1,219 research outputs found
The interplay between Natural Killer cells and Pancreatic Stellate cells in Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a disease with dismal prognosis. With five-year survival rates of less than 11%, PDAC is set to become the second leading cause of cancer related deaths by 2040. The role of pancreatic stellate cells in pancreatic ductal adenocarcinoma has been well established. However, to date, little remains know about the interaction between these crucial stromal cells and the innate lymphocytes, natural killer (NK) cells, in PDAC. Herein we demonstrate that naïve NK cells possess the functional efficacy to target and kill both quiescent (qPSC) and activated (aPSC) pancreatic stellate cells. Furthermore, qPSC, but not aPSC education of NK cells resulted in decreased NK cell-mediated cancer cell cytotoxicity. NK-PSC direct co-culture was found to modulate both PSC and NK phenotype, as well as functional changes within NK cells, an effect not observed with TranswellTM separation. Multiplex Luminex ELISA further revealed upregulation of IFN-γ and related chemokines in NK cells co-cultured with PSC (activated/quiescent), suggesting that this pathway may be involved in phenotypic modulation. Through global proteomic analysis we demonstrate NK cell-induced differential protein changes in aPSC versus qPSC. Furthermore, we demonstrate changes in intracellular NK pathways as a result of direct contact with PSCs, indicating a dynamic, bidirectional interaction between these two key players. Using multiplex immunohistochemical analysis, we demonstrate that NK cell proximity to CAFs, and not total NK cell infiltrate is correlated with overall survival in PDAC. Consequently, we suggest that the spatial biology of NK/CAFs may play a prognostic role in PDAC and may potentially be used as a tool for patient stratification Taken together, our results demonstrate a significant bidirectional relationship between NK cells and PSC/CAFs in the context of PDAC, providing novel insight into this crucial cell-cell interaction
Simultaneous Multiparametric and Multidimensional Cardiovascular Magnetic Resonance Imaging
No abstract available
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)
Assessing the immunomodulatory and haemostatic role of platelets in the type 2 inflammatory response to Schistosoma mansoni
Beyond their role in haemostasis, platelets have been shown to be strongly immunomodulatory, particularly in type 1 inflammatory responses to bacteria and viruses. However, the role of platelets in type 2 inflammation, that characterises helminth infection and allergy is poorly understood. More than 200 million people globally are chronically infected with schistosome parasites which has a massive burden of >3 million disability adjusted life years. Despite large (~1cm long) worms residing in the vasculature for 5-10 years, they do not induce severe inflammation or coagulation. However, infected individuals display a plethora of debilitating symptoms including hepatosplenomegaly and intestinal haemorrhaging due to thousands of schistosome eggs transiting through and lodging within host tissues. This thesis aims to assess the haemostatic alterations and functional consequences of platelet-immune cell cross-talk in schistosomiasis.
We used a murine model of chronic Schistosoma mansoni infection to examine specific platelet-leukocyte interactions and the effect these have on inflammation. Chronic schistosome infection induces thrombocytopenia (~500x10^3/mm^3) that persists after drug-mediated worm clearance. In vivo platelet tracking revealed accelerated hepatic and splenic platelet clearance in schistosome infection, and this occurred in an FcγR-independent manner. Furthermore, there was a significant increase in platelets aggregating with specific hepatic macrophage subsets (Ly6Cˡᵒ MHCIIˡᵒ RELMαʰⁱ). Live cell imaging in vitro experiments revealed that platelets enhanced the phagocytic ability of M2 macrophages without altering MHCII or RELMα expression. Surprisingly, platelets from schistosome-infected mice spontaneously aggregated in the absence of exogenous agonists despite not having an activated platelet phenotype, yet show prolonged clotting time. We used multiple experimental strategies to deplete or increase platelet numbers in schistosome infection, and this highlighted the challenges of separating the haemostatic and immunological roles of platelets in vivo. Work in this thesis demonstrates how schistosome infection disrupts platelet lifespan and functionality, whilst promoting enhanced interactions with immune cells
30th European Congress on Obesity (ECO 2023)
This is the abstract book of 30th European Congress on Obesity (ECO 2023
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