Foundations 2 Week 5 part 1
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What are the main categories of cancer?
- Carcinoma: cancer of epithelial cells
- Sarcoma: cancer of other cells
- Leukemia: cancer of circulating immune cells
- Lymphoma: solid lymphoid tumors
- Myeloma: tumor of plasma cells in bone marrow
What are alloantigens?
MHC and HLA molecules that can be recognized to illicit an immune response.
Contrast tumor-specific and tumor-associated antigens.
- Tumor-specific: Found on tumor cells
- Tumor associated: Found on tumor cells and healthy cells.
Describe the mechanisms of immune evasion by cancer cells
- Some tumor cells can make proteases that cleave MIC receptors, making it difficult for NK cells to recognize them. The MIC receptors are then internalized by NK cells and gamma:delta T cells.
- Proliferating tumor cells often undergo additional mutations, making it more difficult for the immune system to recognize different variations.
- Tumor cells sometimes down regulated MHC 1 receptors, making it difficult for CD8 cells to recognize them.
- Tumors may downregulated B7 (CD80/86) costimulatory molecules, making it difficult for antigen presenting cells to connect their MHC II receptors and become activated. These T cells are considered anergic.
- Tumor cells may produce TGF-ß or recruit Tregs (regulatory T cells) that produce TGF-ß and IL-10, to inhibit the proliferation and cytokine production of TH1 cells and lytic granules. This limits CD4 and CD8 T cells.
What are the characteristics of an apoptotic cell?
- Apoptosis involves Chromatin condensation, Progressive cell shrinkage, Plasma membrane blebbing, Apoptotic bodies, Phagocytosis, but no inflammation.
- Normal on top, apoptotic on bottom.
What are some diseases that are associated with too much or too little apoptosis?
- Viral infections (AIDS), Neurodegenerative disease (Alzheimer’s), Multiple sclerosis, Ischemic injury (Myocardial infarction), Toxin-induced diseases (alcohol-induced hepatitis) are all related to increased apoptosis.
- Apoptosis is a natural part of embryogenesis. Syndactyly (webbed fingers or toes) occurs as a result of apoptosis failure.
- Cancer, atherosclerosis, and autoimmune disorders may all be associated with apoptosis.
Describe the Bcl-2 family of proteins, their relationships, and general functions.
- Pro-apoptotic proteins in the family include Bax, Bak, Bid
- There are 3 subgroups of the BH family.
- Bcl : having domains BH1,2,3,4. This is a pro-survival/antiapoptotic protein.
- Bax, Bak: having domains BH1,2,3
- Bid: having domain BH3
- The fate of the cell is controlled by the balance of pro and anti apoptotic proteins.
- Bid inhibits Bcl, allowing Bax and Bak to cause apoptosis.
Describe the processes involved in the intrinsic pathway of apoptosis.
- Bid (domain BH3 only proteins) bind to Bcl proteins. Bcl proteins are now unable to bind Bax and Bak proteins
- Bak and Bax proteins then create channels in the mitochondrial outer membrane, allowing cytochrome C to leak out.
- Seven molecules of an adaptor protein, Apaf-1 (apoptotic protease activity factor-1), combine with seven cytochrome C protein molecules to form the apoptosome, or the “wheel of death”.
- The apoptosome then recruits procaspase-9 (an inactive form), which then self-processes and becomes activated as caspase-9.
- Caspase-9 activates caspases 3, 6, and 7. Together they cleave over 400 different proteins, causing cell death. 3, 6, and 7 are the executioner caspases
- Also, AIF (Apoptosis Inducing Factor) is released from the mitochondrial intermembrane space by Bax/Bak activity. AIF travels to the center of the nucleus where it induces chromatin condensation of DNA fragmentation.
How does the extrinsic pathway (extracellular ligands binding the cell surface) of apoptosis work?
- External FAS death receptors bind to FADD (FAS-associated death domain) when activated, forming a complex known as the DISC (Death Inducing Signaling Complex).
- The DISC binds an initiator procaspase 8 (or initiator procaspase 10) which activates the executor caspases (3, 6, 7), bypassing the Bcl route.
How does the Granzyme B-mediated pathway for apoptosis work?
- Granzyme B is a protease that is released (along with perforin) by cytotoxic T cells and natural killer cells, causing apoptosis of virally infected cells.
- Granzyme B can activate the BH3-only protein, Bid, by cleaving it, along with directly activating caspases -3 and -8.
What is AIP?
- IAP: Inhibitor of Apoptosis, inhibits caspases.
- Smac, aka diablo: promotes apoptosis by binding to and inhibiting IAPs.
Describe the mechanism that enable replicative immortality.
