Oncology Foundations Flashcards
Endoplasmic reticulum
Produces CYP metabolic enzymes
Circadian regulation
Clock/bmall per/cry regulate each other
Gravity can trigger rather than light
Methylation
Gene in off position
Decreased transcription
Chromosome
Gene: functional unit of heredity
Allele: alternative form of a gene
PXR
CYP 3A4 transcription factor
Gene imprinting
Silenced
Methylation
Can result in Prader-Willi Syndrome
Down syndrome
Trisomy 21
Type of aneuploidy
Genetically dominant
One allele determines phenotype over another allele
Translocation
Chronic leukemia
Philadelphia chromosome
Ring
Infertility
Recessive trait phenotype
Every other generation
Dominant trait
50% inheritance
Genomics
Structure/function character of the genome
Genome(genetic complement of an organism)
Most genomic medicine based on..
A Conformation
Pharmacogenes
2% of all genes
Genome maintenance
Signal transduction
Biochemical balance
Mitochondrial DNA
Circular
From mother
Can tolerate more damage
Contains all genetic information like chromosomes
Multiplicity of RNA
Alternative promoters on DNA
Alternative splicing of mRNA introns
General transcription complex (GTC)
Recognizes promoter TATA box
Promoter controls whether a gene should be transcribed
Expression differentiation
Transcription factor determines if gene is transcribed or not
4 types of transcription factors HHLZ
Proteins of different conformations that regulate gene transcription and expression
Helix loop helix :myo D muscle differentiation
Helix turn helix: pdx1
Leucine zipper
Zinc finger: PXR, estrogen receptor
Transcription factories
Transcription locations with Shared RNA polymerase
Genes with similar functions
Gene expression silencing RNA polymerase
Endo-siRNA
microRNA
Break down and modify mRNA after processed by si/microRNA
Silencing
mRNA production RNA polymerase
Heterogenous nuclear RNA
Protein translation RNA polymerase
pre-rRNA
rRNA
tRNA
Translation
AUG methionine start codon
RCCAUG starting sequence
Post translational modifications
Proteolytic processing generates protein diversity
Protein folding for degradation stability
Acetylation - activate
Methylation - silence
Phosphorylation- signal transduction
P53 tumor suppressor
Phosphorylate to activate and suppress tumor
Stress, UV radiation can activate kinase/acetyltransferase and p53 activation
Argonaute complex
Recognize and modify mRNA after processing small RNA(siRNA, microRNA)
Increase RNA degradation
Repress translation
Decrease transcription
Circular RNA counteract microRNA activity
4 Rules of genetic based diseases
1) genetic diseases are difficult to treat
2) most genetic alterations cause no phenotype changes
3) somatic DNA alterations (after birth) are the ultimate causes for cancer
4) DNA alterations may occur in promoter, coding region, and intron
Silence substitution
Substituted base that results in the same amino acid codon
Missense substitution
Substitution Forms a different amino acid
Frameshift
Insertion, deletion
Severe, changes multiple codons and downstream amino acids
Nonsense substitution
Forms a stop codon
Germline genetics
From parents, before birth
All cells in organism
Inheritable
Polynorphisms
Somatic genetics
After birth
Affected by environment
Small number of cells
Cancer
Most frequently used for sequencing
HiSeq
Cheapest, fastest 98% accurate though
Opposite Sanger: slowest, expensive
Sequencing analysis
DNA: genome
mRNA: expression
ChIP: protein-DNA interaction, global mRNA expression
EcoRI
Recognizes and cleaves DNA sequence
Endonuclease
Restriction fragment length polymorphism
Primer
Determines which gene is amplified in PCR
Short complementary DNA strand
The more PCR cycles needed, the lower the expression
PCR differentiation
Can detect insertion, deletion
Can differentiate by Endonuclease restriction digest
FISH
Fluorescent in situ hybridization
Probe for disease gene
Prenatal testing for trisomy 21
Mothers over 35
Increased prevalence with age
Amniotic fluid, placenta villi, ultrasound
Sickle cell disease
Single gene disease
Viral vector
Efficient
Costly
More dangerous/concerning
Reverse genetics
Determine a phenotype associated with a gene
Forward genetics
Determine a gene responsible for a phenotype
In vivo gene therapy
Nano particle, IV IM, plasmid, virus
insert corrected copy of gene
Ex vivo
Take cells out, introduce DNA sequence, see if working properly, inject back into patient
Carboxylesterases (CES)
Hydrolyze esters for activity
Tamiflu
Irinotecan to SN38 activation CES2
Plavix aspirin deactivation
Regulated by pharmacogenes
Assay that detects proteins
Western blotting uses antibody reveal protein of interest
Inmunocytochemistry-uses antibody to visualize the specific protein location of expression
Assay that detects activity
HPLC - chromatography
LC-MS mass spectrometry
Assay that detects mRNA
Northern blotting
