A framework for informing segmentation of in vivo MRI with information derived from ex vivo imaging: Application in the medial temporal lobe

Abstract Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on conventional 2D histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe (MTL) specimens were used to construct 3D quantitative maps of NFT burden in the MTL at individual and group levels. These maps reveal significant variation in NFT burden along the anterior-posterior axis. While early NFT pathology is thought to be confined to the transentorhinal region, we find similar levels of NFT burden in this region and other MTL subregions, including amygdala, temporopolar cortex, and subiculum/CA1.

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Tumor Targeted Nanoparticles Improve Therapeutic Index of BCL2 and MCL1 dual inhibition

Blood ◽

10.1182/blood.2020008017 ◽

2020 ◽

Author(s):

Neeta Bala Tannan ◽

Mandana T Manzari ◽

Laurie Herviou ◽

Mariana da Silva Ferreira ◽

Connor J Hagen ◽

...

Keyword(s):

Ex Vivo ◽

Therapeutic Index ◽

Drug Dose ◽

Hematological Toxicity ◽

Bcl2 Family ◽

Fold Reduction ◽

Tumor Killing ◽

Toxic Drugs ◽

Ex Vivo Imaging

Cancer and normal cells utilize multiple anti-apoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing, but is also associated with increased systemic toxicity. Here, we demonstrate that the dual targeting of MCL1 and BCL2 proteins, using the small molecules S63845 and venetoclax, induces durable remissions in mice harboring human DLBCL tumors but is accompanied by hematological toxicity and weight loss. To mitigate these toxicities, we encapsulated S63845 or venetoclax into nanoparticles targeting P-selectin that is enriched in tumor endothelial cells. In vivo and ex vivo imaging demonstrated preferential targeting of the nanoparticles to lymphoma tumors over vital organs. Mass-spectrometry analyses after nanoparticle drug administration confirmed tumor enrichment of the drug while reducing plasma levels. Furthermore, nanoparticle encapsulation allowed 3.5 to 6.5-fold reduction in drug dose, induced sustained remissions and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy.

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Automated segmentation of medial temporal lobe subregions on in vivo T1-weighted MRI in early stages of Alzheimer's disease

Human Brain Mapping ◽

10.1002/hbm.24607 ◽

2019 ◽

Vol 40 (12) ◽

pp. 3431-3451 ◽

Cited By ~ 13

Author(s):

Long Xie ◽

Laura E. M. Wisse ◽

John Pluta ◽

Robin de Flores ◽

Virgine Piskin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Automated Segmentation ◽

Early Stages

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Novel ex vivo MRI atlas of the medial temporal lobe can be used to characterize structural changes due to Alzheimer’s disease pathology

Alzheimer s & Dementia ◽

10.1002/alz.041279 ◽

2020 ◽

Vol 16 (S4) ◽

Author(s):

Sadhana Ravikumar ◽

Laura Wisse ◽

Long Xie ◽

Ranjit Ittyerah ◽

Sandhitsu R. Das ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Structural Changes ◽

Ex Vivo

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In-vivo near-infrared optical imaging of growing osteosarcoma cell lesions xenografted in mice: dual-channel quantitative evaluation of volume and mineralization

Acta Radiologica ◽

10.1258/ar.2011.110131 ◽

2011 ◽

Vol 52 (9) ◽

pp. 978-988 ◽

Cited By ~ 8

Author(s):

Hitoshi Nakayama ◽

Tomoyuki Kawase ◽

Kazuhiro Okuda ◽

Larry F Wolff ◽

Hiromasa Yoshie

Keyword(s):

Optical Imaging ◽

Near Infrared ◽

Imaging Technique ◽

Ex Vivo ◽

Acquisition Time ◽

Osteosarcoma Cell ◽

Dual Channel ◽

Nir Imaging ◽

Ex Vivo Imaging

Background In a previous study using a rodent osteosarcoma-grafted rat model, in which cell-dependent mineralization was previously demonstrated to proportionally increase with growth, we performed a quantitative analysis of mineral deposit formation using 99mTc-HMDP and found some weaknesses, such as longer acquisition time and narrower dynamic ranges (i.e. images easily saturated). The recently developed near-infrared (NIR) optical imaging technique is expected to non-invasively evaluate changes in living small animals in a quantitative manner. Purpose To test the feasibility of NIR imaging with a dual-channel system as a better alternative for bone scintigraphy by quantitatively evaluating mineralization along with the growth of osteosarcoma lesions in a mouse-xenograft model. Material and Methods The gross volume and mineralization of osteosarcoma lesions were evaluated in living mice simultaneously with dual-channels by NIR dye-labeled probes, 2-deoxyglucose (DG) and pamidronate (OS), respectively. To verify these quantitative data, retrieved osteosarcoma lesions were then subjected to ex-vivo imaging, weighing under wet conditions, microfocus-computed tomography (μCT) analysis, and histopathological examination. Results Because of less scattering and no anatomical overlapping, as generally shown, specific fluorescence signals targeted to the osteosarcoma lesions could be determined clearly by ex-vivo imaging. These data were well positively correlated with the in-vivo imaging data ( r > 0.8, P < 0.02). Other good to excellent correlations ( r > 0.8, P < 0.02) were observed between DG accumulation and tumor gross volume and between OS accumulation and mineralization volume. Conclusion This in-vivo NIR imaging technique using DG and OS is sensitive to the level to simultaneously detect and quantitatively evaluate the growth and mineralization occuring in this type of osteosarcoma lesions of living mice without either invasion or sacrifice. By possible mutual complementation, this dual imaging system might be useful for accurate diagnosis even in the presence of overlapping tissues.

