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UVic BIOL 439 - Spring 2020 > MT Flashcards > Flashcards

MT Flashcards

1
Q

What did Ignaz Semelweiss observe in Vienna’s General Hospital (1840)?

A

He identified a disparity in the incidence of fatal sepsis between a maternity ward run exclusively by midwives and one which was also attended by doctors (2% vs 10%!).

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2
Q

What did Ignaz Semelweiss conclude from his observation/investigation?

A

That doctors who performed autopsies (who didn’t wash their hands) were bringing infection into these wards from the corpses in the mortuary.

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3
Q

What did Ignaz Semelweiss try to do to remedy the situation he observed?

A

Got all the doctors and medical students to wash their hands, which reduced the incidence of fatal sepsis.

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4
Q

What is John Snow known for accomplishing in 1854?

A

Identified the source of a cholera outbreak in London and effectively neutralized it.

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5
Q

What was causing the cholera outbreak which John Snow addressed?

A

A sink drain used to wash contaminated sheets was leaking into the public well.

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6
Q

What epidemiological tool was John Snow the first to employ during the London cholera outbreak? What are some other examples of times this tool has been used (that we talked about)?

A

The spot map. Also used in Ottawa to map prevalence of MS (coincidence…) and in Haiti to map another cholera outbreak (…not so much).

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7
Q

How are the odds of exposure in cases (diseased) calculated?

A

Divide the # of cases who were exposed by the # of cases who weren’t exposed.

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8
Q

How are the odds of exposure in controls (healthy) calculated?

A

Divide the # of controls who were exposed by the # of controls who weren’t exposed.

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9
Q

How can the odds ratio be calculated from the odds of exposure in cases and the odds of exposure in controls?

A

Divide the odds of exposure in cases by the odds of exposure in controls.

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10
Q

What is the significance of an odds ratio > 1.0?

A

The cases (diseased) were likely to have been exposed (to ___ ).

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11
Q

What is the significance of an odds ratio = 1.0?

A

The cases (diseased) are no more likely to have been exposed than the controls (healthy).

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12
Q

What is the significance of an odds ratio < 1.0?

A

The cases (diseased) were actually less likely to have been exposed (to ___ ) than the controls (healthy) were.

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13
Q

What might be an example of an exposure and a disease condition which would likely give an odds ratio > 1.0?

A

Cystic fibrosis patients are more likely to have a CFTR mutation than the average control (healthy) person.

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14
Q

What might be an example of an exposure and a disease condition which would likely give an odds ratio = 1.0?

A

Parkinson’s Disease patients are no more likely to be named Michael J. Fox than the average (control) person.

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15
Q

What might be an example of an exposure and a disease condition which would likely give an odds ratio < 1.0?

A

Obese individuals are actually less likely to have been exposed to a vegetable than the average control (healthy) person.

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16
Q

Approximately how many people in the US are affected by Cystic Fibrosis? What about in Canada?

A

US: 30,000
Canada: 4,000

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17
Q

What is the birth incidence of Cystic Fibrosis in Canada?

A

1 in 3,600 births.

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18
Q

What are the primary symptoms of Cystic Fibrosis?

A

The body produces an abnormally thick, sticky mucus that clogs the lungs and leads to life-threatening lung infections.

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19
Q

What is a secondary symptom of Cystic Fibrosis?

A

Secreted mucous also obstructs the pancreas, preventing digestive enzymes from reaching the intestines.

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20
Q

What used to be the standard diagnostic test for Cystic Fibrosis?

A

A sweat test, in which high salt levels indicated Cystic Fibrosis.

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21
Q

What is the first step of newborn screening for Cystic Fibrosis in BC? Under what conditions will this test be positive?

A

IRT (immunoreactice trypsinogen) test, which will return positive if pancreatic enzymes fail to enter the intestines and instead end up in the bloodstream.

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22
Q

Which provinces in Canada screen newborns for Cystic Fibrosis as of 2018?

A

All of them :)

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23
Q

If you have two recessive alleles, who else that you know is also likely to have them? How does this relate to Cystic Fibrosis?

A

Probably your family. CF is caused by 2 recessive alleles so the odds that just a rando has BOTH of those is pretty slim.

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24
Q

How did Romeo et al. (1985) get data for their experiments on consanguineous marriages?

