect is mainly due to the fact, that the spatio-temporal resolution of current imaging methods, such as Magnetic Resonance Imaging (MRI) or Positron Emission Tomography (PET), does not offer the desired data repetition rates in the context of real-time data acquisition and thus, can cause artifacts and misinterpretations in accelerated data acquisition approaches. We present a fast non-invasive and quantitative dual-modal in situ cardiovascular assessment using a hybrid imaging system which combines the new imaging modality Magnetic Particle Imaging (MPI) and MRI. This pre-clinical hybrid imaging system provides either a 0.5 T homogeneous B0 field for MRI or a 2.2 T/m gradient field featuring a Field-Free-Point for MPI. A comprehensive coil system allows in both imaging modes for spatial encoding, signal excitation and reception. In this work, 3-dimensional anatomical information acquired with MRI is combined with in situ sequentially acquired time-resolved 3D (i.e. 3D + t) MPI bolus tracking of superparamagnetic iron oxide nanoparticles. MPI data were acquired during a 21 [Formula: see text] (40 μ mol(Fe)/kgBW) bolus tail vein injection under free-breathing with an ungated and non-triggered MPI scan with a repetition rate of 46 volumes per seconds. We successfully determined quantitative hemodynamics as 3D + t velocity vector estimations of a beating rat's heart by analyzing 3 seconds of 3D + t MPI image data. The used hybrid system allows for MR-based MPI Field-of-View planning and cardiac cross-sectional anatomy analysis, precise co-registration of dual-modal datasets, as well as for MPI-based hemodynamic functional analysis using an optical flow technique. We present the first in-vivo results of a new methodology, allowing for fast, non-invasive, quantitative and in situ hybrid cardiovascu
Braga M, Kaliszczak M, Carroll L, et al., 2020, Tracing nutrient flux following monocarboxylate transporter-1 inhibition with AZD3965., Cancers (Basel), Vol: 12, ISSN: 2072-6694
The monocarboxylate transporter 1 (MCT1) is a key element in tumor cell metabolism and inhibition of MCT1 with AZD3965 is undergoing clinical trials. We aimed to investigate nutrient fluxes associated with MCT1 inhibition by AZD3965 to identify possible biomarkers of drug action. We synthesized an 18F-labeled lactate analogue, [18F]-S-fluorolactate ([18F]-S-FL), that was used alongside [18F]fluorodeoxyglucose ([18F]FDG), and 13C-labeled glucose and lactate, to investigate the modulation of metabolism with AZD3965 in diffuse large B-cell lymphoma models in NOD/SCID mice. Comparative analysis of glucose and lactate-based probes showed a preference for glycolytic metabolism in vitro, whereas in vivo, both glucose and lactate were used as metabolic fuel. While intratumoral L-[1-13C]lactate and [18F]-S-FL were unchanged or lower at early (5 or 30 min) timepoints, these variables were higher compared to vehicle controls at 4 h following treatment with AZD3965, which indicates that inhibition of MCT1-mediated lactate import is reversed over time. Nonetheless, AZD3965 treatment impaired DLBCL tumor growth in mice. This was hypothesized to be a consequence of metabolic strain, as AZD3965 treatment showed a reduction in glycolytic intermediates and inhibition of the TCA cycle likely due to downregulated PDH activity. Glucose ([18F]FDG and D-[13C6]glucose) and lactate-based probes ([18F]-S-FL and L-[1-13C]lactate) can be successfully used as biomarkers for AZD3965 treatment.
Clough TJ, Baxan N, Coakley EJ, et al., 2020, Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of beta-cell-dependent contrast enhancement in the pancreas, Dalton Transactions: an international journal of inorganic chemistry, Vol: 49, Pages: 4732-4740, ISSN: 1477-9226
Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.
