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People and Illness > Week 2 > Flashcards

Week 2 Flashcards

1
Q

Define invasion

A

Growth by infiltration and destruction of surrounding tissues

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2
Q

Define metastasis

A

Spread of tumour to, and growth at, ectopic sites (via blood, lymphatics, intraepithelial, or transcoelomic routes)

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3
Q

Define carcinoma

A

Malignant tumour derived from epithelial cells (80% of human cancers)

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4
Q

Define sarcoma

A

Malignant tumour derived from mesenchymal cells

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5
Q

Define melanoma

A

Malignant tumour derived from neural crest cells

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6
Q

Define leukaemia

A

Malignant tumour derived from circulating white blood cells

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7
Q

Define lymphoma

A

Malignant tumour derived from the lymphatic system

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8
Q

What is a basement membrane?

A

Layer of extracellular matrix secreted by basal epithelial cells/endothelial cells which provides a barrier against spread/metastasis of cancer (especially carcinoma cells)

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9
Q

What molecules are found in the basement membrane?

A

Fibronectin, type IV collagen, laminin

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10
Q

Briefly outline the metastatic cascade

A

Local invasion → neovascularisation/angiogenesis → detachment → intravasation to blood/lymph → transport → lodgement/arrest → extravasation out of blood/lymph → growth at ectopic site

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11
Q

What are the properties of metastatic tumour cells?

A 
Reduced cell-cell adhesion 
Altered cell-substratum adhesion 
Increased motility 
Increased proteolytic ability 
Angiogenic ability 
Ability to intravasate and extravasate 
Ability to proliferate (locally and in ectopic sites)
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12
Q

What molecule is involved in cell-cell adhesion and what type of junction does it participate in?

A

E-cadherin

Adherens junction

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13
Q

Describe the main components of an adherens junction

A

2 molecules of E-cadherin from 2 cells joined together
Requires calcium in the ECM
Linker proteins α-catenin and β-catenin

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14
Q

Where is E-cadherin expressed and what is its function?

A

Surface of all epithelial cells

Inhibits invasion

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15
Q

Which of the adherens junction linker proteins is linked to the actin-myosin cytoskeleton?

A

α-catenin

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16
Q

What ion is required for and adherens junction to work?

A

Calcium

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17
Q

How are adherens junctions involved in cancer?

A

Cells undergo an epithelial-mesenchymal transition - loss of E-cadherin allows cancer development

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18
Q

What process affecting cell-cell adhesion occurs in some diffuse-type gastric cancers?

A

Exon-skipping - lack of exons which encode calcium-binding domain

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19
Q

What can happen to the E-cadherin promoter in some carcinomas?

A

Methylation

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20
Q

Give 2 examples of indirect mechanisms of E-cadherin disturbance

A

Mutations in interacting proteins (e.g. β-catenin)

Mutations in transcription factors which regulate is (e.g. snail)

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21
Q

What 3 transcription factors are involved in E-cadherin regulation?

A

Snail
Slug
Twist

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22
Q

What molecule is involved in cell-substratum adhesion and what type of junction is it involved in?

A

Integrins

Focal adhesion

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23
Q

What are integrins?

A

Heterodimers in basal epithelial cells/focal adhesions of migrating cells which bind ECM molecules

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24
Q

What is integrin α5β1?

A

Fibronectin receptor

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25
Q

What is integrin αvβ3?

A

Vitronectin receptor

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26
Q

How are integrins involved in cancer?

A

Decreased adhesion to basement membrane → increased migration through stroma

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27
Q

What is HGF and what is its function?

A

Hepatocyte growth factor

Can induce epithelial cells to dissociate and scatter in culture

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28
Q

What is HGF also known as?

A

Scatter factor

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29
Q

What 3 functions does HGF possess?

A

Mitogen (growth)
Motogen (motility)
Morphogen (development)

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30
Q

How is HGF involved in cancer?

A

Produced by the stromal cells in a tumour microenvironment → binds to and activates c-met (an RTK) on tumour epithelial cells → increased tyrosine phosphorylation of β-catenin in tumour epithelial cells → disruption of ECD-mediated adhesion

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31
Q

What is HGF/c-met an example of and what is this facilitated by?