A

The Pope actually kept an incest record between 1910 and 1962 (classic) that shows all the people in Italy who married their cousins (ew).

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25
Q

What did the results of the Romeo et al. (1985) study into consanguineous marriages and Cystic Fibrosis show?

A

Children with Cystic Fibrosis are 3.4x more likely to have parents that are 1st cousins and 4.3x more likely to have parents that are 2nd cousins than the average population.

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26
Q

What did the results of their study allow Romeo et al. (1985) to conclude about the cause of Cystic Fibrosis?

A

That Cystic Fibrosis is caused by a recessive allele at a single locus.

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27
Q

How does the Logarithm of Odds (LOD) differ from the Odds Ratio (OR)?

A

LOD deals with genetic linkage while OR deals with the risk of exposure.

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28
Q

What two restriction enzymes are used for restriction fragment length polymorphism (RFLP) analysis?

A
  1. Hind III

2. Hinc II

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29
Q

What 5 steps outline restriction fragment length polymorphism (RFLP) analysis?

A
  1. Isolate DNA
  2. Digest (w/ Hind III and Hinc II)
  3. Run fragments on a gel
  4. Transfer DNA from gel to a membrane
  5. Probe with complement (Southern Blot)
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30
Q

What was used by Tsui et al. (1985) to probe their RFLP fragments?

A

A labelled Lam4-9178 with a piece of complementary DNA (Southern blotting).

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31
Q

From their LOD score analysis of 39 families with CF children, what did Tsui et al. (1985) conclude was the linkage distance between the 5.3 cut site and the CF-causing mutation?

A

0.15 or ~15 million base pairs. Means there is an 85% chance that 5.3 is linked to this mutation.

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32
Q

Once Tsui et al. (1985) had found the approximate location of the mutation causing CF, what 2 techniques were used to pinpoint its location?

A
  1. Chromosome jumping

2. Chromosome walking

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33
Q

Describe “chromosome jumping”.

A

DNA is digested with MboI, circularized with supF, re-digested with EcoRI, and cloned into a bacterial “library” before being probed with Lam4-917.

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34
Q

Describe “chromosome walking”.

A

Design a primer to bind to the target sequence, sequence the DNA, go to the end of the new strand and make it the new primer, etc.

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35
Q

What is the likelihood of a caucasian individual being a carrier for CF?

A

1 in 25.

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36
Q

What makes the CFTR protein product non-functional?

A

It misfolds and is degraded before it can make it to the membrane (it would work fine if only it could get there).

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37
Q

What is the most common mutation causing Cystic Fibrosis?

A

A single nucleotide ΔF508 deletion in the exon 10 of the CFTR sequence.

38
Q

ΔF508 causes the last nucleotide of an Ile to be lost. Why does this affect the following Phe and not the Ile?

A

Because the degenerative sequence still recognizes the first two bases as Ile, whereas the resulting frame-shift causes Phe to be lost.

39
Q

How many other mutations (besides ΔF508) have been recorded in the CFTR as of 2020?

A

2075.

40
Q

Is it possible/likely to have more than one mutation in the CFTR? What might be an effect of this?

A

Yes, since there are so many possible mutations. Some can have attenuating effects or cause alteration of clinical presentation of CF.

41
Q

Is it possible/likely to have more than one mutation in the CFTR? What might be an effect of this?

A

Yes, since there are so many possible mutations. Some can have attenuating effects or cause alteration of clinical presentation of CF.

42
Q

What is a microsatellite?

A

A repetitive DNA sequence characterized by short motifs.

43
Q

What can analysis of microsatellite loci tell us about CF?

A

Its a way to date the CF mutation based on the variability of microsatellites. This was used to determine that most CFTR mutations derived from a single ancestral mutation.

44
Q

From analysis of microsatellite mutation rate, how long ago did we previously think the ancestral CFTR mutation occurred? How about now?

A

~50,000 years ago. Now we think it was closer to ~5,000 years ago.

45
Q

Describe the goal of “primary prevention”. Give an example related to Cystic Fibrosis.

A

To prevent disease or injury before it ever occurs. Ex: preimplantation genetic diagnosis.

46
Q

Describe the goal of “secondary prevention”.

A

To reduce the impact of a disease or injury that has already occurred. Ex: Newborn screening.

47
Q

Describe the goal of “tertiary prevention”.

