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MD2002 > WEEK 9 > Flashcards

WEEK 9 Flashcards

1
Q

Describe the structure of a chromosome.

A

Centromere in middle
Has a long arm (q) and a short arm (p)
The tips of it = telomeres. These give the chromosome stability

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2
Q

How is a chromosome recognised? (HINT: there’s 3 ways)

A
  1. Banding pattern with specific stains
  2. Length
  3. Position of centromere
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3
Q

What is an acrocentric chromosome? What chromosome numbers does this happen to?

A

The short arm is almost non existent and so therefore it doesn’t really matter
- Chromosomes 13, 14, 15, 21, 22.

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4
Q

What are the various chromosome changes which cause disease? (HINT: there’s 2)

A
  1. Balanced chromosomal rearrangement
    - all the chromosomal material is present
  2. Unbalanced chromosome rearrangement
    - extra/missing chromosomal material
    - usually 1 or 3 copies of some of the genome
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5
Q

Explain what abnormality has occurred in (i) Down Syndrome (ii) Edwards Syndrome (iii) Patau syndrome (iv) Turner Syndrome.

A

(i) trisomy of chromosome 21
(ii) trisomy of chromosome 18
(iii) trisomy of chromosome 13
(iv) females that lack an X chromsome (45X)

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6
Q

What disease results from a chromosome complement of (i) 47XXX (ii) 47XXY ?

A

(i) triple X (trisomy X)

(ii) Klinefelter Syndrome

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7
Q

What is a robertsonian translocation?

A

When 2 acrocentric chromosomes are stuck end to end
- normally the individual wouldn’t show any phenotype of this
However, if someone with this chromosomal pattern has children, then there’s an increased risk of trisomy:
have a 1 in 4 chance of normal, balanced translocation, trisomy 14 (miscarriage), trisomy 21 (down syndrome)

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8
Q

What is a reciprocal translocation?

A

When fragments of the chromosomes are translocated, can either result in dicentric and acentric translocation (which is not stable in mitosis), or the exchange of 2 acentric fragments which is stable
When a parent with a reciprocal translocation, there offspring have a 1 in 4 chance of:
normal
balanced 1;9 translocation
partial trisomy 9 & monosomy 1
partial trisomy 1 & monosomy 9

E.g. MUM = 46, XX, t(12;17)(p13;p13)
SON = 46, XY, der(17)t(12;17)(p13;p13)

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9
Q

What are the reproductive risks of reciprocal translocations?

A

For most translocations, approx. 50% will have either normal chromosomes or the balanced translocation
Unbalanced products result in:
- Miscarriage (if large segments translocated)
- Dysmorphic delayed child (if small segments)

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10
Q

What is the Philadelphia chromosome?

A

Occurs in leukaemia (very common in CML)
Some of chromosome 9 is translocated onto chromosome 22
=> giving it increased activity compared to normal (this is what drives cancer)
E.g. 46, XY, t(9;22)(q34;q11.2)

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11
Q

What are the types of single chromosome mutations? Give examples of diseases/syndromes that arise as a result of said mutations.

A
  1. DELETION
    - X linked ichthyosis
  2. DUPLICATION
    - Charcot marie tooth disease = damage to the myelin sheath in peripheral nerves => progressive loss of muscle tissue & touch sensation (pain remains intact)
  3. INVERSION
    - inv(9)(p11;q12) = commonest
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12
Q

What is quantitative inheritance?

A

When both genetic and environmental factors contribute to determining the risk of disease.

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13
Q

Why are complex traits probabilistic?

A

Because even if you have all the susceptible alleles, the disease still depends on whether you encounter certain environmental hazards

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14
Q

What is the difference between a mutation and a polymorphism?

A

A mutation is when a gene change directly causes a genetic disorder
A polymorphism is any variation in the human genome that has a population frequency of greater than 1% OR any variation in the genome that doesn’t cause disease in its own right, but it may predispose to disease

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15
Q

What are the 2 ways to measure the genetic contribution to a disease? Describe both.

A
  1. FAMILY STUDIES
    - this method doesn’t take into account a risk caused by a shared environment
    E.g. males are more prone to disease (=> have a lower liability threshold), if a female is affected, she must be at the high end of the curve (i.e. need more “contributing” genes)
  2. TWIN STUDIES
    - monozygotic share all genes, dizygotic share about 50%
    => for a disease w. genetic contribution, you would expect a monozygotic twin to be affected more frequently than a dizygotic twin
    BUT this doesn’t take into account that being a monozygotic twin itself predisposes to disease
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16
Q

What is used to find out whether a polymorphism contributes to a disease? What are the potential problems with these studies? How are these problems overcome?

