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MICROBIO 160 (160)
Lecture

MICROBIO 160 Lecture Notes - Nocebo, Mdm2, Radical Mastectomy

48 Pages
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Spring 2013

Department
Microbiology
Course Code
MICROBIO 160
Professor
Mitchell Walkowicz

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"Principles of Cancer Biology" Lewis J. Kleinsmith
"Biology of AIDS" Wilmore Webley - 2nd ed
Textbooks used as reference materials, individual readings:
So some male-specific cancers decreased, but some female-specific did not
Early detection best way to prevent cancer
HPV has caused oropharyngeal (throat), anal, and vulvar cancers to increase
PAP smears have prevented people from dying, but screening does not necessarily prevent spreading HPV
We have made significant decreases in most other diseases (heart disease, stroke, pneumonia), but only a 5% dent in cancer death rates in
the past 55 years
Cancer rates have decreased since 1975 because 15% decrease in smokers (who are majority male)
Familial 25%
Spontaneous 70%
Breast cancer
10% genetic
90% environmental (obesity, radiation, asbestos, organic solvents (eg dry cleaning fluid), etc.)
Cancer prevention - aim for a healthy weight maintenance, 30 mins of physical activity ea day,
30% cancer is from smoking, 30% from obesity. THESE ARE PREVENTABLE FACTORS. These are lifestyle choices, and so cancer is absolutely
avoidable
Cancer
Looking at a variety of cancers, there are sometimes a lot of new cases and few deaths (ex. Prostate cancer), and sometimes fewer cases with
very high death rates (esophageal)
Better living conditions, water treatment, vaccination, hygiene, health care, decreased infant mortality, nutrition increase life span which
means you now live long enough to develop cancer
Due to relative increases in the quality of sanitation, food, air, etc, the developed world has basically replaced lower respiratory infection and
diarrheal deaths (1 & 3 in 3rd world countries) with cancer and infectious diseases
Cancer is a function of making mistakes in copying DNA, so there cannot be a cure for cancer because it is a side-effect of a natural and necessary
body function, creating new cells
Only been an issue since 1981/1982
34 million infected, mostly in sub-Saharan Africa
HIV: Human immunodeficiency Virus
AIDS decreased in white pop, increased in black
AIDS infection rate highest in Wash DC (2% of pop), equal to rate in sub-Saharan Africa
97% in low/middle-income countries
Over 7000 HIV infections per day in 2009
1000 >15 yo
It is trending downwards, but not very quickly
Because of AIDS life expectancy in placed like Uganda, Botswana remains in 50s while US is around 78 years old
Infection rates facts:
US pays 30-40% more than the rest of the world, yet we have one of the least effective plans among 1st world nations
Saying "socialize medicine" and people run and say "communism!" and hate on you
US refuses to look at other systems
The professor is reaaaaaaaally pro-universal health care
Live longer = more chances to go to the hospital, get sick, get cancer, which means you spend more :(
Health Care
Lifestyle differences - men more likely to engage in risky behavior
Differences in biology - women carry babies, so their bodies are built to protect the mother, biologically tougher, female hormones protect
Women live 5 yrs longer than men
Lecture 1 - INTRO
Wednesday, January 23, 2013
10:06 AM
MicroBio160 Page 1
Differences in biology - women carry babies, so their bodies are built to protect the mother, biologically tougher, female hormones protect
women from heart disease
Among those over 100, 85% are women
In young men, the testosterone storm can induce people to due stupid shit
When they commit suicide, men do it better. Women try more often, but men are more effective.
HIV increases cancer risk
Initially AIDS reduced life expectancy, then drugs helped (in 1st word initially, making an impact in 3rd world nowadays)
MicroBio160 Page 2
Miasma theory of disease - the air makes you sick
The bad air is in the lowlands, in the swamps, so the rich have the highlands and are thereby not
sick (so often)
Nostradamus (plague era doctor)
In humans, any condition that causes discomfort, distress, social problems, dysfunction, or death
to the afflicted or those in contact
Syndrome - a net over a bunch of symptoms, broader definition than disease
Sometimes includes injuries, disabilities, disorders, syndromes, infections, isolated symptoms,
deviant behaviors, and deviant variations of structure and function
Disease - abnormal condition of an organism that impairs bodily functions
The establishment said that ulcers could not be caused by bacteria until a guy drank a batch of
bacteria and gave himself ulcers. People were so convinced that it had to be stress/anxiety that
they limited the truth. Bastards.
