Biology subjects

Pickup, S.

Publications and source records attributed to Pickup, S..

5 recordsLinked to original sources

bioRxiv2025

Characterization of hippocampal subfields using histology-based annotated postmortem MRI: Lessons for in vivo segmentation II

High-resolution in vivo magnetic resonance imaging (MRI) of hippocampal subfields is a rapidly advancing field due to their implication in cognition, disorder, and disease. Hippocampal subfield segmentation on in vivo MRI is generally guided by postmortem reference material, which has been limited by small sample sizes that preclude comprehensive characterization of subfield border locations and their variability. Addressing this, we characterized hippocampal subfield border variability in two ultra-high-resolution postmortem MRI datasets with combined annotated histological sections, including cases with and without dementia. We examined: 1) the order of appearance and disappearance of subfields along the long axis of the hippocampus; 2) the order of appearance and disappearance of subicular subregions; 3) the medial-lateral position of subicular subregional boundaries along the hippocampal body; 4) the location of the CA3 relative to hippocampal head digitations; 5) the subfield borders in the hippocampal body relative to a volume proportion of the dark band; and 6) the association of hippocampal length and subiculum-CA1 border location with diagnosis, demographic factors, and factors related to postmortem imaging. Our findings reaffirmed that there is a consistent order of appearance and disappearance of subfields in the hippocampal head and tail, respectively. The subicular subregions exhibited a first in, last out order of appearance and disappearance, and pre/parasubiculum consistently occupied half of the subicular complex in coronal slices throughout the hippocampal body. Hippocampal head digitations were not a reliable landmark for CA3 appearance, but SRLM proportionality did offer a potentially consistent approach for estimating CA2 and CA3 subfield borders in relation to the hippocampal border. No clear relationship was found between the anatomical features and diagnosis, demographic factors, and factors related to postmortem imaging. These findings have implications for the development and harmonization of hippocampal subfield segmentation protocols and interpretation of high-resolution functional MRI studies of the human hippocampus.

neuroscience↗

bioRxiv2024

Effect of Stroma-directed Drugs in Combination with Chemotherapy Against Pancreatic Cancer- a Preclinical Study

Cytotoxic chemotherapy plays an important role for extending the survival of patients with pancreatic ductal adenocarcinoma (PDAC). To enhance the efficacy of chemotherapy for eradicating the cancer cells, we have compared the standard care chemotherapy (combination of nab-paclitaxel, gemcitabine and cisplatin, NGC) versus NGC plus stroma-directed agents (calcipotriol and losartan, respectively) in a genetically engineered mouse model of PDAC. Over a 2-week study period, MRI was conducted to measure the tumor size and to test the sensitivity of imaging markers derived from diffusion-weighted imaging (DWI), dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) for assessing the tumor cellularity and stromal changes. Detailed immunohistochemistry and preliminary single cell RNA sequencing (scRNAseq) study were applied to tumor tissues collected upon euthanasia on day-14. Our major findings are: 1. Compared the untreated controls, NGC chemotherapy induced significant tumor growth inhibition and stromal changes including pronounced reduction of fibroblast associated protein (FAP) level accompanied by increased matrix collagen content, significantly reduced microvascular permeability revealed by DCE corroborated with reduced microvascular density. 2. Losartan+NGC significantly enhanced inhibition of tumor growth beyond NGC and increased lymphocytes infiltration in the tumor which may contribute to enhanced cancer cells eradication. 3. NGC treatment enriched the fraction of mesenchymal (M) subtype while reducing the epithelial (E) subtype of cancer cells compared to the controls, and this trend was reversed by calcipotriol+NGC. In conclusion, our study captured changes in cancer cell and tumor microenvironment in response to chemo stromal therapy versus chemotherapy alone with mechanistic insights.

cancer biology↗

bioRxiv2024

Quantitative MRI Measurements Capture Pancreatic Cancer and Stroma Reactions to New KRAS Inhibitor

PurposeIn pancreatic ductal adenocarcinoma (PDAC), KRAS mutations drive both cancer cell growth and formation of a dense stroma. Small molecule KRAS inhibitors (KRASi) represent a promising new treatment hence clinical tools that can assess early response, detect resistance and/or predict prolonged survival are desirable to understand clinical biology of KRASi. We hypothesized that diffusion-weighted MRI (DWI) can detect cell death while dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size change induced by KRASi treatment. Experimental DesignMultiple preclinical PDAC models including a genetically engineered mouse model (KPC) received MRTX1133, a KRASi specific for KRASG12D mutation. Quantitative imaging markers were corroborated with immunohistochemistry (IHC) analyses. ResultsSignificant increase of tumor apparent diffusion coefficient (a DWI metric) was detected as early as 48h and persisted to Day7 after initiation of KRASi treatment and was strongly correlated with cell death and reduced cellularity, resulting in greatly prolonged median survival in treated mice. Capillary perfusion/permeability (a DCE metric) exhibited an inverse relationship with microvascular density. Distinct responses of KRASG12C versus KRASG12D tumors to MRTX1133 were captured by the MRI metrics corroborated with IHC. When tumors developed resistance to MRTX1133, the imaging marker values exhibited a reversal from those of responding tumors. ConclusionsMultiparametric MRI provides early biological insights of cancer and stromal response to KRASi treatment and sets the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy. Translational relevanceEmerging small molecule KRAS inhibitors (KRASi) represent a new class of therapy for PDAC. Clinical tools that can provide early biological insights of KRASi therapy are desirable. In PDAC models, we examined a clinically ready imaging protocol that combines MRI-based tumor size, diffusion-weighted MRI (DWI), dynamic contrast enhanced MRI (DCE), and magnetization transfer ratio (MTR) for detection of early response as well as acquired resistance to MRTX1133, a KRASi being evaluated in clinical trials. Our data show that DWI and DCE metrics provided key insights of significant cell death and tumor microenvironment changes underlying tumor size regression as early as 48 hours after KRASi treatment initiation. These MRI metrics also captured resistance to KRASi developed over prolonged treatment. This study has high translational relevance by employing clinically applied MRI methods, an investigational new drug and a genetically engineered mouse model that recapitulates salient features of human PDAC.

cancer biology↗

bioRxiv2021

3D Mapping of Neurofibrillary Tangle Burden in the Human Medial Temporal Lobe

Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimers 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.

neuroscience↗

bioRxiv2018

Murine MPDZ-Linked Hydrocephalus is Caused by Hyperpermeability of the Choroid Plexus

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ. Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast-medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straight-forward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus.

neuroscience↗