Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome.

Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype.

A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease.

Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades.

A Mouse Model with a Frameshift Mutation in the Nuclear Factor I/X () Gene Has Phenotypic Features of Marshall-Smith Syndrome.

The nuclear factor I/X () gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall-Smith syndrome (MSS). mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense-mediated decay (NMD) leading to NFIX haploinsufficiency, whereas mutations associated with MSS are clustered in exons 6-10 and escape NMD and result in the production of dominant-negative mutant NFIX proteins. Thus, different mutations have distinct consequences on expression.

PKN2 deficiency leads both to prenatal 'congenital' cardiomyopathy and defective angiotensin II stress responses.

The protein kinase PKN2 is required for embryonic development and PKN2 knockout mice die as a result of failure in the expansion of mesoderm, cardiac development and neural tube closure. In the adult, cardiomyocyte PKN2 and PKN1 (in combination) are required for cardiac adaptation to pressure-overload. The specific role of PKN2 in contractile cardiomyocytes during development and its role in the adult heart remain to be fully established.

Image-Guided Magnetic Thermoseed Navigation and Tumor Ablation Using a Magnetic Resonance Imaging System.

Medical therapies achieve their control at expense to the patient in the form of a range of toxicities, which incur costs and diminish quality of life. Magnetic resonance navigation is an emergent technique that enables image-guided remote-control of magnetically labeled therapies and devices in the body, using a magnetic resonance imaging (MRI) system. Minimally INvasive IMage-guided Ablation (MINIMA), a novel, minimally invasive, MRI-guided ablation technique, which has the potential to avoid traditional toxicities, is presented.

Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses.

Phase unwrapping with a rapid opensource minimum spanning tree algorithm (ROMEO).

Purpose: To develop a rapid and accurate MRI phase-unwrapping technique for challenging phase topographies encountered at high magnetic fields, around metal implants, or postoperative cavities, which is sufficiently fast to be applied to large-group studies including Quantitative Susceptibility Mapping and functional MRI (with phase-based distortion correction).

Methods: The proposed path-following phase-unwrapping algorithm, ROMEO, estimates the coherence of the signal both in space-using MRI magnitude and phase information-and over time, assuming approximately linear temporal phase evolution. This information is combined to form a quality map that guides the unwrapping along a 3D path through the object using a computationally efficient minimum spanning tree algorithm.

Substantially thinner internal granular layer and reduced molecular layer surface in the cerebellar cortex of the Tc1 mouse model of down syndrome - a comprehensive morphometric analysis with active staining contrast-enhanced MRI.

Down Syndrome is a chromosomal disorder that affects the development of cerebellar cortical lobules. Impaired neurogenesis in the cerebellum varies among different types of neuronal cells and neuronal layers. In this study, we developed an imaging analysis framework that utilizes gadolinium-enhanced ex vivo mouse brain MRI.

Noninvasive diffusion magnetic resonance imaging of brain tumour cell size for the early detection of therapeutic response.

Cancer cells differ in size from those of their host tissue and are known to change in size during the processes of cell death. A noninvasive method for monitoring cell size would be highly advantageous as a potential biomarker of malignancy and early therapeutic response. This need is particularly acute in brain tumours where biopsy is a highly invasive procedure.

Measuring diffusion exchange across the cell membrane with DEXSY (Diffusion Exchange Spectroscopy).

Introduction: To combine numerical simulations, in vitro and in vivo experiments to evaluate the feasibility of measuring diffusion exchange across the cell membrane with diffusion exchange spectroscopy (DEXSY).

Methods: DEXSY acquisitions were simulated over a range of permeabilities in nerve tissue and yeast substrates. In vitro measurements were performed in a yeast substrate and in vivo measurements in mouse tumor xenograft models, all at 9.

q-Space Imaging Yields a Higher Effect Gradient to Assess Cellularity than Conventional Diffusion-weighted Imaging Methods at 3.0 T: A Pilot Study with Freshly Excised Whole-Breast Tumors.

Purpose: To determine whether q-space imaging (QSI), an advanced diffusion-weighted MRI method, provides a higher effect gradient to assess tumor cellularity than existing diffusion imaging methods, and fidelity to cellularity obtained from histologic analysis.

Materials And Methods: In this prospective study, diffusion-weighted images were acquired from 20 whole-breast tumors freshly excised from participants (age range, 35-78 years) by using a clinical 3.0-T MRI unit.

Redistribution of EZH2 promotes malignant phenotypes by rewiring developmental programmes.

Epigenetic regulators are often hijacked by cancer cells to sustain malignant phenotypes. How cells repurpose key regulators of cell identity as tumour-promoting factors is unclear. The antithetic role of the Polycomb component EZH2 in normal brain and glioma provides a paradigm to dissect how wild-type chromatin modifiers gain a pathological function in cancer.

Clustering superparamagnetic iron oxide nanoparticles produces organ-targeted high-contrast magnetic resonance images.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been used as magnetic resonance imaging (MRI) contrast agents; however, a number of T2-weighted imaging SPIONs have been withdrawn due to their poor clinical contrast performance. Our aim was to significantly improve SPION T2-weighted MRI contrast by clustering SPIONs within novel chitosan amphiphiles. Clustering SPIONs was achieved by encapsulation of hydrophobic-coated SPIONs with an amphiphilic chitosan polymer (GCPQ).