Ulcers
Idiopathic - of unknown cause
Psychosomatic (somatoform) - only a mental thing, no physical cause
Pathogen-mediated
Specific organism or organism combo
Infections
Caused by genome mutation
Genetic
Ex molds, cigarette smoke, radon, lead poisoning...
Environmental
Categories of disease
Genetic
Environmental (ex. Radiation, breathing organic solvents…)
"contagious" (viral ) hepatitis, cervical, throat (HPV)
Cells transferred, tumor grows (contagious cellular cancer)
DFTV (Devil Facial Tumor Disease) - contacted when one Tazmanian Devil with DFTV bites a
healthy TazD
What kind of disease is cancer
Observe
Hypothesize
Experiment/data collection
Analysis of data
Results summarization (tables, graphs, etc)
Discussion of limitations and conclusions
ID future research needs
The SCIENTIFIC METHOD (again)
Aristotle - spontaneous generation (living things from nonliving things)
Jean Baptiste Van Helmont - mice come from rotting grains/dirty rags
Cell Theory Development
Lecture 2 - DISEASE
Friday, January 25, 2013
11:08 AM
MicroBio160 Page 3

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Lecture 1 - INTRO Wednesday, January 23, 2013 10:06 AM Textbooks used as reference materials, individual readings: "Principles of Cancer Biology" Lewis J. Kleinsmith "Biology of AIDS" Wilmore Webley - 2nd ed Cancer rates have decreased since 1975 because 15% decrease in smokers (who are majority male) So some male-specific cancers decreased, but some female-specific did not Early detection best way to prevent cancer HPV has caused oropharyngeal (throat), anal, and vulvar cancers to increase PAP smears have prevented people from dying, but screening does not necessarily prevent spreading HPV We have made significant decreases in most other diseases (heart disease, stroke, pneumonia), but only a 5% dent in cancer death rates in the past 55 years Breast cancer Genetic 5% --parents Familial 25% Spontaneous 70% Cancer 10% genetic 90% environmental (obesity, radiation, asbestos, organic solvents (eg dry cleaning fluid), etc.) Cancer prevention - aim for a healthy weight maintenance, 30 mins of physical activity ea day, 30% cancer is from smoking, 30% from obesity. THESE ARE PREVENTABLE FACTORS. These are lifestyle choices, and so cancer is absolutely avoidable Looking at a variety of cancers, there are sometimes a lot of new cases and few deaths (ex. Prostate cancer), and sometimes fewer cases with very high death rates (esophageal) Due to relative increases in the quality of sanitation, food, air, etc, the developed world has basically replaced lower respiratory infection and diarrheal deaths (1 & 3 in 3rd world countries) with cancer and infectious diseases Better living conditions, water treatment, vaccination, hygiene, health care, decreased infant mortality, nutrition increase life span which means you now live long enough to develop cancer Cancer is a function of making mistakes in copying DNA, so there cannot be a cure for cancer because it is a side-effect of a natural and necessary body function, creating new cells HIV: Human immunodeficiency Virus Only been an issue since 1981/1982 34 million infected, mostly in sub-Saharan Africa AIDS decreased in white pop, increased in black AIDS infection rate highest in Wash DC (2% of pop), equal to rate in sub-Saharan Africa Infection rates facts: 97% in low/middle-incomecountries Over 7000 HIV infections per day in 2009 1000 >15 yo It is trending downwards, but not very quickly Because of AIDS life expectancy in placed like Uganda, Botswana remains in 50s while US is around 78 years old Health Care US pays 30-40% more than the rest of the world, yet we have one of the least effective plans among 1st world nations Saying "socialize medicine" and people run and say "communism!" and hate on you US refuses to look at other systems The professor is reaaaaaaaallypro-universal health care Live longer = more chances to go to the hospital, get sick, get cancer, which means you spend more :( Women live 5 yrs longer than men Lifestyle differences - men more likely to engage in risky behavior Differences in biology - women carry babies, so their bodies are built to protect the mother, biologically tougher, female hormones protect MicroBio160 Page 1 Differences in biology - women carry babies, so their bodies are