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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.

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Presentation on theme: "PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster."— Presentation transcript:

1 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

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4 Jennifer Caffarel

5 1/3 of men will have bothersome urinary symptoms at some point in their life

6 … then you might have “Bladder Outlet Obstruction”

7 The prostate gland surrounds the urethra With increasing age, it increases in size and can obstruct the urethra…

8 Urine flow can be quantified by a technique called “uroflowmetry”. … and can cause a slow or “weak” urine flow.

9 Uroflowmetry is performed in clinics, using expensive electronic flowmeters Attending a flow clinic can be a long and tedious experience…

10 … and having to fill and empty your bladder several times in a short period of time is rather unnatural!

11 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

12 The aim is to improve the diagnosis made using uroflowmetry. For example, we tested a very basic flowmeter, to obtain more representative results. vs. Basic Flowmeter Electronic Flowmeter

13 This is how the basic flowmeter is used: The patient takes the device home Makes multiple measurements over several days, in his own time

14 This home flowmeter provided more representative results than in- clinic flows. And 2 patients who could not urinate in the clinic were able to use this device.

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16 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

17 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

18 Questions (and some answers) on research into stomach cancer… Claire Worrall ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?

19 Who 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 gets stomach cancer? So biological markers of early disease would be very useful.

20 What changes occur in stomach cancer? Expression levels of many proteins are altered… We are studying one protein whose expression is lost in the majority of stomach cancers: TFIZ1 is expressed in mucin- secreting cells and secreted into the mucous layer in the stomach. It is virtually undetectable by RT-PCR in our panel of 7 gastric cancer cell lines. Normal stomach Stomach cancer % of cases expressing TFIZ1 0 % 100 % % of normal TFIZ1 expression 0 % % AGS NUGC3 MKN74 KATO III SNU 1 SNU 5 SNU 16

21 Where can we study stomach cancer? These behaviours in patient cancer cells help determine tumour growth and the ability to metastasize. 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

22 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: TFIZ1 TFF1 High expression in oestrogen responsive breast cancer Binds to H. pylori TFF1 Involved in ulcer repair 30% null mice get stomach cancer TFF1

23 How are we studying this protein? By introducing controllable TFIZ1 expression into stomach cancer cells: pTet-Off neoRtTA neoR TRE TFIZ1 pTRE-Tight TFIZ1 TFIZ1 TRE TFIZ1 Off TFIZ1 On 1. Transfect in regulator plasmid 2. Transfect in TFIZ1 plasmid Stomach cancer Cell line Adding doxycycline turns off TFIZ1 expression The cells now express TFIZ1

24 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.

25 Acknowledgements:  Felicity May  Herbie Newell  Northern Institute for Cancer Research Claire Worrall

26 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

27 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. INTRODUCTION: Chemotherapy and radiotherapy- induced 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 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. FUNDED BY: Northern Institute for Cancer Research ‘MRI scan of the breast reveals two discrete areas of abnormality, which proved to be cancer.’ s/mammogram/mri_2.jsp

28 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

29 Forkhead Proteins & Cancer Frances Purtill iCAMB

30 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

31 Forkhead Proteins & Cancer M G2 G1 S M Phase (Mitosis) Replicated DNA is equally distributed into 2 cells Cell proliferation is controlled by a series of events known as the Cell Cycle 1 2 The cell cycle consists of 4 phases: G1 and G2 are ‘gap’ phases which prepare the cell for its next step 3 & 4 Genetic material is copied and 2 identical cells are formed S Phase DNA is replicated

32 Forkhead Proteins & Cancer Forkhead Transcription Factors (FKH-TF) are critical for the regulation of the cell cycle TARGET GENE GENE SWITCHED ON TARGET PROTEIN MADE FKH-TF Forkhead proteins have been associated with various human cancers They bind upstream of genes involved in mitosis, and activate their expression

33 Forkhead Proteins & Cancer Forkhead proteins are vital for mitosis in all eukaryotes, from yeast to man Yeast is easy to manipulate, genetically and biochemically Therefore it is a valuable model to study forkhead proteins, and improve our knowledge of the cell cycle in humans In the future, this knowledge could potentially be used to improve existing cancer therapies

34 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

35 The Development of Small Molecule Inhibitors of the MDM2-p53 Interaction Junfeng Liu

36 p53 is a Tumour Suppressor p53+/+ p53+/- p53-/- 1% at 18 months % mice with tumour 74% at 6 months 2% at 9 months Donehower et al. Nature, 1992 Also suggest to read Donehower et al. Nature genetics, 1993

37 MDM2 controls p53 through an auto- regulatory negative-feedback loop p53 MDM2 mdm2 mRNA mRNA of other targets p53 MDM2 p53’s proteasomal degradation 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

38 Breaking the negative-feedback loop with antagonists 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 p53 MDM2 mdm2 mRNA mRNA of other targets p53’s proteasomal degradation

