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What is the definition of shock? Understand the systemic effects of shock.
Shock is the low delivery of blood to tissues due to blood loss or dehydration. This can result because of reduced cardiac output or reduced circulating blood volume.
What are the systemic effects of shock?
Consequences of shock are hypotension, impaired tissue perfusion, and cellular hypoxia.
Understand the four general categories of shock.
- • Cardiogenic Shock is caused by the failure of cardiac pump.
- • Hypovolemic shock is caused by reduced circulating blood volume.
- • Anaphylactic shock is an excessive immune response
- • Septic Shock is caused by a microbial infection and presence of microbial endotoxins
Describe the four causes of cardiogenic shock.
Infarction or heart attack, Ventricular arrhythmia, Cardiac tamponade, Pulmonary embolism
what is Cardiac tamponade
rapid accumulation of fluid in the pericardium restricting diastolic cardiac filling.
Describe the two causes of hypovolemic shock.
Hemorrhage, Fluid loss- burns, diarrhea, or vomiting
Understand the three attributes of anaphylactic shock.
- o Systemic IgE-mediated hypersensitive immune response
- o Causes vasodilation and increased vascular permeability
- o Increased blood vessel volume and decreased fluid content causes dramatic decrease in blood pressure and blood velocity
Describe the systemic symptoms of septic shock.Systemic effects and symptoms caused by high levels of LPS are•Systemic vasodilation (hypotenstion)•Diminished myocardial contractility•Widespread endothelial injury and activation, causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung•Activation of the coagulation system, causing disseminated intravascular coagulation (systemic blood clotting)•Multiorgan system failure that affects the liver, kidneys, and CNS, among others
- Systemic effects and symptoms caused by high levels of LPS are
- •Systemic vasodilation (hypotenstion)
- •Diminished myocardial contractility
- •Widespread endothelial injury and activation, causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung
- •Activation of the coagulation system, causing disseminated intravascular coagulation (systemic blood clotting)
- •Multiorgan system failure that affects the liver, kidneys, and CNS, among others
Describe the mechanism of septic shock.
LPS in the bacterial cell wall is an endotoxin. LPS binds to circulating LPS-binding protein; and then the complex binds to CD14 on systemic monocytes, macrophages, and neutrophils. CD14 triggers systemic IL1 and TNF release, resulting in local inflammatory responses.
What are Treatment stratagies for septic shock?
- • Control the infection to reduce circulating LPS
- • Inhibitors of inflammatory mediators may be effective
- • Soluble CD14 may antagonize LPS activation of cell surface CD14
What is the definition of edema?
Edema is the increase of fluid in the interstitial tissue spaces
What are the six causes of edema?
- • Increased hydrostatic (blood) pressure causes fluid loss from the vessels to the surrounding tissues
- • Arteriolar dilation and increase in vascular permeability causes the loss of water to tissue and fluid buildup in the tissues
- • Reduced plasma osmotic pressure causes fluid loss to surround tissues in an attempt to achieve homeostasis. Hyperproteinemia is a common cause of this type of edema
- • Lymphatic obstruction prevents drainage of fluid from tissues, resulting in fluid buildup in these tissues.
- • Sodium and water retention causes both increased hydrostatic pressure in the blood and increased transudation. This is typically caused by decreased renal function.
- • Inflammation can also cause edema
Understand the two common causes of increased venous blood pressure and resulting edema.
- o Right ventricle congestive heart failure or venous obstruction or compression. This reduces the ability of the heart to drain the venous circulation. This results in increased venous pressure and congestion.
- o Venous obstruction or compression. This causes increased vanous pressure upstream of the blockage.
Understand the three causes of hypoproteinemia and resulting edema, particularly the mechanisms.
- • Reduced plasma osmotic pressure causes fluid loss to surround tissues in an attempt to achieve homeostasis. Hyperproteinemia is a common cause of this type of edema. Reduced osmotic pressure occurs when albumin (the serum protein responsible for maintaining intravascular colloid osmotic pressure) is low in plasma. Three causes of hypoproteinemia are:
- o Increased loss of plasma proteins- nephritic syndrome (leaking of glomerular capillary walls in kidneys)
- o Reduced synthesis of plasma proteins- liver cirrhosis
- o Inadequate uptake of proteins- malnutrition
Understand the three causes of lymphatic obstruction and resulting edema.
- The three causes of lymphedema are:
- o Lymph node inflammation and swelling. Swelling due to parasitic infection which causes lymphatic and lymph node fibrosis is an example of this.
- o Compression by invasive malignancy
- o Surgical resection or irradiation of lymphatic system in cancer patients
Understand how sodium retention contributes to edema.
Sodium and water retention causes both increased hydrostatic pressure in the blood and increased transudation. This is typically caused by decreased renal function.
Understand how inflammation can cause edema.
- Characteristics of inflammation caused edema are:
- o Increased vascular permeability due to endothelial cell retraction
- o Increased vascular permeability due to leukocyte-dependent endothelial cell injury and extravasation
- o Angiogenesis (new blood vessels are usually leaky)
What are the four general differences between benign and malignant tumors?