Tavana S, Clark JN, Prior J, et al., 2020, Quantifying deformations and strains in human intervertebral discs using Digital Volume Correlation combined with MRI (DVC-MRI), Journal of Biomechanics, Vol: 102, Pages: 1-7, ISSN: 0021-9290
Physical disruptions to intervertebral discs (IVDs) can cause mechanical changes that lead to degeneration and to low back pain which affects 75% of us in our lifetimes. Quantifying the effects of these changes on internal IVD strains may lead to better preventative strategies and treatments. Digital Volume Correlation (DVC) is a non-invasive technique that divides volumetric images into subsets, and measures strains by tracking the internal patterns within them under load. Applying DVC to MRIs may allow non-invasive strain measurements. However, DVC-MRI for strain measurements in IVDs has not been used previously. The purpose of this study was to quantify the strain and deformation errors associated with DVC-MRI for measurements in human IVDs.Eight human lumbar IVDs were MRI scanned (9.4T) for a ‘zero-strain study’ (multiple unloaded scans to quantify noise within the system), and a loaded study (2mm axial compression). Three DVC methodologies: Fast-Fourier transform (FFT), direct correlation (DC), and a combination of both FFT and DC approaches were compared with subset sizes ranging from 8 to 88 voxels to establish the optimal DVC methodology and settings which were then used in the loaded study.FFT+DC was the optimal method and a subset size of 56 voxels (2520 micrometers) was found to be a good compromise between errors and spatial resolution. Displacement and strain errors did not exceed 28 µm and 3000 microstrain, respectively.These findings demonstrate that DVC-MRI can quantify internal strains within IVDs non-invasively and accurately. The method has unique potential for assessing IVD strains within patients.
Morse SV, Boltersdorf T, Harriss BI, et al., 2020, Neuron labeling with rhodamine-conjugated Gd-based MRI contrast agents delivered to the brain via focused ultrasound, Theranostics, Vol: 10, Pages: 2659-2674, ISSN: 1838-7640
Gadolinium-based magnetic resonance imaging contrast agents can provide information regarding neuronal function, provided that these agents can cross the neuronal cell membrane. Such contrast agents are normally restricted to extracellular domains, however, by attaching cationic fluorescent dyes, they can be made cell-permeable and allow for both optical and magnetic resonance detection. To reach neurons, these agents also need to cross the blood-brain barrier. Focused ultrasound combined with microbubbles has been shown to enhance the permeability of this barrier, allowing molecules into the brain non-invasively, locally and transiently. The goal of this study was to investigate whether combining fluorescent rhodamine with a gadolinium complex would form a dual-modal contrast agent that could label neurons in vivo when delivered to the mouse brain with focused ultrasound and microbubbles.Methods: Gadolinium complexes were combined with a fluorescent, cationic rhodamine unit to form probes with fluorescence and relaxivity properties suitable for in vivo applications. The left hemisphere of female C57bl/6 mice (8-10 weeks old; 19.07 ± 1.56 g; n = 16) was treated with ultrasound (centre frequency: 1 MHz, peak-negative pressure: 0.35 MPa, pulse length: 10 ms, repetition frequency: 0.5 Hz) while intravenously injecting SonoVue microbubbles and either the 1 kDa Gd(rhodamine-pip-DO3A) complex or a conventionally-used lysine-fixable Texas Red® 3 kDa dextran. The opposite right hemisphere was used as a non-treated control region. Brains were then extracted and either sectioned and imaged via fluorescence or confocal microscopy or imaged using a 9.4 T magnetic resonance imaging scanner. Brain slices were stained for neurons (NeuN), microglia (Iba1) and astrocytes (GFAP) to investigate the cellular localization of the probes.Results: Rhodamine fluorescence was detected in the left hemisphere of all ultrasound treated mice, while none was detected in the right contr
Baxan N, Papanikolaou A, Salles-Crawley I, et al., 2019, Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multiparametric quantitative cardiac magnetic resonance imaging., Dis Model Mech, Vol: 12
Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the Toll-like receptor 7 (TLR-7) agonist Resiquimod induces auto-antibodies and systemic tissue damage, including in the heart, and is used as an inducible mouse model of systemic lupus erythematosus (SLE). Here, we show that overactivation of the TLR-7 pathway of viral recognition by Resiquimod treatment of CFN mice induces severe thrombocytopenia and internal bleeding, which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2* relaxation times, and compared results with ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2* measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes. In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as an acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2* mapping to CMR protocols for myocarditis diagnosis improves diagnostic sensitivity and interpretation of disease mechanisms.This article has an associated First Person interview with the first author of the paper.
Baxan N, 2019, First person - Nicoleta Baxan, DISEASE MODELS & MECHANISMS, Vol: 12, ISSN: 1754-8403
Rotolo A, Caputo VS, Holubova M, et al., 2018, Enhanced anti-lymphoma activity of CAR19-iNKT cells underpinned by dual CD19 and CD1d targeting, Cancer Cell, Vol: 34, Pages: 596-610.e11, ISSN: 1535-6108
Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.
