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Unit 1 > Unit 1 LGS > Flashcards

Unit 1 LGS Flashcards

1
Q

6What major historical events helped shape the development of modern osteopathic medicine?

A

AT Still and his “first lesson”; Flexner Report; Civil War; AOA founding; ASO opening; COM-CMA Merger

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2
Q

Define somatic dysfunction

A

Impaired or altered function of related components of the body framework system; skeletal, arthrodial, and myofascial structures, and their related vascular, lymphatic, and neural elements.

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3
Q

What are the Four Tenets of Osteopathic Medicine?

A
  1. The human being is a dynamic unit of function
  2. The body possesses self-regulatory mechanisms that are self-healing in nature
  3. Structure and function are interrelated at all levels
  4. Rational treatment is based on these principles
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4
Q

What is cultural humility?

A

A lifelong process of self-reflection whereby the individual learns about another’s culture without assuming their are competent in it; each person is an expert in their own culture. Addresses power imbalances in patient-physician dynamic

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5
Q

What changes occurred thanks to the Flexner Report?

A

Osteopathic schools harshly condemned; Stricter licensing requirements; Most schools for women and POC closed

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6
Q

Define Osteopathy

A

Osteopathy is an outdated version of Osteopathic Medicine, which is a philosophy that combines the needs of the patient with the current practice of medicine, surgery and obstetrics, and emphasizes the interrelationship between structure and function and has an appreciation of the body’s ability to heal itself.

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7
Q

What are the consequences of the COA-CMA merger?

A

DO’s were basically abolished in the state of California aside from ~400; was ruled unconstitutional

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8
Q

Describe the five key aspects of lifestyle medicine.

A

Nourish (nutrition), Move (physical activity), Rest (sleep), Restore (spirituality), Connect (social)

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9
Q

Identify clinical benefits of an overall healthy lifestyle.

A

Lower BP, cholesterol, blood sugar, inflammation, cognitive impairment, anxiety, depression; lowers heart disease >80%; more energy; longevity

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10
Q

What medical conditions can improve with Mediterranean diet?

A

CVD, Diabetes, Fatty Liver Disease, Arthritis. Obesity, COPD, Dementia, IBD

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11
Q

List the five components of fitness

A

Cardiorespiratory, muscle strengthening, balance/agility, flexibility, body composition

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12
Q

What are the “Key Three” strength training exercises?

A

Squat, push up, pull up

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13
Q

Explain the benefits of multimovement physical activity.

A

Using a variety of movements avoids having muscle growth and progress become static; keeps physical activity enjoyable/entertaining

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14
Q

Describe the physiology of the circadian rhythm.

A

Light rays absorbed through eyes sends signal to hippocampus that it’s still daytime. As darkness ensues, signals are sent to indicate nighttime and to release melatonin. Blue light interferes with circadian rhythm bc eyes perceive it to be sunlight (eyes absorb blue wavelengths from sun at its highest point), and slow or stop the release of melatonin.

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15
Q

What is the stress response?

A

Sympathetic nervous system triggers release of cortisol, which triggers gluconeogenesis, which increases HR, BP, and metabolic rate, and suppresses the immune system.

Opposite for relaxation response.

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16
Q

Characterize key components of anti-inflammatory diet.

A

Omega-3 and -6 fatty acids (fish), unsaturated fats (olive oil, nuts); fruits; vegetables; whole grains; legumes and beans

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17
Q

What is functional physical health?

A

Maintaining your body and health to continue living normal day-to-day lives free of disease; being adaptable rather than adapted to

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18
Q

What are the five clinical goals of spiritual assessment and care?

A

Be prepared
Listen intently
Show unity with pt
Form connection
Inquire more using pt’s emotional cues

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19
Q

What is the FITT Principle?

A

Social connection log: Frequency, Interaction, Type, Time

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20
Q

What are the three spiritual assessments?

A

HOPE, FICA, SPIRIT

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21
Q

Describe the three mechanisms of memory formation.

A

Encoding: process of transforming a perceived experience into a memory code
Storage: Representation of the memory in the brain
Retrieval: actively recalling the information

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22
Q

Identify the three primary memory buffers according to the modal model.

A

Sensory information store: deciding what to do with sensory input
Short term memory: Needs continued attention (working memory)
Long term memory: Subject to retrieval failure

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23
Q

Compare and contrast the different types of long term memory, and where they are stored.

A

Procedural memory: memory involved in movement/muscle memory; sports, riding a bike, etc - cerebellum, striatum putamen
Semantic memory: memories of things not experienced; facts, dates, etc - neocortex, medial temporal lobe, hippocampus
Episodic memory: memories of events experienced that can be relived; events that happen at particular place and time, remembering words on a list - amygdala (emotional memory), medical temporal lobe, neocortex, hippocampus

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24
Q

Explain the three principles of evidence-based medicine.

A

Patient preferences and/or circumstances - decision-making requires awareness of best available evidence

Physician’s judgement/expertise - provides guidance to decide trustworthiness of evidence

External evidence- - evidence alone is never sufficient to make a clinical decision

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25
Q

What sources can you find answers to background questions? Foreground questions?

A

Traditional textbooks:
BMJ Clinical Evidence, ACP Journal Club, Coch

Primary Literature:
Pubmed, Trip Database

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26
Q

Provide examples of foreground questions using PICO

A

Patients - “Who are the relevant pts?”
Intervention - “What are management strategies/potential risks we are interested in trying/concerned about?”
Comparator - “What is my control group?”
Outcome - “What are the pt-relevant consequences of exposure we are interested in?”

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27
Q

Define the five types of foreground questions in EBM.

A

Therapy - determining effect of intervention on pt outcomes
Harm - identifying potential risks
DDx - establish frequency of underlying disorder
Diagnosis - use testing to differentiate between conditions/diseases
Prognosis - estimate a pt’s future course

Best types of articles for all: Systematic review/meta-analysis

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28
Q

Explain the acid-base properties of water

A

Water is amphoteric, in that it can act as an acid or base
H20 = H+ + OH-
Cations attracted to O, Anions attracted to H, through ion-dipole interactions
Each water molecule can form four hydrogen bonds

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29
Q

Explain why and how water functions as a solvent in human body

A

Universal Solvent - “like dissolves like”

Ion-dipole interactions
Solvation/Hydration

  • Dissolves and transports inorganic salts and polar organic molecules
  • Provides medium for movement of molecules
  • Separates charges molecules
  • Dissipates heat
  • Participates in chemical reactions
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30
Q

Describe main contributing factors of pH of body fluids and how they are calculated

A

Amount of free H ions in fluid determines pH
Kw = [H+][OH-] = 1*10^-14 (Ion product of water)
pH = pKa + log[A-/HA] (HH equation)
pH = -log[H+]

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31
Q

Bio-macromolecule structure/function is determined by

A

water’s physical and chemical properties

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32
Q

Biochemistry’s three pillars

A

Biomolecules - composition, structure and function
Metabolism - chemical reactions
Molecular Biology - Genetic information

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33
Q

Extracellular fluid is rich in _____ ion(s) and intracellular fluid is rich in ____ ion(s)

A

ECF rich in Na+ and Cl-
ICF rich in K+

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34
Q

List key chemical features of most biomolecules

A
  1. Main elements: H, C, O, N, S, P
  2. Hydrophilicity
  3. Bond types
  4. Functional Groups
  5. Size
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35
Q

