S4C4 Flashcards
(137 cards)
1
Q
What is the biopsychosocial approach to healthcare?
A
Mind-body relationship dynamic system
Cause of disease has multiple factors at different levels
Causality is circular
Psychosocial factors are essential
Holistic approach to illness and treatment
Individuals and society are responsible for health
Physical, psychological and social factors are responsible for treatment
Reduction of physical, psychological and social risk factors are the main focus
2
Q
What is the COM-B framework?
A
Capability and Opportunity lead to motivation.
Behaviour links to them all
3
Q
What is the PRIME theory?
A
Plans, evaluations, motives, and Impulses lead to response impacted by the internal and external environment
4
Q
What is the health belief model?
A
Demographic variable lead to susceptibility, severity, costs, benefits, cues to action, health motivation, and perceived control. These all affect the likelihood of behaviour.
5
Q
What is the self-regulation model?
A
Illness representation links to the emotional reaction. It also links to their coping behaviour for control of illness and emotion.
6
Q
Describe multi-step tumorgenesis
A
The initiating mutation goes under first clonal expansion, representing ~10^6 cells.
A second mutation then occurs and through an increased mutation rate, many multiple independent mutations occur causing multiple parallel clonal expansion
7
Q
What are viral oncogenes?
A
Viral genes that when introduced into cells have dominant transformative effects
8
Q
What are cellular oncogenes?
A
Cancer DNA transfected into normal cells caused transformation, again in a dominant manner
9
Q
What is the two-hit theory?
A
That you need 2 random sporadic hits on a tumour suppressor gene. (unilateral)
10
Q
Describe a signalling pathway
A
Ligand Receptor Signaling cascade Transcription factors Delta gene expression
11
Q
How does RAS become active?
A
GEF (Guanine nucleotide exchange factors) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP) which activates RAS
12
Q
How does RAS become inactive?
A
GAP (GTPase activating proteins) removes an inorganic phosphate making ADP bind to RAS
13
Q
What happens when Wnt isn’t active?
A
GSK-3β is active, meaning Apc is active with an inorganic phosphate and β-catenin gets degraded
14
Q
What happens when Wnt is active?
A
GSK-3β is inactive, meaning Apc is inactive and β-catenin doesn’t get degraded. This can now interact with the DNA in the nucleus.
15
Q
How does Cyclin D1 become activated
A
Growth factors activates Ras which activates Fos/jun. In addition, Ras and Wnt signalling activates β-catenin which activates Tcf/lef. This activates cyclin D1
16
Q
What 2 things consistently change the genome?
A
Continuous damage
Continuous repairs
17
Q
List examples on continuous damage to the genome.
A
oxidation replication errors UV x-rays chemicals mitosis
18
Q
List examples on continuous repair to the genome
A
BER NER proofreading NHEJ DSBR/HR the SAC
19
Q
What is senescence?
A
The condition or process of deterioration with age
20
Q
In what type of cell is telomerase active?
A
Tumour cells
21
Q
What is the end replication problem
A
When the replication fork reaches the end of the chromosome, however, there is a short stretch of DNA that does not get covered by an Okazaki fragment.
Also, the primer of the last Okazaki fragment that does get made can’t be replaced with DNA like other primers.
Meaning part of the DNA at the end of a eukaryotic chromosome goes uncopied in each round of replication, leaving a single-stranded overhang.
Over multiple rounds of cell division, the chromosome will get shorter and shorter as this process repeats.
22
Q
Why are liquid biopsies done?
A
Tumours shed cells and DNA into the blood
Minimally invasive and inexpensive
Advanced detection technology
23
Q
What does CRP indicate?
A
produced in the liver
rises in response to inflammation
24
Q
Why are Chemotherapeutic agents used? How are the classified?
A
directly or indirectly inhibit theproliferationof rapidly growing cells, typically in the context of malignancy. They are classified according to their mechanism of action and includealkylating agents,antimetabolites,topoisomerase inhibitors, andmitotic inhibitors.
25
What side effects are associated with chemotherapy?
It's associated with a range of adverse effects (e.g., nausea, vomiting, increased risk of infection, and impaired growth of healthy cells), and with some agents, an increased risk of secondary neoplasms. Symptomatic management of associated side effects is recommended to improve tolerance.
