Growth Flashcards
What are the 3 cell types?
Labile, stable, permanent
Which cell type are continously cycled?
Labile
What can cause toomuch growth?
- Developmental
- Hamartoma
- Reactive/adaptive
- Hyperplasia
- Hypertrophy
What is a hamartoma?
• tumour-like overgrowth • grows in patient’s growth period • stops growing • tissues are normal for site, but excessive • e.g. pigmented naevi (“moles”) haemangioma
What is hyperplasia?
increase in cell numbers
• response to stimulus
• regression once stimulus removed
• increased size and function
What is normal physiological endocrine hyperplasia?
normal growth and development
puberty and pregnancy
What is pathological endocrine hyperplasia?
parathyroid/thyroids
chronic irritation/inflammation
What is hypertrophy?
increase in cell size • often occurs with hyperplasia • pure hypertrophy • muscle – mechanical stimulus skeletal - exercise smooth - pregnancy cardiac – LVH in hypertension
What is neoplasia?
growth which is uncontrolled and does
not stop and which persists after the
stimulus is removed
What happens in too little growth?
Developmental • agenesis • does not develop at all • aplasia • fails to develop normal structure • hypoplasia • less tissue formed
What is atrophy?
Decrease in size after growth • size and number of cells • can be physiological – in embryology Mechanisms • Imbalance of cell loss and production • apoptosis • not necrosis (mostly) • reduction in structural components of the cell – esp proteins
What is generalised atrophy?
nutritional – e.g. in starvation
• senile
• endocrine
• bone - osteoporosis
What is localised atrophy?
- ischaemic
- pressure
- disuse
- neuropathic/denervation
- immune mediated (autoimmune)
- idiopathic
What is metaplasia?
Abnormal differentiation
• change from one differentiated tissue to another
• within the same germinal layer
• result from changes in environmental demands
- epithelium
- mucous
- squamous
• mesenchymal
What is dysplasia?
abnormal growth and differentiation in a
tissue, with abnormal cells and tissue
architecture
• may be premalignant
What is ectopia?
• developmental
abnormality
• normal tissue
• abnormal site
What is a neoplasm?
• an abnormal mass of tissue
• growth of which is excessive
• and is unco-ordinated with that of normal
tissues
• and persists after the provoking stimulus is
removed
What is invasion?
unconfined growth into CT – the defining feature of
malignant tumours
What is metastasis?
spread distant from the primary tumour
What is cytology?
features of individual cells – often very abnormal
How can we classify neoplasms?
by clinical behaviour
• benign
• malignant
by histogenesis – tissue of origin
• epithelial – lining or glandular
• mesenchymal – various types
What is stroma?
supporting connective tissue of cancer cells
What are the effects of benign tumours?
pressure • obstruction • function – esp hormone secretion these vary by site and tumour • effect is not always “benign”
What is the pathology of malignant tumours?
– invade underlying tissues – cytologically abnormal – differentiation varies – well, moderate, poor – anaplasia
• stroma
– angiogenesis
– immune response
What is the cytology of malignant tumours?
variation in cell shape and size • variation in nuclear shape and size • odd mitoses • altered differentiation
What are 90% of tumours classified as?
Benign …
Which epithelial cancers are odd?
melanoma: melanocytes malignant • lymphoma • leukaemia bone marrow precursors • teratoma germ cell tumours most in testes, most malignant (ovarian tend to be benign) can mimic ANY tissue
Why do tumours arise?
• benign tumours
little known, many be inherited factors
genetic susceptibility to cancer
• inherited cancer syndromes
• single mutant genes, often tumour suppressor genes
• retinoblastoma, some colon cancers.
What is the defining feature of malignant tumours?
Invasion - unconfined growth into CT
What is direct growth by?
Surface apposition (bone added on surface by osteoblasts) and resorption (Bone being removed by osteoclasts)
What is sutural directed growth?
Sutures in membranous bones are growth centres and expression of growth at these sites changes shape
What is cartilage directed growth?
Cartilages are primary factor in craniofacial growth - growing cartilage replaced by bone
Suggested that this growth is genetically determined
Examples - spheno-occipital and spheno-ethmoidal synchondroses, nasal septum, condyle
What is the functional matrix theory?