built to protect the mother, biologically tougher, female hormones protect women from heart disease Among those over 100, 85% are women In young men, the testosterone storm can induce people to due stupid shit When they commit suicide, men do it better. Women try more often, but men are more effective. Initially AIDS reduced life expectancy, then drugs helped (in 1st word initially, making an impact in 3rd world nowadays) HIV increases cancer risk MicroBio160 Page 2 Lecture 2 - DISEASE Friday, January 25, 2013 11:08 AM Nostradamus (plague era doctor) Miasma theory of disease - the air makes you sick The bad air is in the lowlands, in the swamps, so the rich have the highlands and are thereby not sick (so often) Disease - abnormal condition of an organism that impairs bodily functions In humans, any condition that causes discomfort,distress, social problems, dysfunction, or death to the afflicted or those in contact Sometimesincludes injuries, disabilities, disorders, syndromes,infections, isolated symptoms, deviant behaviors, and deviant variations of structure and function Syndrome - a net over a bunch of symptoms,broader definition than disease Ulcers The establishment said that ulcers could not be caused by bacteria until a guy drank a batch of bacteria and gave himself ulcers. People were so convinced that it had to be stress/anxietythat they limited the truth. Bastards. Idiopathic - of unknown cause Psychosomatic(somatoform) - only a mental thing, no physical cause Categories of disease Infections Pathogen-mediated Specific organism or organism combo Genetic Caused by genomemutation Environmental Ex molds, cigarette smoke,radon, lead poisoning... What kind of disease is cancer Genetic Environmental(ex. Radiation, breathing organic solvents…) "contagious" (viral ) hepatitis, cervical, throat (HPV) DFTV (Devil Facial Tumor Disease) - contacted when one Tazmanian Devil with DFTV bites a healthy TazD Cells transferred, tumor grows (contagious cellular cancer) The SCIENTIFIC METHOD (again) Observe Hypothesize Experiment/datacollection Analysis of data Results summarization(tables, graphs, etc) Discussion of limitations and conclusions ID future research needs Cell Theory Development Aristotle - spontaneous generation (living things from nonliving things) Jean Baptiste Van Helmont - mice come from rotting grains/dirty rags Jean Baptiste Van Helmont - mice come from rotting grains/dirty rags Francesco Redi - challenged spontaneous generation, "meat/maggotexperiment" Hypothesized that rotting meat does not turn into flies, only flies make moreflies Anton van Leeuwenhoek - single-lens microscope,observesingle-cell organisms Robert Hooke - compound microscope,coined 'cell' Schleiden and Schwann - Cell Theory 1. All Life forms are made from 1 or more cells 2. Cells only arise from preexisting cells 3. Cell is the smallest form of life Spontaneous Generation 4th century Nonliving objects could give rise to living organisms Louis Pasteur - disproved by forming the germ theory of disease and he process of pasteurization Boil stuff ad then seal it and it will remain sterile It is what is in the air that results in microbial growth Infectious disease -- one in which detrimental changes in the health of the host occur as a result of damage caused by a pathogenic organism Robert Koch showed Bacillus anthracis caused anthrax Proven in 1876 Koch used a set of criteria to demonstratethat the etiology(specific cause) was a microbe Koch's Postulates(rules for assignment of a microbe as the cause of a disease) 1. Microorganismmust be observed in every case of the disease 2. The pathogen must be isolated and grown in a pure culture 3. The pure culture must cause disease when inoculated into a healthy host 4. The same pathogen must be recoveredfrom the diseased host As life expectancy improvesand the role of infectious, parasitic and respiratory infections further diminishes, more people will survive to older ages and chronic degenerative diseases such as stroke, cancer, and heart disease will make up a larger proportion of deaths. Lecture 3 - CANCER Wednesday, January 30, 2013 11:09 AM NOTE: Khan academy recommendedfor review of DNA, RNA, chromosomes, etc History: Recognized by Egyptians ~4000 yrs ago (breast cancer Treated by cauterization and