A

Tumour-stroma interaction

Tumour microenvironment

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32
Q

What cells are found in a tumour microenvironment?

A

Cancer-associated fibroblasts (CAFs)
Infiltrated immune cells
Myofibroblasts
Tumour-associated vasculature pericytes

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33
Q

What do tumour-associated vasculature pericytes secrete?

A

Growth factors
Chemokines
Enzymes

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34
Q

Give examples of tumour-stromal interaction

A 
C-met and HGF
Chemokine receptor and chemokine
Protease receptor and protease
Integrin αvβ3 and MMP-2
TGF and stomelysin 
VEGF and VEGF receptor
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35
Q

What is urokinase plasminogen activator (uPA)?

A

Serine protease

Catalyses cleavage of plasminogen to plasmin which degrades fibrin clots

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36
Q

What are matrix metalloproteins (MMPs)?

A

Enzymes responsible for degradation of ECM proteins
E.g collagenases, gelatinases, stromelysins, membrane-type
Most can bind to integrins

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37
Q

How are MMPs used by breast carcinoma cells?

A

Cancer cells secrete TGF which is picked up by stromal cells → stromal cells induced to produce MMPs → MMPs used by the cancer cells to aid their movement

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38
Q

How is VEGF upregulated by tumour cells?

A

Tumour cells in a hypoxic area (e.g. middle of a large tumour) will stimulate expression of hypoxia-inducible factor which upregulates VEGF expression

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39
Q

How is VEGF used by tumour cells?

A

VEGF binds to receptors on epithelial cells and stimulates them to multiply and form tubes which grow towards the tumour → blood vessels are unstable and leak fibrinogen and protein out → pro-coagulants react with fibrinogen to form fibrin which arranges into a blood clot → clots are a good surface for epithelial cells to migrate to

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40
Q

What is Avastin and what is it used for?

A

Bevacizumab - monoclonal antibody which blocks angiogenesis by inhibiting VEGF-A
Used for cancer treatment (e.g. ovarian) but not very effective

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41
Q

What ability do tumour cells ‘copy’ from WBCs and how does this occur?

A

Ability to intravasate and extravasate

Rolling → activation → adhesion → diapedesis

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42
Q

What is tissue tropism?

A

Preferential growth of tumour cells in particular areas - site-specific metastasis

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43
Q

What are the principle metastasis sites of breast tumours?

A

Bone, lungs, liver, brain

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44
Q

What are the principle metastasis sites of lung tumours?

A

Bone, liver, brain, adrenal gland

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45
Q

What are the principle metastasis sites of skin tumours?

A

Lungs, liver, brain

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46
Q

What are the principle metastasis sites of prostate tumours?

A

Bones

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47
Q

What are the principle metastasis sites of colorectal and pancreatic tumours?

A

Liver, lungs

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48
Q

What are the 2 hypotheses for site-specific metastasis and what are they challenged by?

A

Seed and soil - right tumour microenvironment is needed for tumour cells to grow; lack of contralateral breast/kidney tumours
Mechanical - blood supply dependent; duodenal tumour does not cause liver metastasis

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49
Q

What molecules are important in selective adhesion of tumours to endothelium of target organs?

A

Selectins and CD44

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50
Q

What molecules allow breast cancer cells to establish osteolytic metastases?

A

Parathyroid hormone related peptide

Interleukin-11

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51
Q

How can be used as targets for established metastases?

A

Tumour microenvironment
Immunoediting
Immunotherapy
CTLA-4

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52
Q

What is immunoediting?

A

The evolution of tumours so that the tumour cells are no longer effectively recognised and killed by the immune system

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53
Q

What is CTLA-4 and what is its importance in cancer?

A

Inhibitor of T cell response

Inhibiting the inhibitor via drugs such as ipilimumab may be useful in cancer therapy

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54
Q

What is the MSE?

A

Mental state exam - standardised assessment of a person’s current state of mind

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55
Q

What can the MSE be used for?

A

Assessment
Diagnosis
Monitoring progress

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56
Q

What is the format of the MSE?