A

ASSOCIATION STUDY METHOD
- look at affected and non affected and work out who has polymorphism and who doesn’t in each group
POTENTIAL PROBLEMS:
- how do u know which gene to look at as the disease could be influenced by 1 or 1000 genes
- how do you know which polymorphism to look at as there’s 10-12 mil in the human genome
- when you’re using many polymorphisms, some will give a significant result by chance, so which are true?
- Your control group has to match affected group
OVERCOME:
- Testing the whole genome and then working out what ones are significant

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17
Q

What are some of the characteristic of multifactorial diseases?

A
  • they exclude single gene/syndromic forms (rare)
  • there’s a higher recurrence risk if:
    (i) more affected family members
    (ii) more severely affected family members
  • risk or recurrence data is calculated empirically (gene tests rarely help unless there’s a monogenic form of disease)
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18
Q

What is the definition of (i) Differentiation (ii) Fate (iii) Potency?

A

(i) process by which embryonic cells become different from one another, involving the emergence of cell types such as muscle, nerve, skin and fat cells
(ii) describes what a cell will become in the normal course of development
(iii) the entire repertoire of cell types a particular cell can give rise to in all possible environments

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19
Q

What are the 2 stages of commitment? Describe them.

A

(1) SPECIFICATION (reversible)
- capable of differentiating autonomously if placed in isolation BUT can be respecified if exposed to certain chemicals/signals
(2) DETERMINATION (non-reversible)
- cells will differentiate autonomously, even when exposed to other factors or placed in a different part of the embryo

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20
Q

How does a naive cell become specified?

A 
INTRINSIC SIGNAL (cytoplasmic determinant)
- autonomous signal tells cell "WHO it is"
EXTRINSIC SIGNAL (induction)
- chemical/molecule in environment that gives cell spatial info, tells cell "WHERE it is"
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21
Q

What is competence?

A

The ability of a cell to respond to the chemical stimuli

- A cell can lose competence by changes in the surface receptor or intracellular molecules

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22
Q

How can gene activity be reversed experimentally?

A

By somatic cell reprogramming, if:

  • Therapeutic cloning: creating ES cells through Somatic Cell Nuclear Transfer
  • By defined Factors: creating IPS (induced pluripotent stem) cells
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23
Q

What does differentiation establish?

A

A tissue specific pattern of gene activity, which is passed onto daughter cells

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24
Q

What is the patterning of bone and tissue regulated by?

A

HOX genes

- HoxA and HoxD are very important for limb development

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25
Q

What are the 2 types of stress?

A

DISTRESS
- harmful and damaging

EUSTRESS
- beneficial and constructive

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26
Q

Describe one assessment of major and minor life events.

A

MAJOR = Social Readjustment Rating Scale (SRRS)
- based on the adjustment required for certain life events
- list of life events rated on a scale of 0-100.
- adult indicates what events have happened to them within the past 12 months and the values are added to give a total score
MINOR = Hassels scale
e.g. HASS/Col
- day to day unpleasant OR potentially harmful events

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27
Q

What are the main sources of life event stressors?

A
  1. INDIVIDUAL
    - illness, conflict, personal relationship, lacking control
  2. FAMILY
    - divorce, marriage, illness, disability, death, addition to family
  3. SOCIETY
    - job, environment
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28
Q

What are the stages that a cell undergoes to induce cancer?

A

Normal - Dysplasia - Carcinoma in situ - Invasion - Metastasis

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29
Q

In order to generate neoplastic cells, what must cancer cells undergo?

A

Oncogene activation
AND
Tumour supressor gene inactivation

30
Q

What can oncogenes do? Give examples alongside what cancers they target. (HINT: there’s 4)

A
  1. Growth Factor = sis
    - used for fibrosarcoma
  2. Growth Factor Receptor = erbB2
    - used for breast cancer
  3. Signal Transducer = ras
    - used for colon cancer
  4. Transcription Factor = myc
    - used for Burkitt’s lymphoma
31
Q

What are the 4 ways in which oncogenes work?

A
  1. Direct stimulation of cell cycle dependent transcription
  2. Increased/activation of growth factor receptors
  3. Increased growth factor
  4. Interference with intracellular signalling
32
Q

Within the context of tumour suppressor genes, explain the words caretaker and gatekeeper? Relate these words to p53 and why it is so special.