List key interactions that make biomolecule function possible

A
  1. Dipole-dipole interaction (H bonding)
  2. Ion-dipole interaction
  3. Electrostatic interaction (Salt bridge)
  4. Hydrophobic interaction
  5. Van der Waals Forces
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36
Q

List the 4 classes of biomacromolecules, their monomers, bonds, and how they are broken down

A

Carbohydrates: monosaccharides with glycosidic bonds
Lipids: Triglycerides with ester bonds
Proteins: amino acids with peptide bonds
Nucleic Acids: nucleotides with phosphodiester bonds

All broken down with hydrolysis, synthesized with dehydration

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37
Q

3 main goals of metabolism

A
  1. Synthesize biomacromolecules
  2. Generate energy
  3. Protect homeostasis
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38
Q

4 goals of metabolic processes

A
  1. Fuel Oxidation - creating energy
  2. Fuel Storage and Mobilization - energy and homeostasis
  3. Biosynthesis - synthesizing macromolecules
  4. Detoxification and Waste Disposal - protect homeostasis
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39
Q

Describe the central role that Glucose plays in metabolism

A

Glucose -> Glycolysis -> Pyruvate
Glucose -> Pentose Phosphate Pathway -> Pentose Phosphates
Glucose -> Glycogenesis -> Glycogen

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40
Q

Role of ribosomes

A

Assemble polypeptides from amino acids

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41
Q

Role of smooth ER

A

lipid biosynthesis (adipose tissue)
detoxification (liver)
sequestrations of Ca2+ ions (muscle tissue)

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42
Q

Role of rough ER

A

production and secretion of proteins
assembly of multichain proteins
posttranslational modification

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43
Q

Role of Golgi

A

Completes posttranslational modifications
Address proteins to proper destinations

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44
Q

Role of Secretory granules

A

Stores product until released by exocytosis

Zymogen granules - contain high concentration of digestive enzymes

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45
Q

Role of lysosomes

A

intracellular digestion, turnout over cellular components

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46
Q

Role of Proteasomes

A

Degrade or denature nonfunctional polypeptides
Restrict protein activity

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47
Q

Differentiate euchromatin from heterochromatin

A

Euchromatin - loosely packed gene-expressing DNA available for transcription (middle of chromatid arms)
Heterochromatin - tightly packed non-coding DNA (near
centromere and telomeres)

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48
Q

Differentiate karyotype from FISH

A

Karyotypes provide information on number and morphology of chromosomes
FISH (fluorescence in situ hybridization) detects targeted abnormalities

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49
Q

Briefly describe the steps of Central Dogma

A

Replication: DNA makes copies of chromosomes to be transmitted to new cells
Transcription: RNA copy is produced from parent strand
Translation: RNA copy is used to produce polypeptide

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50
Q

Describe the process of DNA replication

A
  1. Helicase breaks H bonds to unwind double helix creating replication fork
  2. ssDNA binding proteins stabilize unwound DNA
  3. Leading strand is synthesized continuously
  4. Lagging strand is synthesized in Okazaki fragments starting at RNA primers, which are replaced with DNA by DNA polymerase
  5. DNA ligase joins Okazaki fragments
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51
Q

Describe the function of topoisonmerases

A

Breaks and relink DNA strands to prevent supercoiling during replication

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52
Q

What is Bloom Syndome?

What is Werner Syndome?

A

Inherited, autosomal recessive helicase disorders

Bloom: cannot make new healthy cells, so greatly increased risk of cancer, sunlight damages DNA

Werner: Normal growth until puberty, then growth stops; premature aging, pts develop conditions associated with old age in 20s-30s, increased risk of cancer

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53
Q

What is a replisome?

A

the multiprotein complex that carries out DNA replication

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54
Q

What is Xeroderma Pigmentosum

A

Result of defective nuclear excision repair - cannot repair thymidine dimers caused by sunlight; Acute sun sensitivity with marked freckle-like pigmentation on the face before 2 years

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55
Q

Describe the process of Transcription

A

Initiation: RNA polymerase II binds to TATA box, starts to synthesize mRNA from DNA template strand
Elongation: RNA polymerase II reads non-coding template strand in the 3->5 direction and adds complimentary nucleotides
Termination: RNA polymerase reaches stop codon (UAA, UGA, UAG) and releases hnRNA to be processed into mRNA

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56
Q

What is the “death cap mushroom”?

A

Type of mushroom with RNA polymerase II inhibitor (amatoxin) causes disruption of transcription of mRNA. Hepatocytes cannot synthesize key protein coding genes, leading to the disintegration of nucleoli and pathologically centrilobular hepatic necrosis. This leads to the insidious onset of liver failure over 48 hours. Late onset (more than six hours after ingestion) of vomiting and watery diarrhea occur due to the second component in some of these mushrooms which are phallotoxin.

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57
Q

Differentiate hnRNA (pre-mRNA) to mRNA

A

hnRNA is unprocessed mRNA - stays in the nucleus; has introns, has 5 and 3splice sites, and can be used to make more than one specific protein
mRNA is processed and sent out of nucleus for translation - has 5 cap and 3 poly-A tail

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58
Q

What are the purposes of the 5` cap and poly-A tail?

A

Protection of RNA from degrative enzymes and allow it to leave the nucleus for translation

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59
Q

Describe the process of Translation

A

Initiation: tRNA transports start anticodon amino acid to P site to allow for start of chain
Elongation: tRNA molecules continue to bring amino acids to A site that correspond with codons. Another rRNA catalyzes peptide bond formation and transfers growing polypeptide to A site and pushing tRNA to P site. Empty tRNA on E site is ejected
Termination: rRNA runs into stop codon (UAA, UGA, UAG) and release factor bind in A site. Bond between completed polypeptide and tRNA in P site is hydrolyzed, then both are released from ribosome

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60
Q

Differentiate the role of cytoplasmic rRNA and RER rRNA

A

Cytoplasmic rRNA processes mRNA peptides that will remain in the cell
RER rRNA processes mRNA peptides that will be sent to Golgi apparatus to be packaged and sent outside of the cell (or to the cell membrane)

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61
Q

Role of miRNA in translation regulation

A

miRNA binds with complimentary strand of mRNA, destabilizing mRNA and induces mRNA decay

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62
Q

Identify and describe posttranslational modifications

A

Peptide cleaving
Adding chemical groups: Phosphorylation, Glycosylation, Hydroxylation, Methylation, Acetylation
SRP: transports polypeptide to RER for modification

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63
Q

What organelles are involved in I-Cell Disease? When in the cycle of Central Dogma?

A

Golgi during post-translational modification - defective peptides secreted rather than delivered to lysosomes

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64
Q

Describe protein structures and the bonds they use

A

Primary structure - chain - peptide bonds
Secondary structure - a-helix or B-pleated sheets - hydrogen bonds
Tertiary structure - multiple motifs make domains, multiple domains make folds, multiple folds makes structure - ionic, hydrogen, van der waals, disulfide, hydrophobic
Quaternary - multiple polypeptide association, same bonds as tertiary

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65
Q

Basic amino acids (+ charged at phys pH)

A

Arg, Lys, His

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66
Q

Acidic amino acids (- charged at phys pH)

A

Asp, Glu

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67
Q

Sulfur-containing amino acids

A

Cys, Met

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68
Q

Polar amino acids

A

Asn, Gln, Ser, Thr

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69
Q

Aromatic amino acids

A

Phe, Try, Trp

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70
Q

Non-polar amino acids

A

Gly, Ala, Pro, Val, Leu, Ile

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71
Q

What is a zwitterion?

