People and Illness Week 2 Flashcards
(141 cards)
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
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
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
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
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
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
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
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
9
Q
List the side effects associated with tricyclic antidepressants
A
Anti-adrenergic (lowers BP), anticholinergic, ECG changes (arrhythmia, QTc prolongation)
10
Q
List the classes of anti-depressants
A
- Selective serotonin re-uptake inhibitors and similar
- Tricyclics
- Monoamine oxidase inhibitors
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
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
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
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
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
16
Q
Which types of tumours commonly spread haematogenically?
A
- Common mode of spread of sarcomas
- Also some carcinomas e.g. kidney, colorectum, prostate
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
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
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
20
Q
List the types of monoamine oxidase inhibitor antidepressants
A
- Irreversible
- Isocarboxid
- Phenelzine
- Tranylycpromine
- Reversible
- Moclobermide
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
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
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
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
25
How can angiogenesis be targeted in cancer therapy?
* Angiogenesis inhibitors - target tyrosine kinase to turn off hypoxia signal
* E.g. Sunitunib (Sutent), Pazopanib (Votrient), Axitinib (Inlyta)
26
Describe lymphatic spread of tumours
* 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
27
Describe the differential diagnoses of depression
* 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
28
In which cancers can BRAF be present?
* 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
29
Describe the methods of neovascularisation
* 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
30
What are CAR-T cells and how are they used as a cancer therapy?
* 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
31
How is the severity of depression categorised?
* 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
32
How is depression treated?
Treat the biological, social and psychological aspects of the disease
33
What is the role of pericytes in the tumour microenvironment?
Faciliate intravasation and extravasation
34
How does immune surveillance effect tumour growth?
* 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
35
Describe the red pulp of the spleen
* 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
36
How does the angiogenic switch change in cancer?
* 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
37
What is the role of integrins in cancer?
* 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
38
Describe the function of the innate immune system in cancer
1st line of defence - germ-line encoded pattern recognition receptors rapidly detect infected or stressed cells, trigger potent effector mechanisms to contain tumours
39
What are the core clinical features of depression?
Low mood, anhedonia, fatigue
Everyday \>2 weeks
40
Describe the process of extravasation by tumour cells
* 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)
41
How do targeted therapies work in the treatment of cancer?
Drugs which target a specific process in an aberrant molecular pathway - intracellularly or extracellularly (e.g. angiogenesis)
42
Describe the gross structure of the thymus
* 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
43
How are tyrosine kinase inhibitors used in practice?
* 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
44
Describe the properties of epithelial cells compared with mesenchymal cells
* 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
45
Describe angiogenesis in cancer
* 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)
46
Describe the mechanism of action of checkpoint inhibitors
* 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
47
Define depression
Pathological low mood, associated decrease in functioning
Biochemical disorder with genetic component
48
What is the difference between prognostic and predictive markers?
* 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
49
How is hormonal treatment used in prostate cancer therapy?
* 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
50
What is the sentinel lymph node?
* 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
51
How has treatment of chronic myeloid leukaemia changed?
* 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
52
Describe maturation of T cells in the thymus
* 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
53
List the modes of tumour spread
* Intraepithelial
* Lymphatic spread
* Haematogenous spread
* Transcoelomic spread (across the peritoneal cavity)
54
List angiogenic inhibitors
* Thrombospondin
* Angiostatin - plasminogen fragment
* Endostatin - fragment of collagen XVIII
* Tumstatin - fragment of collagen IV
55
What is provenge and how is it used as a cancer therapy?
* 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
56
Describe the use of anti-depressants
* 1st line - SSRIs
* 2nd line - tricyclics
* 3rd - monoamine oxidase inhibitors
57
List the cognitive clinical features of depression
* Low concentration
* Slow/negative thinking
* Guilt
* Loss of self esteem
* Hopeless
* Suicidality
* Cognitive distortions - minimising, magnifying, arbitrary inference, selective abstraction, personalisation, overgeneralisation, catastrophising
58
Describe the mechanism of action of SSRIs
* 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
Describe the psychosis which can present associated with depression
* 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
Describe the advantages of new targeted therapies
* More selective for cancer cells, less selective for normal cells
* Less side effects, higher doses, potentially more anti-cancer effects
61
List the functions of the spleen
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
How do psychological factors contribute to the aetiology of depression?