A

To soften the impact (or arrest progress) of an ongoing illness or injury that has long lasting effects. Ex: Orkambi.

48
Q

What was the sample group for the Handyside et al. (1992).

A

Three couples who all had at least one child with Cystic Fibrosis.

49
Q

What were the major methods of the Handyside et al. (1992) paper?

A
  1. Single blastomere biopsy
  2. PCR (with nested primers) of region containing ΔF508
  3. Heteroduplex analysis
50
Q

Why was heteroduplex analysis used in the Handyside et al. (1992) paper?

A

Because it is difficult to see the 3 base-pair difference in PCR products between the 5.3 and 6.3 cut sites.

51
Q

What were the odds that each couple in the Handyside et al. (1992) study would have had a healthy child without preimplantation genetic diagnosis?

A

75%!

52
Q

What was the goal of the first successful clinical application of preimplantation genetic diagnosis?

A

To screen for males who might be hemizygous for an X-linked fragile X allele.

53
Q

Why is IntraCellular Sperm Injection the standard for in-vitro fertilization with preimplantation genetic diagnosis?

A

Because it avoids the chance of PCR amplifying DNA from sperm which didn’t actually fertilize the egg but where buried in the zona pellucida.

54
Q

Which populations does the Subcommittee on Cystic Fibrosis Screening recommend for Cystic Fibrosis carrier screening?

A

Non-Jewish caucasians and Ashkenazi Jews in particular. Other populations may be tested but detection of mutations will be lower.

55
Q

What is a potential challenge of Cystic Fibrosis screening using mutation panels?

A

Too expensive/time-consuming to test every possible mutation, but if you only test the most common ones then others will be missed.

56
Q

What does the “sequential model” stipulate with regards to Cystic Fibrosis screening?

A

Test one person and then only test the other if the first tested positive. Try to test the most likely candidate first.

57
Q

What does “couple testing” stipulate with regards to Cystic Fibrosis screening?

A

Get both samples, test one. If positive, test the other. If only one is positive then they are a positive/negative couple. No paternity issues…

58
Q

What differentiates the terms antenatal and prenatal?

A

Nothing, they’re synonyms.

59
Q

Describe, in general terms, Cunningham and Marshall’s 1998 study regarding prenatal CF screening and resulting CF births.

A

Offered screening to pregnant couples, then tested fetus if the parents tested positive. Resulted in far fewer CF births (abortion) but some went unscreened or “missed”.

60
Q

What is one of the most convincing arguments for community-wide Cystic Fibrosis screening?

A

Newborn screening has not reduced the number of CF babies, many of which have no family history of CF.

61
Q

How is CF screening performed on newborns in BC?

A
  • Immunoreactive trypsinogen (IRT) heel prick test
  • If positive, CFTR mutation testing
  • If 2 mutations, CF diagnosis
  • If 1 mutation, sweat test
  • If positive, CF diagnosis
62
Q

What were the results of retrovirus-mediated gene transfer in cell culture as a therapy for CF?

A

The virus rescues the defect, allowing the CFTR to translocate to the membrane and function.

63
Q

Why does retrovirus-mediated gene transfer (successful in cell culture) not work as a therapy for CF?

A

It requires cells to be actively dividing in order to access the host genome. Lung epithelial cells (main defect of CF) are non-dividing.

64
Q

Why does adenovirus-mediated gene transfer (successful in rodents) not work as a therapy for CF?

A

The host immune system kills the infected cells very quickly.

65
Q

What differentiates retrovirus-mediated gene transfer from adenovirus-mediated gene transfer?

A

Retro: virus inserts DNA into host genome
Adeno: virus inserts DNA into nucleus for transcription, but it is not integrated into the host genome.

66
Q

What differentiates Adeno-associated virus-mediated gene transfer from adenovirus-mediated gene transfer?

A

Adeno-ass: no viral proteins are encoded by the virus.

Adeno: viral proteins are produced within the host.

67
Q

Why does Adeno-associated virus-mediated gene transfer not work as a therapy for CF?

A

High doses are needed to get any therapeutic effect, which also leads to an immune response.

68
Q

Besides the fact that lung epithelial cells are non-dividing, what also makes it difficult for gene therapies to target these cells?

A

The thick mucous in these areas, characteristic of CF, blocks viral entry to cells.