A

Amino acid with both a positive and negatively charged atom at physiological pH, balancing out to no charge

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72
Q

What factors can cause protein denaturation?

A

Temperature, pH, salt, heavy metals (ionic interaction), detergents

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73
Q

Write the chemical equation that depicts the most important ability proteins require in order to exert their biological function & the mathematical equation used to quantitate this ability

A

[E][S]/[E*S] = k-1 / k1

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74
Q

Briefly describe the pathobiochemical mechanism of the prion protein, and what diseases come from it?

A

The prion is a misfolded PrPc molecule that affects other molecules to misfold
Familial Creutzfeldt-Jakob disease - caused by sporadic or inherited mutations
Variant CJD - Mad Cow
Iatrogenic CJD - cadaveric growth hormone use from infected sample
Kuru - consumption or mishandling of infected cadavers

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75
Q

Why are enzymes necessary for human life?

A

Speed - reactions need to happen quick enough to sustain homeostasis

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76
Q

What are amyloids, what diseases are caused by them and where in the body?

A

Deposition of insoluble fibrils made up of misfolded/defective proteins (B-sheets)

AL amyloidosis - immunoglobin light chains - systemic
Alzheimer’s disease - B-amyloid precursor protein - brain
Parkinson’s disease - a-synuclein - substantia nigra

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77
Q

What kind of enzyme inhibitor increases Km and sustains Vmax?

A

Competitive

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78
Q

What kind of enzyme inhibitor sustains Km and lowers Vmax?

A

Noncompetitive (binds allosterically) or Irreversible (binds covalently)

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79
Q

What kind of enzyme inhibitor lowers Km and lowers Vmax?

A

Uncompetitive

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80
Q

List and describe the 6 classes of enzymes

A
  1. Oxidoreductases - performs redox reactions
  2. Transferases - transfers chemical groups from one molecule to another
  3. Hydrolases - breaks covalent bonds using water
  4. Lyases - forms = bonds by removing chemical groups without using water
  5. Isomerases - convert between isomeric forms
  6. Ligases - form covalent bonds utilizing G of ATP hydrolysis
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81
Q

List and describe catalytic mechanisms employed by enzymes

A
  1. Acid-base catalysis
  2. Covalent catalysis
  3. Metal-ion catalysis
  4. Catalysis by approximation
  5. Cofactor catalysis
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82
Q

List and describe the different ways to regulate enzymes

A

Synthesis and Degradation
Sequestration
Protein-protein interaction
Covalent modification (phosphorylation, acetylation, etc)
Proteolytic cleavage (activate or inactivate)

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83
Q

What are the key characteristics of an allosteric enzyme?

What would a kinetic graph of an allosteric enzyme look like?

A

Multiple active sites
Cooperativity (R/T subunit states)

Sigmoidal graph
Allosteric activator will show left shifted graph (R state predominates)
Allosteric inhibitor will show right shifted (T state predominates)

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84
Q

Describe the effect of environmental changes on enzymes

A

Temperature - reactions accelerated by increased temperature until certain point (bell curve)
pH - optimal pH for enzymatic activity is 6-8, but there are exceptions (bell curve)
Concentration of Substrate - increased substrate gradually increases enzyme reaction with limited range
Concentration of Product - accumulation of product decreases enzyme velocity
Concentration of Enzyme - higher concentration increases velocity of reaction

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85
Q

What makes a mutation pathogenic?

A

When it involves a gene or control region in a way that changes the normal function of the product

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86
Q

List and describe the different types of mutation

A

Silent mutation: point mutation normally at the “wobble” position, doesn’t change amino acid
Missense mutation: point mutation that changes the codon to a different amino acid (Sickle cell Glu506Val)
Nonsense mutation: point mutation that changes codon from amino acid to stop codon (UAA, UGA, UAG)
Frameshift mutation: addition or deletion of nucleotide(s) that are not divisible by three which changes all codons; if equal to three, adds or deletes entire amino acid

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87
Q

What is globin switching?

A

When the fetal (Y) units of hemoglobin decrease and the beta (B) units take their place with alpha

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88
Q

What is aaBB hemoglobin?

A

Hgb A1; normal

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89
Q

What is BBBB hemoglobin?

A

HgH disease; a-thalassemia intermedia when there are 3 defective alpha alleles

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90
Q

What is aaYY hemoglobin?

A

Hgb F, fetal hemoglobin - has high O2 affinity

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91
Q

What is aa88 (delta) hemoglobin?

A

Hgb A2 ; beta-thalassemia; cause of Sickle Cell

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92
Q

What is YYYY hemoglobin?

A

Bart’s disease; a-thalassemia major; hydrops fetalis

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93
Q

Explain the difference between allelic heterogeneity and locus heterogeneity

A

Allelic - different mutations of the same gene leading to the same phenotype

Locus - mutation on different genes leading to the same phenotype

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94
Q

Explain the difference in mitochondrial bottleneck and replicative segregation

A

Mitochondrial bottleneck happens when dividing into oocytes, replicative segregation happens within zygote

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95
Q

What’s a phenotypic threshold?

A

When you need a certain amount of mutated mtDNA before seeing symptoms

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96
Q

What is nuchal translucency?

A

The space between the spinal cord and overlying skin of the fetus; seen on ultrasound; high in trimsomies

97
Q

What does the Quad screen test for?

A

Inhibin A levels
hCG levels
Estriol levels
alpha-feto protein levels

98
Q

What are the three main categories of genetic disorders?

A

Single gene, multifactorial gene, chromosomal abnormality

99
Q

List the other major names that can be used for aerobic metabolism

A

Aerobic respiration
Oxidative metabolism
Cellular respiration

100
Q

List the major fuels that can feed into aerobic metabolism

A

Glucose (Glucose –> Pyruvate –> Acetyl-CoA)
Fatty Acids (Fatty Acids –> Acetyl-CoA)
Amino Acids (Amino Acids –> Pyruvate or Acetyl-CoA)
Ketone Bodies
Ethanol

101
Q

Describe what must happen to pyruvate for it to undergo aerobic metabolism

A

Pyruvate must be transported through the inter mitochondrial membrane to the Pyruvate Dehydrogenase Complex (PDC).

Pyruvate goes through E1 with TPP - releases a carbon as CO2
Then goes through E2 and binds with coenzyme A - releases Acetyl-CoA

102
Q

Describe how PDC is regulated

A

It’s activated by Phosphatase
Activating Phosphatase is induced by Ca2+ when released by muscle contraction

It’s inactivated by phosphorylation from a Kinase
Inactivating Kinase is inhibited by ADP and Pyruvate - saying we’re ready for more ATP
Inactivating Kinase is induced by Acetyl-CoA and NADH - saying we have enough to make ATP

103
Q

List the three regulating enzymes of glycolysis and how are they regulated

A

Hexo(gluco)kinase - uses a P from ATP to get Glucose into the cell
Inhibited by G6P (glycolysis not necessary)

PFK-1 - uses a P from ATP to phosphorylate F6P into F16BP
Inhibited by ATP (enough energy available) and Citrate (other oxidative pathways should proceed), and induced by AMP/ADP (energy is low) and F2,6P (most important regulator)

Pyruvate Kinase - generates 2 ATP by removing 2 P’s from PEP
Inhibited by ATP (enough energy available) and induced by FBP (glycolysis needs to finish)

All irreversible

104
Q

What are the major products per glucose molecule

A

2 pyruvates, 2 NADH, 4 ATP total (2 net)

105
Q

What 3 enzymes regulate the TCA cycle and how are they regulated?