- • Benign tumors are more differentiated, so they are closer to normal
- • Benign tumors grow slowly
- • Benign tumors are less invasive
- • Benign tumors are never metastatic, so they don’t travel to other regions of the body
What are two mechanisms by which cancer risk increases with age?
Aging is accompanied by an accumulation of somatic mutations and a decline in immune function. These both are risk factors that contribute to cancer development.
What are preneoplastic syndromes?
Preneoplastic syndromes are risk factors that make a person predisposed for cancer. It doesn’t mean the person will have cancer, but they have an increased risk.
What are Four classes of genes that are the targets of mutations
- oOncogenes- genes that encode proteins that promoste cell proliferation. Gain of function mutations stimulate cell proliferation.
- oTumor suppressor genes- genes that encode proteins that inhibit cell proliferation. Loss of function mutations cause a loss of inhibition of cell proliferation, so cells divide without inhibition
- oApoptotic Genes- genes that encode proteins involved in apoptosis. Unrepaired DNA damage leads to apoptosis in normal cells. This function is lost in tumor cells, leading to accumulation of cells with genetic defects. Two apoptotic genes are:
- •BAX promotes apoptosis, so a loss of function mutation would contribute to cancer
- •Bcl2 inhibits apoptosis, so a gain of function mutation would contribute to cancer
- oDNA repair genes- Loss of DNA repair genes leads to acquisition of additional mutations that contribute to tumor formation and progression. XP, AT, and blooms syndrome are examples.
What are six examples of aquired preneoplastic syndromes?
- oLong un-healed skin wounds characterized by persistent damage can lead to skin cancer
- oCirrhosis of the liver can lead to hepatocellular carcinoma
- oHyperplastic cell proliferation in bronchial mucosa can lead to lung cancer in smokers
- oChronic gastritis as a result of a long-standing H. pylori infection can lead to gastric cancer
- oChronic ulcerative colitis can lead to colorectal cancer
- oVillous adenomas (hyperplastic polyps) of the colon can lead to colorectal cancer
What are the six characteristics of cancer cells.
- • Self sufficiency in growth signals
- • Resistance to growth inhibitory signals
- • Cancer cells evade apoptosis. Thus disruption of apoptotic pathways may contribute to malignancy
- • Tumor cells have limitless replicative potential
- • Tumor cells can trigger angiogenesis
Understand the “two-hit” hypothesis for growth inhibitory proteins encoded by tumor suppressor genes.
Both alleles must acquire loss-of-function mutations either sporadically or inherited in order to form a tumor.
Understand the three different perturbations that can lead to evasion of apoptosis.
- • Loss of p53 expression or loss of function mutations
- • Loss of BAX expression or loss of function mutations
Understand why normal cells can undergo only 60-70 cell divisions.
Normal cells have telomeres at the ends of their chromosomes and serve as protective caps. Each cell division leads to shortening of telomeres. This leads to abnormalities and thus cell death.
Understand how telomerase overexpression can lead to cell immortalization.
Tumor cells over express telomerase which leads to cell immortalization.
Understand how tumors cause angiogenesis and why Avastin is used to treat colorectal cancer.
- • HIF1α binds to VEGF to induce angiogenesis. In normal tissues VHL binds to HIF1α and it is ubiquitinated for degradation.
- • Avastatin is an antibody that binds to VEGF antagonizing the binding of HIF1α.
what are the steps of the Metastatic Cascade
- o Adhesion and invasion of basement membrane beneath tumor
- o Migration through ECM
- o Invasion of vaccular basement membranes and vascular ingress (intravasation)
- o Travel via the vasculature
- o Adhesion to endothelial cells/ vascular basement membrane at destination
- o Invasion of vascular basement membrane and vascular egress (extravasation)
- o Migration through ECM
- o Formation of metastatic deposit and cell proliferation
What are the steps of Invasion of ECM
- o E-Cadherin function is lost
- o EMT (epithelial to mesenchamal transition) occurs
What causes metastasis to the bone?
PTHrP when expressed by tumor cells promotes bone resorption, promoting tumor cell invasion of the bone
What is the effect of Hereditary nonpolyposis colon carcinoma?
patients defective in mismatch DNA repair
What is the effect of Xeroderma pigmentosum-
patients defective in nucleotide excision repair, causing cross-linking of pyrimidine residues, preventing normal DNA replication by UV light
What is the effect of Bloom’s syndrome and Ataxia telangiestasia-
defective in homologous recombination repair of DNA strand breaks caused by ionizing radiation
Understand the sequence of genetic changes associated with colon carcinogenesis.
- • Loss of APC gene which is a tumor suppressor
- • Loss of DNA methylation which inhibits gene transcription
- • Mutation of RAS gene which enables proliferation
- • Loss of tumor suppressor
- • Loss of p53 gene so the cell can’t maintain genomic integrity
What are chemical carcinogens?
Chemical carcinogens are tumor initiators causing DNA damage.