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The Opportunities and Use of Imaging to Measure Target Engagement

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555219897270 ◽

2019 ◽

Vol 25 (2) ◽

pp. 127-136

Author(s):

Juliana Maynard ◽

Philippa Hart

Keyword(s):

Ex Vivo ◽

Clinical Success ◽

Receptor Occupancy ◽

Accurate Information ◽

Target Engagement ◽

Drug Molecule ◽

Drug Discovery And Development ◽

Ex Vivo Imaging

Lack of efficacy and poor safety outcomes are deemed to be the greatest causes of clinical failure of novel therapeutics. The use of biomarkers that give accurate information on target engagement, providing confidence that pharmacological activity in the target organ is being achieved, is key in optimizing clinical success. Without a measurement of target engagement, it can be very difficult to discern the basis for any lack of efficacy of a drug molecule within the pharmaceutical industry. Target engagement can be measured in both an in vitro and in vivo setting, and in recent years imaging measurements have been used frequently in drug discovery and development to assess target engagement and receptor occupancy in both human and animal models. From this perspective, we assess and look at the advancements in both in vivo and ex vivo imaging to demonstrate the enormous potential that imaging has as an application to provide a greater understanding of target engagement with a correlative therapeutic impact.

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Parametric approaches to micro-scale characterization of tissue volumes in vivo and ex vivo: Imaging microvasculature, attenuation, birefringence, and stiffness (Conference Presentation)

Optical Biopsy XIV: Toward Real-Time Spectroscopic Imaging and Diagnosis ◽

10.1117/12.2218719 ◽

2016 ◽

Author(s):

David D. Sampson ◽

Lixin Chin ◽

Peijun Gong ◽

Philip Wijesinghe ◽

Shaghayegh Es’haghian ◽

...

Keyword(s):

Ex Vivo ◽

Micro Scale ◽

Scale Characterization ◽

Ex Vivo Imaging

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Characterizing interneuron and pyramidal cells in the human medial temporal lobe in vivo using extracellular recordings

Hippocampus ◽

10.1002/hipo.20241 ◽

2006 ◽

Vol 17 (1) ◽

pp. 49-57 ◽

Cited By ~ 40

Author(s):

Indre V. Viskontas ◽

Arne D. Ekstrom ◽

Charles L. Wilson ◽

Itzhak Fried

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Pyramidal Cells ◽

Extracellular Recordings

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Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides

Pharmaceutics ◽

10.3390/pharmaceutics13060817 ◽

2021 ◽

Vol 13 (6) ◽

pp. 817

Author(s):

Tsuyoshi Yamamoto ◽

Yahiro Mukai ◽

Fumito Wada ◽

Chisato Terada ◽

Yukina Kayaba ◽

...

Keyword(s):

Antisense Oligonucleotides ◽

Ex Vivo ◽

The Body ◽

Locked Nucleic Acid ◽

Imaging Studies ◽

Phosphodiester Bond ◽

Chemically Modified ◽

Ex Vivo Imaging ◽

Mirna Targeting

The development of clinically relevant anti-microRNA antisense oligonucleotides (anti-miRNA ASOs) remains a major challenge. One promising configuration of anti-miRNA ASOs called “tiny LNA (tiny Locked Nucleic Acid)” is an unusually small (~8-mer), highly chemically modified anti-miRNA ASO with high activity and specificity. Within this platform, we achieved a great enhancement of the in vivo activity of miRNA-122-targeting tiny LNA by developing a series of N-acetylgalactosamine (GalNAc)-conjugated tiny LNAs. Specifically, the median effective dose (ED50) of the most potent construct, tL-5G3, was estimated to be ~12 nmol/kg, which is ~300–500 times more potent than the original unconjugated tiny LNA. Through in vivo/ex vivo imaging studies, we have confirmed that the major advantage of GalNAc over tiny LNAs can be ascribed to the improvement of their originally poor pharmacokinetics. We also showed that the GalNAc ligand should be introduced into its 5′ terminus rather than its 3′ end via a biolabile phosphodiester bond. This result suggests that tiny LNA can unexpectedly be recognized by endogenous nucleases and is required to be digested to liberate the parent tiny LNA at an appropriate time in the body. We believe that our strategy will pave the way for the clinical application of miRNA-targeting small ASO therapy.

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