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Medicine Year 2 > People and Illness Week 2 > Flashcards

People and Illness Week 2 Flashcards

1
Q

What is PD-1/PDL-1?

A
  • Off-signal of immune system
  • Up-regulated in tumour infiltrating CD8 T cells to evade immune response
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2
Q

Describe transport of tumour cells in the bloodstream

A
  • Most tumour cells do not survive
    • Shear stress of blood flow
    • Immune detection
    • Anoikis - apoptosis, in cells which must be attached to the ECM, when they are unattached apoptosis is triggered
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3
Q

Describe the changes which occur in the thymus throughout life

A
  • Active in children, at the start of puberty throughout life into old age it atrophies, producing fewer T cells - connective tissue fibres and fat cells replace the previously functional tissue (parenchyma) of the organ = involution
  • Reaches greatest size in first two years after birth
  • Decrease in size means elderly people are more susceptible to disease and infection
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4
Q

List the types of cell therapies used in cancer treatment

A
  • Haematopoietic stem cells
  • Tumour-infiltrating T cells
  • Dendritic cell vaccines
  • NK cells
  • Gamma-delta T cells
  • Virus specific T cells
  • Genetically engineered T cells
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5
Q

What is produced by the thymus?

A
  • Immunocompetent T cells
  • Clones of mature T cells
  • Hormones needed for T cell development - thymosin, thymulin, thymopoietin
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6
Q

Describe the gross structure of the spleen

A
  • Between the stomach, left kidney and diaphragm - lies on the greater curvature of the stomach at the tail of the pancreas
    • Attached to the greater curvature by the gastrosplenic ligament, a broad band of mesentery
  • Largest mass of lymphoid tissue in the body
  • Splenic blood vessels and lymphatic vessels enter and leave at the hilum - only efferent lymphatic vessels
    • Supplied by splenic artery, drained by splenic vein which joins the hepatic portal system
  • Covered by fibrous capsule which extends into the parenchyma as trabeculae
  • Majority is red pulp, interspersed with small white pulp nodules
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7
Q

How does the thymus maintain self-tolerance of T cells?

A

Medulla has antigen-presenting cells, present antigens to the matured T cells, any T cells that recognise the self-antigens are removed, preventing the development of an autoimmune disease

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8
Q

What are the common outcomes of a potential depression diagnosis?

A
  • Recurrent depression disorder (60%)
  • Substance misuse (40%)
  • Anxiety (40%)
  • Suicide (attempted 9%), 8x mortality
  • Cardiovascular disease
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9
Q

List the side effects associated with tricyclic antidepressants

A

Anti-adrenergic (lowers BP), anticholinergic, ECG changes (arrhythmia, QTc prolongation)

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10
Q

List the classes of anti-depressants

A
  • Selective serotonin re-uptake inhibitors and similar
  • Tricyclics
  • Monoamine oxidase inhibitors
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11
Q

Describe the barriers to targeted therapies

A
  • Difficult to replace defective/missing components of pathway (e.g. tumour suppressor genes) - easier to suppress abnormal overactive pathways - few drugs which restore aberrant tumour suppressor genes
  • Most patients genes are not driven by a single, druggable oncogene
  • Drug resistance
    • Kinase mutations emerge which are no longer sensitive to imatinib
    • Cancers eventually begin growing again despite on-going treatment
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12
Q

Describe the mechanism of action of monoamine oxidase inhibitors

A

Block MAO-A and B - breaks down serotonin, noradrenaline, dopamine in the CNS

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13
Q

Describe immunoediting of cancer cells

A
  • Cancer identified as abnormal by immune system, leading to cell death, therefore mutated trait not passed on
  • Cells with gene mutations which elude immune system not recognised as foreign, can evolve in more insidious directions
  • Ability to signal slowing of immune response or stopping immune cell reactions is important characteristic for cancer development, growth, metastases and eventual mortality
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14
Q

Define metastases

A

Multi-step process by which tumour cells move from a primary site to colonise a secondary site, discontinous with primary tumour

Local invasion = continuous with primary tumour

Highly challenging, only 0.02% of disseminated tumour cells able to successfully metastasize

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15
Q

List the biological clinical features of depression

A
  • Diurnal variation - worse in morning, better as day progresses
  • Insomnia
  • Low appetite
  • Reduced weight
  • Reduced libido
  • Constipation
  • Amenorrhoea
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16
Q

Which types of tumours commonly spread haematogenically?

A
  • Common mode of spread of sarcomas
  • Also some carcinomas e.g. kidney, colorectum, prostate
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17
Q

Give examples of new cancer therapies

A
  • Cytotoxic T lymphocytes
  • Virus-specific T cells - PTLD, EBV driven B cell lymphoma in transplant patients, first line CHOP or RTX (few treatment options on relapse)
  • EBV specific T cell therapy
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18
Q

Describe the types of donors used for haematopoietic stem cell transplant

A
  • 60% autologous
    • Own stem cells
    • Lymphomas, tumours, autoimmune diseases, regenerative medicine, cardiovascular diseases
  • 21% allogenic from a related donor
    • Leukaemia, haematopoietic disorders, genetic diseases
  • 19% allogenic from an unrelated donor
    • Leukaemia, haematopoietic disorders, genetic diseases
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19
Q

List the functions of the thymus

A
  • Production of immunocompetent T cells
  • Production of mature but naive T cells for peripheral tissues and circulation
  • Immunological self-tolerance
  • Regulation of T cell maturation, proliferation and secretion via secretion of hormones
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20
Q

List the types of monoamine oxidase inhibitor antidepressants

A
  • Irreversible
    • Isocarboxid
    • Phenelzine
    • Tranylycpromine
  • Reversible
    • Moclobermide
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21
Q

Give examples of precision medicine in targeted therapies for cancer

A
  • ALK inhibitors in lung cancer - anaplastic lymphoma kinase present in 2-7% of non-small cell lung cancer, therapy is crizotinib, causes 90% tumour shrinkage
  • Epidermal growth factor receptor mutations in non-small cell lung cancer - therapy is erlotinib
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22
Q

How can the immune system contribute to tumour cell growth?

