1
Q
What is cancer?
A
Genetic disease in which abnormal cells divide without control and can invade other tissues
2
Q
Tumor
A
Mass of tissue that results from growth of the abnormal cells that serves no physiological function
3
Q
Benign tumor properties
A
- Small
- encapsulated
- no metastasis
- well differentiated
- typical organization
- slow growth
4
Q
Malignant tumor properties
A
- Large
- Infiltrative/invasive
- Metastasizing
- poorly differentiated
- atypical tissue structure
- rapid growth
- hemmorage
5
Q
Two fundamental properties of cancer cells
A
- unregulated cell proliferation
- metastatic spread
6
Q
Multi-step concept of Carcinogenesis
A
Cancer does not occur after a single genetic change
7
Q
Clonal
A
Originated from a common ancestral cell that accumulated numerous specific mutations. All cancer cells in primary and secondary tumors are this
8
Q
Types of genomic alterations associated with cancer
A
- single-nucleotide subs
- large-scale chromosomal rearrangements
- amplifications
- deletions
9
Q
Causes of cancer
A
- any substance or event that damages DNA has the potential to be carcinogenic if it cause to occur in proto-oncogenes or tumor suppressor genes
10
Q
what are Carcinogens
A
chemicals, radiation, and some viruses
11
Q
How can DNA mutations result in abnormal cell proliferation
A
- growth and differention of cells are strictly regulated
- Many of the genes that control these functions are mutated or aberrant expressed, leading to uncontrolled cell proliferation
12
Q
What happens normally vs cancer cells
A
normally if DNA damage is so severe that repair is impossible, the cell may initiate apoptosis, or programmed cell death. Cancer cells dont obey these rules
13
Q
Two ways mutations in genes can lead to uncontrolled cell proliferation
A
- Make stimulatory genes hyperactive (oncogenes)
- make inhibitory genes inactive (tumor suppressor genes)
14
Q
Oncogenes
A
- Originate from genes incolced in regulating normal cell growth
- Mutations in these genes result in gain of function of the proteins they encode for
- Accelerator stuck “on”
- act in dominant manner
15
Q
Tumor Suppressor Genes
A
- normal role is to block uncontrolled cell proliferation
- mutations in these genes result in loss of function of proteins they encode for
- eliminates “brake” mechanism
16
Q
Gatekeeper
A
Tumor suppressor genes that controls cell growth
17
Q
Caretaker
A
Tumor suppressor gene that protects integrity of genome
18
Q
Sporadic cancer
A
Two acquired mutations in SAME cell
19
Q
Hereditary cancer
A
- One mutation inherited (present in every cell)
- 2nd mutation is acquired (in any cell)
20
Q
DNA repair genes
A
- normal role is to repair DNA damage caused from DNA damaging agents or spontaneous errors from replication
21
Q
Base excision repair
A
Removal of abnormal bases
22
Q
Nucleotide excision repair
A
Removal of pyrimidine dimers, large chemical adducts
23
Q
Mismatch repair
A
Corrects mismatched bases caused by mistakes in DNA replication
24
Q
How to metastasize from primary tumor
A
Cancer cell must digest components of EM and basal lamina that normally inhibit migration of cells
25
Multistep process of metastasis
- detachment
- invasion
- survival in circulation
- attachment
- extravasation
- proliferation
- induction of neovasculature
- evasion of host defenses
MUST POSSESS ALL OF THESE FUNCTIONS
26
Proteolytic enzymes
Present at higher than normal levels in highly malignant tumors and are not susceptible to normal controls conferred by regulatory molecules
27
Metalloproteinases (MMP)
a type of proteolytic enzyme
28
Tissue inhibitors of metalloproteinases (TIMP)
Regulatory molecules which are normal controls for MMP
29
Angiogenesis
formation of new blood vessels. Required condition for cancer metastasis
30
properties of TIMP
- slow binding, reversible inhibitors
- inhibitory activity resides in N-terminal domain
- inhibit all active MMPs, with different affinities
- TMPs inhibit tumor invasion
31
Is there a way to prevent, cure or slow alzheimer's
no
32
Age factor in AD
- greatest risk factor
| - risk of Alzheimer's doubles every five years after age 65
33
Risk genes (in alzheimers)
Increase the likelihood of developing a disease, but does not guarantee it will happen
34
Deterministic genes
Directly cause a disease, guaranteeing that anyone who inherits one will develop a disorder
35
Inheritance of AD
- 90% of AD cases are sporadic and occur at 60-90 years
| - 10% show autosomal dominant inheritance and have earlier age of onset
36
Autosomal dominant familial AD can be attributed to mutations in one of three genes
- amyloid presursor protein (APP)
- presenilin 1 (PSEN1)
- presenilin 2 (PSEN2)
37
Best known genetic risk factor for AD
Inheritance of the e4 allele of the apoliopoprotein E (APOE)
38
Amyloid beta precursor protein
- Mutations affect its processing or expression levels
| - speculated to bind other proteins on the surface of cells or help cells attach to one another
39
PSEN1 and PSEN2
- proteins identified as part of the enzymatic complex, y-secretase, that cleaves the AB peptide from APP
- mutations increase the AB42/AB40 ratio
40
APP is processed by 3 secretases
- a-secretase
- B-secretase
- y-secretase
41
a-secretase
- Transmembrane protease that cleaves APP within the AB domain, preventing AB generation
- cuts 90% of APP
42
B-secretase
- Directly involved in cleavage of APP at the site which generates the N-term end of AB
43
y-secretase
- multiprotein catalytic complex
| - Cleabes APP after a- or B- cleavage to generate the C-term end of AB
44
If APP is processed by a and y secretases...
