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Summary - Class notes - MOD2
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1508882400 Theme IA LT1-7
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What are the macroscopical aspects of cancer?Benign: small sometimes, well demarcated, slow growing, noninvasive, nonmetastatic, well differentation
Malignant: large, poorly demarcated, rapidly growing with hemorrhage and necrosis, locally invasive metastatic, poorly differentiated -
Waarin verschillen normale cellen van kanker cellen?grote hoeveleheid ovan irregulair gevormde delende cellen
Grote, variablee gevormde ncuclei
Relatief klein cytoplasma
Variatie in celgrootte en vorm
Verlies van normale gespecialiseerde cel eigenschappen
Disorganized arrangement of cells
poorly defined tumor boudnary -
What is HER2?HER2 is a protein that is presence in the membrane of breast cancer cells.
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What information gives immunochemistry?prognostic information of cancer (biomarkers)
predictive information of cancer (biomarkers)
both -
Immunochemistry, tumor typing, keratinepithelial lineage
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Immunochemistry, tumor typing, desminmyogenic tumors
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Immunochemistry, tumor typing, S100/Melan-Amelanoma
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Immunochemistry, tumor subtyping, P40squamous differentaiton
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Immunochemistry, tumor subtyping, TTF-1thyroid tumors, adenocarcinoma of the lung
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Immunochemistry, tumor subtyping, OC125Ovarian tumors
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Immunochemistry, tumor subtyping, GATA-3Breast and urothelial tumors
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What is fine needle aspiration?cytology
You make a cell analysis, used in cancer diagnostics.
It is easily done.
You can stick a needle in the swelling and you can analyze the cells quite easily and rapidly.
You can see size and shape of the nucleus and the amount of cytoplasm, but you can't see any detailed information about the proteins.
Palpable mass (eg thyroid, breast, skin, lymph node)
Rapid, only cellular information
DD reactive vs cancer
Mostly followed by biopsy -
What is molecular pathologyRecognition of the chromosomes in the cells.
Duplication of chromosomes is a general feature of cancer cells.
Chromosome instability will lead to genes which are neede dto grow -
Wat is HER2? hoe kun je dit voorkomen?HER2 receptoren op cellen. HER2 genen worden in grote hoeveelheiden geactiveerd in cancer cellen. Je kunt binding van deze groeifactoren voorkomen met behulp van trastuzumab.
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What is prefereable way in cancer diagnostics?histology
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What does sustaining proliferative signaling mean?Tumor cells are able to constantly signal themselves that they have to proliferate.
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What are agents of carcinogenesis?- Aging (more indolent behaviour)
- Exogenous (enviironmental) factors
- Chronic inflammation -> risk factor to cancer development
- Viruses -> if we can't clear the infection, they can develop malignant transfomrmation
- genetics -
What are exogenous factors in scrotal cancer?Soot. Not completely burned wood waste.
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What are environmental factors in cancer?Smoking <- increase in risk for many cancers: mouth, pharynx, larynx, oesophagus, pancreas, bladder , lung
alcohol consumption: oesophagus, HCC, upper respiratory tract, pancrease
DIet: colorectal and stomach cancer
Obesity and hormones: breast and endometrial cancer
Radiation
Sun: skin cancer -
What kind of cancer can sun exposure cause?UV light is dangerous
Basal cell carcinoma and squamous cell carcinoma are the most common cancer types.
Melanoma accounts for less than 1% of skin cancer cases, but the vast majority of skin cancer leads to death.