Overexpression of telomerase (a reverse transcriptase) prevents cell death due to telomere shortness. A telomere consists of repeating TTAGGG, and each cell loses 50-100 bp per replication. Stem cells do not lose telomerase when replicating.Normal cells do not contain TERT (telomerase) or hTR (the RNA template used to create the telomere).
How do rest and proliferating cells differ in their metabolism?
- Normal, resting cells use fatty acid oxidation and oxidative metabolism of glucose.
- Proliferating cells use more glucose and glutamine that normal cells, to support cell growth and proliferation.
Why do cancer cells have a high glycolytic rate?
Because of the Warburg effect. Anaerobic glycolysis is less effective, so it requires more substrates. Cancer cells produce about 4 ATP per glucose. Aerobic normally produces 36 ATP and anaerobic produces 2 ATP per glucose. Cancer cells still use the aerobic pathway a little.
What are the major components of the tumor microenvironment?
- extracellular matrix, activated fibroblasts, immune cells, pericytes, adipocytes, epithelial cells, glial cells, vascular and lymphatic endothelial cells, and numerous proteins.
- myofibroblasts, endothelial cells, dendritic cells, tumor associated macrophages, and mast cells.
What is Cognitive Behavior Therapy (CBT)?
- Usually focused on the present, time-limited, and skill-based.
- Recognizing that motivation often follows behavior
- Activity Scheduling (mastery & pleasure ratings)
- Relaxation, deep breathing, meditation
- Self-care = self-respect
What is Acceptance & Commitment Therapy (ACT)?
- Accept what is out of your personal control, and commit to action that improves and enriches your life. ACT does this by:
- Teaching psychological skills to deal with painful thoughts and feelings effectively so that they have less influence over people (i.e., mindfulness skills)
- Helping clarify what is truly important and meaningful (i.e., values) and using that knowledge to guide, inspire, and motivate people to change their lives for the better
- A key component of ACT is defusion: learning to let go of unhelpful thoughts, worries, and memories; learning to step back and be an observer of your thinking so you can respond effectively
What is Dignity Therapy?
Short therapy focused on helping patients with terminal illnesses review what has been most meaningful to them and document their legacy.
What is Cognitive Processing Therapy (CPT)?
- One of the most effective treatments for PTSD. Also used for non-military-based trauma
- VA teaching this as part of National Therapist Training Program
- CPT has four main parts:
- Learning about PTSD symptoms
- Developing awareness of thoughts and feelings
- Learning skills to challenge or question thoughts related to trauma
- Understanding changes in beliefs associated with trauma (e.g., safety, trust, control, self-esteem, relationships)
Describe the potential impact of genetic information on insurance coverage and employment status.
None. It is protected by GINA (Genetic Information Nondiscrimination Act)
What is the Ames test?
Salmonella that needs histamine to grow is placed in a pytri dish and given a drug. If the salmonella starts to grow, you know the drug caused a mutation which caused histamine to be produced. Tests carcinogenic potential.
Give a male mouse a drug and see if there is a change in the number of viable offspring.
Give a male mouse a drug and see if there is a change in the number of viable offspring.
Describe the steps in the management of the poisoned patient.
- A - Check airways
- B - Check breathing
- C - Check circulation
- D - Consider giving Dextrose that the brain can use as fuel, or thiamine.
- 2) Decontamination
- Syrup of ipecac (do not use if there is no GAG reflex, or if they ingested corrosives or hydrocarbons. Increased damage may be caused by inhalation of fumes due to vomiting)
- Activated charcoal can be given to interfere with toxins. Note, it may interfere with antidotes as well.
- Enhancement of elimination: Manipulation of urine pH, hemodialysis, or hemoperfusion
- Antidote: N-acetylcysteine for acetaminophen, naloxone for heroine
Describe the clinical aspects of cyanide poisoning.
- Cyanide (HCN, smells of burnt almonds) causes flush appearance → dizziness, confusion, anxiety → respiratory distress → arrest.
- Cyanide binds tightly to heme iron in cytochrome a-a3 complex (cytochrome oxidase).
- Treatment: stabilize the patient, give amyl nitrate and/or I.V. sodium nitrate followed by sodium thiosulfate (producing MetHb to bind the CN).
Describe the clinical aspects of iron poisoning.
- Iron causes vomiting, diarrhea (often bloody) (ie, massive blood and fluid loss) → remission → shock, seizures, liver failure, death.
- Iron has a corrosive effect on mucosal tissue and causes cellular dysfunction (acidosis and liver failure).
- Treatment: Deferoxamine (chelating agent) if serum Fe is > Total Iron Binding Capacity (TIBC). Monitor urine color and serum Fe levels.