Narodden S, Baxan N, Harding S, 2018, Oral Session Bests of Best Moderated ePoster abstracts: Segmental Longitudinal Myocardial Strains Can Distinguish the Healthy, Area-at-risk and Infarcted Myocardial Segments in Acute Ischaemia-Reperfusion Injury, EuroCMR 2018 (Barcelona)
Hasham M, Baxan N, Dent O, et al., 2017, Heart disease in systemic autoimmunity; an inducible mouse model to study regenerative processes and therapies under inflammatory conditions, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy / Joint UK-Regenerative-Medicine-Platform Meeting, Publisher: MARY ANN LIEBERT, INC, Pages: A20-A21, ISSN: 1043-0342
Narodden S, Baxan N, Harding SE, 2017, The feasibility and superiority of high frame rate strainimaging compared to ejection fraction in a rat model ofischamia-reperfusion myocardial infarction using cardiac MRI, The 34th Annual Meeting, European Section of the International Society for Heart Research, Publisher: Elsevier BV, Pages: 55-55, ISSN: 0022-2828
Background: In the fields of cardiac regeneration and cardioprotection,robust quantification of the cardiac function is paramount for theassessment of the effects of experimental interventions on theheart. We hypothesized the feasibility of performing cardiac MRI strainimaging and assessed its superiority to ejection fraction (EF) in I/RMI rats.Methods: Lewis rats (normal versus 24–48-hour post I/R MI, each n =6) were imaged using cine FLASH and high-frame rate IntraGate cine(Bruker BioSpec 9.4T MRI, Ettlingen) conforming to AHA's planes recommendations. MI was confirmed using multi-slice IR LGE. Segment(Medviso AB, Lund) and 2D CPA MR (Tomtec) were used respectivelyfor volumes measurements and strain analysis.Results: Normal rat versus MI rats: EF (mean 64.0%, SD 2.3% versus mean59.5%, SD 5.1%), p = 0.089; endo peak GLS (global longitudinal strain)(mean -21.9.0%, SD 1.1% vs. -14.1%, SD 5.5%), p = 0.017; endopeak GCS (global circumferential strain) (mean -34.0%, SD 1.4% versusmean -26.1%, SD 6.4%), p = 0.028; myo peak GCS (mean -23.5%,SD 1.7% vs -17.0%, SD 5.4%), p = 0.032; GRS (global radial strain)(mean 45.8%, SD 5.3% versus mean 33.7%, SD 9.8%), p = 0.029.Conclusion: Strain imaging indices show statistically significantchanges after MI where EF does not. A small change in EF was observeddespite large infarct sizes. Increase in heart rate and alterations ofremote regional strain and tissue velocities (data not shown) are suggested to be compensatory mechanisms which preserve EF.
Hasham MG, Baxan N, Stuckey D, et al., 2017, Systemic autoimmunity induced by Toll-like receptor 7/8 agonist Resiquimod causes myocarditis and dilated cardiomyopathy: a new model of autoimmune heart disease, Disease Models & Mechanisms, Vol: 10, Pages: 259-270, ISSN: 1754-8411
Systemic autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) show significant heart involvement and cardiovascular morbidity, which can be due to systemically increased levels of inflammation or direct autoreactivity targeting cardiac tissue. Despite high clinical relevance, cardiac damage secondary to systemic autoimmunity lacks inducible rodent models. Here we characterize immune-mediated cardiac tissue damage in a new model of SLE induced by topical application of the TLR-7/8 agonist Resiquimod. We observe a cardiac phenotype reminiscent of autoimmune-mediated dilated cardiomyopathy, and identify auto-antibodies as major contributors to cardiac tissue damage. Resiquimod-induced heart disease is a highly relevant mouse model for mechanistic and therapeutic studies aiming to protect the heart during autoimmunity.
Goebel K, Gruschke OG, Leupold J, et al., 2015, Phased-array of microcoils allows MR microscopy of ex vivo human skin samples at 9.4 T, SKIN RESEARCH AND TECHNOLOGY, Vol: 21, Pages: 61-68, ISSN: 0909-752X
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- Citations: 10
Bredel M, Ferrarese R, Harsh GR, et al., 2014, ABERRANT SPLICING OF A BRAIN-ENRICHED ALTERNATIVE EXON ELIMINATES TUMOR SUPPRESSOR FUNCTION AND PROMOTES ONCOGENE FUNCTION DURING BRAIN TUMORIGENESIS, Neuro-Oncology, Vol: 16, Pages: iii19-iii20, ISSN: 1522-8517
Ferrarese R, Harsh GR, Yadav AK, et al., 2014, Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression, JOURNAL OF CLINICAL INVESTIGATION, Vol: 124, Pages: 2861-2876, ISSN: 0021-9738
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- Citations: 65
Schwab L, Goroncy L, Palaniyandi S, et al., 2014, Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage, NATURE MEDICINE, Vol: 20, Pages: 648-654, ISSN: 1078-8956
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- Citations: 185
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