1,323 research outputs found
Investigating the impact of lung cancer cell-of-origin on tumour metabolic phenotype and heterogeneity
Non-small-cell lung cancer has been described as highly heterogenous which results in different metabolic phenotypes. There are multiple factors which contribute to this heterogeneity, one of which is the tumour cell-of-origin. In the lung, there are five cell types reported to be cells-of-origin: alveolar epithelial type 2, club, basal, neuroendocrine and bronchioalveolar stem cells. This project focuses on the interaction between the cell-of-origin and the metabolic phenotype of lung cancer, and we aim to assess the contribution of the cell-of-origin to lung cancer metabolic resultant phenotype and heterogeneity.
To accomplish this, we have established two complementary model systems, one in vitro and one in vivo. In our in vitro model, we isolated specific lung cell types, including AT2 cells, basal cells, and club cells, utilising their unique cell surface markers. By introducing oncogenic KRAS mutations and deleting the P53 gene, we are creating lineage-restricted organoids. These organoids will serve as valuable tools for characterizing the metabolic aspects of tumours arising from different cell-of-origin backgrounds within an in vitro setting.
In our in vivo model, we induced NSCLC tumours in mice with genetic modifications using viral vectors, namely Ad5-mSPC-Cre, Ad5-CC10-Cre, and Ad5- bk5-Cre. These vectors are selectively expressed in AT2, club, and basal cells, respectively. To ensure the validity of our comparisons, we have carefully monitored tumour growth dynamics and burden in these mouse models. Our comprehensive analysis has revealed three distinct transcriptomic subtypes (S1, S2, and Acetate) within these NSCLC tumours. Notably, S1 and Acetate subtypes are enriched in tumours originating from specific cell types. Positron emission tomography (PET) imaging has unveiled metabolic variations, with S1 tumours displaying heightened [18F]FDG uptake and the Acetate subtype exhibiting increased [11C]acetate uptake. Furthermore, our multi-omics approach, encompassing transcriptomics, proteomics, and metabolomics, has exposed disparities in critical metabolic pathways, such as glycolysis, hypoxia response, and apoptosis.
In summary, our research provides a comprehensive examination of the metabolic heterogeneity of NSCLC based on the cell-of-origin independently of genomic alterations
Multimodality treatment for esophageal squamous cell carcinoma
This thesis aims to optimize multimodality treatments for locally advanced esophageal squamous cell carcinoma (ESCC), specifically in East-Asia, recognizing that ESCC may differ in biology and response to treatment in different parts of the world. Part I of the thesis introduces the subtype ESCC and its characteristics from different geographical perspectives followed by an exposition of the differences between ESCC in eastern and western worlds. Part II optimizes trimodal therapy of ESCC in Taiwan, as a representative region of East-Asia. Finally, in Part III, the accuracy of liquid biopsies in identifying patients who may not need surgery after trimodal therapy is assessed.
Combining gene-editing with brain imaging: from genes to molecules to networks
"Receptors, transporters and ion channels are important targets for therapy development in neurological diseases, [...] but their mechanistic role in pathogenesis is often poorly understood. Gene-editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on whole-brain level. Here, we combine CRISPR/Cas9 gene-editing with in vivo PET and fMRI to investigate the direct link between genes, molecules, and the brain connectome. The extensive knowledge of the Slc18a2 gene encoding the VMAT2, involved in the storage and release of DA, makes it an excellent target for studying the gene networks relationships while structurally preserving neuronal integrity and function. We edited the Slc18a2 in the SNc of adult rats and used in vivo molecular imaging besides behavioral, histological, and biochemical assessments to characterize the CRISPR/Cas9-mediated VMAT2 KD.
Simultaneous PET/fMRI was performed to inspect the molecular and functional brain adaptations, beyond the predicted dopaminergic changes.
We found a regional increase in postsynaptic DA receptor availability, preceded by a reorganization of brain networks that adapt to reduced DA transmission states by becoming functionally connected and organized. We observed that FC adaptations are stage-specific and follow the selective impairment of presynaptic DA storage and release. Further, the observed hyperconnectivity within and between brain networks spreads from the contralateral thalamus and prefrontal cortical regions to the striata and hippocampi.
Our study reveals that recruiting different brain networks is an early response to the dopaminergic dysfunction preceding neuronal cell loss. Our combinatorial approach is a novel tool to investigate the impact of specific genes on brain molecular and functional dynamics which will help to develop tailored therapies for normalizing brain function. The method can easily be transferred to higher- order species allowing for a direct comparison of the molecular imaging findings" [1].
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Future studies could benefit from in vivo reporter gene PET probes to quantitatively assess and monitor the Cas9 and sgRNA brain expression over time [38, 220]. Indeed, in vivo reporter gene imaging is a powerful tool to monitor gene therapy and image exogenous gene expression in the brain of preclinical models of neurological diseases. Despite several reporter genes have been developed in the last years, these show major limitations. Indeed, most available reporter gene systems are based on endogenously expressed genes, resulting in high background binding or low brain uptake.