A

CARETAKER:
- maintain the integrity of the genome by promoting DNA repair (nucleotide excision repair, mismatch repair or DNA double strand break repair)
GATEKEEPER:
- inhibits proliferation (or promotes cell death in those with DNA damage)
- sends negative signals to the cell

33
Q

What does p53 do? (HINT: there’s 4 things)

A

cell cycle arrest
DNA repair
block of angiogenesis
(apoptosis)

34
Q

What problem can arise in tumour suppressor genes?

A

RETINOBLASTOMA

  • tumour in the eye that is common in children
  • in order for cancer to arise, must have the mutation in BOTH suppressor genes (as stated by Knudson’s 2 hit hypothesis)
35
Q

What are the “7 deadly sins” that occur in cancer?

A
  1. self sufficiency in growth signals
  2. insensitivity to growth-inhibitory signals
  3. Evasion of apoptosis
  4. Defects in DNA repair
  5. Limitless replicative potential
  6. Sustained angiogenesis
  7. Ability to invade & metastasise
36
Q

What occurs during metastasis?

A

Tumour cells detach from each other because of reduced adhesiveness
Cells then attach to the BM via the laminin receptors
Cells secrete proteolytic enzymes - including type IV collagenase & plasminogen activators
Degradation of the BM & tumour cell migration follow

37
Q

What is the process of angiogenesis? Describe the difference between a normal blood cell and that containing cancerous cells.

A

Cancer cell secretes the protein VEGF, which stimulates endothelial cells to grow
- the endothelial cells then secrete MMPs which digest the surrounding matrix
NORMAL:
mature network, stable
structure&function of wall & network appropriate to location
TUMOUR:
evolving network, unstable
abnormal structure & function
inappropriate to location

38
Q

What is the process of endochondrial ossification?

A

Bone growth occurs in a process called endochondrial ossification.
A cartilage model is first formed from mesenchymal cells differentiating into chondroblasts.
Ossification (osteoblasts replace the cartilage) begins in the diaphysis at the primary ossification centre BEFORE birth. After birth bone will continue to grow in a similar way but starting at the epiphyses (secondary ossification centre).

39
Q

What is the epiphyseal plate?

A

The cartilage between the primary and secondary ossification centres.
It continues to form new cartilage, which is replaced by bone, in a process that results in an increase in length of the bone.

40
Q

Describe the cessation of bone growth.

A

Growth in height ceases at the end of puberty

  • sex steroids stimulate the growth spurt but they also promote the closure of the epiphyseal plate(s)
  • growth in length ceases, cell proliferation slows, and the plate(s) thins
  • the plate is invaded by blood vessels, and the epiphyseal & diaphyseal blood vessels unite
  • this may leave a line visible on x-rays
41
Q

What does normal growth and development of bone require?

A

Calcium, Phosphorus, Vitamin A,C,D

- and a balance between growth hormone, thyroid & parathyroid hormones, oestrogen & androgens

42
Q

What is the function of the resting zone in epiphyseal plates? What disease can occur in this zone and as a result of what defects? (HINT: there’s only 1 disease)

A

(i) Matrix production
(ii) Diastrophic dwarfism
(iii) Defective collagen synthesis OR processing of proteoglycans

43
Q

What is the function of the growth zone in epiphyseal plates? What diseases can occur in this zone and as a result of what defects? (HINT: there’s 4 diseases)

A

(i) Cell proliferation
(ii) Achondroplasia
Malnutrition
Irradiation injury
Gigantism
(iii) Deficiency in cell proliferation and/or matrix synthesis
Increased cell proliferation

44
Q

What is the function of the hypertrophic zone in epiphyseal plates? What diseases can occur in this zone and as a result of what defects? (HINT: there’s 2 diseases)

A

(i) Calcification of matrix
(ii) Rickets
Osteomalacia
(iii) Insufficiency of calcium or phosphate for normal calcification

45
Q

What is the function of the metaphysis zone in epiphyseal plates? What diseases can occur in this zone and as a result of what defects? (HINT: there’s 3 diseases)

A

(i) Bone formation, vascularisation
(ii) Osteomyelitis
Osteogenesis Imperfecta
Scurvy
(iii) Bacterial infection
Abnormality of osteoblast & collagen synthesis
Inadequate collagen turnover

46
Q

Describe the difference between (i) cortical and (ii) cancellous bone in terms of location, structure, function, periosteum, turnover, blood supply and fracture patterns.