26
what are the general side effects of chemotherapy?
Gastrointestinal mucosa: mucositis → stomatitis, esophagitis, enteritis associated with diarrhoea
Hematopoiesis (myelosuppression)
Granulocytopenia and lymphocytopenia (increased risk of infection)
Thrombocytopenia (increased bleeding risk)
Anemia (fatigue)
Hair follicles: hair loss
Chemotherapy-induced peripheral neuropathy
Pain, burning, tingling, and loss of sensation in the distal extremities that spread from the hands and feet.
Typically spreads in a “stocking-glove pattern”
Causative agents include platinum-based medications (e.g., cisplatin), taxanes (e.g., paclitaxel), and vinca alkaloids (e.g., vincristine).
Centrally induced vomiting
Gonadal damage
27
What is neoadjuvant cytostatic therapy?
Administered preoperatively to reduce tumor mass
28
What is adjuvant cytostatic therapy?
Administered postoperatively to reduce risk of recurrence and/or to improve prognosis
29
What is Palliative cytostatic therapy?
Administered if curative therapy is not possible; indications vary
30
What is cytoreductive conditioning?
high-dose cytostatic therapy (sometimes in combination with whole body radiation) to suppress bone marrow before bone marrow or stem cell transplantation.
31
What are the benefits of oral chemotherapy?
Oral administration of cytostatic drugs allows for outpatient treatment and avoids the need for inpatient hospitalization (e.g., for patients in need of palliative chemotherapy).
32
What cytostatic drugs can be administered orally? (classification : name)
Anthracyclines: idarubicin
Pyrimidine analogs: capecitabine
Alkylating agents: temozolomide
Topoisomerase inhibitors: etoposide
33
What is the effect of immunotherapy with APC?
An anti CTLA-4 antibody can block the binding between CD80/86 on the APC and CTLA-4. This activates the T-cell allowing elimination of tumour cells
34
What is the effect of immunotherapy with Tumour cells?
Anti-PD-L1 binds to PD-L1 on a tumour cell.
Anti-PD-1 binds to PD-1 on a T-cell.
This stops binding between PD-L1 and PD-1 meaning the T-cell can be activated leading to the elimination of tumour cells
35
What is ALT involved in? What does an increase show?
Involved in gluconeogenesis - specific to hepatic cells
| Shows hepatocyte damage
36
What is ALP involved in? What does an increase show?
Responsible for cleaving phosphate groups off various substances under alkaline conditions
Increased during pregnancy, cholestasis and increased osteoblast activity
37
What causes increased serum bilirubin?
Cholestasis
38
What is C reactive protein?
An acute phase reactant involved in the opsonization of pathogens with a half-life of 24 hours. It is a highly sensitive marker for inflammation but is not specific to any disease or organ. Increases about 6–12 hours after the inflammatory process begins
39
What does ESR measure?
Measures the distance that erythrocytes have fallen after one hour in a vertical tube of anticoagulated blood
Elevated in infection
40
What causes increased urea levels?
Increased in severe renal failure, catabolic states and dehydration
41
What is GFR?
volume of primary urine that is filtrated by the kidneys over a certain amount of time per standardized body surface area
42
What is eGFR based on?
creatinine levels
43
What causes decreased ferritin?
iron deficiency and nephrotic syndrome
44
What causes increased ferritin?
acute phase reaction and iron overload
45
How do you collect a stool sample?
make sure the sample doesn't touch the inside of the toilet
use the spoon or spatula that comes with the container to place the sample in a clean screw-top container and screw the lid shut
if you've been given a container, aim to fill around a third of it – that's about the size of a walnut if you're using your own container
46
What is a carcinoma in situ?
abnormal cells have not spread beyond where they first formed
47
Define a malignant tumour.
Cancerous cells which have invaded and destroyed nearby tissue, possibly spread to other parts of the body
48
What happens in the S-phase of the cell cycle?
Genome duplication
49
What happens in the G2-phase of the cell cycle?
Genome segregation
50
How do you get from genes to tissues?
Genome undergoes transcription to form transcriptome.