A
  • Immunoediting produces resistant tumour cells
  • Promote tumour cel growth, invasion and metastasis through the elaboration of inflammatory mediation and cytokines
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23
Q

Describe the control of angiogenesis in tumour growth

A
  • Cancer more than 2mm away from capillary - cells in centre are hypoxic
  • Hypoxia detected and factors e.g. VEGF, FGF, PDGF released into surrounding tissues
  • Diffuse out and form gradient towards starving cell, when reaches capillary it traces back to starving cell and capillary grows to provide blood supply
  • Production of factors e.g. VEGF controlled by hypoxia inducible factors - bind to DNA, transcriptional factors
  • VEGF binds to tyrosine kinase to trigger signal cascade for new blood supply
  • In cancer the off-switch for hypoxic signal off - hypoxia signal permanently on
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24
Q

Explain the structure of adherens junctions

A
  • E-cadherin is important in maintaining adherens junctions
  • Homotypic - E-cadherin on one cell binds to E-cadherin on opposite cell
  • Calcium dependent - loss/disruption of calcium causes disruption of cell binding
  • Alpha and beta catenin bind E-cadherin to actin cytoskeleton
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25
Q

How can angiogenesis be targeted in cancer therapy?

A
  • Angiogenesis inhibitors - target tyrosine kinase to turn off hypoxia signal
  • E.g. Sunitunib (Sutent), Pazopanib (Votrient), Axitinib (Inlyta)
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26
Q

Describe lymphatic spread of tumours

A
  • Common mode of spread of carcinomas, e.g. breast, colon and lung
  • Travel to draining lymph nodes, e.g. breast cancer to axillary lymph nodes
  • Thereby to thoracic duct and systemic blood circulation
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27
Q

Describe the differential diagnoses of depression

A
  • Dysthymia
    • Low mood, chronic >2 years but not enough depression
    • Cyclothymia - alternating low mood and high mood, both mild
  • Atypical depression
    • Low mood, reversed associated symptoms
    • Seasonal affective disorder (SAD) - winter
  • Adjustment reaction
    • Adaptation to stressor
    • Can include low mood
    • Onset <1 month from stress
    • Duration >6 months maximum
    • Grief
      • Bereavement - any loss event, usually death
      • Grief - feelings, thoughts, behaviour associated with bereavement
      • Abnormal grief - intense, prolonged (>6 months), delayed (>2 weeks), absent (inhibited)
      • Kubler-Ross model - denial, anger, bargaining, depression, acceptance
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28
Q

In which cancers can BRAF be present?

A
  • Approximately 40-60% of melanomas
  • Non-Hodgkin lymphoma
  • Colorectal cancer
  • Malignant melanoma
  • Papillary thyroid carcinoma
  • Non-small cell lung carcinoma
  • Adenocarcinoma of lung
  • Brain tumours
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29
Q

Describe the methods of neovascularisation

A
  • Vasculogenesis - formation of new BV from progenitors, in embryogenesis
  • Angiogenesis - formation of new BV from existing vasculature, in embryogenesis, adult wound healing, reproductive cycle, cancer
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30
Q

What are CAR-T cells and how are they used as a cancer therapy?

A
  • Chimeric antigen receptor T cells
  • Genetic modification of patients T cell (autologous)
  • No graft vs host disease, but risk of off-tumour toxicity and cytokine release syndrome
  • Kymriah now licensed in US/UK for treating B cell lymphoma
  • Issues - cost/complexity/kill-switch/single target
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31
Q

How is the severity of depression categorised?

A
  • Mild - >2 core symptoms and >2 associations, function ok
  • Moderate - >2 core symptoms and >4 associations, function reduced
  • Severe - >2 core symptoms and >6 associations, function severely reduced +/- psychosis
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32
Q

How is depression treated?

A

Treat the biological, social and psychological aspects of the disease

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33
Q

What is the role of pericytes in the tumour microenvironment?

A

Faciliate intravasation and extravasation

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34
Q

How does immune surveillance effect tumour growth?

A
  • Immune system constantly monitors body for tumour cells, majority destroyed by immune system before they can give rise to clinically manifest tumours
  • Immune system provides pressure, along with genomic instability causes cancer cells evolution meaning that only the immunogenic survive (immunoediting), selection for escape, increasing genetic instability/tumour heterogenity
  • Anti-tumour response of the immune system changes the immunogenecity of tumours, resulting in the emergence of immune resistant variants
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35
Q

Describe the red pulp of the spleen

A
  • Vascular, has parenchyma and lots of vascular sinuses (sinusoids)
  • Lining endothelial cells are elongated-rod cells and are fenestrated, act as filter
  • Defective RBC detected then phagocytosed by macrophages in red pulp
  • Healthy RBC can squeeze through the walls of the sinuses and are transported out of the organ by the splenic vein
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36
Q

How does the angiogenic switch change in cancer?