A

Citrate synthase - OAA + Acetyl-CoA –> Citrate + CoA
Inhibited by ATP

Isocitrate dehydrogenase - Isocitrate + NAD+ –> α-ketoglutarate + NADH + CO2 + H+
Inhibited by NADH, and induced by ADP and Ca2+

a-ketoglutarate dehydrogenase - α-ketoglutarate + COA + NAD+ –> Succinyl-CoA + CO2 + NAHD + H+
Inhibited by NADH, ATP, and Succinyl-CoA, and induced by Ca2+

106
Q

What enzymes and substrates are involved with the substrate-level phosphorylation in the TCA cycle?

A

Succinyl-CoA —> Succinate + CoA
Uses GDP and Pi to make GTP

107
Q

What is a cataplerotic reaction and what are the major ones?

A

A reaction that depletes intermediates from the TCA cycle

Citrate - Fatty Acid/Cholesterol Synthesis
a-ketoglutarate or Oxaloacetate - Amino acid synthesis/NT
Succinyl CoA - Heme synthesis
Malate - Gluconeogenesis

108
Q

What is an anaplerotic reaction and what are the major ones?

A

A reaction that replenishes intermediates of the TCA cycle

Carbohydrates, Fatty Acids replenish Acetyl-CoA
Glutamate replenishes a-ketoglutarate
Valine/Isoleucine replenishes Succinyl CoA
Amino Acids replenish Fumarate, Pyruvate, Acetyl-CoA
Aspartate replenishes Oxaloacetate

109
Q

List the shuttle systems used to transport NADH into the inner mitochondrial membrane (IMM), and explain the path of the electrons.

A

Glycerol 3-Phosphate Shuttle (Glucose -> NADH -> G3P -> FAD -> ETC)

Malate-Aspartate Shuttle (Glucose -> NADH -> Malate -> NADH -> ETC)

110
Q

Describe the path of electrons in the ETC

A

NADH -> Complex I -> CoQ ubiquinone -> Complex III -> Cytochrome C -> Complex IV -> Mitochondrial Matrix

FADH2 -> Complez II -> CoQ -> Complex III -> Cytochrome C -> Complex IV -> Mitochondrial Matrix

111
Q

How many H+ ions does each Complex contribute to the H+ gradient?

A

Complex I - 4
Complex II - 0
Complex III - 4
Complex IV - 2
Complex V - 0 (ATP Synthase)

112
Q

List and describe the ETC associated diseases with mtDNA mutations

A

MERRF - tRNA Lysine point mutation
MELAS - tRNA Leucine point mutation
LHON - NADH dehydrogenase (Complex I) missense mutation

113
Q

How is lactic acidosis correlated with oxidative metabolism?

A

Overproduction or underutilization of lactic acid, commonly caused by impairment of oxidative metabolism. PFK-1 is stimulated by low energy and large amounts of lactate are formed by glycolysis. ETC cannot oxidize the NADH and the accumulation makes the LDH irreversible in the direction of lactate formation

114
Q

What is the benefit of anaerobic metabolism?

A

100x faster ATP production which is an excellent short-term source for rapid ATP-consuming tissues

115
Q

What three energy systems replenish ATP in muscle?

A

Glycolysis, ETC, Phosphagen

116
Q

Describe the roles of cyclins, CDKs and CDKIs in the normal cell cycle

A

Cyclin proteins bind to cyclin-dependent kinases to activate them.

Cyclin/CDKs then phosphorylate target molecules (enzymes or other kinases) to stimulate the cell cycle into S phase

CDKIs are inhibitors that inactivate the Cyclins/CDKs, pausing cell cycle

At G1/S checkpoint - p53 and Rb tumor suppressor genes activate CDKIs if damage is detected before cell cycle begins
At G2/M checkpoint - check for damaged DNA and DNA replication completeness before entering mitosis

117
Q

What are the major regulators of Oxidative Metabolic Processes?

A

NADH/NAD+ ratio - high ratio indicates NADH is produced faster than it is oxidized; the Pyruvate Dehydrogenase Complex and TCA cycle are inhibited; low ratio indicates NADH is produced slower than oxidized, PDC and TCA activated

ATP/ADP ratio - high ratio indicates cell energy levels are high - PDC and TCA inhibited; low ratio indicates cell energy levels low - PDC and TCA activated

118
Q

Explain how the insulin tyrosine kinase receptor is activated

A

Insulin tyrosine kinase receptor is a heterotetramer with two identical a-chains and two identical B-chains joined by disulfide bonds.

Insulin binds to the extracellular cysteine-rich a-chains initiating the receptor to dimerize. The B-chain tyrosine kinase region phosphorylates itself as well as other insulin-receptor substrates (IRS).

119
Q

What are the monomeric G-proteins and their roles

A

Ras - signaling pathways that control cell division, proliferation, and death
Rho - regulate actin cytoskeletal organization, cell cycle progression, gene expression
Rab - regulate intravesicular transport and trafficking of proteins between organelles
Ran - regulates nucleocytoplasmic transport of RNA and proteins
Arf - regulate vesicular transport

120
Q

What are the two types of GTP-binding proteins and what is their purpose?

A

monomeric G-proteins : “small GTPases”, RAS, RHO, RAN, ARF

heterotrimeric G proteins β and γ subunits - activate ion channels; α subunits - activate enzymes

121
Q

Outline Glycolysis

A

Glucose -> Glucose-6-Phosphate -> Fructose-6-Phosphate -> Fructose-1,6-Bisphosphate -> Glyceraldehyde-3-Phosphate -> 1,3 Bisphosphoglycerate -> 3-Phosphoglycerate -> 2-Phosphoglycerate -> Phosphoenolpyruvate (PEP) -> Pyruvate

122
Q

Outline TCA

A

Pyruvate -> Acetyl-CoA -> Citrate -> Isocitrate -> α-ketoglutarate -> Succinyl-CoA -> Succinate -> Fumarate -> Malate -> Oxoacetylacetate

123
Q

Outline the pathways of cholera toxin and pertussis toxin

A

Cholera toxin catalyzes G-protein alpha S subunit –> inhibits GTPase activity –> remains activated –> increased adenylyl cyclase –> increased cAMP –> increased PKA –> increased CFTR –> secretory diarrhea & loss of fluids
(Gas –> AC –> cAMP –> PKA –> CFTR)

Pertussis toxin ribolayses G-protein alpha i subunit –> reduces inhibition of adenylyl cyclase –> increased cAMP –> …

124
Q

Outline the Gaq pathway

A

Gaq –> PLC –> IP3 –> Ca2+ –> PLA –> AA

Gaq –> PLC –> DAG –> PKC

125
Q

Explain the Ras/Raf pathway

A

Growth factor binds to EGF receptor –> proliferative signal sent out –> G-protein Raf binds to GTP (becomes activated) –> binds/activates Raf (MAPKKK) –> phosphorylates/activates MEK1/2 (MAPKK) –> phosphorylates/activates ERK1/2 (MAPK) –> phosphorylates/activates transcription factors –> cellular response (proliferation/development/differentiation/cell survival)

126
Q

A lab studying growth factor “GF” signaling adds GF
to cells with GF receptors known to have the
signaling in the diagram.