UV causes DNA damage in making a pyrimidine dimer. -
What are the risks of asbest?vezels hopen zich op in de narrow branhces of de longen en zorgen voor inflammation en scarring van de airways. Dit geeft een chronische hoest en pijn op e borst
- longkanker of mesothelioma
- pleural lining, plaque builds up and may restrict breathing
het heeft een latente periode van 20 jaar -
Hoe werkt viral carcinogenesis?Invloed op de celcyclus en apoptosis door:
- coderen voor eiwitten die de progressie van de celcyclus beïnvloeden
- integreren dichtbij cellulaire genen die de celcyclus progressie controleren. -
Wat zijn de meest voorkomende oncogenic viruses?HPV (cervical, vulva, penile, anal cancer)
Hepatitis B/C (liver)
EBV (hogdkin lymphoma, naso-pharyngeal cancer)
Human herpes virus (Kaposi sarcoma) -
What are central items of viral carcinogenesisHost susceptibility factors are important determinants
Viruses are seldom carcinogenic on their own
Viral infections are far more common than viral cancers
Prolonged periods are usually required
Viral strains may be different in their capcaity to cause cancer
Can be used for both preventive and therapeutic vaccination
One virus species can be associated with multiple tumor types -
What are the most common types in HPV?16 and 18, cause cervical cancer
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What do HPVE6?E6 binds to TERT -> increased telomerase expression, zodat tumorcellen oneindig kunnen blijven delen
E6 binds to p53 -> inhibition of P53 -
What does HPV E7?E7 binds to p21, inhibtion of P21, dat zorgt voor increased CDK4/cyclin D
E7 binds to RB-E2F -> inhibition of RB-E2F -
How does a EBV carcinogenesis exist?Latent infection with EBV
Polyclonal B cell expansion
Increased MYC protein because of DNA breaks
Outgrowth of neoplastic clone: burkitt lymphoma -
What are proto-oncogenes?promote tumor development, you don't have these genes in the genome, they have a role in embryogenesis and repair
they only become oncogenes, if they have tumor context, very much related to the hallmark of cancer, sustaining proliferative signals -
What are tumor suppressor genes?Gate keepers, they prevent that cells with damage survive. so they do cell cycle arrest and apoptosis
loss of expression
inactivting mutations
chromosomal loss -> los of genetic material -
What do oncogenes?Oncogenes are for proliferation and cell surivval
- increased expression
- activating mutations
- chromosomal gains -
You have a proto-oncogene, which mutations can occur?Translocation or transposition: new promoter: -> normal grwoth stimulating protein in ecess
Gene amplificiation: normal growth stimulation protein in excess
Point mutation: within a control element of an oncogene -> normal growth stimlating protein in ecess
Point mutation: within the gene: hyperactive or degradation resistant protein -
Which chekpoints do you have in the cell cycle (amongst others)After G1: G1/S checkpoint, check for DNA damage
Before mitosis: G2/M checkpoint, check for damaged or unduplicated DNA -
What is TP53?Central monitor of stress in the cell.
Can be activated by anoxia, DNA damage or inappropriate signaling by mtuated oncoproteins.
P53 is involved in cellcycle arrest, DNA repair, cellulair senescence and apoptosis.
If DNA damage is not successful, p53 induces apoptosis or senescence.
P53 can be inactivated by bi-allellic loss of functio TSG or by binding of viral oncoproteins, HPV E6 -
What stages of development are there from normal to neoplastic tissue with many non-malignant intermediate stages?Normal epithelium
Proliferation
Local invasion
Lymph node invasion
Distant metastases -
What kind of chromosome mutations are there?chromosome losses/gains
translocations
multi-locus deletions -
What kind of gene mutations are there?deletions/insertions
base pair substituions
frameshifts -
What are multi-locus deletions?Part of chromosome is lost. All the genes present on the deleted part are lost.
If this occurs on a chromosome you have two copies.
Leads to loss of function of the deleted alleles
Deletion on an autosomal chromosome: hemizygosity for multiple genes -
Wat houdt truncation van the gene in?Het eiwit kan door delete kleiner zijn, maar je hebt geen veranderend reading frame. Het eiwit is dan nog functioneel.
Een andere optie is dat je wel veranering in reading frame hebt.
Dan heb je een truncated protein en is je gen warschijnlijk niet meer functioneel. -
Wat gebeurt er met gen mutatie in de promotor?transcriptie efficiente beïnvloeden,
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Op welke plekken kunnen gene mutations plaatsvinden?intron: most often no effect on the function of the gene
promoter: may affect transcription efficiency
splice site: may affect splicing (eg exon skipping), nucleotides are 100% conserved, if you get a mutation in the intron this will cause skipping of the exon, and this can lead to loss of function
exon: may affect protein composition -
Welke soorten mutaties kunnen optreden?-1 frameshift: protein trunctation, er kan een stopcodon worden ingebouwd, geeft (partial) loss of function
nonsense mutation: er wordt een andere base ingebouwd, protein truncation: partial loss of function, kan een stopcodon geven
missense mutation: non-synonymous amino acid change: partial loss of function, maar hoeft niet, er wordt een andere aminozuur ingebouwd, kan nog steeds dezelfde functi hebben -
What are SNP?single nucleotide polymporphisms.
originally a sequence variant found in > 1 % within a population
common SNP; in 10% of all individuals
Will mostly not affect biological function, because if they would effect it, there would bes seltion
frequency is 1/100 bp, dus million SNP -
Whate are SNV?Differences in the DNA sequence between individuals (or within the human reference genome)
Does not need to affect biological function
Frequency ~1 /300 BP -
How much mutations before a malignant tumor?6-7 mutations
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How do you get oncogene activation?Coding mutation: amino acid will change, this will lead to abnormal protein which is always actiated .