RT-qPCR
ChIP
Gel electrophoresis
Separate based on charge and molecular weight
Protein expression
Histone acetyltransferase (HAT)
Increased transcription by acetylation
Co-activator with ligand
HDAC histone deacetylase
Remove acetyl to decrease transcription
Co-repressor
CAR transcription factor
Phenobarbital CYP2B activator
Overlaps with PXR to compensate if necessary
PXR
Rifampicin CYP3A4 activator
Largest binding domain
Flexible, lipophilic
Transcription factor (nuclear receptor) mutants
Contributes to individual variation of certain enzymes and transporter gene expression
Genetics
Individual gene-based
Genomics
Genome wide based variation and environment interaction
Histone methyltransferase
Leads to decreased transcription
Aryl hydrocarbon receptor (AhR)
Dioxin CYP 1A coactivator via AhR
PPAR peroxisome proliferator activated receptor
Clofibrate CYP4A coactivator
Poor 2C19 metabolism polymorphism
20% Asian
Aspirin resistance pharmacogenomics
Increased hydrolysis via increased CES2
Excessive COX expression
Aspirin irreversible COX inhibition
Plavix pharmacogenomics
Clopidogrel oxidized by CYP for activity
Lower activity if higher CES1 hydrolysis to metabolite
Resistance with decreased oxidation, increased hydrolysis, and ADP P2Y12 receptor mutations
Hyper responder decreased hydrolysis, increased CYP induction, low CYP competitive inhibition , high risk for bleeding
Senescence
Prevent further cell proliferation
Area for cancer research
Blastocyst
Embryo with stem cells inside for possible extraction
Induced pluripotent stem cells (iPS)
Adult cells able to undergo viral transduction to stem cells
Mature cells can be reprogrammed to become pluripotent stem cells
Trandifferentiation
Pancreas to liver cell
Specialized to specialized
Regenerative medicine
Replacing, regenerating human cells, tissues, organs to restore/establish normal function
Fetal liver stem cell enrichment with..
EpCAM epithelial cell adhesion molecule
Somatic cell cloning
Embryo developed from somatic cell genome
Molecular cloning
Common isolation of single gene sequence
Embryonic cloning
Blastocysts from one fertilized egg are developed into multiple embryos
Proliferation
Increase in cell number
Hyperplasia
Increase in cell number
Dysplasia
Increase cell number Abnormal morphology (pathological)
Carcinoma in situ
Cancer without spreading
Metastatic cancer
Carcinoma plus spreading
Five truths about cancer PRICD
Preventable Refractory Informative Curable Diagnosable
Malignant cancer suffixes
Carcinoma
Sarcoma
Hodgkin lymphoma
Features of neoplasm (benign and malignant)
Excessive growth
Apoptosis evasion
Limitless replication
Malignant features distinct
Sustained angiogenesis (ability to grow a blood vessel)
Invasion and metastasis
Abatable growth, migration, soft agar growth
Cancer progression
Initiated by DNA damage
Damaged cell proliferation
Progressive invasion and spreading
Metastasis is point of no return
Cancer stem cells
Induce cancer
Want to target CSC in addition to chemotherapy
Carcinogens
Full - no activation needed
Radiation, solid gel materials
Microorganisms bacteria, virus, parasite
H. Pylori stomach cancer chronic inflammation
HepB/C liver cancer, transfer of oncogenes that transform normal cells
Carcinogenesis
P53 tumor suppressor weakened More free radical damage Aging of telomeres Increased inflammation Immune cell apoptosis
Oncogene function/oncogenesis
Growth factor Cytokines Kinase Signal transducer Transcription factors
Immortalization Growth signal Enhanced survival via DEC1 Invasion Angiogenesis
Enhanced when tumor-suppressor genes are dysfunctional, silenced by epigenetic mechanisms: methylation, deacetylation, microRNA
Activated by mutation, overexpression, amplification, and translocation MOAT
Antioncogene function
Tumor suppressor genes
Antiproliferation Rb
Antimetastasis
Cell suicide
DNA repair BRCA
P53 does all 4!
Irinotecan
SN38 anti cancer activity by inhibition of topoisomerase
Want to promote CES hydrolysis to SN38
And ABC efflux into the blood from hepatocyte
Cancer cell resistant if able to efflux SN38
Perfect irinotecan candidate
Effective uptake in liver
Hydrolysis
Efflux SN38 from the liver
Nontoxic systemic levels
Effective uptake of SN38 and irinotecan
Hydrolysis
Minimal efflux of SN38
Topoisomerase dependence
Effective cancer therapy
Assessable oncogenes signaling in cancer
Known systemic and cancer exposure/perfusion
Fast therapeutic outcomes
Liquid biopsy
Circulating tumor cells/ CT DNA in blood
Sequence analysis for sensitivity/resistance
Xlinked dominance
Affects all female offspring from dominant father
X linked recessive
Primarily affects male offspring from recessive mother
Y linked
Affects male offspring
Karyotype
Number, gender, description of affected
Polyploid
Extra set
Lethal
Autopsy
Multi sampling
Non-designed
Tissue quality