AB NOT produced
45
If APP processed by B and y secretases
AB produced
46
Processive Processing
Multiple sequential cuts take place within transmembrance domain of APP to generate the AB peptides implicated in AD
47
In vitro assay for gamma secretase
monitor cleave of substrate by looking for the accumulation of either AB or AICD-Flag
48
Plaques (AD)
microscopic clumps AB peptide. May block signaling at synapses and may activate immune system cells that trigger inflammation and devour disabled cells
49
Tangles (AD)
Hyperphosphorylated microscopic strands of the protein tau. This causes neurofibrility tangles and disintegrates the neuron's transport system
50
Hallmark changes in AD
- Plaques
- Tangles
- Loss of connections among brain cells responsible for memory, learning and communication
- Inflammation resulting from brain's effort to fend off the lethal effects of the other changes
- eventual death of brain cells and severe tissue shrinkage
51
Protein misfolding disease
-Cause by accumulation of abnormally folded AB and tau proteins in the brain
52
Effects of Alzheimer's on brain
- Cortex shrivels
- Hippocampus shrinks
- Ventricles grow larger
53
Cholinesterade inhibitors (AD)
Slows down the disease activity that breaks down a key neurotransmitter
54
NMDA Receptor antagonist (AD)
regulates the activity of glutamate, a chemical messenger involved in learning and memory.
55
Diagnosis of AD
- ask Qs about overall health, past medical problems, ability to carry out daily activities, changes in behavior and personality
- conduct tests of memory, problem solving
- standard medical tests such as blood or urine
- Perform brain scans such as CT or MRI
56
Tests used in animal models of AD
- morris water maze
- novel object recognition
- passive avoidance
57
Problems with animal model in AD
- mouse models are incomplete models of the human phenotype-most represent familial form of AD, which is small % of total AD cases
- Behavioral results not as robust
58
Stroke definition
Brain damage caused by a sudden and sustained loss of blood flow to the brain
59
Who has high risk of stroke
- Elderly
- Men have higher risk, but more women die
- African Americans have almost twice the risk
60
Other risk factors of stroke
- Previous stroke
- High cholesterol
- high clood pressure
- heart disease
- carotid artery disease
- smoking/drinking
61
Infarction
Tissue death
62
Reperfusion
Reestablishment of blood flow
63
Embolus
An abnormal particle circulating in the blood
64
Thrombus
Clot of blood formed within a blood vessel and remaining attached to its place of origin
65
Thromboembolism
Blocking of a blood vessel by a particle that has broken away from a blood clot at its site of formation
66
Cardioembolism
Blood clot formed in the Heart
67
Artherosclerosis
Hardening of the arteries, caused by cholesterol or plaque build up
68
Ischemic stroke
- loss of blood flow
| - Occurs when arteries are blocked by blood clots or by gradual build-up of plaque and other fatty deposits
69
Hemorrhagic stroke
- bleeding
| - occurs when a blood vessel in the brain breaks leaking blood into brain
70
Embolic stroke
Blood clot or plaque fragment forms somewhere in the body and moves through the bloodstream to the brain. Once in the brain, clot blocks a blood vessel and leads to a stroke
71
Thrombotic stroke
Formation inside an artery that supplied blood to the brain
72
Aneurysm
Weak spot on wall of an artery that may balloon out, forming a thin-walled bubble. As it gets bigger, the aneurysm gets weaker and can burst, leaking blood into or outside the brain
73
Intercerebral hemorrhage
Hemorrhagic stroke. caused when a burst blood vessel bleeds into brain
74
Subarachnoid hemorrhage
Blood vessel bursts near surface of brain and blood pours into area around outside of brain
75
when strok strikes act FAST
Face, does one side droop?