VERDICT MRI validation in fresh and fixed prostate specimens using patient-specific moulds for histological and MR alignment.

The VERDICT framework for modelling diffusion MRI data aims to relate parameters from a biophysical model to histological features used for tumour grading in prostate cancer. Validation of the VERDICT model is necessary for clinical use. This study compared VERDICT parameters obtained ex vivo with histology in five specimens from radical prostatectomy.

Non-invasive imaging of CSF-mediated brain clearance pathways via assessment of perivascular fluid movement with diffusion tensor MRI.

The glymphatics system describes a CSF-mediated clearance pathway for the removal of potentially harmful molecules, such as amyloid beta, from the brain. As such, its components may represent new therapeutic targets to alleviate aberrant protein accumulation that defines the most prevalent neurodegenerative conditions. Currently, however, the absence of any non-invasive measurement technique prohibits detailed understanding of glymphatic function in the human brain and in turn, it's role in pathology.

Investigating Low-Velocity Fluid Flow in Tumors with Convection-MRI.

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow.

Low frequency oscillating gradient spin-echo sequences improve sensitivity to axon diameter: An experimental study in viable nerve tissue.

Mapping axon diameters within the central and peripheral nervous system could play an important role in our understanding of nerve pathways, and help diagnose and monitor an array of neurological disorders. Numerous diffusion MRI methods have been proposed for imaging axon diameters, most of which use conventional single diffusion encoding (SDE) spin echo sequences. However, a growing number of studies show that oscillating gradient spin echo (OGSE) sequences can provide additional advantages over conventional SDE sequences.

Apparatus for Histological Validation of and Magnetic Resonance Imaging of the Human Prostate.

This article describes apparatus to aid histological validation of magnetic resonance imaging studies of the human prostate. The apparatus includes a 3D-printed patient-specific mold that facilitates aligned and imaging, tissue fixation, and tissue sectioning with minimal organ deformation. The mold and a dedicated container include MRI-visible landmarks to enable consistent tissue positioning and minimize image registration complexity.

Microstructural models for diffusion MRI in breast cancer and surrounding stroma: an ex vivo study.

The diffusion signal in breast tissue has primarily been modelled using apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM) and diffusion tensor (DT) models, which may be too simplistic to describe the underlying tissue microstructure. Formalin-fixed breast cancer samples were scanned using a wide range of gradient strengths, durations, separations and orientations. A variety of one- and two-compartment models were tested to determine which best described the data.

Monitoring the Growth of an Orthotopic Tumour Xenograft Model: Multi-Modal Imaging Assessment with Benchtop MRI (1T), High-Field MRI (9.4T), Ultrasound and Bioluminescence.

Background: Research using orthotopic and transgenic models of cancer requires imaging methods to non-invasively quantify tumour burden. As the choice of appropriate imaging modality is wide-ranging, this study aimed to compare low-field (1T) magnetic resonance imaging (MRI), a novel and relatively low-cost system, against established preclinical techniques: bioluminescence imaging (BLI), ultrasound imaging (US), and high-field (9.4T) MRI.

Increased cerebral vascular reactivity in the tau expressing rTg4510 mouse: evidence against the role of tau pathology to impair vascular health in Alzheimer's disease.

Vascular abnormalities are a key feature of Alzheimer's disease (AD). Imaging of cerebral vascular reactivity (CVR) is a powerful tool to investigate vascular health in clinical populations although the cause of reduced CVR in AD patients is not fully understood. We investigated the specific role of tau pathology in CVR derangement in AD using the rTg4510 mouse model.

In amnio MRI of mouse embryos.

Mouse embryo imaging is conventionally carried out on ex vivo embryos excised from the amniotic sac, omitting vital structures and abnormalities external to the body. Here, we present an in amnio MR imaging methodology in which the mouse embryo is retained in the amniotic sac and demonstrate how important embryonic structures can be visualised in 3D with high spatial resolution (100 µm/px). To illustrate the utility of in amnio imaging, we subsequently apply the technique to examine abnormal mouse embryos with abdominal wall defects.

Is your system calibrated? MRI gradient system calibration for pre-clinical, high-resolution imaging.

High-field, pre-clinical MRI systems are widely used to characterise tissue structure and volume in small animals, using high resolution imaging. Both applications rely heavily on the consistent, accurate calibration of imaging gradients, yet such calibrations are typically only performed during maintenance sessions by equipment manufacturers, and potentially with acceptance limits that are inadequate for phenotyping. To overcome this difficulty, we present a protocol for gradient calibration quality assurance testing, based on a 3D-printed, open source, structural phantom that can be customised to the dimensions of individual scanners and RF coils.

Multimodality characterization of microstructure by the combination of diffusion NMR and time-domain diffuse optical data.

Combining datasets with a model of the underlying physics prior to mapping of tissue provides a novel approach improving the estimation of parameters. We demonstrate this approach by merging near infrared diffuse optical signal data with diffusion NMR data to inform a model describing the microstructure of a sample. The study is conducted on a homogeneous emulsion of oil in a dispersion medium of water and proteins.