Week 2 Flashcards
1
Q
Define invasion
A
Growth by infiltration and destruction of surrounding tissues
2
Q
Define metastasis
A
Spread of tumour to, and growth at, ectopic sites (via blood, lymphatics, intraepithelial, or transcoelomic routes)
3
Q
Define carcinoma
A
Malignant tumour derived from epithelial cells (80% of human cancers)
4
Q
Define sarcoma
A
Malignant tumour derived from mesenchymal cells
5
Q
Define melanoma
A
Malignant tumour derived from neural crest cells
6
Q
Define leukaemia
A
Malignant tumour derived from circulating white blood cells
7
Q
Define lymphoma
A
Malignant tumour derived from the lymphatic system
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)
9
Q
What molecules are found in the basement membrane?
A
Fibronectin, type IV collagen, laminin
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
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)
12
Q
What molecule is involved in cell-cell adhesion and what type of junction does it participate in?
A
E-cadherin
Adherens junction
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
14
Q
Where is E-cadherin expressed and what is its function?
A
Surface of all epithelial cells
Inhibits invasion
15
Q
Which of the adherens junction linker proteins is linked to the actin-myosin cytoskeleton?
A
α-catenin
16
Q
What ion is required for and adherens junction to work?
A
Calcium
17
Q
How are adherens junctions involved in cancer?
A
Cells undergo an epithelial-mesenchymal transition - loss of E-cadherin allows cancer development
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
19
Q
What can happen to the E-cadherin promoter in some carcinomas?
A
Methylation
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)
21
Q
What 3 transcription factors are involved in E-cadherin regulation?
A
Snail
Slug
Twist
22
Q
What molecule is involved in cell-substratum adhesion and what type of junction is it involved in?
A
Integrins
Focal adhesion
23
Q
What are integrins?
A
Heterodimers in basal epithelial cells/focal adhesions of migrating cells which bind ECM molecules
24
Q
What is integrin α5β1?
A
Fibronectin receptor
25
What is integrin αvβ3?
Vitronectin receptor
26
How are integrins involved in cancer?
Decreased adhesion to basement membrane → increased migration through stroma
27
What is HGF and what is its function?
Hepatocyte growth factor
| Can induce epithelial cells to dissociate and scatter in culture
28
What is HGF also known as?
Scatter factor
29
What 3 functions does HGF possess?
Mitogen (growth)
Motogen (motility)
Morphogen (development)
30
How is HGF involved in cancer?
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
31
What is HGF/c-met an example of and what is this facilitated by?
Tumour-stroma interaction
| Tumour microenvironment
32
What cells are found in a tumour microenvironment?
Cancer-associated fibroblasts (CAFs)
Infiltrated immune cells
Myofibroblasts
Tumour-associated vasculature pericytes
33
What do tumour-associated vasculature pericytes secrete?
Growth factors
Chemokines
Enzymes
34
Give examples of tumour-stromal interaction
```
C-met and HGF
Chemokine receptor and chemokine
Protease receptor and protease
Integrin αvβ3 and MMP-2
TGF and stomelysin
VEGF and VEGF receptor
```
35
What is urokinase plasminogen activator (uPA)?
Serine protease
| Catalyses cleavage of plasminogen to plasmin which degrades fibrin clots
36
What are matrix metalloproteins (MMPs)?
Enzymes responsible for degradation of ECM proteins
E.g collagenases, gelatinases, stromelysins, membrane-type
Most can bind to integrins
37
How are MMPs used by breast carcinoma cells?
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
38
How is VEGF upregulated by tumour cells?
Tumour cells in a hypoxic area (e.g. middle of a large tumour) will stimulate expression of hypoxia-inducible factor which upregulates VEGF expression
39
How is VEGF used by tumour cells?
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
40
What is Avastin and what is it used for?
Bevacizumab - monoclonal antibody which blocks angiogenesis by inhibiting VEGF-A
Used for cancer treatment (e.g. ovarian) but not very effective
41
What ability do tumour cells 'copy' from WBCs and how does this occur?
Ability to intravasate and extravasate
| Rolling → activation → adhesion → diapedesis
42
What is tissue tropism?
Preferential growth of tumour cells in particular areas - site-specific metastasis
43
What are the principle metastasis sites of breast tumours?
Bone, lungs, liver, brain
44
What are the principle metastasis sites of lung tumours?
Bone, liver, brain, adrenal gland
45
What are the principle metastasis sites of skin tumours?
Lungs, liver, brain
46
What are the principle metastasis sites of prostate tumours?
Bones
47
What are the principle metastasis sites of colorectal and pancreatic tumours?
Liver, lungs
48
What are the 2 hypotheses for site-specific metastasis and what are they challenged by?