Arms does one arm drift downward
Speech repeat a sentance
Time time is critical
76
Antithrombotics
Prevent formation of blood clots that can cause stroke
77
Antipletlet drugs
Prevent clotting by decreasing activity of platelets. Ex. aspirin
78
Anticoagulants
Reduce stroke risk by reducing clotting property of blood. ex. warfarin, heparin, enoxaparin
79
Thrombolytic drugs
Dissolve thrombi by activating plasminogen to form plasmin, which breaks crosslinks between fibrin molecules to destabilize structural integrity of blood clots
80
Tissue plasminogen activator (tPA)
Thrombolytic drug that is only effective within 3 hours of stroke
81
Endovascular procedure (ischemic stroke)
Try removing blood clot by sender catheter to site of the blocked blood vessel in the brain.
82
Hemorrhagic stroke Treatment
- Endovascular procedures. Use of catheter to deposit a mechanical agent to prevent rupture
- Surgical treatment. Metal clip may be placed at base of aneurysm to secure it
83
Penumbra
Hyroperfused tissue that will die unless reperfused properly
84
Infarct core cell death
Necrosis occurs within a few minutes of vessel occlusion
85
Penumbra cell death
Apoptotic cell death may occur and progress more slowly than necrosis
86
Neuroprotection
Designed to block cascades that lead to ischemic brain injury
87
In Vitro models of stroke
Osygen-Glucose deprivation. Cell or tissue culture incubated in glucose free medium. Then incubated in glucose containing medium, which simulated reperfusion stage/
Pro: Eliminates technical challenges
Con: too simple
88
TTC-Staining
Ischemic areas do not metabolize TCC and appear white
89
Limitation with animal models of stroke
- Timing, in some human trials, treatments given outside effective window
- Age. Animal studies conducted on healthy, young animals under control
- Morphological and anatomical differences in animal and human brain
- Plasma conc. of drugs and side effects
90
Obesity Definition
abnormal or excessive fat accumulation that presents a risk to health
91
BMI calculation
a person’s weight (in kg) divided by the square of his or her height (in m).
92
As a person's BMI increases
so does their mortality rate
93
Feeding is a...
complex motivational behavior
94
Fundamental cause of obesity
cause of obesity and overweight is an energy imbalance between calories consumed and calories expended.
95
(Obesity) Globally there has been an
- an increased intake of energy-dense foods that are high in fat
- an increase in physical inactivity due to the increasingly sedentary nature of many forms of work, changing modes of transportation, and increasing urbanization
96
Calories burned depend on
- activity level
- age
- height and build
97
How does the body deal with excess dietary calories?
1 convert excess fuel to fat and store it in adipose tissue
2 burn excess fuel by extra exercise
3 “waste” fuel by diverting it to heat production
98
Long-term maintenance of body weight
- Periods of food deprivation are followed by periods of increased food intake
- Periods of forced feeding are followed by periods of lower food intake.
99
Adiposity indirectly influences food intake
- Loss of body fat reduces the efficacy of meal-generated “satiety” signals and increases the efficacy of “hunger” signals.
- Gain of body fat increases the efficacy of meal-generated satiety signals and reduces the efficacy of “hunger” signals
100
Heritability
describes the proportion of total phenotypic variation in a population due to genetic factors
101
heritability estimate
tells the proportion of phenotypic variation that can be attributed to genetic variation within a certain population in a particular environment
102
For identical twins obesity observations
phenotypic variance equals environmental variance, as there is no genotypic variance
103
For fraternal twins obesity observations
phenotypic differences represent both environmental variance and approximately half the genotypic variance
104
adipokines
produce changes in fuel metabolism and feeding behavior that reestablish adequate fuel reserves and maintain body mass.
105
Adipose tissue
synthesizes, stores, and mobilizes triacylglycerides
106
Leptin
upon reaching the brain, acts on receptors in the hypothalamus to curtail appetite.
107
Central weight-control center
Hypothalamus
108
When leptin is injected into ob/ob mice
lose weight and increase their activity and thermogenesis
109
Mice with two defective copies of Leptin gene (ob/ob) show the behavior and physiology of animals in a constant state of starvation
- they are unable to stay warm
- exhibit unrestrained appetite (become severely obese)
- they have metabolic disturbances very similar to those seen in diabetes (are insulin-resistant)
110
Leptin’s Central Actions
- Increase energy expenditure (via physical activity, sympathetic nervous system activity)
- Decrease food intake
- Decrease body weight
- Increase insulin sensitivity
- Help signal the onset of puberty
- Regulate other pituitary hormone axes
111
neuropeptide Y (NPY)
appetite-stimulating neurons stimulate eating by producing and releasing NPY
112
melanocyte– stimulating hormone (melanocortin)
appetite-suppressing neurons in the brain produce this
113
The DB gene encodes for
leptin receptor
114
Ghrelin
a powerful appetite stimulant that works on a shorter time scale (between meals) than leptin and insulin.
BIOL 317
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