Bone growth takes place in response to growth of surrounding tissues. Craniofacial growth as a response to functional needs that is mediated by adjacent soft tissue growth
2 matrices:
Periosteal matrix
Capsular matrix
Function of jaw changed to influence growth - orthodontics
What is the growth of the head dictated by in the early years?
Growth of the brain
What are facial changes in the early years 0-12 related to?
Synchondroses
What does post natal growth of the maxilla occur by?
Surface and sutural deposition
What is the change in position of bone called?
Drift
What does growth in length of the mandible occur by?
Cartilage replacement in the secondary growth cartilage at the condylar head
How does the mandible grow in height and length?
Resorption from the anterior surface and deposition on the posterior surface
Mandibular growth in height?
K
Condylar cartilage is not a true cartilage ..
.
Where are the existing stable anatomical locations of the mandible?
Mandibular canal
Retromoalr region
Mandibular symphysis
What are the two types of rotation of the mandible?
Matrix rotation - around the condyle
Intra-matrix rotation - within body of mandible
What happens to the face with backward rotation?
Gets longer with time, matrix rotation centred on the condyle
What can cause an anterior open bite?
Mandible growing downwards and backwards
What happens to the face in forward rotation?
Becomes shorter with time
What do children with adenoidal fancies have?
Increases in lower and total face height, narrow upper arches, retroclined incisors, difficulties in nasal breathing etc
What are the 2 phases of facial soft tissue growth during puberty?
Phase 1 ..
What are the 5 ways of assessing growth timing and rate of growth of the craniofacial structures?
Measurement of change in height. Secondary sexual characteristics Hand-wrist radiographs Radiographic assessment of cervical spine maturation Average growth increment s
Wha is a scammons growth curve?
Shows growth patterns of most systems of the body including the skeleton and muscle mass - height
What is the neural curve?
Graph of the growth of the brain, nervous system and associate structures
What is the atlas technique?
Ulnar sesamoid bone ossified at the start of pubertal growth spurt - looking for this bone on hand-wrist radiograph - comapred with the reference atlas
What is a cephalogram?
x ray of the craniofacial area
Assesses growth spurt in body height and mandibular size
3 cervical vertebrae examined on radiograph
What is the growth pattern and determinant of growth in infancy?
Rapid foetal growth
In infancy deceleration of the foetal growth rate
nutrition is determinant
What is the growth pattern and determinant of growth in Childhood?
Slow deceleration except mid childhood adrenal spurt
Growth hormone is determinant
What is the growth pattern and determinant of growth in puberty?
Pubertal growth spurt
sex steroids and growth hormone is determinant
What are 3 ways to measure bone growth?
- Growth charts - height/weight
- Bmi
- Bone age
What is the equation for BMI?
Mass (kg)/ height (m))^2
How is bone age used to measure growth?
Uses standardised x-rays to measure the maturity of each epiphyseal centre of the left hand wrist to derive a score
the age at which the score is on the 50th centile is the bone age of the individual
What is the name of one of the standard systems of bone age calculations?
Tanner and Whitehouse - quantify how much growth has occurred and how much is to come
What are the common causes of short stature or failure to thrive?
under nutrition, malabsorption - intestinal infection, CF, Crohns, Coeliac
individual and familial short stature
damage by alcohol, drugs, genetic e.g. downs
systemic disease - heart, lung, renal, haematological, diabetes mellitus, endocrine - hypothyroid/hypopituitary
iatrogenic - steroid excess
inherited - acondroplasia, hypophosphatasia, Noonan’s syndrome
What are environmental factors that can affect growth?
Drugs/Chemicals -
Thalidomide, Epanutin, Warfarin, Alcohol, Fluoride (teeth)
Radiation Infection Metabolic defects Hyperthermia Vascular Amniotic bands
What are some examples of multiple defects?
Associations
Sequences
Field complexes
Syndromes
What type of defect is common and often multifactorial?
Single system defect e.g. abnormal failed completion of embryonic process
What are associations?
Combinations of anomalies which are associated
statistically but underling mechanism not clear
What does VATER stand for? (association)
V Verterbral
anomalies
A Anal atresia
T Tracheo –
E Esophageal
atresia
R Radial and Renal anomaliesWhat does atresia mean?
Abscence or abnormal narrowing of a normal opening or passage in the body?