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
49
What molecules are important in selective adhesion of tumours to endothelium of target organs?
Selectins and CD44
50
What molecules allow breast cancer cells to establish osteolytic metastases?
Parathyroid hormone related peptide
| Interleukin-11
51
How can be used as targets for established metastases?
Tumour microenvironment
Immunoediting
Immunotherapy
CTLA-4
52
What is immunoediting?
The evolution of tumours so that the tumour cells are no longer effectively recognised and killed by the immune system
53
What is CTLA-4 and what is its importance in cancer?
Inhibitor of T cell response
| Inhibiting the inhibitor via drugs such as ipilimumab may be useful in cancer therapy
54
What is the MSE?
Mental state exam - standardised assessment of a person's current state of mind
55
What can the MSE be used for?
Assessment
Diagnosis
Monitoring progress
56
What is the format of the MSE?
```
Appearance and behaviour
Speech
Mood and affect
Thought form and content
Perception
Cognition
Insight
```
57
Give examples of what is included in the appearance section of the MSE
```
Clothing
Build
Self-neglect
Intoxication
Illness
Distinguishing features
```
58
Give examples of what is included in the behaviour section of the MSE
Motor activity
Eye contact
Body language and posture
Unusual/inappropriate behaviour
59
Give examples of what is included in the speech section of the MSE
Rate, rhythm, volume, tone
60
Give examples of what is included in the mood section of the MSE
Subjective
| Objective
61
Define mood
A person's overall emotional state
62
Define affect
Changes in a person's emotion on a moment-to-moment basis
63
Give examples of what is included in the affect section of the MSE
Reactive (appropriate reaction)
Flattened (limited reaction)
Blunted (no reaction)
Labile (excessive fluctuations)
64
Give examples of what is included in the thought form section of the MSE
Pattern/flow of the patient's thoughts
Includes specific quotes
Descriptive terms - flight of ideas (mania), loosening of association/knight's move thinking (schizophrenia)
65
Give examples of what is included in the thought content section of the MSE
Topics discussed more than others
Delusions
Over-valued ideas
Obsessions
66
Define delusion
A fixed, false belief that is out of keeping with the person’s religious and cultural background (e.g. psychosis)
67
Define an over-valued idea
A false belief, not totally fixed but causing great disability (e.g. anorexia, hypochondriasis)
68
Define obsession
Recurrent, intrusive, distressing ideas, impulses or images that the patient recognises as their own (e.g. OCD)
69
What types of delusions are there?
```
Persecutory
Grandiose
Nihilistic
Delusions of reference
Thought interference
```
70
What is a persecutory delusion?
Perceived threat from others
71
What is a grandiose delusion?
Considerable overestimate of abilities or possession of special powers
72
What is a nilistic delusion?
Belief that they are dead or do not exist
73
What is a delusion of reference?
Belief that external events/objects are directly related to them (e.g. TV programme)
74
What is a thought interference delusion?
Insertion, withdrawal or broadcast
75
Give examples of what is included in the perception section of the MSE
Difference between what the patient tells you and what you observe
Hallucination
Illusion
76
Define hallucination
Perception without external stimulus
| Can occur in any sensory modality - auditory, visual, olfactory, gustatory, tactile
77
Define illusion
False perception of a real stimulus (e.g. seeing a person in a shadow)
78
Give examples of what is included in the cognition section of the MSE
Alertness and orientation
Attention and concentration
Memory
MMSE can be used
79
Give examples of what is included in the insight section of the MSE
The patient's understanding of their presentation and need for treatment
80
What must always be included/documented for an MSE?
Risk - harm to self or others (planning and intent)
81
Define nascent
Just coming into existence and beginning to display signs of future potential - point at which cancer should ideally be detected
82
What is the normal immune response to cancer?
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
What are the 3 E's of immunoediting?
Elimination
Equilibrium
Escape
84
What is the result of immunoediting?
Produces low antigenicity tumour cells by selection
85
What are the main strategies by which disease can be targeted using the immune system?
Vaccination
Antibody therapies
Cell-based therapies
Non-specific therapies
86
Give an example of a non-specific immune targeted therapy
Aldara/imiquimod - mixture of Streptococcus pyogenes and Serratia marcescens used to treat various superficial skin cancers
87
Which interleukin has shown promise as a target for cancer immunotherapy?
IL-2
88
Give an example of an interleukin-2 immunotherapy
Ontak/denileukin diftitox
| IL-2 and diphtheria toxin combination which destroys cells expressing IL-2 receptors
89
What monoclonal targets CD20 and what malignancy is this for?
Rituximab
| B cell lymphoma/non-Hodgekin's lymphoma
90
What monoclonal targets CD52 and what malignancy is this for?
