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PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster Jennifer Caffarel 1/3 of men will have bothersome urinary symptoms at some point in their life … then you might have “Bladder Outlet Obstruction” The prostate gland surrounds the urethra With increasing age, it increases in size and can obstruct the urethra… … and can cause a slow or “weak” urine flow. Urine flow can be quantified by a technique called “uroflowmetry”. Uroflowmetry is performed in clinics, using expensive electronic flowmeters £4 0 0 0 Attending a flow clinic can be a long and tedious experience… … and having to fill and empty your bladder several times in a short period of time is rather unnatural! The data obtained from flow clinics is variable, due to a number of factors: • Time of day • Volume of urine in the bladder • Emotional state of patient The aim is to improve the diagnosis made using uroflowmetry. Electronic Flowmeter 0 £ 0 40 vs. £5 Basic Flowmeter For example, we tested a very basic flowmeter, to obtain more representative results. This is how the basic flowmeter is used: • The patient takes the device home • Makes multiple measurements over several days, in his own time • This home flowmeter provided more representative results than inclinic flows. • And 2 patients who could not urinate in the clinic were able to use this device. PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster ? ? ? ? ? ? ? ? Questions (and some answers) on ? research into stomach cancer… ? ? ? Claire Worrall ? ? ? ? ? ? Who gets stomach cancer? It is difficult to predict. It depends on: If you have H. pylori infection What you eat If you have stomach ulcers How much alcohol you drink If you smoke Your Body Mass Index What country you live in Your genetic background Your gender So biological markers of early disease would be very useful. What changes occur in stomach cancer? 100 % 100.00% Expression levels of many proteins are altered… 90.00% 80.00% % of cases expressing TFIZ1 70.00% 60.00% 20.00% 10.00% 0% 0.00% Normal stomach Stomach cancer 0.005 % MKN74 KATO III SNU1 SNU5 SNU 16 NUGC3 SNU 5 AGS SNU 1 0% KATO III % of normal TFIZ1 expression MKN74 It is virtually undetectable by RT-PCR in our panel of 7 gastric cancer cell lines. 30.00% NUGC3 TFIZ1 is expressed in mucinsecreting cells and secreted into the mucous layer in the stomach. 40.00% AGS We are studying one protein whose expression is lost in the majority of stomach cancers: 50.00% SNU16 Where can we study stomach cancer? There is limited supply of patient samples. However, we can grow stomach cancer cells in the lab to perform tests on. These cells grow and divide, allowing us to measure the effects of different conditions on: How fast they grow and divide How easily they die How quickly they move These behaviours in patient cancer cells help determine tumour growth and the ability to metastasize. When do we study a protein in stomach cancer? When we have evidence linking it to stomach cancer… TFIZ1 is bound in the stomach to TFF1, which has many links to cancer: High expression in oestrogen responsive breast cancer TFF1 TFIZ1 Involved in ulcer repair 30% null mice get stomach cancer Binds to H. pylori TFF1 TFF1 How are we studying this protein? By introducing controllable TFIZ1 expression into stomach cancer cells: 1. Transfect in regulator plasmid neoR tTA TFIZ1 Off TFIZ1 On pTet-Off The cells now express TFIZ1 TRE 2. Transfect in TFIZ1 plasmid TFIZ1 pTRE-Tight TFIZ1 neoR tTA TRE TFIZ1 Stomach cancer Cell line Adding doxycycline turns off TFIZ1 expression Why do we study a protein in gastric cancer? If we know WHY the expression changes WHAT the protein does In the normal stomach In stomach cancer WHEN the expression changes It can Help us decide whether it might be a good early indicator of cancer. Help us decide whether it might be a good therapeutic target. Acknowledgements: Felicity May Herbie Newell Northern Institute for Cancer Research Claire Worrall [email protected] PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster INTRODUCTION: [email protected] ‘MRI scan of the breast reveals two discrete areas of abnormality, which proved to be cancer.’ Chemotherapy and radiotherapyinduced second cancers are the leading cause of death in patients cured of Hodgkin Lymphoma (cancer of the lymphatic system). Young women treated for Hodgkin Lymphoma with radiotherapy at the chest are at a high risk of developing breast cancer AIM: To develop an in vitro model system of radiogenic breat cancer, so that the molecular genetic events associated with transformation and the development of a radio-resistant phenotype can be investigated. PROCEDURE: 1. This project will involve exposing transformed (MCF-7) and non-transformed (MCF-10) breast cell lines to increasing doses of ionising radiation. 