Transcriptome undergoes translation to form proteome
Proteome undergoes biogenesis to form functioning cells
Cells undergo metabolism and proliferation to form the tissue architecture
51
What is another name for Cdc2?
Cdk1
52
What is the R point in the cell cycle?
The point at G1 at which commitment occurs and the cell no longer requires growth factors to complete the cell cycle has been termed the restriction (R) point. The R point has been temporally mapped at 2–3 hours prior to the onset of DNA synthesis.
53
Describe the Cyclin-CDK involvement in the cell cycle.
From the start of G1 to the R point: D-CDK4/6
From R point to just into S phase: E-CDK2
From start of S to midway: A-CDK2
Just before midpoint of S to end of G2: A-CDC2
M: B-CDC2
54
What inhibits cyclin-Cdks?
Cyclin-dependent kinase inhibitor (CKI)
55
What does p57, p27 and p21 inhibit?
E-CDK2
A-CDK2
A-CDC2
B-CDC2
56
What does p15, p16, p18 and p19 inhibit?
D-CDK4/6
57
What is the pRb-E2F pathway?
D-CDK4 phosphorylates pRb on E2F making it hypophosphorylated.
E-CDK2 phosphorylates it more making it hyperphosphorylated.
This meand the pRb releases the E2F
This acts at G1 phase
58
How does p53 work in normal cells?
In normal cells, the p53 protein level is low. DNA damage and other stress signals may trigger the increase of p53 proteins, which have three major functions: growth arrest, DNA repair and apoptosis (cell death). The growth arrest stops the progression of cell cycle, preventing replication of damaged DNA. During the growth arrest, p53 may activate the transcription of proteins involved in DNA repair. Apoptosis is the "last resort" to avoid proliferation of cells containing abnormal DNA.
59
What can cause p53 activation?
```
lack of nucleotides
UV radiation
ionising radiation
Oncogene signalling
Hypoxia
blockage of transcription
```
60
What are the 4 mechanism that p53 controls?
Cell cycle arrest
DNA repair
Block of angiogenesis
Apoptosis
61
How does p53 cause cell cycle arrest?
```
Activates p21
This causes inhibition of:
E-CDK2
A-CDK2
A-CDC2
B-CDC2
```
62
How does p53 cause apoptosis?
Activates Noxa and Puma
These inhibit Bcl-2/Bcl-Xl (which is pro-survival)
This stops Bcl-2/Bcl-Xl inhibiting Bax/Bak (pro-apoptosis)
Causes cell death
63
What are the 3 subtypes of cancers?
POLE hyper mutated <1%
Microsatellite instability 9%
(Prioritised for immune checkpoint therapy)
Microsatellite stable 90%
64
What are the T stages of rectal cancer?
Tis (in situ) - growing into the mucosa
T1 - in the submucosa
T2 - grown into muscle layer
T3 - grown into serosa (outer lining) but no further
T4 - grown through serosa and through the peritoneum
T4a - grown to other nearby structures (i.e. other bowel or organs)
T4b - perforated the bowel can cancer cells have spread
65
What are the N stages of rectal cancer?
N0 - no lymph nodes affected
N1 - <3 lymph nodes affected
N2- >4 lymph nodes affected
66
What are the M stages of rectal cancer?
M0 -no distant organs affected
| M1 - spread to distant organs
67
What are the stages of rectal cancer? (0-4)
0 - Only in the mucosa (TisN0M0)
1 - Grown into submucosa or muscle but not to lymph nodes or other organs (T1N0M0 and T2N0M0)
2 - Grown through muscle wall or outer layer of bowl, potentially into nearby tissue (T3N0M0 and T4N0M0)
3 - Tumour of any size and has spread to just lymph nodes (TnN1M0 and TnN2M0)
4 - Tumour of any size and may have spread to lymph nodes. Has spread to other parts of the body (TnNnM1)
68
What are the 3 cancer grades?
Low grade - grow slow, and look similar to normal cells (well differentiated), less likely to spread
Moderate grade - look more abnormal
High grade - cancer cells tend to grow more quickly and look very abnormal (poorly differentiated), likely to spread
69
What are the intrinsic pathway to inflammation in tumour cells?