A 
Appearance and behaviour
Speech
Mood and affect
Thought form and content
Perception
Cognition
Insight
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57
Q

Give examples of what is included in the appearance section of the MSE

A 
Clothing
Build
Self-neglect
Intoxication 
Illness
Distinguishing features
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58
Q

Give examples of what is included in the behaviour section of the MSE

A

Motor activity
Eye contact
Body language and posture
Unusual/inappropriate behaviour

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59
Q

Give examples of what is included in the speech section of the MSE

A

Rate, rhythm, volume, tone

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60
Q

Give examples of what is included in the mood section of the MSE

A

Subjective

Objective

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61
Q

Define mood

A

A person’s overall emotional state

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62
Q

Define affect

A

Changes in a person’s emotion on a moment-to-moment basis

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63
Q

Give examples of what is included in the affect section of the MSE

A

Reactive (appropriate reaction)
Flattened (limited reaction)
Blunted (no reaction)
Labile (excessive fluctuations)

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64
Q

Give examples of what is included in the thought form section of the MSE

A

Pattern/flow of the patient’s thoughts
Includes specific quotes
Descriptive terms - flight of ideas (mania), loosening of association/knight’s move thinking (schizophrenia)

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65
Q

Give examples of what is included in the thought content section of the MSE

A

Topics discussed more than others
Delusions
Over-valued ideas
Obsessions

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66
Q

Define delusion

A

A fixed, false belief that is out of keeping with the person’s religious and cultural background (e.g. psychosis)

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67
Q

Define an over-valued idea

A

A false belief, not totally fixed but causing great disability (e.g. anorexia, hypochondriasis)

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68
Q

Define obsession

A

Recurrent, intrusive, distressing ideas, impulses or images that the patient recognises as their own (e.g. OCD)

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69
Q

What types of delusions are there?

A 
Persecutory
Grandiose 
Nihilistic
Delusions of reference 
Thought interference
70
Q

What is a persecutory delusion?

A

Perceived threat from others

71
Q

What is a grandiose delusion?

A

Considerable overestimate of abilities or possession of special powers

72
Q

What is a nilistic delusion?

A

Belief that they are dead or do not exist

73
Q

What is a delusion of reference?

A

Belief that external events/objects are directly related to them (e.g. TV programme)

74
Q

What is a thought interference delusion?

A

Insertion, withdrawal or broadcast

75
Q

Give examples of what is included in the perception section of the MSE

A

Difference between what the patient tells you and what you observe
Hallucination
Illusion

76
Q

Define hallucination

A

Perception without external stimulus

Can occur in any sensory modality - auditory, visual, olfactory, gustatory, tactile

77
Q

Define illusion

A

False perception of a real stimulus (e.g. seeing a person in a shadow)

78
Q

Give examples of what is included in the cognition section of the MSE

A

Alertness and orientation
Attention and concentration
Memory
MMSE can be used

79
Q

Give examples of what is included in the insight section of the MSE

A

The patient’s understanding of their presentation and need for treatment

80
Q

What must always be included/documented for an MSE?

A

Risk - harm to self or others (planning and intent)

81
Q

Define nascent

A

Just coming into existence and beginning to display signs of future potential - point at which cancer should ideally be detected

82
Q

What is the normal immune response to cancer?

A

Innate immune response recognises tumour cell establishment → NK cells and other effectors are recruited to site by chemokines (which also target tumour growth directly) → tumour-specific T cells and macrophages eliminate tumour cells

83
Q

What are the 3 E’s of immunoediting?

A

Elimination
Equilibrium
Escape

84
Q

What is the result of immunoediting?

A

Produces low antigenicity tumour cells by selection

85
Q

What are the main strategies by which disease can be targeted using the immune system?

A

Vaccination
Antibody therapies
Cell-based therapies
Non-specific therapies

86
Q

Give an example of a non-specific immune targeted therapy

A

Aldara/imiquimod - mixture of Streptococcus pyogenes and Serratia marcescens used to treat various superficial skin cancers

87
Q

Which interleukin has shown promise as a target for cancer immunotherapy?

A

IL-2

88
Q

Give an example of an interleukin-2 immunotherapy

A

Ontak/denileukin diftitox

IL-2 and diphtheria toxin combination which destroys cells expressing IL-2 receptors

89
Q

What monoclonal targets CD20 and what malignancy is this for?

A

Rituximab

B cell lymphoma/non-Hodgekin’s lymphoma

90
Q

What monoclonal targets CD52 and what malignancy is this for?