Alemtuzumab
| B cell lymphoma, acute/chronic myeloid leukaemia
91
What monoclonal targets Her-2/neu and what malignancy is this for?
Trastuzumab
| Breast cancer, lymphoma
92
What monoclonal targets EGFR and what malignancy is this for?
Cetuximab
| Colorectal/lung/head and neck cancer
93
What monoclonal targets VEGF and what malignancy is this for?
Bevacizumab
| Breast/lung/liver/pancreas/prostate cancer
94
What monoclonal targets PDGFR and what malignancy is this for?
Olaratumab
| GI stromal/solid tumours
95
How does ipilimumab work?
CTLA-4 blockade
96
How does nivolumab work?
PD-L1 blockage
97
Give examples of targets for cancer cell therapies
```
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
What are bone marrow and stem cell transplants used for?
Treatment of blood disorders (e.g. BM failure, SCID) and leukaemia
99
What is plerixafor and how does it work?
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
What are allogeneic and autologous stem cell transplants and which is used most?
Allogeneic - same species; related or unrelated donor (20% each)
Autologous - own (60%)
101
What can allogeneic stem cell transplants be used to treat?
Leukaemia
Haematopoiesis disorders
Genetic diseases
102
What can autologous stem cell transplants be used to treat?
```
Lymphoma
Tumours
Autoimmune disease
Regenerative medicine
Cardiovascular disease
```
103
What is provenge and how does it work?
Sipuleucel-T
Patient-specific treatment for prostate cancer
Dendritic cells are extracted → infused with PAP (antigen) and GM-CSF (maturation factor) → reinfusion
104
What is PTLD and how can it be treated?
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
What is CAR-T?
Chimeric antigen receptor T cells
| Cell therapy for cancer - genetic modification of patient's T cells by addition of CAR
106
Give and example of a CAR-T cell therapy and what are its limitations?
Kymriah (licenced in US for B cell lymphoma)
| Cost, complexity, kill-switch, single target, off-tumour toxicity, cytokine release syndrome
107
Define psychiatry
Medical specialty concerned with diagnosis, treatment and prevention of mental health disorders
108
What is an organic disorder?
Change in mental function; secondary physical process rather than psychiatric illness
109
What are the biological causes of depression?
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
What are the psychological causes of depression?
Personality traits/disorders (anxious, obsessive)
Coping skills
Adverse life events
111
What are the social causes of depression?
Poor social support
| Socioeconomic disadvantage
112
Outline the epidemiology of depression
Mean age onset 30 years
Females most affected (2:1)
4th commonest cause of disability
1/3rd never seek treatment
113
What is the monoamine hypothesis of depression?
Neurochemical decrease in serotonin, noradrenaline and dopamine are responsible for the pathogenesis of depression
114
What are the core clinical features of depression?
Decreased mood +/- anhedonia +/- fatigue every day for >2 weeks
115
What are the biological symptoms of depression?
Diurnal variation, insomnia, decreased appetite/weight/libido, constipation, amenorrhoea
116
What are the cognitive symptoms of depression?
Decreased concentration, slow/negative thinking, guilt, loss of self-esteem, hopeless, suicidality
117
What cognitive distortions are associated with depression?
Minimising, magnifying, arbitrary inference, selective abstraction, personalisation, overgeneralisation, catastrophising
118
What features of psychosis are associated with depression?
Delusions - (mood congruent (‘nihilistic’), guilt, poverty, hypochondriasis, persecutory, Cotard’s syndrome that self/part of self is dead)
Hallucinations - (auditory 2nd person)
119
How is depression scored?
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
What are the outcomes of depression?
```
Recurrent depressive disorder (60%)
Substance misuse (40%)
Anxiety (40%)
Suicide (attempted 9%)
8x mortality
Cardiovascular disease
```
121
What are the differentials for depression?
Dysthymia
Atypical depression
Adjustment reaction
Grief
122
What is dysthymia?
Decreased mood
Chronic >2yrs but not enough to be depression E.g. cyclothymia - alternating decreased mood (mild) and increased mood (mild)
123
What is atypical depression?
Decreased mood
Reversed associated symptoms
E.g. seasonal affective disorder (SAD) occurring in winter
124
What is adjustment reaction?
Adaptation to stressor
Can include low mood
Onset <1 month from stress and duration <6 months maximum
125
What is normal and abnormal 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)
126
What is the Kubler-Ross model of grief?
DABDA - denial, anger, bargaining, depression, acceptance
127
How is a patient with suspected depression assessed?
```
Clinical history
Risk assessment
MSE
Physical exam
Baseline bloods
```
128
How is depression treated?