```
Normal tissue homeostasis disrupted
Sequential mutations
Epigenetic alterations
Oxidative stress
Proliferation / apoptosis dysregulation
```
70
What is the extrinsic pathway driven by chronic inflammation?
Inflammatory tumour micro-environment
Inflammatory cytokines (TNF-α, IFNγ, IL1, IL6)
Reduced regulatory cytokines (IL10, TGF-β)
Disrupted homeostasis
Proliferation / apoptosis disregulation
71
What lines the large intestine? What is their function?
mucosa with crypts of Lieberkühn containing glands and mucus-producing goblet cells. These protect the intestinal wall from the plethora of anaerobic bacteria in the colon and from the pressure exerted on the walls by the concentrated chyme (soon to become faeces).
The walls also contain gastrointestinal lymphoid tissue (GALT) that contributes to the body’s immune defences.
72
Why does the colon only absorb a small volume of water?
As the chyme is very concentrated by the time it reaches here, the colon must work against a larger osmotic pressure gradient than in the rest of the GIT
73
How much H20 is absorbed a day?
8. 4L absorbed in total per day
6. 5L in small intestine
1. 9L in colon
74
What is the route of H20 through the large intestine?
Via junctional complexes between cells or
| Via SGLT1 And a.a. Transporters
75
What does aldosterone do?
Produced by the zona glomerulosa of the adrenal cortex
Increases net absorption of water and electrolytes by stimulating the basolateral sodium-potassium ATP-ase.
This increases the electrochemical gradient and driving force for sodium absorption
It also increases transcription of epithelial sodium channels
76
What do glucocorticoids and somatostatin do?
Increases net absorption of water and electrolytes by increasing the action the basolateral sodium-potassium ATP-ase.
77
What type of surface does the GI tract have?
Undulating - increases SA
78
What is a Peyers patch?
Lymph follicle
79
What do M cells do?
Antigen sampling
| Transports antigens from lumen
80
What antimicrobial peptides can be found in the pre-epithelium?
α and β defensins
Direct activity against bacteria
α is more broad spectrum
Interact with microbial membrane
81
What are paneth cells?
residing at the bottom of the intestinal crypts are the key effectors of innate mucosal defense. Paneth cells produce large amounts of α-defensins and other antimicrobial peptides
Stem cells niche maintenance
82
What antibody is GI specific?
IgA
Responsible for primary defence against bacteria
IgA coats colitogenic bacteria with high affinity in Crohn's and Ulcerative colitis patient
83
What are the components of IgA antibodies?
Light and Heavy chains
Looks like an X
J chain in the middle
Secretory component wrapped around the antibody
84
How do IgA antibodies get into the lumen?
Plasma cells secrete IgA
IgA binds to poly-IgR on surface of epithelium
Travel through the cell
Secreted into lumen still attached to the poly-IgR
85
What cell type is the epithelium?
Simple columnar
86
What are Oxyntic glands? Where are they found?
found in the fundus and body of the stomach. They are simple almost straight tubes, two or more of which open into a single duct. Oxyntic means acid-secreting and they secrete hydrochloric acid (HCl) and intrinsic factor.
87
What cells are found in Oxyntic glands? (from base of gland)
```
Chief cells
Endocrine cells
Parietal cells
Mucous neck cells
Surface mucous cells
```
88
What do enterocytes do?
Absorb nutrients
| make up 1% of mucosal cells
89
What do CBC cells do?
Tissue self-renewal
90
What do enteroendocrine cells do?
Endocrine signalling
91
What do goblet cells do?
Mucus secretion
92
What do tuft cells do?
Opioid release
| Prostanoids production
93
Where can dendritic cells be found? What are their role?
```
Subepithelial
Migratory
Excellent primers of T cells via antigen presentation
Discrete subset with different functions
CD11+/-
CD103+/-
Derived from committed progenitor
```
94
Where can Intestinal macrophage cells be found? What are their role?
```
Subepithelial
Non-migratory
Express:
CD64
CD11b
CD11c
CX3CR1
Control translocation of luminal bacteria to the draining lymph node
Replenished by blood monocytes
Phagocytes
```
95
What cytokines and transcription factors are needed for Th1 differentiation?
IL-12, IFNγ
| STAT1, STAT4, T-bet
96
What cytokines and transcription factors are needed for Th2 differentiation?