What changes in the cells would/could they measure to show that receptor activation had (assuming the lab has the necessary
equipment, reagents, and expertise)?

A

expression of specific genes; GTP turnover; GTP binding to Ras; increased phosphorylation (and of specific proteins); receptor phosphorylation on tyrosines; increased [Ca2+] intracellularly; PKC and AKT activation

127
Q

How does G6P deficiency affect RBC

A

RBC metabolism uses the hexose monophosphate shunt to destroy oxidizing agents

No G6P means no NADP+ –> NADPH –> no glutathione reduction –> inactivation of free radicals –> denatures into Heinz bodies –> less O2 carrying capacity in blood –> hemolytic anemia

128
Q

Outline the stages Erythropoiesis

A

EPO released from kidney –> EPO binds to EPO receptor in bone marrow –> JAK/STAT pathway –> intercellular cascade sends signal for gene expression for RBC regeneration –> progenitor cell –> proerythroblast –> basophilic erythroblast –> polychromatophilic erythroblast –> normoblast (nucleus ejected) –> reticulocyte –> RBC

129
Q

What the role of Hepcidin in Iron uptake and homeostasis?

What inhibits/activates Hepcidin synthesis?

A

Hepcidin binds with Ferroportin to inhibit iron absorption and release from storage

Increased plasma transferrin saturation and IL6 activate hepcidin synthesis –> increased Fe absorption inhibition

Increased erythroblasts, hypoxia, Erythropoietin and Matriptase inhibit Hepcidin synthesis –> decreased Fe absorption inhibition

130
Q

Outline the pathway of iron absorption

A

Dietary Fe3+ –> reduced by Ferrireductase or Vit C to Fe2+ –> enters GI epithelial cell through DMT-1 channel –> exits cell through Ferroportin channel –> Fe2+ oxidized by ferrioxidase –> binds to transferrin for transport through plasma

131
Q

What type of antibodies cause agglutination of RBCs? Why?

A

IgM antibodies cause agglutination of RBCs because they have multiple binding sites and can bind to multiple RBCs at the same time.

IgM are the ABO antibodies

132
Q

How does hemolysis lead to an increase in indirect bilirubin?

A

When RBCs are lysed, free floating hemoglobin is metabolized into heme, which is turned into biliverdin which is turned into indirect bilirubin

133
Q

How does a low haptoglobin result correlate with hemolysis?

A

Haptoglobin binds to free floating hemoglobin molecules. When hemolysis is occurring, there is an increase in free floating hemoglobin, which leads to a decrease in available haptoglobin.

134
Q

How does Chronic inflammation effect ferritin levels with regard to anemia?

A

Chronic inflammation leads to increase in IL6 markers which activate hepcidin synthesis. An increase in hepcidin synthesis leads to an increase in Ferroportin inhibition. This prevents iron from being absorbed in the gut or released from Ferritin storage.

135
Q

What lab test checks if anemia is caused by autoimmune disorder?

A

Coombs/DAT (direct antiglobulin test) - Anti-IgG reagent added to erythrocytes –> reagent causes IgG-coated erythrocytes to agglutinate –> shows there were antibodies bound to RBC antigens

136
Q

Which anemias will show increased MCV?

A

Megaloblastic anemia (B12 or Folate deficiency)
Liver disease

137
Q

Which anemias will show decreased MCV?

A

Iron deficiency
Thalassemia

138
Q

Which anemias will show normal MCV?

A

Anemia of chronic kidney disease
Combined nutritional deficiency (iron & B12, or iron & Folate)
Hemolysis
Blood loss

Some cases of chronic disease and iron anemia

139
Q

Hemolysis would lead to a ________ reticulocyte count

A

High

140
Q

Lab and PBS results you might see on anemia caused by acute blood loss

A

Low Hgb, low Hematocrit, increased reticulocytes
Normal iron serum, TIBC, Iron saturation and ferritin

PBS: normocytic, normochromic

141
Q

Lab and PBS results you might see on anemia caused by iron deficiency

A

Low Hgb, low hematocrit, low MCV
Low Iron serum, high TIBC, low iron saturation, low ferritin
Positive fecal occult blood test
Pica - wanting to eat ice, weird things

PBS: microcytic, hypochromic, poikilocytosis

142
Q

Lab and PBS results you might see on anemia caused by chronic disease/inflammation

A

Low Hgb, low Hct, normal MCV
Low iron serum, low TIBC, low iron saturation, high ferritin
Increased inflammatory markers

143
Q

Lab and PBS results you might see on anemia caused by beta thalassemia

A

Low Hgb, low Hct, low MCV
Normal iron, TIBC, iron saturation, ferritin

PBS: target cells, poikilocytosis

144
Q

Lab and PBS results you might see on anemia caused by B12 or Folate deficiency

A

Low Hgb, low Hct, high MCV
Normal serum iron, TIBC, iron saturation, ferritin
Low B12 or Folate serum
B12 deficiency shows neurologic deficits

PBS: macrocytic, ovoid in shape, nuclear-cytoplasmic dyssynchrony, hyper-segmented neutrophils

145
Q

EPO is secreted by ______ and is regulated by ________

A

The kidney
regulated through transcription factor HIF (Hypoxia inducible factor)
Low O2 –> increased HIF –> release of EPO from kidney to EPO receptor in bone marrow

146
Q

Vitamin C (increases/decreases) iron absorption by….

A

increases; reducing Fe3+ to Fe2+

147
Q

Ceruloplasm (increases/decreases) iron absorption by

A

decreases; oxidizes from Fe2+ to Fe3+

148
Q

Role of Ferritin in iron transport

A

Intracellular storage, protects cell from toxicity

149
Q

Role of hepcidin in iron transport

What activates hepcidin synthesis? Inhibits?

A

controls absorption of iron from gut and release of iron stores

Inflammatory markers (IL6)
Transferrin saturation

Hypoxia
EPO
Erythroblasts

150
Q

Role of haptoglobin

A

binds to free-floating hemoglobin

Increase of haptoglobin could mean hemolysis

151
Q

What are the intracellular signaling pathways activated by EPO

A

JAK/STAT - phosphorylation, dimerization

PLC –> IP3, DAG

PI3 –> Akt

Grb2/SOS –> Ras –> Raf –> MEK –> ERK

152
Q

Binds to E2F transcription factor
prevents G1/S transition
hypo- and hyperphosphorylated state controls its action

A

RB protein

153
Q

Causes cell cycle arrest and apoptosis
Acts through p21 activation
induces transcription of pro-apoptotic genes such as BAX
a main component of G2/M checkpoint
Negatively regulated by MDM2
tumor suppressor altered in a majority of cancers

A

p53

154
Q

Inhibitor of PI3K/AKT signaling

A

PTEN

155
Q

What are GEF, GAP and GTPase?

A

GEF - guanine exchange factor, removes GDP from receptor
GAP - dephosphorylates receptor to release GTP
GTPase - hydrolysis of GTP

156
Q

Tumor suppressor genes are most active at what point in the cell cycle?