cutting Hippocratesrecognized the difference between benign and malignant tumors Cancer named after the fact that the swollen bloodvessels around tumors tend to look like crab claws, so he called the disease karkinos(Greek for 'crab') "Cancer" is an umbrella term referring to over 200 diseases that share the two common characteristics: 1. An uncontrolled growth of cells 2. The ability to invade and damage normal tissues either locally or at distant sites in the body a. Tumors dissolveand eat into the tissue they form in b. They can shed, and travel to distant sites in the body, growing and shedding and traveling again Differentmutations make differentcancers, but just because one treatment works on one set of cancerous tumors does not mean that it will work on the rest How Cancer develops -The body is made up of hundredsof types of cells, which all behave differently -Same DNA but performscompletelyseparate roles (iris DNA activates in iris cell, not in musclecells) -Life of each cell mapped out in advance by genes in the nucleus -When instruction related to cell regeneration/multiplication/dying are wrong (usually multiplemistakes, not just one),cells may start dividing uncontrollably and not die when it should -Angiogenesis - any blood vessels that grow after embryonic stages. Different vasculogenisis, Cancer uses angiogenesis to create a greater food source/waste removal system for itself, so it can grow even larger rather than imploding -Metastasis - cancerous cells make it into the circulatorysystem and travel throughout the body -Apoptosis - cell suicide as a result of damage (not present in cancer cells); programmed cell death Major types of new tissue growth Hypertrophy (beingsuper meaty, jacked, muscular) Increase in cell size Normal organization Hyperplasia (callouses, chub) Increase in cell number Normal organization Dysplasia Disorganized growth Neoplasia Disorganized growth Net increase in # dividing cells Tumors Neoplasm - abnormal tissue growth in which cells proliferate in an uncontrolled autonomous fashion leading to a tumor Tumor - swelling caused by fluid build up or cell accumulation Can be benign (good)or malignant (bad) Usuallybenign tumors are not cancerous,but they can change to becomecancerous Malignant Benign -not self-contained, not necessarily localized -generally self-contained, localized -grow quickly, do not always compress tissues -grow slow -no or less clean margin -well-defined perimeter -can metastasize and spread -dangerous when they compresssurrounding tissues (blood vessels, passageways, brain tissue,) Nuclear to --have bigger nucleus, stains dark purple spot --smallernucleus, MicroBio160 Page 5 Nuclear to --have bigger nucleus, stains dark purple spot --smallernucleus, cytoplasmic ratio (High) (Low) Mitotic index High (large number od dividingcells, relatively) Low Tissue Disorganized normal organization Tumor grade If a tumor is suspected malignant, a doctor biopsies it Tumor grade: based on the microscopic appearance of cancer cells GX: grade cannot be assessed (looks like surrounding tissue) G1: well-differentiated (low grade) G2: moderatelydifferentiated (intermediategrade) G3: poorly differentiated (high grade) G4: undifferentiated (high grade) Higher number = less favorableprognosis Tumor stage: how large a tumor has grown and how far it has spread Based on location,tumor size, number of tumors, lymph node involvement (whether the cancer has spread into the lymph nodes) Its bad to have it spread to lymph nodes because lymph nodes are an excellent avenuefor cancer cells to spread aka metastisize Cancer Names Adeno - gland Chrondro - cartilage Erythro - red blood cell Hemangio - blood vessels Hepato -liver Lipo - fat Lympho - lymphocyte Melano - pigment cell Myelo - bone marrow Myo - muscle Osteo - bone Carcinomas Majority of cancers are carcinomas(85%) Types Squamous cells:line different parts of the body (ex. Mouth,esophagus,airways) Adeno cells: lining od all glands and found in organs like stomach, ovaries, kidneys,prostate Transitionalcells: found in the lining of the bladder and parts of the urinary system Basal cells: one of the layers of the skin MicroBio160 Page 6 *Lecture4 - CELL Wednesday, February 06, 2013 11:50 AM Lecture 5 - CELL PROFILE Wednesday, February 06, 2013 11:06 AM