What is Potter’s sequence?
atypical physical appearance of a baby due to oligohydramnios experienced when in the uterus. It includes clubbed feet, bowed limbs, joint contractures, squashed faces. pulmonary hypoplasia and cranial anomalies related to the oligohydramnios (deficiency of amniotic fluid).
What is Pierre-Robin sequence?
a set of abnormalities affecting the head and face, consisting of a small lower jaw (micrognathia), failed palatal closure, a tongue that is placed further back than normal (glossoptosis), and blockage (obstruction) of the airways
What is a sequence?
a series of ordered consequences due to a single cause. It differs from a syndrome in that seriality is more predictable: if A causes B, and B causes C, and C causes D, then D would not be seen if C is not seen
What areas will need to be managed in Pierre Robin sequence
Breathing difficulties Feeding difficulties Cleft Palate Speech therapy Dental care Possible learning disability
What is a field complex?
Insult to a localised part of an embryo resulting in abnormalities in adjacent structures of disparate embryonic origin
What is an example of a field complex?
Eg Stapedial artery interruption in rodents hemifacial microsomia
What is an example of a syndrome?
Trisomy 21 - Downs’
What are some symptoms of trisomy 21?
Learning delay Cardiac Defects (70%) Relatively short neck, unstable atlanto-axial joint Short stature Increased risk of Leukaemia Hypotonia Hypothyroidism Epilepsy, Alzheimers Large, fissured tongue Periodontal disease Hypodontia Microdontia Enamel Defects Class 3 malocclusion due to maxillary retrognathia
What is williams syndrome?
- deletion of genes chromosome 7 Fault in calcium metabolism leading to xs calcium Failure to thrive in infancy Highly verbal and overly sociable Characteristic facial appearance “Elfin” Short stature Delayed growth Variable learning delay & behavioural problems Heart defects Susceptible to loud noise Renal calculi
Give some examples of general disorders of growth and development? (from lecture)
Osteogenesis imperfecta Down’s syndrome X-linked Vitamin D resistant rickets Cleidocranial dysostosis Achondroplasia Gigantism Acromegaly
Give some examples of dental disorders of growth and development? (from lecture)
Dentinogenesis imperfecta
amelogenesis imperfecta
What can DI be associated with?
Osteogenesis imperfecta
What are the three types of DI?
1) Mutation in Type I collagen. Associated with OI, Chromosome 7 and 17
2) Mutation in Dentine Sialophosphoprotein I Gene, Chromosome 4
3) Brandywine Isolate, Maryland Chromosome 4
DSPP mutation affecting non-collagenous proteins (DSP, DPP, DGP); variation in severity of presentation
What does DD stand for?
dentin dysplasia
What is DD type II a mild form of and what is DI type III a severe form of?
DI
What are the dental features of DI?
Amber, grey to purplish discolouration
Pulpal obliteration
relatively bulbous crowns, short narrow roots
enamel may be lost following tooth eruption, exposing soft dentine which wears rapidly
normal mantle dentine
affects primary> permanent
What are some of the signs of OI?
Bone fragility Multiple fractures Unstable vertebral column Blue sclera Progressive hearing loss Bisphosphonates- risk of osteonecrosis Dentinal changes
What are the signs and symptoms of X -linked vitamin D-resistant rickets?
Aka Hypophosphatemic rickets Rachitic changes in long bones Failure of distal tubular phosphate reabsorption Short stature Bowing of legs ↓Serum phosphate, ↑Alkaline phosphatase Large pulp chambers and elongated pulp horns Abscesses in the absence of caries
What defect causes achondroplasia?
defect in FGFR3 gene
Sporadic mutation in 75% and AD
What are the signs of achondroplasia?
Shortened arms and legs. Upper arms & thighs > than forearms and lower legs
Large head size, frontal bossing
Flattened nasal bridge
Crowding due to small jaws especially maxilla
What is cleidocranial dysotosis?
Defective development of intramembraneous ossification Short in stature Delayed closure of sutures Absent clavicles - can touch each shoulder together Frontal & parietal bossing Hypoplastic maxilla & zygoma Multiple unerupted teeth Multiple supernumeraries
What is gigantism caused by?