* Personality traits - anxious, obsessive, paranoid
* Personality disorders
* Coping skills
* Adverse life events
63
List the properties needed by cancer cells in order to metastasise
* 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
List the types of clinical cancer treatments
Surgery, chemo/radiotherapy, immunotherapy
65
Which types of tumours commonly metastasise by transcoelomic spread?
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
When should driving be restricted/the DVLA be contacted in depression?
* Severe
* Attention/memory impairment
* Severe agitation
* Suicidality
67
Which properties are needed by metastatic tumour cells for invasion?
* Reduced cell-cell adhesion
* Altered cell-substratum adhesion
* Increased motility
* Increased proteolytic ability
* Ability to proliferate
68
Describe the increase in proteolytic activity in tumour cells to allow metastases
* 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
List the functions of lymph nodes
* 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
List the cells which make up the tumour microenvironment
* 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
Describe the high endothelial vessels of lymph nodes
* 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
Describe the anatomical position of the thymus
Within the anterior mediastinum, posterior to the upper sternum
73
List the problems with precision medicine in cancer treatment
* 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
Compare the humoral and cell-mediated immune responses
* 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
Describe the mechanism of action of monoclonal antibodies in treating cancer
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
How are the social features of depression managed?
* OT activity scheduling
* Social worker - housing, financial
* Employment
77
Define benign and malignant cancers
* Benign - remain localised at site of origin
* Malignant - invade and spread to different sites = cancer
78
Which cells link the innate and adaptive immune system in cancer?
* 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
What do the hallmarks of cancer represent?
The requirements which must be met for cancer to survive and become malignant
80
Compare primary and secondary lymphoid organs
* 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
Give examples of targetting the endocrine axis to treat cancer
* 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
What is chronic myeloid leukaemia?
* 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
Which type of cancer can interleukin 2 immunotherapy be used to treat?
Can cause complete regression of liver/bone cancer
84
How does prognosis compare in local tumours only compared with metastases on diagnosis?
Much better prognosis in only local tumours
85
How is life-threatening depression determined and dealt with?
* Suicidal, self-neglect (e.g. not eating and drinking)
* Needs hospitalisation, likely need Mental Health Act (detention)
86
What is responsibile for increased cell motility allowing metastases?
* 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
What are the side effects associated with SSRIs?
Nausea, vomiting, weight gain, dizziness, discontinuation syndrome, anxiety, suicidality, mania, serotonin syndrome, cardiac effects (QTc)
88
What is the normal role of integrins?
* 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
How is the thymus blood supply specialised to its function?
* 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
How do epithelial cells become mesenchymal cells?
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
Which factors contribute to a better prognosis in depression?
* Male
* Mild/short/first episode
* No psychosis
* Short hospital stay
* Good social functioning
* No co-morbid psychological diagnosis
92
What is the role of tumour associated macrophages in the tumour microenvironment?
* 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
Describe the mechanism of action of tricyclic antidepressants
Block serotonin and nor-adrenaline re-uptake
94
Compare intravasation and extravasation of tumour cells
* 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
How is E-cadherin altered in tumour cells?
* 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
How are the psychological features of depression managed?
* 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
How are developing T cells 'protected' from antigens while developing?
* 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
Describe the role of the adaptive immune system in cancer
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
Describe the epidemiology of depression
* 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
What are selectins?
* 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
What is the role of cancer-associated fibroblasts in the tumour microenvironment?
Secrete MMPs, cytokines, IL-8 and VEGF
102
How are the biological aspects of depression treated?