A

Alemtuzumab

B cell lymphoma, acute/chronic myeloid leukaemia

91
Q

What monoclonal targets Her-2/neu and what malignancy is this for?

A

Trastuzumab

Breast cancer, lymphoma

92
Q

What monoclonal targets EGFR and what malignancy is this for?

A

Cetuximab

Colorectal/lung/head and neck cancer

93
Q

What monoclonal targets VEGF and what malignancy is this for?

A

Bevacizumab

Breast/lung/liver/pancreas/prostate cancer

94
Q

What monoclonal targets PDGFR and what malignancy is this for?

A

Olaratumab

GI stromal/solid tumours

95
Q

How does ipilimumab work?

A

CTLA-4 blockade

96
Q

How does nivolumab work?

A

PD-L1 blockage

97
Q

Give examples of targets for cancer cell therapies

A 
Haematopoietic stem cells
Tumour-infiltrating T cells (TILs)
Dendritic cell vaccines
NK cells 
Gamma-delta T cells
Virus-specific T cells
Genetically engineered T cells
98
Q

What are bone marrow and stem cell transplants used for?

A

Treatment of blood disorders (e.g. BM failure, SCID) and leukaemia

99
Q

What is plerixafor and how does it work?

A

An immunostimulant which blocks CXCR4 (chemokine receptor) and is used to mobilise hematopoietic stem cells in cancer patients into the bloodstream
The stem cells are then extracted from the blood and transplanted back to the patient

100
Q

What are allogeneic and autologous stem cell transplants and which is used most?

A

Allogeneic - same species; related or unrelated donor (20% each)
Autologous - own (60%)

101
Q

What can allogeneic stem cell transplants be used to treat?

A

Leukaemia
Haematopoiesis disorders
Genetic diseases

102
Q

What can autologous stem cell transplants be used to treat?

A 
Lymphoma
Tumours
Autoimmune disease
Regenerative medicine
Cardiovascular disease
103
Q

What is provenge and how does it work?

A

Sipuleucel-T
Patient-specific treatment for prostate cancer
Dendritic cells are extracted → infused with PAP (antigen) and GM-CSF (maturation factor) → reinfusion

104
Q

What is PTLD and how can it be treated?

A

Post-transplant lymphoproliferative disorder - B-cell proliferation due to therapeutic immunosuppression after organ transplantation
T-cell bank - IFN-γ secreting cells transferred to patient from donor

105
Q

What is CAR-T?

A

Chimeric antigen receptor T cells

Cell therapy for cancer - genetic modification of patient’s T cells by addition of CAR

106
Q

Give and example of a CAR-T cell therapy and what are its limitations?

A

Kymriah (licenced in US for B cell lymphoma)

Cost, complexity, kill-switch, single target, off-tumour toxicity, cytokine release syndrome

107
Q

Define psychiatry

A

Medical specialty concerned with diagnosis, treatment and prevention of mental health disorders

108
Q

What is an organic disorder?

A

Change in mental function; secondary physical process rather than psychiatric illness

109
Q

What are the biological causes of depression?

A

Genetics
Medical co-morbidities (thyroid, HF, MS, CVA)
Psychiatric co-morbidities (schizophrenia)
Medications (steroids)
Neurochemical (decreased serotonin, noradrenaline, dopamine)
Neuroendocrine (decreased T3 and TSH, increased cortisol)

110
Q

What are the psychological causes of depression?

A

Personality traits/disorders (anxious, obsessive)
Coping skills
Adverse life events

111
Q

What are the social causes of depression?

A

Poor social support

Socioeconomic disadvantage

112
Q

Outline the epidemiology of depression

A

Mean age onset 30 years
Females most affected (2:1)
4th commonest cause of disability
1/3rd never seek treatment

113
Q

What is the monoamine hypothesis of depression?

A

Neurochemical decrease in serotonin, noradrenaline and dopamine are responsible for the pathogenesis of depression

114
Q

What are the core clinical features of depression?

A

Decreased mood +/- anhedonia +/- fatigue every day for >2 weeks

115
Q

What are the biological symptoms of depression?

A

Diurnal variation, insomnia, decreased appetite/weight/libido, constipation, amenorrhoea

116
Q

What are the cognitive symptoms of depression?