Overproduction of pituitary growth hormone
Usually due to adenoma - a benign tumour formed from glandular structures in epithelial tissue
What happens if there is overproduction of the pituitary growth hormone before and after fusion of the epiphyses in gigantism?
results in gigantism of whole skeleton
after - results in acromegaly
What is gigantism called in adults?
Acromegaly
What are the signs and symptoms of acromegaly?
Continued growth at the mandibular condyle Gross prognathism Macroglossia Spacing of the dentition Thickening of the facial soft tissues Overgrowth of hands and feet
What is a pseudogene?
section of a chromosome that is an imperfect copy of a functional gene
What are some functions of junk DNA?
used to produce noncoding RNA components such as transfer RNA, regulatory RNA and ribosomal RNA.
Landing spots for proteins that influence gene activity
Strands of RNA with myriad roles
Places where chemical modifications silence stretches of
chromosome
What is a promoter sequence?
Short sequence of bases upstream of the start of each gene where RNA polymerase recognises and binds to
What are the three types of RNA polymerase found in eukaryotes and what do they do?
Polymerase I - nucleolar region of nucleus, transcribes
large ribosomal RNA
Polymerase II - mRNA precursors
Polymerase III - small RNAs (tRNA), 5S ribosomal RNA
and other small DNA sequences
What is the importance of TFIID?
TFIID is the first protein to bind to DNA during the formation of the pre-initiation transcription complex of RNA polymerase II (RNA Pol II). Binding of TFIID to the TATA box in the promoter region of the gene initiates the recruitment of other factors required for RNA Pol II to begin transcription
where do most POL II genes have a TATA box?
25 – 35 bases upstream
of initiation site
What promotor contains the TATA box?
basal promoter
What are enhancers?
DNA sequences which can control efficiency
and rate of transcription. Regulate expression of genes in
specific cell type and control timing of gene expression
Why are promoter sand enhancers ‘cis’ acting elements?
they are on the same molecule of DNA as the gene they regulate
How can tumour promoting viruses and translocations cause cancer?
Tumour promoting viruses transform healthy cells by inserting strong promoters in vicinity of growth-stimulating genes, while translocations in some cancer cells place genes that should be “turned off” in the proximity of strong promoters and enhancers
Which end of the strand is transcription started?
5’
how can enhancers be brought closer to promoters?
Looping of the DNA due to interactions between proteins bound to the enhancer and those bound to the promoter
these proteins are called activators and the proteins that inhibit the looping are called repressors
What do enhancers contain?
binding site sequences for
transcription factors (TF)
and enhance/upregulate
transcription.
Active enhancers are bound by activating TF and brought into proximity of target promoters by looping.
Where do transcription factors bind?
bind to promoter and enhancer sequences
and recruit RNA polymerase. Basal transcription factors are
required at every promoter site for RNA polymerase interaction
(TFIID).
Why are transcription factors ‘trans’ acting elements?
they are encoded by a different gene to that they are regulating
What does RNA polymerase catalyse?
the sugar-phosphate bond between 3’-OH of ribose and 5’ PO4
What allows RNA molecules to have structural and catalytic functions?
The ability to fold into complexthree-dimensional shapes
What causes POL I to pause and release transcript? (transcription strand)
Termination of pol I genes by a termination factor = hair pin loop
What is the sequence AAUAAA required for?
The sequence AAUAAA is found near the polyadenylation site of eucaryotic mRNAs. This sequence is required for accurate and efficient cleavage (needed for release of polymerase from DNA template) and polyadenylation of pre-mRNAs in vivo
At which end are mature pol II mRNA’s polyadenylated?
3’ end
What 3 things happen as RNA polymerase moves down the strand?
- CAP on 5’ end - to stabilize the pre-mRNA,
essential for transport of RNA out of nucleus - Alternative splicing
- Poly(A) tail on 3’ end - cleavage at AAUAAA
(stop codon) by endonuclease then multiple adenosine
added, up to 250. This step needed for release
of polymerase from DNA template
Why does pre-mRNA need to be capped?
Protects from degradation
Serves as assembly point for proteins needed to recruit
small subunit of ribosome to begin translation
What is alternative splicing?
A mechanism by which different forms of mature mRNAs (so different proteins) (messengers RNAs) are generated from the same gene
- different splicing sites are selected - splicesomes
- plasticity allows for diseae development
What is an exon?
a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.
What are the two types of spliceosome?