A

G1/S Checkpoint

157
Q

Differentiate Howell-Jolly bodies and Heinz Bodies

A

Howell-Jolly bodies –> basophilic nuclear remnants (appear purple on PBS) - SCD

Heinz bodies –> misfolded hemoglobin (appear red on PBS)

158
Q

Thrombopoietin is released by what organs and what does it signal

A

Released by the liver and kidney

Signals megakaryocyte production in red bone marrow which forms platelets, which are then stored in the spleen or float in the blood

159
Q

Dense granules release

A

ADP, Ca2+, serotonin

160
Q

alpha granules release

A

fibrinogen, vWF, PDGF (platelet-derived growth factor)

161
Q

Describe primary hemostasis through adhesion

A

endothelial injury –> alpha granules and endothelial cells release vWF –> vWF binds to exposed collagen while subendothelial releases thrombin –> platelets bind to GpIb vWF receptor

162
Q

Describe primary hemostasis through activation

A

endothelial injury –> alpha granules and endothelial cells release vWF –> vWF binds to exposed collagen while subendothelial releases thrombin –> platelets bind to GpIb vWF receptor –> binding platelets activate other platelets –> activated platelets release ADP & Ca2+ –> ADP bind to P2Y12 receptor on platelet ADP receptor to cause confirmational change and expose GpIIb receptor –> activated platelets release COX –> COX converts arachnidonic acid –> TXA2 – increases vasoconstriction and platelet activation with positive feedback loop

163
Q

Describe primary hemostasis through aggregation

A

endothelial injury –> alpha granules and endothelial cells release vWF –> vWF binds to exposed collagen while subendothelial releases thrombin –> platelets bind to GpIb vWF receptor –> binding platelets activate other platelets –> activated platelets release ADP & Ca2+ –> ADP bind to P2Y12 receptor on platelet ADP receptor to cause confirmational change and expose GpIIb receptor –> activated platelets release COX –> COX converts arachnidonic acid –> TXA2 – increases vasoconstriction and platelet activation with positive feedback loop –> GpIIb receptor and fibrinogen cross-link platelets to create white thrombus

164
Q

Outline the extrinsic pathway of secondary hemostasis

A

Endothelial trauma –> releases TFIII –> TFIII activates VII –> TFIII + VIIa aid in X activation

3+7=10

165
Q

Outline the intrinsic pathway of secondary hemostasis

A

Activating surface (glass) activates XII –> XIIa activates XI –> XI + Ca2+ activate IX –> IX + VIII (activated by vWF) + Ca2+ activate X

12, 11, 9, 8, 10

166
Q

Outline the common pathway of secondary hemostasis

A

Xa + activated V activate II (prothrombin) –> IIa activates I (fibrinogen) and creates feedback loop activating V, VIII, X –> Ia + XIIIa crosslinks fibrin mesh forming fibrin clot

5 x 2 x 1 = 10 … and 13 is last

167
Q

What does Bleeding Time (PFA) test for and what lab results would be seen in an increased Bleeding Time?

A

Marker of primary hemostasis - how long until platelet plug forms

Increase BT with thrombocytopenia (decreased platelet quantity)
Increase BT with defective platelet function (dec. platelet quality)

168
Q

What does Prothrombin time (PT) test for and what lab results would be seen in increased PT?

A

Marker of secondary hemostasis - extrinsic pathway function (Playing Tennis)

Increase with Vit K deficiency (VII, X)
Increase with liver disease (VII, X)
Increase with Warfarin (VII, X)
Increase with DIC

169
Q

What does Activated Partial Thromboplastin Time (PTT, aPTT) test for and what lab results would be seen in increased PT?

A

Marker of secondary hemostasis - intrinsic pathway function (Playing Table Tennis)

Increase with hemophilia, DIC
Increase with vWF disease (VIII)
Increase in Vit K deficiency (IX, X)
Increase with liver disease (IX, X)
Increase with Warfarin (IX, X)

170
Q

Identify the key coagulation factors

A

VII, II, X, IX

171
Q

Identify the role of Vit K-dependent coagulation factors and describe the role of Vit K in their activation

A

Vitamin K–dependent carboxylation of specific glutamic acid residues in the region adjacent to the propeptide adds an additional negative charge which facilitates the binding of calcium ions, an essential cofactor for optimal function.

172
Q

Describe how the coagulation cascade functions in the body (in vivo) and how it differs from the in vitro model.

A

In vitro - the glass of the test tube activating XII and subsequent activation of XI of the intrinsic pathway is responsible for initiating the cascade

In vivo - the extrinsic pathway activation of TFIII and subsequent binding to VII initiates the cascade. In vivo, XI is activated by thrombin

173
Q

Describe how clot formation is limited and how a clot is dissolved, with particular reference to the roles of tissue factor pathway inhibitor, antithrombin, proteins C and S, and tissue plasminogen activator.

A

TFPI - blocks extrinsic coagulation by binding to Xa –> inactivates VIIa –> shuts down extrinsic pathway

Antithrombin - heparin cofactor –> inactivates thrombin and VIIa, IXa, Xa, and XIa

Protein C - inactivates factors Va and VIIIa after undergoing Vit K carboxylation

Plasmin - converted by zymogen plasminogen by tissue plasminogen activator (tPA inhibited by PAI-1) degrades fibrin - promotes dissolution of unwanted clot

174
Q

What is Ristocetin and what disorder(s) is it not useful for?

A

antibiotic that causes agglutination of platelets

Not useful against vWF disorders because platelets bind to each other via GpIb receptors on vWF

No vWF –> no platelet linking

175
Q

Features characteristically seen in reversible cell damage are:

A

Generalized swelling of the cell, blebbing of the plasma membrane, detachment of ribosomes, clumping of nuclear chromatin

176
Q

Features characteristically seen in irreversible cell damage are:

A

Inability to reverse mitochondrial dysfunction (lack of ATP generation), profound disturbances to membrane function due to lysosomal activation

177
Q

The cytoplasm of injured cells appear ____ when stained with H&E because…

A

red/pink

due to the loss of RNA which binds the blue dye - becomes more pronounced with progression toward necrosis

178
Q

What are the key differences between necrosis and apoptosis?

A

Cell swelling, inflammation, loss of membrane integrity, patterns of cell loss

Cell size:
necrosis -increases (swelling)
apoptosis - decreases (fragmentation)

Nucleus:
necrosis -pyknosis (shrinkage), karyorrhexis (fragmentation), karyolysis (dissolution)
apoptosis - fragmentation into apoptotic bodies

Plasma membrane:
necrosis - breaks down
apoptosis - stays in tact

Cellular contents:
necrosis - enzymatic digestion - leaks out of cell
apoptosis - intact, released in apoptotic bodies

Adjacent inflammation:
necrosis - yes
apoptosis - no

179
Q

How does BCL2 play a role in apoptosis?

A

BCL2 is anti-apoptotic by maintaining the mitochondrial membrane and preventing leakage of Cytochrome C. It does this by blocking BAX/BAK.

Overexpression can cause damage or mutated cells not to be destroyed and risk replication
Underexpression can cause healthy cells to initiate apoptosis

180
Q

How do BAX/BAK play a role in apoptosis?

A

BAX/BAK are pro-apoptotic proteins. They allow leakage of Cytochrome C by dimerizing and forming pores in the mitochondrial membrane.