* Moderate - anti-depressants
* Severe - + anti-psychotics, electroconvulsive therapy
103
Give examples of drugs which target checkpoint inhibitors
* 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
How do biological factors contribute to the aetiology of depression?
* 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
List the side effects associated with MAOIs
* Hypertensive crisis - 'cheese reaction', interaction with tyramine in cheese
* MOA-A also in GI tract, breaks down tyramine
* If blocked, increase in BP
106
Define mood and affect
Mood = subjective feeling of sustained emotion (happy, sad)
Affect = objective immediate conveyance of emotion (blunt, labile)
107
How is a haematopoietic stem cell transplant carried out?
* Mobilise donor/patient, store cells
* Kill cancer
* Re-infuse HSC into 'clean' system
* Innate immune response recovers, adaptive immune response recovers
* Cure?
108
List the cytotoxic antitumour mechanisms
* Perforin
* TNF-related apoptosis-inducing ligand
* Fas and Fas ligand - control of metastases
109
Which drugs target BRAF positive cancers?
Vemurafenib
Dabrafenib
110
How do social factors contribute to the aetiology of depression?
* Poor social support
* Socioeconomic disadvantage
* Northernisation
111
Describe the use of imatinib in the treatment of chronic myeloid leukaemia
* Once daily oral medication
* Generally well-tolerated
* Most patients benefit
112
Describe the gross structure of lymph nodes
* 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
List the steps in the metastatic cascade
1. Invasion
2. Intravasation
3. Transport
4. Extravasation
5. Colonisation
6. Angiogenesis
114
How is depression diagnosed?
* 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
List the ten major characteristics of cancer
* 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
List types of SSRIs/similar and give examples
* 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
List the types of tricyclic antidepressants
* Tertiary amines (1st generation)
* Amitryptiline
* Maprotiline
* Doxepine
* Tianeptine
* Clomipramine
* Imipramine
* Lofepramine
* Dosulepin
* Secondary amines (2nd generation)
* Nortryptiline
* Protryptiline
* Amoxapine
* Desipramine
118
What determines where tumours will metastasise to?
* 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
Describe the structure and function of the white pulp of the spleen
* 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
List angiogenic activators
* VEGF
* EGF
* bFGF
* HGF
121
Compare production of lymphocytes by red bone marrow and the thymus gland
* Bone marrow produces B and T cells
* B cells mature in the bone marrow, T cells migrate to the thymus to mature
122
What is the role of selectins in cancer?
* 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
How is ECT used to treat depression?
* 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
Describe the typical prognosis for a person with depression
* 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
Describe the difference between benign and malignant tumours
* 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
Describe the lymphatic supply of the thymus
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
How does metastases cause death?
* 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
Describe the mechanism of action of Vemurafenib and its effectiveness
* 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
What is BRAF?
* 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
Which cells are involved with the innate immune system response to cancer?
Macrophages, granulocytes, mast cells, dendritic cells, NK cells
131
List the mechanism used by tumour cells to escape immune elimination
* 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
List the factors which contribute to the aetiology of depression
Biological, psychological, social
133
How does Enzalutamide work?
* 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
What distinct histological features can be seen in the thymus?
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
What are the areas of clinical features of depression?
* Core
* Biological
* Cognitive
* Psychosis
136
Describe the ways in which tumour cells can move
* 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
How are CAR-T cells produced?
* Blood collection
* T cell isolation and activation
* T cell modification
* T cell expansion and product formulation
* Preconditioning and T cell infusion
138
Describe the structure and function of the regions of lymph nodes
* 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
How are monoclonal antibodies used clinically?
* 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
Which factors contribute to a poorer diagnosis in depression?
* Female
* Severe/long/multiple episodes
* Psychosis
* Longer hospital stay
* Poor social function
* Co-morbid psychological diagnosis
141
Which cells are involved with the adaptive immune response to cancer?
B cells secreting antibodies, CD4+ and CD8+ T cells
