Three-dimensional organization of fenestrae labyrinths in liver sinusoidal endothelial cells

- Background/Aims Liver sinusoidal endothelial cell (LSEC) fenestrae are membrane-bound pores that are grouped in sieve plates and act as a bidirectional guardian in regulating transendothelial liver transport. The high permeability of the endothelial lining is explained by the presence of fenestrae and by various membrane-bound transport vesicles. The question as to whether fenestrae relate to other transport compartments remains unclear and has been debated since their discovery almost 40 years ago. - Methods In this study, novel insights concerning the three-dimensional (3D) organization of the fenestrated cytoplasm were built on transmission electron tomographical observations on isolated and cultured whole-mount LSECs. Classical transmission electron microscopy and atomic force microscopy imaging was performed to accumulate cross-correlative structural evidence. - Results and Conclusions The data presented here indicate that different arrangements of fenestrae have to be considered: i.e. open fenestrae that lack any structural obstruction mainly located in the thin peripheral cytoplasm and complexes of multifolded fenestrae organized as labyrinth-like structures that are found in the proximity of the perinuclear area. Fenestrae in labyrinths constitute about one-third of the total LSEC porosity. The 3D reconstructions also revealed that coated pits and small membrane-bound vesicles are exclusively interspersed in the non-fenestrated cytoplasmic arms.

The application of islanded photovoltaic cells and battery storage on the reliability of distribution networks

Renewable energy resources, in particularly PV and battery storage are increasingly becoming part of residential and agriculture premises to manage their electricity consumption. This thesis addresses the tremendous technical, financial and planning challenges for utilities created by these increases, by offering techniques to examine the significance of various renewable resources in electricity network planning. The outcome of this research should assist utilities and customers for adequate planning that can be financially effective.

Investigation of the interaction between non-small cell lung cancer cells and immortalised normal bronchial epithelial cells

Non-small cell lung cancer consists of a diverse range of molecular and pathological features. This may be due in part to the critical interaction between normal and lung cancer cells. Consequently resulting in ‘normal’ cells acting in a malignant fashion. This project aims to identify pathways responsible for this altered ‘normal’ behaviour.

The overexpression of SASH1 stimulates cell death in lung cancer cells

SASH1 (SAM and SH3 domain-containing protein 1) is a recently identified gene with tumour suppressor properties with a role in the induction of apoptosis. Previous work has shown that 90% of lung cell lines have a decrease in SASH1 mRNA levels, however little characterisation of SASH1 function in lung cancer has been undertaken.

Lung cancer stem cells: The root of resistance

In the absence of specific treatable mutations, platinum-based chemotherapy remains the gold standard of treatment for lung cancer patients. However, 5-year survival rates remain poor due to the development of resistance and eventual relapse. Resistance to conventional cytotoxic therapies presents a significant clinical challenge in the treatment of this disease. The cancer stem cell (CSC) hypothesis suggests that tumors are arranged in a hierarchical structure, with the presence of a small subset of stem-like cells that are responsible for tumor initiation and growth. This CSC population has a number of key properties such as the ability to asymmetrically divide, differentiate and self-renew, in addition to having increased intrinsic resistance to therapy. While cytotoxic chemotherapy kills the bulk of tumor cells, CSCs are spared and have the ability to recapitulate the heterogenic tumor mass. The identification of lung CSCs and their role in tumor biology and treatment resistance may lead to innovative targeted therapies that may ultimately improve clinical outcomes in lung cancer patients. This review will focus on lung CSC markers, their role in resistance and their relevance as targets for future therapies.

Stimulating immune responses to fight cancer: Basic biology and mechanisms

Chronic inflammation is now recognized as a major cause of malignant disease. In concert with various mechanisms (including DNA instability), hypoxia and activation of inflammatory bioactive lipid pathways and pro-inflammatory cytokines open the doorway to malignant transformation and proliferation, angiogenesis, and metastasis in many cancers. A balance between stimulatory and inhibitory signals regulates the immune response to cancer. These include inhibitory checkpoints that modulate the extent and duration of the immune response and may be activated by tumor cells. This contributes to immune resistance, especially against tumor antigen-specific T-cells. Targeting these checkpoints is an evolving approach to cancer immunotherapy, designed to foster an immune response. The current focus of these trials is on the programmed cell death protein 1 (PD-1) receptor and its ligands (PD-L1, PD-L2) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Researchers have developed anti-PD-1 and anti-PDL-1 antibodies that interfere with the ligands and receptor and allow the tumor cell to be recognized and attacked by tumor-infiltrating T-cells. These are currently being studied in lung cancer. Likewise, CTLA-4 inhibitors, which have had success treating advanced melanoma, are being studied in lung cancer with encouraging results.