69
Q

Why could a gene therapy still fail even if you could get a gene into the host cell, block the immune response, and potentially generate a therapeutic effect?

A

The insertion site for your gene is difficult to control, and insertion might cause the loss of a necessary cell function.

70
Q

For what condition has gene therapy been successful in treating? What kind of gene therapy was used?

A

A type of blindness has been treated by using HIV retroviruses which can infect non-dividing cells.

71
Q

What CF therapy came immediately before the current treatment methodology and showed little success?

A

CFTR-bearing plasmids associated with lipids that get injected into cells

72
Q

What were the results of Alton et al.’s (2015) experiments involving treating CFTR with non-viral therapy?

A

They didn’t see any improvement in the trial group but there was a decline in the control group.

73
Q

What method did Van Goor et al. (2006) use to find compounds which improved CFTR function in cell lines? How many compounds did they test?

A

High-throughput screening of ~164,000 compounds. They basically just ordered everything from the Sigma catalog and tested it all in cell cultures.

74
Q

With regards to Van Goor et al.’s (2006) high throughput screening experiment, what is a “corrector”?

A

A compound which helps to move the mutated CFTR to the membrane.

75
Q

With regards to Van Goor et al.’s (2006) high throughput screening experiment, what is a “potentiator”?

A

A compound which enhances the function of mutated CFTR once it reaches the membrane.

76
Q

How did Van Goor et al. (2006) know when CFTR was moving Cl ions?

A

If the cytosol is positive (Cl movement) then dye binds to the inner membrane and disrupts the FRET pair, emitting blue light.

77
Q

How did Van Goor et al. (2006) know when CFTR was not moving Cl ions?

A

If the cytosol is negative (no Cl movement) then dye binds to the outer membrane and FRET proceeds, emitting yellow/green light.

78
Q

Besides using a “corrector”, what is another way to cause the CFTR protein to move to the membrane in cell culture?

A

By maintaining the culture at 27C (not great for people though).

79
Q

What is an example of a “corrector” that Vertex identified? What about a “potentiator”?

A

Corrector: VRT-768 (+VX-809)
Potentiator: VRT-532 (+VX-770)

80
Q

What was the first real successful treatment for CF patients with the G551D mutation?

A

Regular doses of Kalydeco/Ivacaftor.

81
Q

What was the major breakthrough in CF treatment associated with VX-809? What is another name for this drug?

A

It is a “corrector” that works in human bronchial epithelia cells. Called Lumacaftor when it entered the market.

82
Q

What were the limitations of Kalydeco? What drug replaced it?

A

It only worked for a small number of people with certain mutations. Orkambi combined Lumacaftor and Ivacaftor, replacing Kalydeco.

83
Q

Why was Orkambi an improvement over Kalydeco?

A

Orkambi contains both a “corrector” and a “potentiator”. It works on CF patients regardless of their specific mutation.

84
Q

Why are the number of cancer diagnoses and cancer deaths in Canada greater now than they were in 2017?

A

Only because there’s more people now and they’re older. “We’re making progress I swear!” - John.

85
Q

How many new cases of cancer were there in 2019? How many deaths?

A

Cases: 220,400
Deaths: 82,100

86
Q

Is geography an important factor in relation to cancer incidence and mortality in Canada?

A

Yes. Incidence and mortality varies depending where you are in Canada. Higher in the East than in the West.

87
Q

Which is more likely to be diagnosed with cancer: males or females? Which is more likely to survive?

A

Males are more likely to get cancer and females are more likely to survive (sucks).

88
Q

What are the 5 major risk factors for cancer?

A
  1. Age
  2. Geography
  3. Sex
  4. Behaviour
  5. Family history
89
Q

How did Hall et al. (1990) show that breast cancer has a genetic component?

A

Family study determining the likelihood that familial breast cancer is linked to a gene.

90
Q

What is a challenge for identifying cases and controls in a cancer study that isn’t present in a CF study?

A

Controls may later develop cancer.

91
Q

What did Hall et al.’s (1990) analysis of LOD scores for familial breast cancer pedigrees show?

A

That the strongest evidence for linkage at the VNTR locus was in pedigrees with an average age of diagnosis < or = 45.

92
Q

What gene was discovered later as being linked to the microsatellite locus VNTR which Hall et al. (1990) used in their study?

A

BRCA1.

UVic BIOL 439 - Spring 2020 (1 decks)

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