Medicine

MRI Assessment of Lesion heterogeneity with textural analysis in patients with breast cancer

Tumour heterogeneity, as measured in various imaging modalities including MRI, has been reported to useful in prognostication and in the identification of patients who will achieve a complete response to neoadjuvant chemotherapy (NAC). Heterogeneity considers microscopic image ‘texture’, by mapping and modelling grey-level distributions of individual pixels within regions of interest; textural analysis (TA). It has been hypothesised that TA indirectly links to lesion pathology via tissue structure, which influences the contrast in the final MR image.

Developmental rodent models for the study of cognitive disorders.

The Langston lab aims to characterise the ontogeny of different types of learning and memory in laboratory rodents, with a particular emphasis on episodic memory which is a key diagnostic in many human cognitive disorders. In humans, learning occurs over an extended time period with different types of memory capability emerging at different stages of development. We have discovered that this is mirrored in rodents.

Early-life adversity and depression: nature versus nurture.

Adverse early life experiences, in the form of poor maternal care, are recognized to program an abnormal stress response, which increases the risk of psychiatric disorders e.g. depression in adulthood. Moreover, the impact of adverse early-life experiences has the potential to extend to future generations, suggesting a contribution by genetic and possibly, epigenetic factors. The mechanisms of stress dysfunction are complex, but may involve inhibitory GABAA receptors (GABAARs), as these receptors crucially curtail stress-induced activation of the HPA axis.

Cocaine Addiction and α2-GABAA Receptors

The laboratory is part of an MRC-funded multidisciplinary “addiction cluster”. Understanding the basic neurobiological mechanisms by which drugs of abuse become addictive is essential for the future development of strategies to combat drug addiction. Addictive drugs have in common that they influence the function of the pathways in the brain mediating reward, particularly the nucleus accumbens, a region which consists almost exclusively GABA-ergic neurones. Our collaborators studying cocaine addicts have implicated the α2-GABAA receptor isoform in cocaine abuse.

Mutations in the Garb1 gene promote ethanol consumption: Exploring a genetic and physiological basis for alcoholism.

Alcohol addiction is difficult to study in humans due to genetic and environmental complexities. Two mouse lines have been identified that exhibit a greatly increased voluntary consumption of ethanol and harbour single but distinct nucleotide mutations of the GABAA receptor (GABAAR) β1 subunit gene. Importantly, in the nucleus accumbens, a region associated with reward/addiction, we found GABAAR inhibition to be greatly enhanced in these mice as the mutant receptors now open spontaneously i.e. without the neurotransmitter GABA.

TGF-beta signalling in cancer stem cells and metastasis

TGF-beta can act as both a potent tumour promoter and tumour suppressor in a context dependent fashion. During cancer progression tumour cells can modify their response to TGF-beta from anti-proliferative to pro-tumourigenic whereby they can utilise TGF-beta to promote tumour cell proliferation, survival, motility, invasion, intravasation, extravasation, metastatic colonisation and promotion of cancer stem cell straits.

Control of apoptosis during mitosis and in response to anti-cancer drugs

Cancer chemotherapeutic drugs such as taxol (paclitaxel) and vinca alkaloids target dividing cells by interfering with the function of the mitotic spindle, thereby inhibiting cell proliferation and inducing cell death by the process of apoptosis. These drugs are often effective in treating cancers but their use is limited by toxic side effects and the development of resistance. In order to improve their use, we need to understand the mechanisms that determine how cancer cells react to these drugs.

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