A

Decreased concentration, slow/negative thinking, guilt, loss of self-esteem, hopeless, suicidality

117
Q

What cognitive distortions are associated with depression?

A

Minimising, magnifying, arbitrary inference, selective abstraction, personalisation, overgeneralisation, catastrophising

118
Q

What features of psychosis are associated with depression?

A

Delusions - (mood congruent (‘nihilistic’), guilt, poverty, hypochondriasis, persecutory, Cotard’s syndrome that self/part of self is dead)
Hallucinations - (auditory 2nd person)

119
Q

How is depression scored?

A

Mild - >2 core symptoms and >2 associated; function is okay
Moderate - >2 core symptoms and >4 associated; function is decreased
Severe - >2 core features and >6 associated; function decreased, psychosis may be present

120
Q

What are the outcomes of depression?

A 
Recurrent depressive disorder (60%) 
Substance misuse (40%) 
Anxiety (40%) 
Suicide (attempted 9%)
8x mortality
Cardiovascular disease
121
Q

What are the differentials for depression?

A

Dysthymia
Atypical depression
Adjustment reaction
Grief

122
Q

What is dysthymia?

A

Decreased mood
Chronic >2yrs but not enough to be depression E.g. cyclothymia - alternating decreased mood (mild) and increased mood (mild)

123
Q

What is atypical depression?

A

Decreased mood
Reversed associated symptoms
E.g. seasonal affective disorder (SAD) occurring in winter

124
Q

What is adjustment reaction?

A

Adaptation to stressor
Can include low mood
Onset <1 month from stress and duration <6 months maximum

125
Q

What is normal and abnormal grief?

A

Bereavement - any loss event, usually death
Grief - feelings, thoughts, behaviour associated with bereavement
Abnormal grief - intense, prolonged (>6 months), delayed (2 weeks), absent (inhibited)

126
Q

What is the Kubler-Ross model of grief?

A

DABDA - denial, anger, bargaining, depression, acceptance

127
Q

How is a patient with suspected depression assessed?

A 
Clinical history 
Risk assessment 
MSE
Physical exam 
Baseline bloods
128
Q

How is depression treated?

A 
Life threatening (e.g. suicidal, self neglect) - needs hospitalisation and/or Mental Health Act   
Biological - moderate depression (antidepressants), severe depression (antidepressants, antipsychotics, ECT)
129
Q

What are the 3 main groups of antidepressant drugs? Give examples

A

Selective serotonin reuptake inhibitors (SSRIs) - citalopram, fluoxetine
Tricyclic antidepressants (TCA) - amitriptyline, imipramine
Monoamine oxidase inhibtors (MAOIs) - phenelzine, moclobermide

130
Q

How do SSRIs work?

A

Block re-uptake of serotonin which increases the amount present at the synapse, magnifying its effects

131
Q

What are the side-effects of SSRIs?

A

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

132
Q

How do TCAs work?

A

Block serotonin and noradrenaline re-uptake

133
Q

What are the side-effects of TCAs?

A

Anti-adrenergic (e.g. hypotension), anti-cholinergic, ECG changes (arrythmia, QTc prolongation)

134
Q

How do MAOIs work?

A

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

135
Q

What are the side-effects of MAOIs?

A

Hypertensive crisis (in reaction to cheese), hypertension (MOA-A involved in break down of tyramine in GI tract)

136
Q

What causes hypertensive crisis in MAOI use?

A

Foods high in tyramine increase release of noradrenaline - this is normally inhibited by MAO but is inhibited when on MAOIs

137
Q

What is ECT, what is is used for and what are its risks?

A

Electroconvulsive therapy - electrical current administered to cause controlled seizure under anaesthetic
Used for depression, mania, catatonia
More effective than drugs but risk of anaesthesia and memory loss

138
Q

What psychological treatment is available for depression?

A

Cognitive behavioural therapy
Psychotherapy
Family therapy

139
Q

What is a lymphoid organ?

A

An organ which is composed primarily of lymphocytes

140
Q

What is lymphoid tissue?

A

Lymphocytes supported by skeleton of reticular fibres (fine collagen)

141
Q

Name 5 lymphoid organs of the body

A 
Tonsils
Thymus
Lymph nodes
Spleen
Mucosa-associated lymphoid tissue (e.g. Peyer’s patches in the ileum)
142
Q

What is the thymus?

