S4C4 Flashcards
What is the biopsychosocial approach to healthcare?
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
What is the COM-B framework?
Capability and Opportunity lead to motivation.
Behaviour links to them all
What is the PRIME theory?
Plans, evaluations, motives, and Impulses lead to response impacted by the internal and external environment
What is the health belief model?
Demographic variable lead to susceptibility, severity, costs, benefits, cues to action, health motivation, and perceived control. These all affect the likelihood of behaviour.
What is the self-regulation model?
Illness representation links to the emotional reaction. It also links to their coping behaviour for control of illness and emotion.
Describe multi-step tumorgenesis
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
What are viral oncogenes?
Viral genes that when introduced into cells have dominant transformative effects
What are cellular oncogenes?
Cancer DNA transfected into normal cells caused transformation, again in a dominant manner
What is the two-hit theory?
That you need 2 random sporadic hits on a tumour suppressor gene. (unilateral)
Describe a signalling pathway
Ligand Receptor Signaling cascade Transcription factors Delta gene expression
How does RAS become active?
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
How does RAS become inactive?
GAP (GTPase activating proteins) removes an inorganic phosphate making ADP bind to RAS
What happens when Wnt isn’t active?
GSK-3β is active, meaning Apc is active with an inorganic phosphate and β-catenin gets degraded
What happens when Wnt is active?
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.
How does Cyclin D1 become activated
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
What 2 things consistently change the genome?
Continuous damage
Continuous repairs
List examples on continuous damage to the genome.
oxidation replication errors UV x-rays chemicals mitosis
List examples on continuous repair to the genome
BER NER proofreading NHEJ DSBR/HR the SAC
What is senescence?
The condition or process of deterioration with age
In what type of cell is telomerase active?
Tumour cells
What is the end replication problem
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.
Why are liquid biopsies done?
Tumours shed cells and DNA into the blood
Minimally invasive and inexpensive
Advanced detection technology
What does CRP indicate?
produced in the liver
rises in response to inflammation
Why are Chemotherapeutic agents used? How are the classified?
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.
What side effects are associated with chemotherapy?
It’s associated with arangeof 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.
what are the general side effects of chemotherapy?
Gastrointestinal mucosa:mucositis→ stomatitis,esophagitis, enteritis associated withdiarrhoea
Hematopoiesis(myelosuppression)
Granulocytopeniaandlymphocytopenia(increased risk of infection)
Thrombocytopenia(increased bleeding risk)
Anemia(fatigue)
Hair follicles:hairloss
Chemotherapy-induced peripheral neuropathy
Pain, burning, tingling, and loss of sensation in the distal extremitiesthat spread from the hands and feet.
Typically spreads in a“stocking-glovepattern”
Causative agents includeplatinum-basedmedications (e.g.,cisplatin),taxanes(e.g.,paclitaxel), andvinca alkaloids(e.g.,vincristine).
Centrally inducedvomiting
Gonadal damage
What is neoadjuvant cytostatic therapy?
Administeredpreoperatively to reducetumormass
What is adjuvant cytostatic therapy?
Administeredpostoperatively to reduce risk of recurrence and/or to improve prognosis
What is Palliative cytostatic therapy?
Administered if curative therapy is not possible; indications vary
What is cytoreductive conditioning?
high-dosecytostatic therapy(sometimes in combination with whole body radiation)to suppress bone marrowbeforebone marroworstem cell transplantation.
What are the benefits of oral chemotherapy?
Oral administration of cytostatic drugsallows for outpatient treatment and avoids the need for inpatient hospitalization(e.g., for patients in need of palliative chemotherapy).
What cytostatic drugs can be administered orally? (classification : name)
Anthracyclines:idarubicin
Pyrimidine analogs:capecitabine
Alkylating agents:temozolomide
Topoisomerase inhibitors:etoposide
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
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
What is ALT involved in? What does an increase show?
Involved in gluconeogenesis - specific to hepatic cells
Shows hepatocyte damage
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
What causes increased serum bilirubin?
Cholestasis
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
What does ESR measure?
Measures the distance that erythrocytes have fallen after one hour in a vertical tube of anticoagulated blood
Elevated in infection
What causes increased urea levels?
Increased in severe renal failure, catabolic states and dehydration
What is GFR?
volume of primary urine that is filtrated by the kidneys over a certain amount of time per standardized body surface area
What is eGFR based on?
creatinine levels
What causes decreased ferritin?
iron deficiency and nephrotic syndrome
What causes increased ferritin?
acute phase reaction and iron overload
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
What is a carcinoma in situ?
abnormal cells have not spread beyond where they first formed
Define a malignant tumour.
Cancerous cells which have invaded and destroyed nearby tissue, possibly spread to other parts of the body
What happens in the S-phase of the cell cycle?
Genome duplication
What happens in the G2-phase of the cell cycle?
Genome segregation
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
What is another name for Cdc2?
Cdk1
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.
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
What inhibits cyclin-Cdks?
Cyclin-dependent kinase inhibitor (CKI)
What does p57, p27 and p21 inhibit?
E-CDK2
A-CDK2
A-CDC2
B-CDC2
What does p15, p16, p18 and p19 inhibit?
D-CDK4/6
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
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.
What can cause p53 activation?
lack of nucleotides UV radiation ionising radiation Oncogene signalling Hypoxia blockage of transcription
What are the 4 mechanism that p53 controls?
Cell cycle arrest
DNA repair
Block of angiogenesis
Apoptosis
How does p53 cause cell cycle arrest?
Activates p21 This causes inhibition of: E-CDK2 A-CDK2 A-CDC2 B-CDC2
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
What are the 3 subtypes of cancers?