Here, we characterized the pharmacokinetics and metabolism of [11C]TMP, a novel PET reporter probe which binds to EcDHFR-engineered cells and shows potential for imaging ectopic gene expression in xenografted tumor models in vitro and in vivo [47].
We found that [11C]TMP presents several unfavorable characteristics; dependency on PgP efflux transport at the BBB, hindering its brain uptake in the rat species, and in vivo metabolism, hampering the PET data quantification.
Our study shows that [11C]TMP is not a suitable PET reporter gene probe to image exogeneous gene expression in the rat brain, presenting low brain uptake and fast metabolism.
Future studies should focus on the investigation of different targets and the development of [11C]TMP analogs with more favorable pharmacokinetics and detectability, which are neither PgP substrate nor rapidely metabolized.
[1].Marciano et al., PNAS, 202
Development and validation of novel and quantitative MRI methods for cancer evaluation
Quantitative imaging biomarkers (QIB) offer the opportunity to further the evaluation of cancer at presentation as well as predict response to anti-cancer therapies before and early during treatment with the ultimate goal of truly personalised medical care and the mitigation of futile, often detrimental, therapy. Few QIBs are successfully translated into clinical practice and there is increasing recognition that rigorous methodologies and standardisation of research pipelines and techniques are required to move a theoretically useful biomarker into the clinic.
To this end, I have aimed to give an overview of what I believe to be some of key elements within the research field beginning with the concept of imaging biomarkers, introducing concepts in development and validation, before providing a summary of the current and future utility of a range of quantitative MR imaging biomarkers techniques within the oncological imaging field.
The original, prospective, research moves from the technical and analytical validation of a novel QIB use (T1 mapping in cancer), first in vivo qualification of this biomarker in cancer patient response assessment and prediction (sarcoma and breast cancer as well as prostate cancer separately), and then moving on to application of more established QIBs in cancer evaluation (R2*/BOLD imaging in head and neck cancer) as well as how existing MR data can be post-processed to improved cancer evaluation (further metrics derived from diffusion weighted imaging in head and neck cancer and textural analysis of existing clinical MR images utility in prostate cancer detection)
Thyroid Immune Related Adverse Events Following Immune Checkpoint Inhibitor Treatment
The efficacy of immune checkpoint inhibitor (ICI) treatment rivals traditional anti-tumor therapies and in most cases results in significantly less drug related toxicity. However, ICI-use can result in a myriad of immune and inflammatory side effects termed immune related adverse events (irAEs). Thyroid irAEs are the most common endocrine toxicity related to ICI-treatment. In affected patients, permanent thyroid dysfunction can result, necessitating lifelong thyroid hormone replacement and long-term clinical follow-up is required. Prior to this candidature, clinical descriptions of thyroid irAEs were predominately based on small, heterogeneous patient cohorts and little was known about the underlying pathogenesis responsible for their development. This thesis produced a detailed phenotypic report of 1246 patients with melanoma undergoing ICI-treatment. We clearly showed that prevalence of thyroid irAEs was substantially higher than previously reported, and that most patients developed subclinical disease only. We demonstrated that overt thyrotoxicosis had distinct clinical features from other thyroid irAE presentations and was uniquely associated with improvements in survival. We prospectively measured anti-thyroid antibody levels and showed they were highly specific for identifying patients likely to experience a thyroid irAE. Our antibody work was complemented by preclinical studies including development of an animal model to test for autoantibodies against novel thyroid antigens, a genetic study to test for an association with FLT3 gene polymorphism and immunophenotyping peripheral blood to identify key immune cell populations involved in the pathogenesis of thyroid irAEs. In totality, the work in this thesis significantly advances understanding of thyroid irAEs and the mechanisms underpinning their development
30th European Congress on Obesity (ECO 2023)
This is the abstract book of 30th European Congress on Obesity (ECO 2023
Health Risk Measurement and Assessment Technology: Current State and Future Prospect
With accelerated technologies, different kinds of health technology devices have been provided to customers that continuously record bio and vital signals. Some of these products are wearable that can be used all day long and during sleeping time. Due to the wearability feature and continuous recording, a vast amount of data can be achieved and analyzed. The recorded data are usually shared with a cloud to implement comprehensive analysis methods where deep and machine learning algorithms play the main role. Finally, they can assess some health factors of the customer and most likely predict future health risks. This chapter shall review the role of the clinical scanners and their valuable data in risk detection, more portable modalities, home-used commercial devices, and emerging techniques which are so potent for future home-used health risks analysis. In the end, we conclude the state-of-the-art and provide our vision about the future of health risk analysis
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