Overexpression can cause unregulated apoptosis of healthy cells
Underexpression can cause lack of apoptosis in mutated cells

181
Q

What are the apoptotic pathways?

A

Extrinsic (death receptor) pathway - binding of a ligand to the death receptor of a cell activates capsases.
Cytotoxic T cells can also bind to MHC to mark the cell as infected, which activates capsases

Intrinsic (mitochondrial) pathway - DNA damage or decreased cell proliferation regulation causes activation of p53 –> increase expression of BAX/BAK –> release cytochrome C into cytosol –> activation of capsases

182
Q
A

Top is apoptosis
Bottom is necrosis

First cell is macrophage, second is neutrophil

183
Q

Explain why the left can be identified as necrosis and the right is apoptosis

A

The image of necrosis is very pink meaning there is a loss of nuclei

The photo of apoptosis shows purple, meaning the nuclei are still in tact

184
Q

Main difference between hypoxia and ischemia

A

With hypoxia, the blood is still flowing and still delivering nutrients to the cells, there is just a low quantity of oxygen being delivered - energy can still be made via anaerobic metabolism

In ischemia, there is a complete blockage not allowing oxygen or nutrients to the cells

185
Q

Outline the different types of necrosis

A

Coagulative necrosis - ischemia, myocardial infarction, lactic acidosis

Liquefactive necrosis - brain

Caseous necrosis - macrophage granuloma

Gangrenous necrosis - limb ischemia
-Dry gangrene - coagulative necrosis
-Wet gangrene - coagulative and liquefactive necrosis

Fat necrosis - breakdown of triglycerides - breast tissue injury or pancreatitis

Fibrinoid necrosis - small vessel damage –> increase fibrin levels –> vasculitis

186
Q

List the different types of cell injury adaptation

A

Hypertrophy - increased cell size due to increased workload (muscle building)

Hyperplasia - increased cell quantity due to growth factor proliferation (liver regeneration)
-pathologic hyperplasia - increased size of prostate

Atrophy - decreased cell size due to decreased workload, loss of innervation/blood supply/nutrition, tissue compression (limb in cast)

Metaplasia - reprogramming of local tissue stem cells in which one cell type replaces another that better suits the environment (Barret’s esophagus)

187
Q

List the signs of inflammation

A

Calor - warmth - increased blood flow
Rubor - redness - vasodilation and stasis
Tumor - swelling - exudation of fluid
Dolor - pain - action of prostaglandins and kinins on sensory nerves
Functional laesa - loss of fx

188
Q

Steps of the inflammatory process (5 R’s)

A

Recognition of injury
Recruitment of leukocytes
Removal of agent
Regulation of response
Repair

189
Q

Describe how microbial pathogens are recognized and the different types of receptors used

A

Pattern Recognition Receptors (PRR) detect Pathogen Associated Molecular Patterns (PAMP)

Membrane-bound Signaling Receptors: TLR, Mannose, Scavenger

Cytoplasmic PRRs: Nod-like Receptors, RIG-I-like Helicases

Soluble Receptors in Serum: Complement, CRP, MBL

190
Q

What type of receptor does dsRNA/DNA bind to?

ssRNA?

A

TLR3

TLR7/8

191
Q

How do dead cells stimulate inflammation?

A

Damage Associated Molecular Patterns (DAMP) - Alarmin

192
Q

What type of inflammation is infiltrated by these cells?

A

Acute - neutrophils

193
Q

What type of inflammation is infiltrated by these cells?

A

Chronic - macrophages

194
Q

Name the cell type and it’s distinguishing feature(s)

A

Eosinophil - red staining cytoplasm

195
Q

Name the cell type and it’s distinguishing feature(s)

A

Phagocyte - large, light colors nuclei with debri in cytoplasm

196
Q

Name the cell type and it’s distinguishing feature(s)

A

Plasma cell - nuclei sitting to the side, purple cytoplasm due to increased RNA activity producing antibodies

197
Q

Name the cell type and it’s distinguishing feature(s)

A

Lymphocyte - extremely dark nuclei, little/no cytoplasm due to metabolic inactivity

198
Q

Differentiate between exudate and transudate

A

Exudate is protein-rich, inflammatory cell-rich fluid pushed out of the blood vessels during increased vascular permeability.

Transudate is low protein, low cell fluid which leaks out of the vessel due to increased hydrostatic and osmotic pressure.

199
Q

Explain the role of “rolling” to activate leukocytes and the subsequent actions

A

Leukocytes “roll” by slowing migrating across the vessel wall attaching to P-selectin and E-selectin receptors until the Integrin receptor is in a high-affinity state and attaches to migrate across the wall into the tissues.

200
Q

Acute inflammation response subsides because…

A

Stimulus no longer exists
Mediators have short half life
Neutrophils die
Switch in the arachidonic acid pathway in macrophages –> production of anti-inflammatory cytokines (TGF-b and IL-10)

201
Q

Role of Leukotriene B4 (LB4) in inflammation

A

Neutrophil chemotaxis

202
Q

What mediators aid in vasodilation during inflammation?

A

Histamine, prostaglandins, platelet-activating factor, kinins

203
Q

Principal mediators aiding in chemotaxis, leukocyte recruitment and activation during inflammation

A

TNF, IL-6
Chemokines
C3a, C5a
LB4

204
Q

What type of inflammation is seen here?

A

Chronic

205
Q

What are the 5 features of inflammation

A

Rubor (redness)
Dolor (Pain)
Tumor (Swelling)
Calor (warmth)
Loss of function

206
Q

What type of inflammation is seen here?

A

Granulomatous inflammation

207
Q

What forms giant cells?

A

Fusion of macrophages during chronic inflammation

208
Q

What is the role of a Cd4/Th1 cell in chronic inflammation?

A

Cd4/Th1 cells identify the antigen-presenting cell and release cytokines for leukocyte recruitment. CD4/Th1 cells then release IFN-y to aid monocytes in differentiation into activated macrophages. Macrophages then release cytokines to act on CD4/Th1 in a positive feedback loop.

209
Q

What are the six stages of infection?

A

Encounter
Entry/Establishment
Spread
Survival/Multiplication
Damage/Dysfunction
Outcome

210
Q

List Koch’s postulates and explain how they differ from the molecular Koch’s postulates

A
  1. The microorganism (MO) must be found in all subjects suffering from the disease, but not in any healthy ones
  2. MO must be isolated from diseased subject and grown in pure culture
  3. Cultured MO should cause disease when introduced to healthy subject
  4. MO must be re-cultured and identified as being identical to original causative agent

The molecular postulates state to identify the gene affected rather than the MO

211
Q

What are the four ways microorganisms can cause disease/establish infection?

A

Toxin-mediated infections - bacteria
Acute pyogenic infections - organisms that establish, grow, and cause damage quickly
Subacute infections - slower growth rate, lay low to establish and not set off alarms - typically grow in areas that eventually affect the heart
Chronic infections - organisms that grow very slow, harder to get rid of, usually intracellular - Tb

212
Q

How would you build a “Pathogenesis story” for a pathogen?

Build one for Staph A.

A

(Identify structure) (mode of transmission) (where it travels in the body ie receptors/cells/ect) (virulence factors that allow it to remain in the environment) (how pathogen results in clinical presentation/timeline)

Staphylococcus aureus, a circular-shaped, gram-positive bacterium that arrange in clusters, enters the body to the dermis, through a disruption of the epidermis such as a cut. S. aureus causes infection by binding to the fC section of the antibody, preventing an immune cell from binding and destroying the pathogen. This allows the bacteria to establish and replicate causing an inflammatory response, leading to the clinical presentation of swelling, warmth and pain in the area.