IL-4
| STAT6, GATA3, IRF4
97
What cytokines and transcription factors are needed for Th17 differentiation?
IL-6, TGFβ
| RORγt, RORα, STAT3, IRF4
98
What cytokines and transcription factors are needed for Treg differentiation?
TGFβ
| SMAD, FoxP3
99
What effector cytokines does Th1 produce? What do they inhibi?
IL-2, IFNγ
| Inhibit Th2 and Th17
100
What effector cytokines does Th2 produce? What do they inhibi?
IL-4, IL-5, IL13
| Inhibit Th1, Th17
101
What effector cytokines does Th17 produce? What do they inhibi?
IL-17, IL-22, IL-21
| Inhibit Th2 and Th1
102
What effector cytokines does Treg produce? What do they inhibi?
IL-10, TGFβ
| Inflammatory suppression of Th1, Th2, Th17
103
What are ILCs?
```
Innate lymphocytes
Derived from common lymphoid progenitor
Rely on IL2R signalling
Involved in homeostasis and inflammation
Stimulated by cytokines or microbes
Present in steady state at low numbers
Characterised as 1, 2, or 3
```
104
What is the function of ILC1?
IFN-gamma producers
Includes NK cells
Express T-bet
105
What is the function of ILC2?
```
IL5/ IL13 producers
Express RORα/GATA3
Seen in allergy
Respond to IL25/IL33
Aka natural helper cells
```
106
What is the function of ILC3?
```
Contribute to mucosal homeostasis
IL17A, IL17F and IL22 producers
Express RORγt
Respond to IL23
Important in foetal lymphoid organogenesis
Lost in HIV patients
Important in GALT formation
Important in mucosal homeostasis
```
107
What is the function of Treg cells?
Develop in thymus
Essential for control and homeostasis
Inducible Tregs develop in response to TGFbeta and trans Retinoic acid in the periphery
Foxp3 expression critical for the suppressive function of Foxp3+ Tregs
Tr1 Tregs secrete IL10 and TGFbeta in the absence of Foxp3
108
How do Treg cells contribute to homeostasis?
TGF-β and retinoic acid allows for Treg to produce IL-10 and more TGF-β
It also allows Il-22 to be produced by NK cells
109
What happens in Dysbiosis?
Dendrite decretes IL-23, IL-12 and TNF
| Causes differentiation to Th1 and Th17 causing an inflammatory environment
110
What can stop T cell activation?
CTLA4 / B7 interaction between T cell and antigen presenting cell
111
What can reduce T cell activation?
PD-1 / PD-L1 interaction
Expressed by infected cells – prevents efficient immunity to virally infected cells
Expressed on APCs and tissue – prevents immune recognition of self
Expressed on tumour cells - tumour evasion mechanism
112
What are positive regulators of inflammatory microenvironments?
TNFα
IL-6
CCL2
CC chemokines
113
What are positive regulators of inflammatory microenvironments?
```
TGFβ
IL-10
TIR8
D6
Cox-2
```
114
What is the MOA of amlodipine?
Long-acting calcium channel blocker
Acts on vascular smooth muscle by stabilizing voltage-gated L-type calcium channels
Prevents myocyte contraction and vasoconstriction
For hypertension
115
What is the MOA of citalopram?
SSRI
116
What is the MOA of ventolin inhaler?
Aka salbutamol
Short-acting selective beta2-adrenergic receptor
Bronchospasm prevention
117
What is the MOA of Oxaliplatin?
Chemotherapy drug
Administered in combination with fluorouracil and leucovorin (combo known as Folfox)
Treatment of colorectal cancer
Selectively inhibits the synthesis of DNA
At high concentrations, cellular RNA and protein synthesis are also suppressed
118
What is the MOA of Fluorouracil (5-FU)?
A pyrimidine analogue that is an antineoplastic antimetabolite
Affects the "S" phase of the cell cycle
Inhibits DNA and RNA synthesis and causes cell death
Injections can also be given in palliative management
119
What is the MOA of Folinic acid (OxMdG)?
Aka leucovorin
Folate analogue
Used to diminish the toxicity and counteract the effects of impaired methotrexate elimination
Prolongs survival in palliative treatment of advanced colorectal cancer
120
Describe the epidemiology of Colo-rectal cancer.