A
  • Switch - usually angiogenic activators are only turned on when phsyiologically required, then inhibitors are turned on to stop unwanted angiogenesis
  • Tumour cells cause the switch to be constantly turned on - angiogenic inhibitors never expressed, BV never fully mature so are leaky
  • Switch from angiogenic inhibitors to angiogenic activators = cancer
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37
Q

What is the role of integrins in cancer?

A
  • Altered integrin expression is frequently detected in tumours - melanoma, breast, prostate, pancreatic, ovarian
  • Support oncogenic growth factor receptor (GFR) signalling
    • Cell migration and invasion
    • Extravasation from blood vessels
    • Colonisation of metastatic sites
    • Survival of circulating tumour cells
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38
Q

Describe the function of the innate immune system in cancer

A

1st line of defence - germ-line encoded pattern recognition receptors rapidly detect infected or stressed cells, trigger potent effector mechanisms to contain tumours

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39
Q

What are the core clinical features of depression?

A

Low mood, anhedonia, fatigue

Everyday >2 weeks

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40
Q

Describe the process of extravasation by tumour cells

A
  • Migration - from central blood flow to periphery (less turbulent blood flow)
  • Rolling - selectins
  • Slow rolling
  • Arrest - integrins
  • Adhesion strengthening, spreading - CAMs (cell adhesion molecules)
  • Intravascular crawling
  • Diapedesis - JAMs (junctional adhesion molecules)
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41
Q

How do targeted therapies work in the treatment of cancer?

A

Drugs which target a specific process in an aberrant molecular pathway - intracellularly or extracellularly (e.g. angiogenesis)

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42
Q

Describe the gross structure of the thymus

A
  • 2 lobes divided into many lobules
  • Outer more darkly staining region = cortex (highly cellular)
  • Inner lighter staining region = medulla (less cellular)
  • Outer connective tissue capsule and septa
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43
Q

How are tyrosine kinase inhibitors used in practice?

A
  • In cancer cells
    • Raf kinase mutations in melanoma
    • MAP kinase in melanoma
    • EGF receptor kinase mutations in lung cancer
    • ALK kinase mutations in lung cancer
    • Kit kinase mutations in GI stromal tumours
    • Ret kinase mutations in medullary thyroid cancers
    • JAK kinase mutations in myelodysplastic syndrome
    • Her2 in breast cancer
    • Bcr-Abl fusion in chronic myeloid leukaemia
  • In the stroma
    • VEGF receptors in renal cancer
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44
Q

Describe the properties of epithelial cells compared with mesenchymal cells

A
  • Epithelial
    • Cohesive interactions between cells, forming continuous cell layers
    • Three membrane domains - apical, lateral and basal
    • Presence of tight junctions between apical and lateral domains
    • Polarised distribution of cell components
    • Lack of mobility with respect to their local environment
  • Mesenchymal
    • Loose or no interactions between cells
    • No clear apical/basolateral membranes
    • No cell-cell junctions
    • No apicobasal polarised distribution of organelles/cytoskeleton
    • Motile cells that may have invasive properties
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45
Q

Describe angiogenesis in cancer

A
  • Low oxygen, tumour cells sense hypoxic state and release hypoxic inducible factor
  • HIF release triggers production of proteins for angiogenesis e.g. VEGF
  • VEGF interacts with receptor on endothelial cells to express genes needed for angiogenesis
    • Allows for migration (integrins), sprout formation (proliferation) and invasion (proteases)
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46
Q

Describe the mechanism of action of checkpoint inhibitors

A
  • Targets immune checkpoints - key regulators of the immune system that stimulate or inhibit actions, which tumours can use to protect themselves from attacks by the immune system
  • Can block inhibitory checkpoints, restoring immune function
  • Increase overall survival
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47
Q

Define depression

A

Pathological low mood, associated decrease in functioning

Biochemical disorder with genetic component

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48
Q

What is the difference between prognostic and predictive markers?

A
  • Prognostic markers
    • Inform about outcome regardless of treatment
    • May help choose which patients to treat, but not how to treat them
    • Examples include CTCs in breast cancer
  • Predictive markers
    • Predict which patients will benefit from specific treatment
    • Help choose which drug to use
    • The basis of precision medicine
    • Examples include EGFR mutations in lung cancer, Raf mutations in melanoma
  • Some markers are prognostic and predictive e.g. oestrogen receptors in breast cancer, ER positive have >90% survival and benefit from tamoxifen
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49
Q

How is hormonal treatment used in prostate cancer therapy?

A
  • Surgical castration - still first treatment for metastatic prostate cancer
  • GnRH agonists - overstimulates anterior pituitary until it stops producing FSH/LH e.g. Goserelin, Triptorelin, Leuprorelin
  • GnRH antagonists e.g. Degarelix
  • Oestrogens
  • Androgen receptor antagonists
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50
Q

What is the sentinel lymph node?

A
  • The hypothetical first lymph node or group of nodes draining a cancer
  • If a cancer is undiagnosed, the tumour and the sentinel lymph nodes are ideally removed, to prevent further metastases
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51
Q

How has treatment of chronic myeloid leukaemia changed?