2. Post treated cell lines will be compared to untreated parental cells across the whole genome to identify regions characterised by loss of heterozygosity, copy number alterations and uniparental disomy. 3. Candidate locations of interest will be further investigated in treated cell lines and in breast tissue from patients with breast cancer following radiotherapy for Hodgkin Lymphoma. http://www.breastcancer.org/pictures/diagnosi s/mammogram/mri_2.jsp FUNDED BY: Northern Institute for Cancer Research PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster Forkhead Proteins & Cancer Frances Purtill iCAMB Forkhead Proteins & Cancer Unregulated cell proliferation is a characteristic of all cancers Understanding the mechanisms behind cell proliferation will help in the treatment and prevention of cancer Forkhead Proteins & Cancer Cell proliferation is controlled by a series of events known as the Cell Cycle The cell cycle consists of 4 phases: 3&4 G1 and G2 are ‘gap’ phases which prepare the cell for its next step 2 M Phase (Mitosis) Replicated DNA is equally distributed into 2 cells 1 S Phase DNA is replicated M G2 G1 S Genetic material is copied and 2 identical cells are formed Forkhead Proteins & Cancer Forkhead Transcription Factors (FKH-TF) are critical for the regulation of the cell cycle Forkhead proteins They bind upstream of genes have involvedbeen in mitosis, and activate their expression associated with various human FKH-TF cancers GENE SWITCHED ON TARGET GENE TARGET PROTEIN MADE Forkhead Proteins & Cancer Forkhead proteins for mitosis in all Therefore it isarea vital valuable model eukaryotes, from yeast to man to study forkhead proteins, and Yeast is easy toour manipulate, genetically and improve knowledge of the biochemically cell cycle in humans In the future, this knowledge could potentially be used to improve existing cancer therapies PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster The Development of Small Molecule Inhibitors of the MDM2-p53 Interaction Junfeng Liu p53 is a Tumour Suppressor % mice with tumour p53-/- 74% at 6 months p53+/- 2% at 9 months p53+/+ 1% at 18 months Donehower et al. Nature, 1992 Also suggest to read Donehower et al. Nature genetics, 1993 MDM2 controls p53 through an autoregulatory negative-feedback loop p53 p53 MDM2 p53’s proteasomal degradation MDM2 mdm2 mRNA mRNA of other targets Three mechanism to repress p53 by activation of MDM2-expression: 1. MDM2 binds p53 at transactivation domain and blocks its ability to activate transcription 2. MDM2 acts as an E3 ubiquitin ligase that promotes p53’s proteasomal degradation 3. MDM2 is involved in the nuclear export of p53 Breaking the negative-feedback loop with antagonists p53 p53 MDM2 p53’s proteasomal degradation MDM2 mdm2 mRNA mRNA of other targets Therapeutic potential Rescue of p53 Function by Disrupting the p53–MDM2 Interaction. Blocking MDM2 Expression Inhibiting MDM2 Ubiquitin Ligase Activity Disruption of the p53–MDM2 binding Possible Methods Disruption of the p53–MDM2 Binding Interaction Antibody microinjection Peptide analogues corresponding to the MDM2 binding domain of p53 Small molecular weight compounds The p53-MDM2 interaction: Unique binding site Unique & Good for Small Molecule Drug Design and Development Structure based drug design MDM2 Binding Domain (Binding area high lighted) PyMOL Software were applied for the followed cartoons. MDM2 protein and p53 peptide structures come from Protein Data Bank. Structure based drug design 8mer p53 peptide Binding with MDM2 Structure based drug design Three key residues of p53 in the hydrophobic pocket of MDM2 Structure based drug design Three key residues of p53 were picked out for drug design Structure based drug design Drug design based on the three key residues of p53 Structure based drug design Designed small molecule scaffold Structure based drug design Manual docking of the compound with MDM2 binding domain Inhibitor Screen Using ELISA Biotinylated IP3 Peptide M M M Addition of: Y Y Y M M M M Incubation of MDM2 with antagonist Incubation with MDM2 Y M M MDM2 primary antibody, HRP conjugated secondary antibody M ECL detection ECL detection LIGHT M YY M M M Streptavidin DECREASED LIGHT Cellular activity Confirmation via Western Blotting Assay Effect of MDM2 inhibitors on the cellular levels of p53, MDM2 and p21 Nutlin-3 DMSO 0.5 1 10 NU8XXX 1 10 20 mM MDM2 p53 p21 Actin Thank you for your attention! PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster …and tools to diagnose Lower Urinary Tract Dysfunction 1 in 3 men will suffer urinary symptoms in their life: struggling to begin pain while peeing peeing inability to pass any having to rush to water the toilet Incontinence having to go often Poor stream having to go in the ‘Terminal dribble’ middle of the night Incomplete emptying