A 
Location: (i) shafts of long bones (ii) ends of long bones, vertebral bodies, flat bones
Structure: (i) Haversian systems (ii) trabeculae w. intercommunicating spaces
Function: (i) mechanically strong (ii) metabolic
Periosteum (i) Thick (ii)Thin
Turnover (i) Slow (ii) Rapid
Blood Supply (i) Slow (ii) Rich
Fracture Patterns (i) Direct/indirect violence may result in deficits at fracture site leading to non-union
(ii) Honeycomb structure fails as a result of compression (e.g. a fall from height compacts the bone)
47
Q

What are the various types of fracture patterns? (HINT: there’s 7)

A 
Transverse
Linear
Oblique displaced
Oblique non-displaced
Spiral 
Greenstick 
Comminuted
48
Q

Describe (i) Avulsion fracture (ii) Buckled fracture (iii) Compression/wedge fracture (iv) Pathologic fracture (v) Stress fracture.

A

(i) Fragment of bone is separated from the main mass
(ii) Aka impacted/torus fracture. End are driven into each other, is most commonly seen in arm fractures in children
(iii) Usually involves the vertebrae
(iv) Caused by a disease that weakens the bone
(v) Hairline crack

49
Q

What fractures are limb threatening/ impose a risk of non-union?

A 
dislocation
comminuted
compound
compartment syndrome
vascular/nerve injury
significant soft tissue injury
pathological bone
50
Q

Describe what happens in bone healing following a fracture.

A

Fracture healing depends on the activity of osteoblasts in the local periosteum
- it takes 2-20 weeks for healing depending on (1) the severity & position of the fracture (2) the age of the patient

51
Q

What are the 3 major phases of callus formation? Describe each phase.

A

(1) REACTIVE PHASE
- fracture & inflammation phase (haematoma)
- fibroblasts in the periosteum proliferate to form granulation tissue around the fracture site
(2) REPARATIVE PHASE
- callus formation: osteoblasts quickly form woven bone, to bridge the gap
- woven bone: weak, as the collagen fibres are arranged irregularly
- lamellar bone: laid down. Collagen is organised in regular sheets to give strength and resilience
(3) REMODELLING PHASE
- remodelling by osteoclasts restore the original shape of bone

52
Q

What is the (i) conservative and (ii) intervention treatment used for fracture healing?

A

(i) =simple fracture with a low risk of non union
- is dependent on the natural healing process
- +/- immobilisation
- rehabilitation
(ii) = fractures with a limb threat/risk of non-union
- augment natural healing with replacement or strengthening
- +/- immobilisation
- rehabilitation

53
Q

What are the 5 major categories of chemical carcinogens?

A
  1. Chemical Carcinogens
  2. Cigarette Smoking
  3. Risk from Carcinogens in Diet
  4. UV-Light Carcinogenesis
  5. Radiation Carcinogenesis
54
Q

What are the 4 stages in the mechanism of chemical carcinogenesis? Describe each stage.

A

INITIATION (mutagenic): involves cellular genome mutations in TSG & oncogenes. Carcinogen is involved in this process
PROMOTION (reversible): not mutagenic. Stimulates proliferation & causes both normal & mutated cells to proliferate. E.g. TPA (phorbol esters), dioxin (polycyclic aromatic compounds)
PROGRESSION (irreversible): Enhancement/repression of gene expression. Selection fo neoplastic cells for optimal growth of genotype/phenotype in response to the cellular environment.
MALIGNANCY

55
Q

In what two situations do tumours develop, in terms of carcinogen & promoter dose?

A

High dose carcinogen

Low dose carcinogen & promoter

56
Q

Discuss chemical carcinogenesis of the bladder, including the mechanism of action.

A

Common in dye industry, carcinogenic compound = 2NTA (used in dyes & rubber). Its use is now banned.
MoA: Aromatic amines (2NTA) are pre-carcinogens, requiring activation.
LIVER: converts 2NTA to 2 amino-napthol (carcinogenic metabolite). Then detoxified to glucuronide & excreted by the kidneys. BUT, when it reaches the bladder, where human urothelial cells express beta-glucuronidase, which converts glucuronide to a carcinogen.

57
Q

What did Percival Pott discover? Mention the carcinogenic substance responsible for said discovery.

A

A link to scrotal cancer to chimney sweeps exposed to soot

3,4-Benzpyrene

58
Q

What is asbestosis? What does it predispose to? What is the significance of “blue” asbestos fibres?

A

The formation of scar tissue in the lung as a result of asbestos exposure
Predisposes to bronchogenic carcinomas, increasing the risk by a factor of 5
Carry risk of mesothelioma - a rare tumour that has a 25-45 yr latent period.