A
  • Increased life expectancy since 2003 after introduction of imatinib (30% alive after 5 years in 2003, 75% now)
  • Imatinib mimics ATP, switches off overactive kinase
  • Well-tolerated - switches off abnormal protein so few side effects, most have abnormal protein so respond well
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52
Q

Describe maturation of T cells in the thymus

A
  • Immature lymphocytes differentiate in the cortex
  • T-cell progenitors proliferate in the outer cortex
    • Differentiating T cells accummulate in between epithelial reticular cells, pass into venules and efferent lymphatics along the border of the cortex and medulla
    • Or they pass into the medulla, where they are further selected by thymic dendritic cells and matured before passing out of the medullary venules and efferent lymphatics
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53
Q

List the modes of tumour spread

A
  • Intraepithelial
  • Lymphatic spread
  • Haematogenous spread
  • Transcoelomic spread (across the peritoneal cavity)
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54
Q

List angiogenic inhibitors

A
  • Thrombospondin
  • Angiostatin - plasminogen fragment
  • Endostatin - fragment of collagen XVIII
  • Tumstatin - fragment of collagen IV
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55
Q

What is provenge and how is it used as a cancer therapy?

A
  • Immunostimulant, dendritic cells for therapy
  • Patient-specific treatment for prostate cancer
    • Isolation of monocyte dendritic precursors
    • Generation of dendritic cells, loading with prostate cancer antigen
    • Reinfusion to generate anti-tumour response
  • Licensed in 2010, increases survival over 20+ months compared with control
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56
Q

Describe the use of anti-depressants

A
  • 1st line - SSRIs
  • 2nd line - tricyclics
  • 3rd - monoamine oxidase inhibitors
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57
Q

List the cognitive clinical features of depression

A
  • Low concentration
  • Slow/negative thinking
  • Guilt
  • Loss of self esteem
  • Hopeless
  • Suicidality
  • Cognitive distortions - minimising, magnifying, arbitrary inference, selective abstraction, personalisation, overgeneralisation, catastrophising
58
Q

Describe the mechanism of action of SSRIs

A
  • Block the re-uptake of serotonin, which increases the amount present in the synapse and magnifies its effects
  • 4-5 weeks to have an effect
59
Q

Describe the psychosis which can present associated with depression

A
  • Delusions - mood congruent (nihilistic)
    • Guilt, poverty, hypochondriasis, persecutory
    • Cotard’s syndrome - self/part of self is dead
  • Hallucinations - auditory 2nd person (you’re stupid, you should die)
60
Q

Describe the advantages of new targeted therapies

A
  • More selective for cancer cells, less selective for normal cells
  • Less side effects, higher doses, potentially more anti-cancer effects
61
Q

List the functions of the spleen

A
  1. Removal of abnormal blood cells and particulate matter via phagocytosis
  2. Storage of iron from recycled RBC
  3. Initiation of immune responses by B cells and T cells in response to antigens circulating in the blood
  4. Haematopoiesis in foetus and sometimes in adult
62
Q

How do psychological factors contribute to the aetiology of depression?

A
  • Personality traits - anxious, obsessive, paranoid
  • Personality disorders
  • Coping skills
  • Adverse life events
63
Q

List the properties needed by cancer cells in order to metastasise

A
  • Reduced cell-to-cell adhesion
  • Altered cell-substratum adhesion
  • Increased motility
  • Increased proteolytic ability
  • Angiogenic ability
  • Ability to intravasate and extravasate
  • Ability to proliferate (locally and ectopic sites)
64
Q

List the types of clinical cancer treatments

A

Surgery, chemo/radiotherapy, immunotherapy

65
Q

Which types of tumours commonly metastasise by transcoelomic spread?

A

Incidence higher in tumours which arise from the peritoneal cavity e.g. ovarian (up to 70% of patients at presentation) and colorectal (up to 28% of patients at presentation)

66
Q

When should driving be restricted/the DVLA be contacted in depression?

A
  • Severe
  • Attention/memory impairment
  • Severe agitation
  • Suicidality
67
Q

Which properties are needed by metastatic tumour cells for invasion?

A
  • Reduced cell-cell adhesion
  • Altered cell-substratum adhesion
  • Increased motility
  • Increased proteolytic ability
  • Ability to proliferate
68
Q

Describe the increase in proteolytic activity in tumour cells to allow metastases

A
  • Proteases expressed by both tumour and stroma
  • Facilitate invasion of ECM at primary and secondary sites
    • Digestion of endothelial BM
    • Angiogenesis
    • Activate proteases
  • Serine proteases
    • Urokinase plasminogen activator - cleaves plasminogen to plasmin
    • Plasmin activates MMPs and degrades ECM
  • Matrix metalloproteinases
    • MMP-2 degrates type IV collagen (in BM)
  • Cysteine proteases
    • Cathepsin K collagenolytic activity leads to matrix degradation
69
Q

List the functions of lymph nodes

A
  • Filter debris and microorganisms via phagocytosis by fixed macrophages
  • Facilitate the interaction between antigen-presenting cells and circulating lymphocytes to initiate an immune response
  • B lymphocytes - activation and proliferation, plasma cell formation and antibody production in response to antigens
  • T lympocyte - activation to become CD4 and CD8 cells
70
Q

List the cells which make up the tumour microenvironment

A
  • Cancer stem cells
  • Cancer cells
  • Immune inflammatory cells - macrophages, neutrophils, mast cells
  • Invasive cancer cells
  • Local bone marrow derived stromal cells and progenitor cells
  • Pericytes
  • Endothelial cells
  • Cancer associated fibroblasts
71
Q