Incidence: ∼ 130,000 new cases per year
Third most common cancer in women and men
Age: continuous increase in incidence after the age of 50
Mortality: third leading cause of cancer-related deaths in the US overall
Develops of several years (10-20)
Males have 1 in 17 chance
Woman has 1 in 18 chance
10% of all cancer deaths
121
List some predisposing factors.
Colorectal adenomas (see colonic polyps)
Family history
Hereditary syndromes
Familial adenomatous polyposis: 100% risk by age 40
Hereditary nonpolyposis colorectal cancer (HNPCC): 80% progress to CRC.
Inflammatory bowel disease (IBD): ulcerative colitis and Crohn's disease
Chronic inflammation → hyperplasia → non-polypoid dysplasia→ neoplasia
Endocarditis and bacteremia due to Streptococcus gallolyticus
Diet and lifestyle
Smoking
Alcohol consumption
Obesity
Type 2 diabetes
Processed meat; high-fat, low-fiber diets
Older age
122
What impact does IBD have on overall risk of CRC?
4-20 times higher
123
What impact does T2DM have on overall risk of CRC?
Increase by 50%
124
What are the protective factors of CRC?
Physical activity
Diet rich in fiber and vegetables and lower in meat
Long-term use of aspirin and other NSAIDs
125
What are the non-specific symptoms of CRC?
Constitutional symptoms (weight loss, fever, night sweats), fatigue, abdominal discomfort
In general, right-sided tumors chronically bleed, and left sided tumors cause obstruction
126
What are the RHS -specific symptoms of CRC?
Iron deficiency anemia
Melena
Diarrhea
127
What are the LHS -specific symptoms of CRC?
Changes in bowel habits (size, consistency, frequency)
Blood-streaked stools
Colicky abdominal pain due to obstruction
128
What are the rectum/sigmoid -specific symptoms of CRC?
```
Hematochezia
↓ Stool caliber (pencil-shaped stool)
Rectal pain
Tenesmus
Flatulence with involuntary stool loss
```
129
How many CRC are adenocarcinomas?
95%
130
What is the pathology of CRC?
Adenocarcinoma (most common): 95% arise from adenomatous polyps
The adenoma-carcinoma sequence is the progressive accumulation of mutations in oncogenes(e.g., KRAS) and tumor suppressor genes (e.g., APC, TP53) that results in the slow transformation of adenomas into carcinomas.
APC gene mutation (loss of cellular adhesion and increased cellular proliferation) → KRAS genemutation (unregulated cellular signaling and cellular proliferation) → TP53 and DCC genemutation (malignant transformation of adenoma to carcinoma)
Microsatellite instability: due to methylation or mutations in mismatch repair genes (MLH-1 and MSH-2)
131
Why is long-term use of aspirin and NSAIDs protective?
COX-2 overexpression: associated with colorectal cancer. Thus, the possible protective effect of long-term use of aspirin and other NSAIDs
132
When should you take a palliative approach to CRC?
distant metastases beyond the liver and/or lung or if the patient is not a surgical candidate due to poor general health
Treatment involves palliative chemotherapy.
133
What is the prognosis of CRC?
```
Overall 5-year survival rate: 65%
57% survive 10+ years
Survival rate according to disease stage
• Stage I: 95%
• Stage II: ∼80%[31]
• Stage III: 60%
• Stage IV: 5–10%
```
134
What are the side effects of Opiates?
Vomiting in 30% of patients - central action on vomiting centre
Dysphoria - agitation
Constipation which needs to be managed as part of palliative care
135
What opioid receptors can be found in the GI tract? What are the MOA?
μ, δ, κ receptors expressed in GI tract
μ-receptors of paramount importance in GI
Receptor activation: G protein (G0) - direct interactions with channel proteins
Activates K+ channels
Inhibits Ca2+ channels
Main mechanism for analgesia and for decreased for motility
Increase transit time in colon so more H20 absorbed
Constipation
136
What do μ-receptors agonist cause?
Peristalsis and decrease gastric emptying
137
What do Enkephalinase inhibitors cause?
Enhance actions of endogenous enkephalins