What is the difference between direct and indirect chemical carcinogens?
Direct-acting agents don’t require any change to act as a carcinogen, while indirect-acting agents require metabolic conversion into a carcinogen.
What are examples of chemical carcinogens?
Nitrogen mustards, polycyclic aromatic hydrocarbons
What are tumor promoters?
Tumor promotors promote cell proliferation but do not cause DNA damage. Cells are replicated before the cell is able to fix a mutation.
What are examples of tumor promoters?
Phorbol esters, hormones, phenols, and drugs
how does IR cause lesions?
Inonizing radiation induces DNA strand breaks. This can lead to increased expression of oncogenes or reduced expression of tumor suppressors.
How does UV cause lesions?
UV light cross-links DNA bases. This can lead to increased expression of oncogenes or reduced expression of tumor suppressors.
What are the 2 ways RNA viruses cause cnacer
- • Some Oncogenic RNA viruses carrie viral oncogenes that cause malignancy
- • Some insert a viral promoter near a cellular oncogene
What is the mechanism of HTLV-1?
HTLV-1 (Human T cell leukemia virus-1) is an oncogenic RNA virus. HTLV-1 TAX is a transcription factor that stimulates expression of cytokines and cytokine receptors. It also represses the expression of tumor suppressor genes such as p53
How do DNA viruses cause cancer?
DNA oncogenic viruses have genes whose proteins disrupt cellular growth control pathways.
How does HPV cause cancer?
HPV has E6 protein which binds and mediates degradation of p53 and BAX, and E7 protein which binds Rb and release E2F
How does EBV cause cancer?
EBV has LMP-1 which stimulates B-cell proliferation by activating the CD40 signaling pathway and inhibiting apoptosis by activating the anti apoptotic protein BCL-2, and EBNA-2 is a transcription factor that stimulates expression of cyclin D and SRC
how can normal cells irradiate cancer?
Tumor cells are foreign to the immune system so the body can form an immune response and eradicate the cancer. Tumor antigens are proteins expressed in tumor cells but not normal cells.
What are the 5 antigens the immune system uses to recognice cancer?
- o Mutated oncogenes and tumor suppressor genes such as mutant β-caterin, Ras, p53, and CDK4
- o Products of other genes that are mutated in tumor cells
- o Viral proteins encoded by oncogenic viruses
- o Proteins that are overexpressed by tumors
- o Oncofetal antigens are found in the developing fetus but not normal adults. The immune system will not mount an attack, but they can be used to detect cancer treatment success.
What are examples of proteins over expressed in cancer?
- • Tyrosine kinase are overexpressed in melanomas but normally expressed in melanocytes
- • MAGE-1 is overexpressed in melanomas but normally expressed in testis
- • HER2/Neu is overexpressed in breast tumors
What are examples of oncofetal genes that can be used to detect cancer prognosis?
CEA and AFP
Understand the four responses of the immune system to tumor cells.
- • Cytotoxic T lymphocytes-recognize tumor-specific antigen presented in the context of an MHC class 1 molecule on tumor cells
- • Natural Killer cells are activated by IL2 or through antibody-binding to a foreign antigen on tumor cell surface
- • Macrophages activated by interferon and kill cells by release of tumor necrosis factor (TNF)
- • Humoral mechanism- complement system or ADCC
What are the three effects of cancer on the host?
- • Tumor compresses surrounding tissues leading to its destruction
- • Cause cachexia (wasting of muscles due to lack of appetite)
- • Paraneoplastic syndromes like hypercalcemia or crushing syndrome
What is tumor grading?
Grading is the estimate of aggressiveness or level of malignancy based on microscopic examination of tumor cell morphology. Poorly differentiated cells means high grade. (qualitative)
What is tumor staging?
Staging is the estimate of aggressiveness of level of malignancy based on size of the primary lesion, extent of spread to lymph nodes, and the presence of absence of metastatsis. More metastasis means higher stage. quantitative
Understand laboratory assays for cancer and their limitations
Assays detect presence and concentration of circulating tumor markers or proteins that are specific for tumor cells (CEA, PSA, AFP). These assays lack specificity and sensitivity to detect cancers. However they are useful in monitoring treatment response and recurrence.
Understand the correlation between HER2/Neu expression and outcome in breast cancer? How is HER2/Neu expression used to guide clinical proactice?
HER2/Neu overexpression correlates with poor prognosis but is a condition for treatment with the HER2/Neu antagonists Lapatinib/tykerb or trastuzumab/herceptin.
Understand the principle of gene expression profiling and how these tests can be used to individualize cancer therapy.
- Chip based analysis of gene transcription and mass spectromy analyses of protein expression are two common omic approaches.
- oOncotype DX is a set of 21 genes that predict chemotherapy benefit and recuurence in breast cancer
- oMammaPrint is a set of 70 genes that can be used to predict reccurence and outcome in breast cancer
- oThese introduce individualized therapy in which a patient’s profile dictates the course of pharmacotherapy
- oThis is a new target for anticancer drugs