Major – removes 99.5% of introns
Minor – removes remaining 0.5%
What are the two main functions of a spliceosome?
- Recognition of intron/exon boundaries
- Catalysis of cut and paste reactions which remove non-coding introns and stitch flanking exons back together
spliceosome contains both proteins and RNA’s
How are spliceosomes linked to disease?
Mis-splicing = rapid degeneration of mRNA
Mis-regulation of splicing factor levels = cancer
What are the 7 types of RNA?
- mRNA
- rRNA
- tRNA
- Non-coding RNA (ncRNA)
- Small nuclear RNA (snRNA)
- small nucleolar RNA (snoRNA)
- micro RNA (miRNA)
What does rRNA do?
Build ribosomes
What are the 4 kinds of rRNA?
18S - one of these along with other proteins
make the small subunit of the ribosome.
28S, 5.8S and 5S - one each of these, along with 45 other
proteins used to make the large subunit of the ribosome.
S = (Svedberg unit) sedimentation rate, related to mass and shape
What does tRNA do?
Each kind carries, at 3’ end, one of 20 amino acids
i.e. most amino acids have more than one tRNA
What does small nuclear RNA do?
RNA biogenesis and processing
several are part of spliceosomes
What does snoRNA do?
Participate in making ribosomes by helping to cut large precursor of 28S, 18S and 5.8S.
Modify many nucleotides in rRNA, tRNA and snRNA e.g. can add methyl groups to ribose
Implicated in alternative splicing of pre-mRNA
Template for synthesis of telomeres
What do miRNA do?
Tiny RNA molecules regulate gene function post-transcriptionally - estimated more than one third of protein
18-25 nucelotides long
Bind to mRNA and cause degradation – inhibits protein synthesis
what does DNA fingerprinting use to differentiate?
variable number of tandem repeats (VNTRs)
Repeating nucleotides (15 -100) 1kb to 20kb. Number of repeats and loci are inherited from your parents. Large variation of number of these regions between individuals
repeat regions bounded by specific restriction enzyme sites - restriction enzymes can cut the DNA at specific sequences - cuts the VNTR’s out
How is cDNA produced for PCR?
RNA is used to make cDNA from mRNA, then cDNA is multiplied by PCR , DNA can then be detected
What 5 things do you need for PCR?
template - DNA/cDNA nucelotides - A,C, G, T primers Taq buffer
What are the 3 steps of PCR?
- denaturation to break the cDNA double bonds - 94 degrees
- annealing - temperature lowered to 54 degrees to allow the primers to bond to the DNA template (45 seconds)
- Extending - when the temperature is raised and the new strand of DNA is made by the Taq polymerase enzyme. (2 mins 72 degrees)
Why does PCR detect the accumulation of DNA during the reaction?
Different amounts of DNA in starting sample and if measurements taken
at plateau the data would not truly represent the starting material.
Exponential phase is optimal point for analyzing data.
What does SYBR green bind to?
Any double stranded DNA
What are the advantages of real-time PCR?
Traditional measure at end-point and real-time collects data in
exponential growth phase
Increase in reporter fluorescence directly proportional to number of
amplicons generated
Increased dynamic range of detection
No post-PCR processing
Detection down to 2-fold change
What does in situ hybridisation detect?
localization technique for the detection of a gene product (RNA) in tissues
What is the transcriptome?
The transcriptome is the set of all RNA molecules in one cell or a population of cells.
What is proteomics?
– large scale study of proteins, particularly their structures and functions, includes post-translational modifications
What is metabolomics?
comprehensive characterization of small molecule metabolites in biological systems
What is a single nucleotide polymorphism?
DNA sequence variations when single nucleotide in genome sequence is altered
Many have no effect on cell function, others predispose to disease, influence response to drugs or environmental insults (bacteria, viruses, toxins, chemicals).
What specific gene is associated with periodontal disease?
An increase in a specific genotype of IL-1 gene
What molecule could control the inflammatory periodontal response caused by increased IL-1?
IL-1RA - interleukin-1 receptor antagonist is similar in structure to IL-1α and IL-1β and so competes with these for the surface receptor. It doesn’t cause ”normal” signaling ie acts as competitive inhibitor and could control the inflammatory response.
How many repeats of VNTRs is associated with perio?