To diagnose the cause we need to measure: •Bladder pressure •Urine flow rate •Volume of urine voided … among other tests Well, how do you take a blood pressure measurement? How do you take a bladder pressure measurement? Use the same principle… Place Pressure a small,isinflatable measuredcuff around the penis… Pressure Flow rate Volume …and measure the pressure to Flow is interrupted stop urine flow! Penile Cuff Machine Conventionally, pressureWe can can also now use use We itthis to flow measurements non-invasive machine measure the bladder would require urethral clinically to diagnose characteristics in catheterisation, an Bladder people Outlet to healthy uncomfortable Obstruction inprocedure patients. further understand the with risk of infection. mechanics of the lower urinary tract. With this tool we hope to: • Verify theoretical bladder models • Understand better how the bladder copes with obstruction • Apply this to diagnosis and treatment of patients PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster Heart Physiology: “The role of p50” Silvia Gaspar Pereira PhD student with the Cell Signaling Group Institute of Cellular Medicine Light from the Heart Nebula - apod.nasa.gov Heart Physiology: “The role of p50” What does p50 do? When the cell receives a signal, the protein p50 is released from the cytoplasm into the nucleus. p5 0 p5 0 In the nucleus, p50 binds DNA and thereby induces a cellular response to the signal. In the absence of p50, this signaling pathway is impaired. Aim: Is p50-dependent signaling important in heart muscle cells? Heart Physiology: “The role of p50” To answer this question, we use mice lacking p50: In mice without p50, hearts are significantly bigger than in normal mice. p5 0 p5 0 The p50-deficient hearts are more sensitive to certain injuries, e.g. lack of oxygenation in the tissue. Future Work: Does p50 help to prevent injury in the heart tissue? Is p50 necessary during heart formation pre- or postnatally? If p50 is directly involved in these events, it could become a potential target for heart disease treatments! PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster Regulation of the oxidative stress response in the pathogenic fungi Candida albicans Miranda Patterson Supervisor – Dr Janet Quinn http://www.chuv.ch/imul/euresfun Candida albicans But, in immunocompromised people, such as Candida albicans is the major systemic people with HIV/AIDS, some cancer patients pathogenic fungi of humans or transplant patients, C.albicans can cause In immunocompetent people C.albicans is the life threatening infections, a cause of common systemic superficial infectionswith such≈ as rate oral38% andmortality vaginal thrush http://pathmicro.med.sc.edu/mycology/mycology-3.htm http://pathmicro.med.sc.edu/mycology/mycology-3.htm C.albicans invasion of blood vessels C.albicans invasion of a kidney from in the oesophagus an immunocompromised rabbit Why are we interested in C.albicans oxidative stress responses? Neutrophils But C.albicans are important can kill macrophages! in killing C.albicans Macrophages andbyneutrophils of the Neutrophils kill producing are toxiccells reactive Macrophage innate immune system responsible for killing oxygen species in a respiratory burst Full understanding of mechanisms used by micro-organisms C.albicans to overcome oxidative stresses C.albicans C.albicans lacking key proteins involved in C.albicans Macrophage may reveal novel therapeutic targets! hyphae oxidative stress responses are more sensitive to www.biology.uark.edu/dmcnabb/dmcnabb.html www.biology.uark.edu/dmcnabb/dmcnabb.html killing by neutrophils and have reduced C.albicans cells are virulenceAfter ingestion C.albicans ingested by the macrophage starts growing hyphae and escape the macrophage What are we doing? Oxidative Stress -ive Cap1 Nucleus Anti-oxidant genes Previous research shows that following oxidative Investigating the major stress, Cap1 translocates to oxidative stress pathway in We wantnucleus to know whatand is the C.albicans – the Cap1 regulating Cap1? upregulates transcription pathway of anti – oxidant genes so that cells can survive oxidative stress. How are we doing this? H2O2 concentration (mM) Control Wild type strain Deleting potential key regulators of Cap1 Cap1 delete strain Ybp1 delete strainseeing how cells survive an oxidative and stress challenge Wild type cells grow until high concentrations of H2O2 Have weC.albicans found regulator Cap1 atnothigh Cells lacking Cap1 areasensitive to H2of 02 and grow We grow in the presence ofcan hydrogen even concentrations peroxide (HHOat tooxidative induce oxidative stress levels of 0) low challenge? 2 22 2 Continuing will hopefully answer Cells lacking the research potential regulator of Cap1, Ybp1, are question! also sensitive to H2this 02 but only at high concentrations