POLE hyper mutated <1%
Microsatellite instability 9%
(Prioritised for immune checkpoint therapy)
Microsatellite stable 90%
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
What are the N stages of rectal cancer?
N0 - no lymph nodes affected
N1 - <3 lymph nodes affected
N2- >4 lymph nodes affected
What are the M stages of rectal cancer?
M0 -no distant organs affected
M1 - spread to distant organs
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)
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
What are the intrinsic pathway to inflammation in tumour cells?
Normal tissue homeostasis disrupted Sequential mutations Epigenetic alterations Oxidative stress Proliferation / apoptosis dysregulation
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
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.
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
How much H20 is absorbed a day?
- 4L absorbed in total per day
- 5L in small intestine
- 9L in colon
What is the route of H20 through the large intestine?
Via junctional complexes between cells or
Via SGLT1 And a.a. Transporters
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
What do glucocorticoids and somatostatin do?
Increases net absorption of water and electrolytes by increasing the action the basolateral sodium-potassium ATP-ase.
What type of surface does the GI tract have?
Undulating - increases SA
What is a Peyers patch?
Lymph follicle
What do M cells do?
Antigen sampling
Transports antigens from lumen
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
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
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
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
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
What cell type is the epithelium?
Simple columnar
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.
What cells are found in Oxyntic glands? (from base of gland)
Chief cells Endocrine cells Parietal cells Mucous neck cells Surface mucous cells
What do enterocytes do?
Absorb nutrients
make up 1% of mucosal cells
What do CBC cells do?
Tissue self-renewal
What do enteroendocrine cells do?
Endocrine signalling
What do goblet cells do?
Mucus secretion
What do tuft cells do?
Opioid release
Prostanoids production
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
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
What cytokines and transcription factors are needed for Th1 differentiation?
IL-12, IFNγ
STAT1, STAT4, T-bet
What cytokines and transcription factors are needed for Th2 differentiation?
IL-4
STAT6, GATA3, IRF4
What cytokines and transcription factors are needed for Th17 differentiation?
IL-6, TGFβ
RORγt, RORα, STAT3, IRF4
What cytokines and transcription factors are needed for Treg differentiation?
TGFβ
SMAD, FoxP3
What effector cytokines does Th1 produce? What do they inhibi?
IL-2, IFNγ
Inhibit Th2 and Th17
What effector cytokines does Th2 produce? What do they inhibi?
IL-4, IL-5, IL13
Inhibit Th1, Th17
What effector cytokines does Th17 produce? What do they inhibi?
IL-17, IL-22, IL-21
Inhibit Th2 and Th1
What effector cytokines does Treg produce? What do they inhibi?
IL-10, TGFβ
Inflammatory suppression of Th1, Th2, Th17
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
What is the function of ILC1?
IFN-gamma producers
Includes NK cells
Express T-bet
What is the function of ILC2?
IL5/ IL13 producers Express RORα/GATA3 Seen in allergy Respond to IL25/IL33 Aka natural helper cells
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
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
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
What happens in Dysbiosis?
Dendrite decretes IL-23, IL-12 and TNF
Causes differentiation to Th1 and Th17 causing an inflammatory environment
What can stop T cell activation?
CTLA4 / B7 interaction between T cell and antigen presenting cell
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
What are positive regulators of inflammatory microenvironments?
TNFα
IL-6
CCL2
CC chemokines
What are positive regulators of inflammatory microenvironments?
TGFβ IL-10 TIR8 D6 Cox-2
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
What is the MOA of citalopram?
SSRI
What is the MOA of ventolin inhaler?
Aka salbutamol
Short-acting selective beta2-adrenergic receptor
Bronchospasm prevention
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
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
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
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
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
What impact does IBD have on overall risk of CRC?
4-20 times higher
What impact does T2DM have on overall risk of CRC?
Increase by 50%
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
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
What are the RHS -specific symptoms of CRC?
Iron deficiency anemia
Melena
Diarrhea
What are the LHS -specific symptoms of CRC?
Changes in bowel habits(size, consistency, frequency)
Blood-streaked stools
Colicky abdominalpaindue to obstruction
What are the rectum/sigmoid -specific symptoms of CRC?
Hematochezia ↓ Stoolcaliber(pencil-shapedstool) Rectalpain Tenesmus Flatulence with involuntary stool loss
How many CRC are adenocarcinomas?
95%
What is the pathology of CRC?
Adenocarcinoma(most common):95% arise from adenomatous polyps
Theadenoma-carcinoma sequenceis the progressive accumulation of mutations inoncogenes(e.g.,KRAS) andtumor suppressor genes(e.g.,APC,TP53) that results in the slow transformation ofadenomasintocarcinomas.
APC genemutation (loss of cellular adhesion and increased cellularproliferation) →KRAS genemutation (unregulated cellular signaling and cellularproliferation) →TP53andDCC genemutation (malignant transformation ofadenomatocarcinoma)
Microsatellite instability: due tomethylationor mutations inmismatch repair genes (MLH-1 andMSH-2)
Why is long-term use of aspirin and NSAIDs protective?
COX-2overexpression: associated with colorectal cancer. Thus, the possible protective effect oflong-termuse ofaspirinand otherNSAIDs
When should you take a palliative approach to CRC?
distantmetastasesbeyond theliverand/orlungor if the patient is not a surgical candidate due to poor general health
Treatment involves palliativechemotherapy.
What is the prognosis of CRC?
Overall5-yearsurvival 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%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
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
What do μ-receptors agonist cause?
Peristalsis and decrease gastric emptying
What do Enkephalinase inhibitors cause?
Enhance actions of endogenous enkephalins