```
Life threatening (e.g. suicidal, self neglect) - needs hospitalisation and/or Mental Health Act
Biological - moderate depression (antidepressants), severe depression (antidepressants, antipsychotics, ECT)
```
129
What are the 3 main groups of antidepressant drugs? Give examples
Selective serotonin reuptake inhibitors (SSRIs) - citalopram, fluoxetine
Tricyclic antidepressants (TCA) - amitriptyline, imipramine
Monoamine oxidase inhibtors (MAOIs) - phenelzine, moclobermide
130
How do SSRIs work?
Block re-uptake of serotonin which increases the amount present at the synapse, magnifying its effects
131
What are the side-effects of SSRIs?
Nausea, vomiting, weight gain, dizziness, discontinuation syndrome, anxiety, suicidality, mania, serotonin syndrome, cardiac effects (QTc)
132
How do TCAs work?
Block serotonin and noradrenaline re-uptake
133
What are the side-effects of TCAs?
Anti-adrenergic (e.g. hypotension), anti-cholinergic, ECG changes (arrythmia, QTc prolongation)
134
How do MAOIs work?
Block MAO-A and B which break down serotonin, noradrenaline and dopamine in the CNS
135
What are the side-effects of MAOIs?
Hypertensive crisis (in reaction to cheese), hypertension (MOA-A involved in break down of tyramine in GI tract)
136
What causes hypertensive crisis in MAOI use?
Foods high in tyramine increase release of noradrenaline - this is normally inhibited by MAO but is inhibited when on MAOIs
137
What is ECT, what is is used for and what are its risks?
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
What psychological treatment is available for depression?
Cognitive behavioural therapy
Psychotherapy
Family therapy
139
What is a lymphoid organ?
An organ which is composed primarily of lymphocytes
140
What is lymphoid tissue?
Lymphocytes supported by skeleton of reticular fibres (fine collagen)
141
Name 5 lymphoid organs of the body
```
Tonsils
Thymus
Lymph nodes
Spleen
Mucosa-associated lymphoid tissue (e.g. Peyer’s patches in the ileum)
```
142
What is the thymus?
Primary lymphoid organ upon which the other organs rely to program T cells
143
What is Di George syndrome?
Congenital condition in which there is a lack of a thymus
| No T cell programming = depletion of other lymphoid organs
144
What are B cells named after?
Birds have a bursa of fabricius – works like a thymus for B cells
B cells in humans are programmed by bone marrow
145
What does the lymphoreticular system encompass?
Lymphoid organs and bone marrow
146
What is a sentinel node?
AKA 1st regional node - first lymph node receiving lymph from a particular area (first to pick up cancer)
147
Outline the anatomy of a lymph node
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
How does lymph travel in the lymph node?
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
What are lymphoid nodules?
Areas of active cell division in the outer cortex of a lymph node – indicate an active/ongoing immune response involving B cells
150
Where in the lymph node are B and T cells found?
B cells - outer cortex and medullary cords
| T cells - inner cortex
151
How is lymph filtered in the lymph node?
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
What cells form a loose lattice network in the medullary sinus?
Stellate macrophages
153
What are trabeculum?
Areas of the capsule that can extend into the centre of larger lymph nodes
154
Describe the structure of the cortex and medulla
Cortex - tight
| Medulla - loose
155
How can actively dividing sites be defined within a lymph node?
Increased size/concentration of lymphocytes
| Nodule formation
156
What process do B cells undergo when activated by presence of foreign antigen?
Monoclonal expansion
157
What cells are created in lymphoid nodules?
Memory B cells
158
What is the arrangement of cells in the lymphoid nodules?
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
Do T cells form lymphoid nodules?
No
160
What is the red and white pulp of the spleen?
Red - filters blood
| White - lymphoid tissue with central artery
161
How are immune cells arranged around central arteries in the spleen?
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
Where can lymphoid tissue be seen in the appendix?
Mostly submucosa but some mucosa as well
163
What type of epithelium is found in the tonsil?
Stratified squamous non-keratinised epithelium which is highly infiltrated with lymphocytes
164
What tonsil has deep tonsillar crypts and what are they?
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
What is tonsilloliths?
White mark on tonsil ('tonsil stone') – debris build up which can spontaneously discharge
166
What are Hassall's corpuscles?
Special cells lining the cortex which form the blood-thymus barrier (also form a sheath around vessels in this area)
167
What cells are found in the cortex and medulla of the thymus and how are they distinguished?
Cortex - maturing T cells (dark lobules)
| Medulla - clumps of degenerating epithelioreticular cells (light circles)
168
When are T cells programmed?
Childhood
| Progress to fat in old age
169
Which lymphoid organ does not engage directly in immune response?
Thymus
170
What is the developmental origin of the thymus?
3rd pharyngeal pouch