Describe the clinical aspects of lead poisoning.
- Lead causes nausea, constipation or diarrhea, abdominal pain, change in personality, blue lead line on gums, wrist drop/foot drop (peripheral neuropathy).
- Lead binds sulfhydryl groups, interfering with enzymatic processes, decreasing Hb synthesis and RBC life span. Demyelinates peripheral nerves.
- Treatment: Maintain urinary output and chelate with dimercaprol and/or calcium EDTA.
Describe the clinical aspects of ricin poisoning.
- Ricin causes delayed GI irritation (nausea, vomiting, diarrhea, abdominal pain) → remission → hemmorrhagic gastritis and dehydration → tissue necrosis leading to death.
- Ricin disrupts protein synthesis by binding the 60S ribosomal subunit.
- Treatment: Administer activated charcoal, treat fluid and electrolyte loss.
Describe the clinical aspects of Ethylene glycol poisoning.
- Ethylene glycol (anti freeze) causes intoxication, hyperventilation, reversible renal failure, and increased osmolar gap leading to anion gap acidosis.
- Ethylene glycol metabolizes to toxic organic acids.
- Treatment: Hemodialysis, ethanol (competes with alcohol dehydrogenase), fomepizole (inhibits alcohol dehydrogenase).
Describe the clinical aspects of Amanita mushroom poisoning.
- Amanita mushrooms nausea, vomiting, diarrhea, abdominal pain, increased liver enzymes, acidosis, jaundice.
- Cyclopeptides inhibit RNA polymerase II.
- Treatment: Treat fluid and electrolyte loss aggressively, activated charcoal, liver transplant.
Describe the clinical aspects of Acetaminophen overdose.
- Several hours after ingestion, Acetaminophen causes nausea, vomiting, sweating, and pain as acute liver failure starts.
- Treatment: Administer N-Acetylcysteine.
What is potentiation?
Drugs with… 0 efficacy + 1 efficacy → 10 efficacy. There is an order of magnitude change.
What is synergy?
Drugs with… 1 efficacy + 1 efficacy → 3 efficacy.
What is the effect of Ginkgo biloba + NSAIDS?
Ginkgo biloba can reduce platelet aggregation, as do NSAIDS. Together, they may cause bleeding problems.
What is the effect of Calcium channel blockers + Grapefruit juice?
Grapefruit juice interferes with enterocyte CYP3A4 activity so presystemic clearance of susceptible drugs decreases and bioavailability increases.
Describe how pharmacokinetic drug interactions may affect toxicity due to alteration in absorption, distribution, metabolism, and excretion.
- Absorption: Laxatives decrease absorption, antibiotics result in less vitamin K from gut bacteria resulting in increased response to oral anticoagulants. H2 blockers may change the pH, altering dissolution properties.
- Distribution: Affected by plasma protein binding and tissue displacement
- Metabolism: Can cause induction (slow, eg, phenylbarbital) or inhibition (fast, eg, ketoconazole). Cip384
- Excretion: Increasing the pH increases the rate of weak acid elimination Decreasing pH increases the rate of weak base elimination (ie, ammonium chloride and ascorbic acid),
What is the therapeutic index?
- TI = LD50/ED50
- or in humans...
- TI = ED50/ED50
What is the margin of safety?
What is Bioaccumulation?
Increasing concentration of a persistent environmental chemical in the tissues or organs.
What is Biomagnification?
The increasing accumulation of a chemical with each progressive link of the food chain.
What are Threshold limit values?
- Can be...
- TLV-TWA (time weighted average): The average time exposure allowed
- TLV-C: ceiling values: The amount that should never be passed.
What are general functions of the various cell types in the tumor microenvironment?
- •Myofibroblasts / Fibroblasts: Tumor initiation, growth and tumor invasion by incorporation of α-smooth muscle actin fibers. AKA cancer associated fibroblasta, CAF’s.
- •Adipocytes: Adipokines lead to increased tumor cell migration and tumor invasion by regulating expression and activation of MMPs
- •Tumor endothelial cells: Leukocytes recruitment and tumor cell behavior and metastasis
- •Pericytes: Stabilize blood vessels, inhibit endothelial cell proliferation, maintain capillary diameter, regulate blood flow, provide endothelial survival signals.
- •Tumor associated macrophages: Immune regulation, promote cell growth and promote tumor development. M2 TAMs promote cancer.
- •Dendritic cells: Induce vascularity and involved in tumor immune-pathogenesis
- •Immune cells: Promote growth and progression of cancer
- •Mast cells: Promote tumor development by disturbing the normal stroma-epithelial communication, facilitating tumor angiogenesis, releasing growth factors, and inducing state of immunosuppression.
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