Describe the high endothelial vessels of lymph nodes

A
  • Post-capillary venule lined by simple cuboidal epithelium - high endothelial venules
  • Lymphocytes recognise and adhere to these endothelial cells, and squeeze them into the deep cortical regions of the nodes
  • Lots of T-cells and dendritic cells, T cells entering here become activated in the cortex, between lymphoid follicles
72
Q

Describe the anatomical position of the thymus

A

Within the anterior mediastinum, posterior to the upper sternum

73
Q

List the problems with precision medicine in cancer treatment

A
  • There isn’t a targeted drug for most patients
  • Cancer isn’t a single mutation disease - how can we target complex biology
    • Some mutations are present throughout an individual tumour (clonal), some are only present in subsets of copies (subclonal)
    • Multiple tumours within one patient with different genotypes, different genotypes within one tumour
  • Need to perform biopsies to understand the current tumour - patients don’t like them, can’t always be done (risk of damage to important surrounding structures)
74
Q

Compare the humoral and cell-mediated immune responses

A
  • Humoral response (antibody-mediated) - B cells recognise circulating antigens, co-stimulated by interleukins/CD4 T cells, B cells and proliferate and produce plasma cells, which bear antibodies with identical antigen specificity as the activated B cells. B cells produce memory cells, which provide future immunity
  • Cell-mediated response - mostly T cells, responds to any cell that displays aberrant MHC markers, including cells invaded by pathogens, tumour cells or transplanted cells. Production of CD8 T cells
75
Q

Describe the mechanism of action of monoclonal antibodies in treating cancer

A

Administration of monoclonal antibodies which target either tumour-specific or over-expressed antigens

Apoptosis induction, complement mediated cytotoxicity, antibody dependent cellular cytotoxicity, conjugated to toxin/isotope

76
Q

How are the social features of depression managed?

A
  • OT activity scheduling
  • Social worker - housing, financial
  • Employment
77
Q

Define benign and malignant cancers

A
  • Benign - remain localised at site of origin
  • Malignant - invade and spread to different sites = cancer
78
Q

Which cells link the innate and adaptive immune system in cancer?

A
  • NK cells and alpha-gamma T cells connect the innate and adaptive, adaptive activated by dendritic cells
  • Dendritic cells capture dying tumour cells, process antigens for MHC class I/II presentation, migrate to lymph nodes and stimulate antigen specific T and B cells
79
Q

What do the hallmarks of cancer represent?

A

The requirements which must be met for cancer to survive and become malignant

80
Q

Compare primary and secondary lymphoid organs

A
  • Primary lymphoid organs - where lymphocytes are formed and mature, provide an environment for stem cells to divide and mature into B and T cells
    • Red bone marrow and thymus
  • Secondary lymphoid organs - arranged as a series of filters monitoring the contents of extracellular fluids i.e. lymph, tissue fluid and blood, where lymphocytes are activated
    • Lymph nodes, tonsils, spleen, Peyer’s patches, mucosa-associated lymphoid tissue (MALT)
81
Q

Give examples of targetting the endocrine axis to treat cancer

A
  • Castration in prostate cancer - surgical/hormonal
  • Reduced androgen (testosterone) production = remission of metastatic prostate cancer
  • Castration (oophorectomy) in breast cancer - smaller reduction in mortality
82
Q

What is chronic myeloid leukaemia?

A
  • Cancer of bone marrow (myeloid cells)
  • Average age at diagnosis 65
  • 0.8% of new cancers
  • Caused by translocation of chromosome 22 onto chromosome 9, produces BCR Abl fusion protein (kinase - causes phosphorylisation)
    • Abl is a tyrosine kinase - usually highly regulated
    • BCR abl translocation - spliced through regulatory part, becomes permanently switched on (doesn’t respond to upstream regulators), uncontrolled cell proliferation
83
Q

Which type of cancer can interleukin 2 immunotherapy be used to treat?

A

Can cause complete regression of liver/bone cancer

84
Q

How does prognosis compare in local tumours only compared with metastases on diagnosis?

A

Much better prognosis in only local tumours

85
Q

How is life-threatening depression determined and dealt with?

A
  • Suicidal, self-neglect (e.g. not eating and drinking)
  • Needs hospitalisation, likely need Mental Health Act (detention)
86
Q

What is responsibile for increased cell motility allowing metastases?

A
  • Hepatocyte growth factor and c-met
    • HGF is a mitogen (growth factor) and a motogen (motility factor)
    • Produced by the stromal cells in a tumour (tumour microenvironment)
    • Binds to c-met, a receptor tyrosine kinase on tumour epithelial cells
    • Activation of c-met leads to increased tyrosine phosphorylation of beta-catenin
    • In tumour epithelial cells - disrupted E-cadherin mediated cell-to-cell junctions
87
Q

What are the side effects associated with SSRIs?

A

Nausea, vomiting, weight gain, dizziness, discontinuation syndrome, anxiety, suicidality, mania, serotonin syndrome, cardiac effects (QTc)

88
Q

What is the normal role of integrins?

A
  • Cell-substratum junction
  • Bind to and respond (bidirectional signalling - from within cell and outside cell) to the ECM
  • Composed of two noncovalently associated transmembrane glycoprotein subunits alpha and beta
  • 24 possible heterodimers -
    • Alpha 7 beta 1 - laminin in muscle
    • Alpha 6 beta 4 - laminin in epithelial hemidesmosomes
    • Alpha v beta 3 - vitronectin, widespread
  • Found in basal epithelial cells and focal adhesions of migrating cells
89
Q

How is the thymus blood supply specialised to its function?