Regulatory mutation: excessive amount of protein
Translocation: fusion in gene which will produce novel proteins
Gene ampfliciation: instead of one allele you might have multiple alleles, so excessively amount of protein.
So either you produce aprotein which is always active, or you produce way too much of the normal proteins
It always leads to gain of function -
Hoe werkt de activatie van RAS?GEF uitwisselaar van GDP naar GTP
GAP: verhoogt GTP ase activiteit, Pi wordt van GTP los gekoppeld -
What can go wrong in gene amplification?Double minutes (specules next to the normal chromosomes)
Homogenously staining regions (HSR) -> amplifcation on a normal chromosomal location -
Leg aan de hand van Burkitt Lymphoma hoe overproductie van een normaal eiwit kan plaatsvinden.~85% van de gevallen van Burkitt lymphoma is er een t(8;14) (q24;q32) translocation.
Hierbij komt MYC aan IGH vast te zetten
dit zorgt voor een up-regulated expression of structurally normal MYC protein (exon 1 is non-coding) -
Wat is fusion genes?mRNA with part of the BCR gene and part of the ABL gene.
- you get fusion protein which is constantly active and cannot be switched off
- you get fusion protein which is constantly active and cannot be switched off
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How to treat a bleed in DOAC use, IIa inhibitors?
stop the drug
give idarucizumab
give idarucizumab
How to treat a bleed in DOAC use, XA inhibitors
stop the drug
give prothrombin complex
if not effective give FEIBA or NOvoseven
give prothrombin complex
if not effective give FEIBA or NOvoseven
What can you do when you have bleeding dure to VKA?
skipping the VKA medication
small amount of oral vitamin K
vitamin K IV
prothrombin complex concentrate (II, VII, IX, X)
life threatening:
- c10 mg vitamin K intravenously
- prothromboin complex concentrate, dosage dpending on the INR and body weight
small amount of oral vitamin K
vitamin K IV
prothrombin complex concentrate (II, VII, IX, X)
life threatening:
- c10 mg vitamin K intravenously
- prothromboin complex concentrate, dosage dpending on the INR and body weight
What are vitmin K antagonists?
Vitamin K antagonists are used for the prevention and treatment of arterial and venous thrombotic disease.
In the netherlands phenprocoumon and acenocoumara..
There is a small therapeutic index.
The difference in the anticoagulant effect between thrombosis and bleeding is small.
Treatment with VKA has to be monitored with measurement of the INR.
The VKA inhibit the recyclling of vitamin K in the liver during syntehsis of vitamin K dependent clotting factors II< VII< IX< X
In the netherlands phenprocoumon and acenocoumara..
There is a small therapeutic index.
The difference in the anticoagulant effect between thrombosis and bleeding is small.
Treatment with VKA has to be monitored with measurement of the INR.
The VKA inhibit the recyclling of vitamin K in the liver during syntehsis of vitamin K dependent clotting factors II< VII< IX< X
What are side effects of factor concentrates?
allergic reactions: fever, urticaria, glottic oedema, anaphylactic shock, dizziness, nausea
Development of antibodies against the factor, inhibitor
Viral infections int he past: hepatitis A, b, c, hiv
Development of antibodies against the factor, inhibitor
Viral infections int he past: hepatitis A, b, c, hiv
What are side effects of DDAVP?
Headache, flushing, hypotension, fluid retention, hyponatremia.
How to treat hemophili?
Concentrates of factor VIII or X
Plasma derived or made by recombinant DNA techniques
prophylactically or on demand
Plasma derived or made by recombinant DNA techniques
prophylactically or on demand
What is the mode of action of tranexamic acid?
You have lysine binding sites at plasminogen.
Tranexamic acid is a lysine analogue, which binds to those binding sites.
Thereferore there will not be fibrin degradaation, since plasminogen can't bind to fibrin.
Tranexamic acid is a lysine analogue, which binds to those binding sites.
Thereferore there will not be fibrin degradaation, since plasminogen can't bind to fibrin.
How do you treat VWD?
DDAVP: release from VWF and FVIII from weibel-palade bodies. Depends on type VWD, not in type 2b, always to be tested
Clotting factor concentrate: intermediate purity factor VIII concentrate, contains both VWF and factor VIIIIc
Plasma dervied
recombinant conentrate is available
tarnexamic acid: inhibits fibrinoolysis
Clotting factor concentrate: intermediate purity factor VIII concentrate, contains both VWF and factor VIIIIc
Plasma dervied
recombinant conentrate is available
tarnexamic acid: inhibits fibrinoolysis
A 13 month old boy with severe hemophilia A presents with a bleed in his right knee. How to treat him?
Recombinat clotting factor VIII