2 repeats
What are the phases of the cell cycle?
S phase - replication of DNA G2 - cell prepares to divide M phase - cell division and cytokineses G0 - cells leave cell cycle that cease division G1 - cell grows S phase
Which phases of the cell cycle are collectively known as interphase?
G1, S, G2
What are the stages of the M phase?
Prophase - condensation of chromatin and disappearance of nucleolus
prometaphase - the nuclear membrane breaks apart into numerous “membrane vesicles”, and the chromosomes inside form protein structures called kinetochores. Kinetochore microtubules emerging from the centrosomes at the poles (ends) of the spindle reach the chromosomes and attach to the kinetochores, throwing the chromosomes into agitated motion.
metaphase - These chromosomes, carrying genetic information, align in the equator of the cell
anaphase - replicated chromosomes are split and the daughter chromatids are moved to opposite poles of the cell.
telophase -During telophase, the effects of prophase and prometaphase (the nuclear membrane and nucleolus disintegrating) are reversed. As chromosomes reach the cell poles, a nuclear envelope is re-assembled around each set of chromatids, the nucleoli reappear, and chromosomes begin to decondense back into the expanded chromatin that is present during interphase. The mitotic spindle is disassembled and remaining spindle microtubules are depolymerized
How is the cell cycle regulated? (3 places)
Extra & Intracellular signals
G1 checkpoint – growth & environment
G2 checkpoint – DNA replication
M checkpoint – chromosome alignment on spindle
What are cyclins?
Proteins that control the cell cycle
Where is cyclin D present?
G1 - cdk 4 and 6
Where is cyclin E and A present?
S phase
Where is cyclin B and A present?
M phase
What molecule has to associate with cyclin for it to carry out its task? What controls its activity?
Cyclin dependent kinases - phosphorylate cyclins to activate them
activity controlled by cdk inhibitors
Give some examples of cells that enter G0 phase?
Neuron, epithelial cell, red blood cells - specialised cells
How is the g0 phase activated?
Active repression of genes
Which protein blocks the cell cycle if DNA is damaged? (G2 checkpoint)
p53 (mutated in approx 50% of cancers including oral- hence tumour forms as cell cycle continues)
Which protein with reduced levels predicts a poor outcome in breast cancer?
p27 - less of an aid to cyclins if reduced levels
What type of genes are many cell regulatory genes?
Tumour suppressor genes
Why does apoptosis occur?
Destroys cells that may be a threat - virus infected, immune after inflammation has been dealt with, DNA damaged cells
What signals can trigger apoptosis?
Withdraw of positive signals such as growth factors, hormones
or if the cell receives negative signals e.g. UV, death activators, hypoxia
What processes happen to the cell in apoptosis?
Mild convulution chromatin compaction and margination condensation of cytoplasm breakup of nuclear envelope blebbing cell fragentation apoptotic bodies are phagocytosed
What are the differences in apoptosis and necrosis?
Apoptosis Controlled Energy dependent cells shrink Membrane intact Non-inflammatory No scarring Indiv. or small cell groups Nuclear fragmentation Physiological (or Pathol.)
Necrosis Uncontrolled No ATP required Cells swell No membrane integrity Inflammatory Scarring Large cell groups Nuclear dissolution Pathological
What is the intrinsic pathway of apoptosis?
Mitchondria senses various apoptotic stimuli
releases cytochrome C - involved in electron transport chain
binds to Apaf-1 protein
forms complex that initiates a cascade of proteolytic enzyme reactions - carry out degradation processes = apoptosis
What does bcl-2 bind to?
oncogene that binds to Apaf-1 protein - prevents complex formation with cytochrome C, which prevents apoptotic cells dying, this allows DNA damaged cells etc to stay alive
What is the intrinsic pathway of apoptosis?
Ligand binds to membrane receptor e.g. FasL to Fas
intiates cascade of phosphorylation reactions within cell transducing signal to activate enzyme cascade that carry out apoptosis
What are caspases?
Family of proteolytic enzymes - affectors of apoptosis (do the digesting)
- present as inactive proenzymes as don’t need them all the time
activated by proteolytic cleavage which activates another enzyme etc = cascade (all enzymes have different substrates and controlled by different mechanisms)
What does caspase 9 activate?
caspase 2, 3, 6, 7, 8, 10