A
  • Arteries enter through capsule, through capsule via connective septae, enter parenchyma
  • Capillaries not permeable to macromolecules, prevents antigenic contact with developing T cells
  • Postcapillary venules are permeable to macromolecules and lymphocytes, immunocompetent T cells move into venules and eventually join the general circulation
  • Some capillaries extend to medulla to supply the tissue, continue to join postcapillary venules
90
Q

How do epithelial cells become mesenchymal cells?

A

Epithelial to mesenchymal transition - process in which epithelial cells lose their characteristic polarity, disassemble cell-cell junctions and become more migratory

Due to growth factors e.g. TNF-beta, morphological change, organised sheet of epithelial cells becomes disorganised and lose cell-to-cell junctions, become spindle shaped

91
Q

Which factors contribute to a better prognosis in depression?

A
  • Male
  • Mild/short/first episode
  • No psychosis
  • Short hospital stay
  • Good social functioning
  • No co-morbid psychological diagnosis
92
Q

What is the role of tumour associated macrophages in the tumour microenvironment?

A
  • A major component of the TME - can compromise 50% of the tumour mass, abundance is associated with poor prognosis in most cancers
  • M1 macrophages - tumoricidal
  • M2 macrophages - promote tumour growth
  • Chronic inflammation leads to increased risk of cancer
  • Colony stimulating factor - tells macrophages to make EGF and proteinases, directs cancer cell towards BVs
93
Q

Describe the mechanism of action of tricyclic antidepressants

A

Block serotonin and nor-adrenaline re-uptake

94
Q

Compare intravasation and extravasation of tumour cells

A
  • Intravasation
    • Attachment
    • Degrade BM
    • Diapedesis
    • New blood vessels are weak and leaky - easy to enter
    • Assisted by tumour-associated macrophages - chemotactic signals
  • Extravasation
    • Attachment
    • Degrade BM
    • Diapedesis
    • Blood vessels structurally sound - harder to escape
    • Similar mechanism used by WBCs
95
Q

How is E-cadherin altered in tumour cells?

A
  • E-cadherin converted to N-cadherin, loss of cell-to-cell glue
  • Somatic mutations e.g. in calcium binding domain
  • Chromosomal deletions
  • Silencing of the CDH1 promoter by methylation
  • Mutations in proteins that interact with E-cadherin e.g. beta-catenin
  • Mutations in transcription factors (slug, snail and twist) that regulate E-cadherin expression
96
Q

How are the psychological features of depression managed?

A
  • Education - myth busting, ‘just snap out of it’
  • Core principles - talk, keep active, eat well, sleep well (no quick fixes)
  • CBT - interaction between thoughts, feelings, behaviour, physical and external environment
  • Psychotherapy
  • Family therapy
97
Q

How are developing T cells ‘protected’ from antigens while developing?

A
  • Need to keep developing T cells protected so that they can develop surface receptors in a climate not influenced by antigens - thymic epithelial cells form continuous layer on inner surface of capsule = blood-thymus barrier
  • Keeps T cells separate from bloodstream - maintained by desmosomes between adjacent epithelial cells and close contact with endothelial cells of capillaries
98
Q

Describe the role of the adaptive immune system in cancer

A

Evolves over the course of several days, activation/expansion of rare tumour-associated antigen specific lymphocytes harbouring somatically rearranged immunoglobulin or T cells receptors

99
Q

Describe the epidemiology of depression

A
  • Point prevalence - 4-7%
  • Lifetime incidence - 20%
  • Onset any age (mean is 30 y/o)
  • Females:males, 2:1
  • 4th commonest cause of disability
  • Mean episodes per lifetime = 5
  • 33% never seek treatment
100
Q

What are selectins?

A
  • Carbohydrate binding transmembrane molecules
    • P-selectins - platelets and endothelial cells
    • E-selectins - endothelial cells
    • L-selectins - leukocytes
  • Main physiological function is to mediate leukocyte recruitment to sites of inflammation or to lymphoid tissue
101
Q

What is the role of cancer-associated fibroblasts in the tumour microenvironment?

A

Secrete MMPs, cytokines, IL-8 and VEGF

102
Q

How are the biological aspects of depression treated?

A
  • Moderate - anti-depressants
  • Severe - + anti-psychotics, electroconvulsive therapy
103
Q

Give examples of drugs which target checkpoint inhibitors

A
  • CTLA-4 blockage (ipilumab)
  • PD-L1 blockage (nivolumab)
    • PD-L1 - immune checkpoint, protects cancer from immune attack
    • Significant improvements in cancer response
    • Concommitant side-effects - 45% skin/gut/kidney, autoimmunity
104
Q

How do biological factors contribute to the aetiology of depression?

A
  • Genetics (60% maternal to zygote transition, 40% 1st degree relative)
  • Medical co-morbidities - thyroid, heart failure, MS, cerebrovascular accident
  • Psychiatric co-morbidities - schizophrenia
  • Medication - steroids
  • Neurochemical - low serotonin, noradrenaline, dopamine
  • Neuroendocrine - low T3, TSH, high cortisol
105
Q

List the side effects associated with MAOIs

A
  • Hypertensive crisis - ‘cheese reaction’, interaction with tyramine in cheese
  • MOA-A also in GI tract, breaks down tyramine
  • If blocked, increase in BP
106
Q

Define mood and affect

A

Mood = subjective feeling of sustained emotion (happy, sad)

Affect = objective immediate conveyance of emotion (blunt, labile)

107
Q

How is a haematopoietic stem cell transplant carried out?