A

Primary lymphoid organ upon which the other organs rely to program T cells

143
Q

What is Di George syndrome?

A

Congenital condition in which there is a lack of a thymus

No T cell programming = depletion of other lymphoid organs

144
Q

What are B cells named after?

A

Birds have a bursa of fabricius – works like a thymus for B cells
B cells in humans are programmed by bone marrow

145
Q

What does the lymphoreticular system encompass?

A

Lymphoid organs and bone marrow

146
Q

What is a sentinel node?

A

AKA 1st regional node - first lymph node receiving lymph from a particular area (first to pick up cancer)

147
Q

Outline the anatomy of a lymph node

A

Bean/kidney-shaped
Outer cortex, inner medulla
Hilum where vessels enter/exit
Thin connective tissue capsule
Subcapsular space/sinus between capsule and cortex
Medullary sinuses/spaces between medullary cords

148
Q

How does lymph travel in the lymph node?

A

Lymph can go around the subcapsular space and then into the medullary space or straight from subcapsular space to medullary space via cortical space/sinus short-cut

149
Q

What are lymphoid nodules?

A

Areas of active cell division in the outer cortex of a lymph node – indicate an active/ongoing immune response involving B cells

150
Q

Where in the lymph node are B and T cells found?

A

B cells - outer cortex and medullary cords

T cells - inner cortex

151
Q

How is lymph filtered in the lymph node?

A

Mechanical - rate of flow of lymph slows down when entering from afferent lymphatic vessel which allows particles/debris to settle and land on lymphocytes
Biological - phagocytosis by stellate macrophages in the medullary sinus

152
Q

What cells form a loose lattice network in the medullary sinus?

A

Stellate macrophages

153
Q

What are trabeculum?

A

Areas of the capsule that can extend into the centre of larger lymph nodes

154
Q

Describe the structure of the cortex and medulla

A

Cortex - tight

Medulla - loose

155
Q

How can actively dividing sites be defined within a lymph node?

A

Increased size/concentration of lymphocytes

Nodule formation

156
Q

What process do B cells undergo when activated by presence of foreign antigen?

A

Monoclonal expansion

157
Q

What cells are created in lymphoid nodules?

A

Memory B cells

158
Q

What is the arrangement of cells in the lymphoid nodules?

A

Macrophages are located closer to the subcapsular sinus and the pole here (directed to source of foreign matter) is lighter in colour compared to the pole away from the sinus which has mostly B cells and is darker
Corona/cap of small lymphocytes can be seen covering the top of the light pole

159
Q

Do T cells form lymphoid nodules?

A

No

160
Q

What is the red and white pulp of the spleen?

A

Red - filters blood

White - lymphoid tissue with central artery

161
Q

How are immune cells arranged around central arteries in the spleen?

A

Thymic-like inner area composed of T cells (e.g. inner cortex of lymph node) with outer area composed of B cells (e.g. outer cortex of lymph node

162
Q

Where can lymphoid tissue be seen in the appendix?

A

Mostly submucosa but some mucosa as well

163
Q

What type of epithelium is found in the tonsil?

A

Stratified squamous non-keratinised epithelium which is highly infiltrated with lymphocytes

164
Q

What tonsil has deep tonsillar crypts and what are they?

A

Palatine tonsil
Invaginations of the surface which are lined by the epithelium – harbour organisms/pathogens/sloughed cells so that lymphocytes are exposed to them

165
Q

What is tonsilloliths?

A

White mark on tonsil (‘tonsil stone’) – debris build up which can spontaneously discharge

166
Q

What are Hassall’s corpuscles?

A

Special cells lining the cortex which form the blood-thymus barrier (also form a sheath around vessels in this area)

167
Q

What cells are found in the cortex and medulla of the thymus and how are they distinguished?

A

Cortex - maturing T cells (dark lobules)

Medulla - clumps of degenerating epithelioreticular cells (light circles)

168
Q

When are T cells programmed?

A

Childhood

Progress to fat in old age

169
Q

Which lymphoid organ does not engage directly in immune response?

A

Thymus

170
Q

What is the developmental origin of the thymus?

A

3rd pharyngeal pouch

People and Illness (4 decks)

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