39 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

40 The p53-MDM2 interaction: Unique binding site Unique & Good for Small Molecule Drug Design and Development

41 MDM2 protein and p53 peptide structures come from Protein Data Bank. PyMOL Software were applied for the followed cartoons. Structure based drug design MDM2 Binding Domain (Binding area high lighted)

42 Structure based drug design 8mer p53 peptide Binding with MDM2

43 Structure based drug design Three key residues of p53 in the hydrophobic pocket of MDM2

44 Structure based drug design Three key residues of p53 were picked out for drug design

45 Structure based drug design Drug design based on the three key residues of p53

46 Structure based drug design Designed small molecule scaffold

47 Structure based drug design Manual docking of the compound with MDM2 binding domain

48 Inhibitor Screen Using ELISA Incubation with MDM2 M M M M M Y YY YYY Biotinylated IP3Peptide Streptavidin MMM Y HRP conjugated secondary antibody Y Addition of: MDM2 primary antibody,

49 Cellular activity Confirmation via Western Blotting Assay Effect of MDM2 inhibitors on the cellular levels of p53, MDM2 and p21 Nutlin-3NU8XXX MDM2 p53 p21 Actin DMSO  M

50 Thank you for your attention!

51 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

52 …and tools to diagnose Lower Urinary Tract Dysfunction

53 having to go in the middle of the night inability to pass any water 1 in 3 men will suffer urinary symptoms in their life: struggling to begin peeing having to rush to the toilet having to go often pain while peeing Poor stream ‘Terminal dribble’ Incontinence Incomplete emptying

54 To diagnose the cause we need to measure: Bladder pressure Urine flow rate Volume of urine voided … among other tests

55 Well, how do you take a blood pressure measurement? How do you take a bladder pressure measurement? Use the same principle…

56 …and measure the pressure to stop urine flow! Place a small, inflatable cuff around the penis… Pressure Flow rate Volume Flow is interrupted Pressure is measured

57 We can also use it to measure the bladder characteristics in healthy people to further understand the mechanics of the lower urinary tract. Conventionally, pressure- flow measurements would require urethral catheterisation, an uncomfortable procedure with risk of infection. Penile Cuff Machine We can now use this non-invasive machine clinically to diagnose Bladder Outlet Obstruction in patients.

58 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

59 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

60 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

61 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. 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? p5 0

62 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. The p50-deficient hearts are more sensitive to certain injuries, e.g. lack of oxygenation in the tissue. p5 0 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!

63 PLASMA POSTER COMPETITION All Staff and Students are invited to use the ballot papers below to vote for your favourite plasma poster

64 Regulation of the oxidative stress response in the pathogenic fungi Candida albicans Miranda Patterson Supervisor – Dr Janet Quinn

65 Candida albicans Candida albicans is the major systemic pathogenic fungi of humans In immunocompetent people C.albicans is the cause of common superficial infections such as oral and vaginal thrush But, in immunocompromised people, such as people with HIV/AIDS, some cancer patients or transplant patients, C.albicans can cause life threatening systemic infections, with ≈ a 38% mortality rate C.albicans invasion of blood vessels in the oesophagus C.albicans invasion of a kidney from an immunocompromised rabbit

66 Why are we interested in C.albicans oxidative stress responses? Macrophages and neutrophils are cells of the innate immune system responsible for killing micro-organisms Macrophage C.albicans C.albicans cells are ingested by the macrophage After ingestion C.albicans starts growing hyphae and escape the macrophage Macrophage C.albicans hyphae Neutrophils are important in killing C.albicans Neutrophils kill by producing toxic reactive oxygen species in a respiratory burst C.albicans lacking key proteins involved in oxidative stress responses are more sensitive to killing by neutrophils and have reduced virulence Full understanding of mechanisms used by C.albicans to overcome oxidative stresses may reveal novel therapeutic targets! But C.albicans can kill macrophages!

67 What are we doing? Nucleus Cap1 Oxidative Stress Anti-oxidant genes Previous research shows that following oxidative stress, Cap1 translocates to the nucleus and upregulates transcription of anti – oxidant genes so that cells can survive oxidative stress. We want to know what is regulating Cap1? Investigating the major oxidative stress pathway in C.albicans – the Cap1 pathway -ive

68 How are we doing this? Deleting potential key regulators of Cap1 and seeing how cells survive an oxidative stress challenge Control H 2 O 2 concentration (mM) Wild type strain Cap1 delete strain Ybp1 delete strain Wild type cells grow until high concentrations of H 2 O 2 Cells lacking Cap1 are sensitive to H and can not grow even at low concentrations Cells lacking the potential regulator of Cap1, Ybp1, are also sensitive to H but only at high concentrations Have we found a regulator of Cap1 at high levels of H oxidative challenge? We grow C.albicans in the presence of hydrogen peroxide (H 2 O 2 ) to induce oxidative stress Continuing research will hopefully answer this question!


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