A
  • Mobilise donor/patient, store cells
  • Kill cancer
  • Re-infuse HSC into ‘clean’ system
  • Innate immune response recovers, adaptive immune response recovers
  • Cure?
108
Q

List the cytotoxic antitumour mechanisms

A
  • Perforin
  • TNF-related apoptosis-inducing ligand
  • Fas and Fas ligand - control of metastases
109
Q

Which drugs target BRAF positive cancers?

A

Vemurafenib

Dabrafenib

110
Q

How do social factors contribute to the aetiology of depression?

A
  • Poor social support
  • Socioeconomic disadvantage
  • Northernisation
111
Q

Describe the use of imatinib in the treatment of chronic myeloid leukaemia

A
  • Once daily oral medication
  • Generally well-tolerated
  • Most patients benefit
112
Q

Describe the gross structure of lymph nodes

A
  • Small bean-shaped organs, found along lymphatic vessels
  • Covered by a capsule of dense connective tissue, have capsular extensions of connective tissue - trabeculae, provide support for BVs entering the nodes
  • Lymph enters the lymph node via afferent lymphatic vessels which enter the subscapular sinus
  • Runs through the cortical sinus into medullary sinuses and leave through efferent lymphatic vessels at hilum as efferent lymph
  • All blood sinuses lined by discontinuous layer of simple squamous endothelium, contains lymphocytes and macrophages
  • Reticular fibres provide additional support to matrix/stroma
  • Cortex divided into outer and inner
113
Q

List the steps in the metastatic cascade

A
  1. Invasion
  2. Intravasation
  3. Transport
  4. Extravasation
  5. Colonisation
  6. Angiogenesis
114
Q

How is depression diagnosed?

A
  • Clincal history
  • Risk assessment
  • MSE - mental state exam
    • Psychiatric assessment
    • History and objective assessment
    • Covers appearance, behaviour, speech, eye contact, mood, thoughts, perceptions, cognition, insight
  • Physical examination
  • Baseline bloods
115
Q

List the ten major characteristics of cancer

A
  • Unlimiting multiplication
  • Escaping from growth suppressors
  • Promoting invasion and metastases
  • Resisting apoptosis
  • Stimulating angiogenesis
  • Maintaining proliferative signalling
  • Elimination of cell energy limitation
  • Evading immune destruction
  • Genome instability and mutation
  • Tumour enhanced inflammation
116
Q

List types of SSRIs/similar and give examples

A
  • SSRIs - citalopram, escitalopram, fluoxetine, paroxetine, sertraline
  • SNRI (serotonin and noradrenaline reuptake inhibitor) - venlafaxine, duloxetine
  • SARI (serotonin agonist and reuptake inhibitor) - trazodone
  • NASSA (noradrenaline and specific serotonin antagonist) - mirtazapine
  • NRI (noradrenaline reuptake inhibitor) - reboxetine, atomoxetine
  • DRI (dopamine reuptake inhibitor) - modafinil
  • NDRI (noradrenaline dopamine reuptake inhibitor) - bupropion
  • SPARI (serotonin partial agonist reuptake inhibitor) - vilazodone
  • Other - agomeltaine, St John’s wort
117
Q

List the types of tricyclic antidepressants

A
  • Tertiary amines (1st generation)
    • Amitryptiline
    • Maprotiline
    • Doxepine
    • Tianeptine
    • Clomipramine
    • Imipramine
    • Lofepramine
    • Dosulepin
  • Secondary amines (2nd generation)
    • Nortryptiline
    • Protryptiline
    • Amoxapine
    • Desipramine
118
Q

What determines where tumours will metastasise to?

A
  • Seed and soil theory - secondary growth of cancer cells (the ‘seed’) is dependent on the microenvironment of the distant organ (the ‘soil’)
    • Breast carcinoma spreads to bone, lung, brain, colorectal/pancreatic carcinoma spreads to liver and lung
  • Mechanical theory - mechanical factors influence the initial fate of cancer cells after they have left a primary tumour
    • E.g. blood flow patterns - first capillary bed they encounter
119
Q

Describe the structure and function of the white pulp of the spleen

A
  • Lymphoid aggregations (mostly lymphocytes) and macrophages which are arranged around the arteries, lymphocytes are T (mostly CD4) and B cells
  • Central arteriole close to centre of each area of white pulp
  • T cells around central artery form sheath - periarterial lymphoid sheath (PALS)
  • At border of PALS is the follicle - mostly B cells (secondary follicle)
    • Around follicle = narrow mantle zone - packed lymphocytes, wider marginal zone - more diffuse lymphocytes
    • Marginal zone separates the follicle from the red pulp
120
Q

List angiogenic activators

A
  • VEGF
  • EGF
  • bFGF
  • HGF
121
Q

Compare production of lymphocytes by red bone marrow and the thymus gland

A
  • Bone marrow produces B and T cells
  • B cells mature in the bone marrow, T cells migrate to the thymus to mature
122
Q

What is the role of selectins in cancer?

A
  • Enhanced expression of selectins (sialyl-Lewisx antigen) by cancer cells is correlated with metastasis and poor prognosis for cancer patients
    • Facilitating tumour cell dissemination
    • Formation and maintenance of tumour microenvironment
123
Q

How is ECT used to treat depression?