59
Q

Discuss asbestos exposure as a chemical carcinogen.

A

Asbestos = fibrous silicase substance
When inhaled, needle like fibres coated in proteins & their presence excites macrophage & giant cell response.
Risk of asbestos related cancer is higher (1:50) in smokers compared with non-smokers.

60
Q

What is the ratio of increased risk of lung cancer for a non-smoker vs a smoker?

A

1:22

61
Q

What is the function of Benzopyrene?

A

Leads to guanine mutations in K-Ras & p53 in regions found to be mutated in smoking-induced lung cancer.
K-Ras (ch12) & p53 (ch17) = 2 genes most frequently mutated in smoking related lung cancers. If not corrected by the cell’s DNA repair mechanism, this guanine ‘adduct’ is misread as a thymine by DNA polymerase. Ultimately, the original G-C base pair may be replaced by a T-A base pair (=TRANSVERSION)

62
Q

What is the relation of Benzopyrene to cigarette smoking?

A

Cells treated with benzopyrene show the same spectrum of G-T transversions as found on the K-Ras & p53 of smokers
These mutational ‘hot spots’ map well to the guanine binding sites of the Benzopyrene derivative Bap epoxide

63
Q

What is the active carcinogen in tobacco smoke? What is it converted to?

A

The polycyclic aromatic hydrocarbon 3,4-benzpyrene (benzo[a]pyrene)
Converted by Aryl Hydrocarbon Hydroxylase (AHH - which is upregulated in smokers) into Benzo[a]pyrene diol epoxide that binds to the DNA, forming damaging adducts.

64
Q

What is the function of Glutathione S Transferase?

A

It detoxifies caricnogens.
GSTM1 is polymorphic in population, being null in 30-50% of ppl depending on their ethnic group.
Homozygous null individuals have an increased risk of lung cancer & smoking induced bladder cancer.
NOTE: In some heavy smokers, AHH may not be expressed and so DNA binding epoxides are not generated.

65
Q

What is transitional cell carcinoma?

A

Can arise anywhere in the urothelium, but is most common in the bladder.
Is often multifocal & has a tendency to recur.

66
Q

Discuss the risk that passive smoking has on cancer.

A

Increases risk of lung cancer by about 15-24%.
Many potentially toxic gases are present in higher concentrations in sidestream smoke than in mainstream smoke.
Nearly 85% of smoke in a room results from sidestream smoke.

67
Q

What is the risk from carcinogens in the diet (with respect to nitrites & nitrates)?

A

The gut bacteria converts nitrites & nitrates to nitrosamines (carcinogens that can lead to cancers of the GI tract & the liver)

68
Q

What is aflatoxicosis?

A

Poisoning (especially of the liver) that results from ingestion of aflatoxins from contaminated food
Aflatoxins are a group of structurally related toxic compounds produced by certain strains of the fungi Aspergillus flavus & A.parasiticus
Under certain conditions of temp & humidity the moulds developo on nuts, seeds & on cooked & stored rice and other cereals
The moulds penetrate the shells of peanuts & secrete aflatoxins that contaminate the kernels

69
Q

What predisposes liver cancer?

A

A combination of aflatoxins & hep B infection

70
Q

Why is the incidence of GI tumours greater in the large intestine than in the small intestine?

A

Bcl2 (which suppresses apoptosis) is expressed in colonic epithelium (especially in the crypts)
But Bcl2 isn’t expressed in the crypts of the SI.
Bcl over expression by Gene Amplification is seen in some cancers e.g. lung cancer.

71
Q

What is the significance of UV light to carcinogenesis? What is Xeroderma Pigmentosum?

A

Damages DNA, it forms pyrimidine dimers but can also break DNA by indirect
(caucasians are susceptible to melanoma & basal cel carcinoma)
Under UV, pyrimidine dimers & p53 protein expression are found in the epidermal keratinocytes

A rare autosomal recessive disease

  • inherited deficiency of endonuclease (an enzyme in pathway of thymine dimer removal => repair of DNA damage from UV is defective.
  • children show freckling skin, multiple squamous & basal cell carcinomas & melanomas.
  • protection from the sunlight delays/prevents tumour formation
72
Q

What is radiation induced skin cancers?

A

Necroses & skin cancers common in early radiologists before risks were appreciated. No protection was used for x-ray sources.
Radiation induced leukemia
Radiation induced bone cancer in radium-dial painters (radium follows calcium into bone during ca turnover)

MD2002 (17 decks)

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