213
Q

What are the hallmarks of cancer?

A
  1. Self-sufficiency in growth signals - tumors proliferate without external stimuli
    i. Usually due to oncogene activation - excessive cell growth in absence of growth factors
  2. Insensitivity to growth-inhibitory signals - tumors may not respond to molecules that inhibit proliferations
    i. Usually because of inactivation of tumor suppressor genes
  3. Altered cellular metabolism - tumor cells undergo metabolic switch to aerobic glycolysis
    i. Warburg effect
  4. Evasion of apoptosis
  5. Limitless replicative potential - unrestricted proliferative capacity
    i. Stem-cell like property that permits tumor cells to avoid cellular senescence
  6. Sustained angiogenesis - need vascular supply to bring nutrients and oxygen, thus induce angiogenesis
  7. Ability to invade and metastasize - arise from interplay of processes that are intrinsic to tumor cells and signals initiated by tissue environment
  8. Ability to evade host immune system - exhibit a number of alterations that allow them to evade innate and adaptive immune systems
214
Q

What is the most likely mutation of RAS pathways to cause cancer?

A

Mutation of GTPase which prevents inactivation of RAS –> unregulated proliferation

215
Q

Modes of oncogene activation in tumor cells

A

Overexpression
Amplification
Translocation
Point or other mutations
Small duplications

216
Q

Role of Toll-Like Receptors in inflammation

A

Cell receptor that recognizes foreign bodies/microbes –> triggers production of inflammatory molecules including adhesion molecules

217
Q

Role of NOD-like Receptors in inflammation

A

Receptors that recognize diverse molecules that are liberated or altered as a consequence of cell damage –> activate inflammasome –>induces production of cytokine interleukin-1 (IL-1) –> recruits leukocytes –> induces inflammation

Uric acid (product of DNA breakdown)
ATP (released from damaged mitochondria)
cytoplasmic DNA (not in nucleus)

218
Q

Outline the JAK/STAT pathway

A

Ligand binds to cytokine receptor –> receptor dimerizes and activates JAK –> JAK phosphorylates receptor –> STAT binds to phosphorylated section –> JAK phosphorylates STAT –> STAT dimer forms –> STAT dimer detaches from receptor and travels to nucleus –> STAT dimer binds DNA and activates transcription factors –> gene expression

219
Q

Outline what happens after JAK phosphorylates EPOR

A

PI3-K, PLC and growth factor receptor-bound protein 2 bind to the receptor and become activated –> multiple intercellular signaling processes

PI3-K activates AKT
PLC catalyzes PIP2 hydrolysis –> creates IP3 and DAG –> PKC and Ca2+
GFRB2 activates Ras –> Raf –> MEK —> ERK

220
Q

Inhibitor of PI3-K signaling cascade

A

PTEN

221
Q

Outline PLC signaling cascase

A

PLC catalyzes PIP2 hydrolysis –> creates IP3 and DAG

222
Q

What are the hallmarks of cancer cells?

A

Self-sufficiency in growth signals - proliferate w/o external stimuli
Insensitivity to growth-inhibitory signals
Altered cellular metabolism - Warburg effect
Evasion of apoptosis - inhibition of BAX/BAK/p53, ↑ BACL2
Limitless replicative potential - hayflick limit
Sustained angiogenesis
Ability to invade and metastasize
Ability to evade host immune system

223
Q

Types of necrosis

A

Coagulative - caused by tissue ischemia
Liquefactive - lysosomes release hydrolytic enzymes (brain)
Caseous - macrophage isolates pathogen –> pathogen and surrounding cells destroyed –> granular debri
Gangrenous - limb ischemia (dry –> coagulative, wet –> coag + liquefactive)
Fat - enzymatic breakdown of triglycerides –> fatty acids binds to Ca2+ –> fat saponification and calcification
Fibrinoid - small vessel damage –> fibrin deposited in vessel walls

224
Q

Outline the process of NER

A

Nucleotide excision repair - Occurs during G1

Endonucleases remove damaged bases –> DNA polymerase adds new bases –> DNA ligase links new bases together

225
Q

Outline process of BER

A

Base excision repair - Occurs throughout cycle - GEL PLease
Glycosylase excises base and creased apurinic site
Endonuclease cleaves 5 end of backbone Lyase cleaves 3 end of backbone
DNA Polymerase adds new nucleotides
Ligase links nucleotides together

226
Q

Outline process of Mismatch repair

A

Occurs at S checkpoint

New daughter strand –> MSH proteins identify mismatched bases –> endonuclease breaks strand –> exonuclease removes bases –> DNA polymerase adds correct bases –> DNA ligase seals strand

227
Q

BRCA1 and BRCA2 are involved in…

A

homologous recombination repair

Breast cancer

228
Q

Describe the role of VEGF

A

Vascular endothelial growth factor

Given off by tumor cells to tell endothelial cells to grow vessels toward the tumor

inhibited by Bevacixumab

229
Q

Contrast benign vs malignant tumor characteristics

A

Benign are small, well demarcated, non-invasive, slow growing

Malignant are large, poor demarcated, rapidly growing with necrosis, metastatic, poorly differentiated

230
Q

Four steps of invasion

A

Loosening of intracellular junctions
Degradation of ECM
Develop novel ways to attach to ECM
Migrate through ECM

231
Q

Steps of Metastasis

A

Intravasation into circulation
Interaction with host lymphoid cells
Tumor cell embolus
Adhesion to basement membrane
Extravasation
Metastatic deposit
Angiogenesis
Growth

232
Q

Major classes of cellular and molecular processes that accompany aging

A

Oxidative damage - ROS, UV radiation
Inadequate repair processes - decreased autophagy
Dysregulation of cell number homeostasis - hayflick limit

233
Q

Describe glycation and glycoxidation

A

Nonenzymatic reaction between C group of sugar and N group of macromolecules to form AGE

Oxidation of AGE (chain to circle)

AGEs alter structure and functional properties

234
Q

Changes in blood vessels with age

A

stiffness, diameter

↑ AGE –> ↑ collagen –> ↑ deposits in cell walls

235
Q

Changes in skin with age

A

Lipofuscin accumulation in dermis
Atrophy
Degradation of collagen and elastin from sun exposure

236
Q

Changes in muscle with age

A

Sarcopenia

↑ cytochrome C oxidase –> less efficient oxidation of NADH –> ↑ ROS –> damages mtDNA –> decreased number/size of myofibers
Progressive loss of neuro function

237
Q

Changes in bones with age

A

bone mass, joint cartilage

Apoptosis of osteoblasts with ROS, decreased IGF-1, ↑ parathyroid hormone (inhibits calcium)

238
Q

Changes in joints with age

A

Fatigue, strength, tensile stiffness
Cartilage thinning

↑ collagen cross-linking

239
Q

How does a caloric restriction delay aging

A

Decreased plasma glucose –> decrease glycation/glycoxidation
Decreased mt workload –> decreased oxidative stress
Decreased plasma levels of insulin and IGF-1
Mild repeated stress –> stimulates maintenance and repair processes

Unit 1 (9 decks)

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