A
  • Electrotherapy - uses electrical current
  • Controlled seizure and anaesthetic
  • Depression, mania, catatonia
  • NICE - ECT is more effective than drugs
  • Anaesthetic risks
  • Side effect - memory (rare)
124
Q

Describe the typical prognosis for a person with depression

A
  • Average episode - 6 months (with treatment), 3 months (no treatment)
  • After one episode:
    • 50% no future episodes
    • 50% recurrence <5 years
    • >2 = 70%, >3 = 85%
125
Q

Describe the difference between benign and malignant tumours

A
  • Growth pattern
    • Benign - expansion, remain localised
    • Malignant - infiltrate locally, spread to distant sites (metastases)
  • Growth rate
    • Benign - generally slow
    • Malignant - faster
  • Mitotic figures
    • Benign - few, normal
    • Malignant - Numerous, atypical
  • Nuclei
    • Benign - small, uniform, regular
    • Malignant - larger, pleomorphic (with increased DNA content)
  • Histology
    • Benign - resembles tissue of origin
    • Malignant - less differentiated
126
Q

Describe the lymphatic supply of the thymus

A

Only efferent lymphatics, not afferent, transports lymph and lymphocytes away

T cells leave thymus, go into circulation and eventually enter lymph nodes, MALT or the spleen

127
Q

How does metastases cause death?

A
  • Physical obstructions
  • Compromise organ function
  • Compete with healthy tissue for nutrients and oxygen
  • In many, by time of diagnosis metastases has already occurred, metastatic spread accounts for over 90% of mortality associated with solid cancers
128
Q

Describe the mechanism of action of Vemurafenib and its effectiveness

A
  • Drug which attacks the BRAF protein directly - Vemurafenib is a reversible, ATP-competitive inhibitor of the kinase domain of BRAF
  • Shrink tumours in about half of the people whose metastatic melanoma has a BRAF gene change
  • Can also prolong the time before tumours start growing again and help some patients live longer, although the melanoma typically starts growing again eventually
129
Q

What is BRAF?

A
  • Gene that codes for the protein B-Raf - protooncogene
  • B-Raf is a member of the Raf kinase family, which are a family of growth signal transduction protein kinases
  • Role in regulating the MAP kinase/ERKs signalling pathway, which effects cell division, differentiation and secretion
  • Leads to contitiutive activation of downstreaming signalling in the MAP kinase pathway
  • Can be inherited or appear later in life and cause cancer
130
Q

Which cells are involved with the innate immune system response to cancer?

A

Macrophages, granulocytes, mast cells, dendritic cells, NK cells

131
Q

List the mechanism used by tumour cells to escape immune elimination

A
  • Antigenic modulation e.g. HLA down-regulation
  • Antigen mashing
  • Production of soluble tumour antigens or other tumour products e.g. transforming growth factor beta (TGF-beta)
  • Induction of tolerance
  • Weakening of the defence system itself
132
Q

List the factors which contribute to the aetiology of depression

A

Biological, psychological, social

133
Q

How does Enzalutamide work?

A
  • An androgen receptor signalling inhibitor that directly targets three stages of the androgen receptor signalling pathway
    • Blocks AR binding
    • Impairs nuclear translocation
    • Blocks DNA binding and activation
  • Cancer due to alternative splicing of RNA to produce mRNA for androgen receptor
134
Q

What distinct histological features can be seen in the thymus?

A

Hassal’s corpuscles - degenerate epithelial cells, made of concentric layers of flattened reticular epithelial cells filled with keratohyalin granules and keratin, in the medulla

135
Q

What are the areas of clinical features of depression?

A
  • Core
  • Biological
  • Cognitive
  • Psychosis
136
Q

Describe the ways in which tumour cells can move

A
  • Mesenchymal migration
    • Spindle, send out actin processes (stress fibres), proteases on side of direction of travel
  • Ameboid
    • Lymphoma cells, send out processes in every direction until they find a favourable path
  • Cluster
    • Leading cells drag the rest along, proteases at front
137
Q

How are CAR-T cells produced?

A
  • Blood collection
  • T cell isolation and activation
  • T cell modification
  • T cell expansion and product formulation
  • Preconditioning and T cell infusion
138
Q

Describe the structure and function of the regions of lymph nodes

A
  • Cortex divided into inner (paracortex) and outer
    • Outer cortex - lymphatic nodules that mostly contain B cells, small lymphocytes in spaces between reticular fibre meshwork
    • Lighter staining areas are germinal centres - where B cells proliferate into antibody-secreting plasma cells, also macrophages, follicular dendritic cells and some T cells in these areas
    • Germinal centre surrounded by ring of darker staining cells = Mantle zone (corona)
    • Inner cortex mostly T cells
    • Deep cortical and medullary cords - B cells and plasma cells
  • Medulla - medullary cords interspersed between medullary sinuses
139
Q

How are monoclonal antibodies used clinically?

A
  • Over 400 monoclonal antibodies in development/clinical trials/therapeutic use - more than 60% for cancer
  • Also for conjugates, autoimmune diseases, infections, blood disorders, allergies, eye/brain diseases
140
Q

Which factors contribute to a poorer diagnosis in depression?

A
  • Female
  • Severe/long/multiple episodes
  • Psychosis
  • Longer hospital stay
  • Poor social function
  • Co-morbid psychological diagnosis
141
Q

Which cells are involved with the adaptive immune response to cancer?

A

B cells secreting antibodies, CD4+ and CD8+ T cells

Medicine Year 2 (41 decks)

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