Multicellular humans There are about 210 types of cells in the human body Avg adult has 50-75trillion cells total Groups of cells doing similar shit --> tissues Group of tissues doing similar shit --> organ Groups of organs doing similar shit --> organ system Cell Cycle Normal cell characteristics Reproduce themselvesexactly Stop reproducing at the right time Stick together at the right place Self-destruct if damages Becomespecialized or mature Cancer begins with DNA damage or mutation as a result of Exposure to radiation Exposure to toxins Hormonal abnormalities Nutrition/diet Tobacco use Viral infection How cancer cells develop Normal cell -> 1st mutation Cell seems normal but is predisposed to proliferate excessively 1st -> 2nd mutation Cell begins to proliferate too much but is otherwise normal 2nd -> 3rd mutation Cell proliferates more rapidly Undergoes structural changes 3rd -> 4th mutation Cell grows uncontrollably Looksobviously deranged Oncogenes tumor suppressor genes repair genes Protease(ASE = enzyme) Transfection: Contact-inhibited : stop growing when they touch something Anchorage-dependent: must adhere to something (the dish, other cells) or they will die Hallmarks of cancer cells (p. 195-197in textbook) Exhibit decreased dependence on external growth factors Need less growth factor/no growth factor, and grow as a lump on top of everything else Exhibit decreased density dependent growth inhibition Exhibit decreased density dependent growth inhibition Keep dividing even when other cells touch them Cancer cell proliferation is anchorage independent Can grow free-floating Have limitless replicative potential Stimulates sustained angiogenesis Makes new blood vessels so it can grow denser than normal Able to evade apoptosis Are involved in tissue invasion and metastasis How growth Factors work Cells grow because they receive a specific signal Growth factors reach receptors,which release signaling moleculesthat travel to the nucleus and activate transcription factors, and the cell undergoes division Decreased dependence on external growth factor Mutant receptorssignal constantly that the cell needs to divide Telomeres(DNA unlaces) Seal off the ends of chromosomes,made of junk DNA so that you don't lose important DNA during replication As they replicates, telomeresfrau, allowing chromosomesto becomedamaged Telomerase - an enzyme that maintains the telomeres,keeping the chromosomesintact longer Act as a DNA clock; long telomeres= young cell, short telomeres= cue for apoptosis Telomerasemakestelomeresduring embryonicdevelopment Cancer cells keep their telomereslong (unlimited replicative potential) Telomerasemakescancer cells immortal Progeria Genetic, premature aging Telomerasewas not "on" long enough to apply enough telomeres,their telomeresare too short, so their body is destroying cells too fast Density dependent inhibition of growth by cancer cells Normal cells stop dividing at a monolayerstage after attaching to bottom of flask Cancer cells continue dividing, piling up on one another, growing at a faster rate Anchorage independence Cancer cells grow well both suspended and attached to a flask Normal cells grow poorly when suspended Cancer cells have lost the moleculeon their surface that keep cells in it's "right place;" they don't stick to other cells properly Cancer cells only talk to other cancer cells. Shun the nonbelievers! Angiogenesis Vascular Endothelial Growth Factor (VEGF) - blood vessel making cells Tumor produces VEGF to grow blood vessels to it, allowing it to increase in size, and gives it a means of metastasis once the tumor is all grown up Summary: 1. Self-sufficiency in growth signals 2. Insensitivity to anti-growth signals 3. Tissue invasion and metastasis 3. Tissue invasion and metastasis 4. Limitless replicative potential 5. Sustained angiogenesis 6. Evading apoptosis Lecture 6 - SPREAD Monday, February 11, 2013 11:06 AM Typical Cancer progression 1. Mutation inactivates tumor suppressor gene 2. Cells proliferate 3. Mutation inactivates DNA repair gene 4. Mutation of proto-oncogenecreates an oncogene 5. Mutation inactivates several more tumor suppressor genes 6. CANCER D:< Primary and Secondary cancer main reason cancer is difficult to cure is that is can spread to anywhere Cancer growing here it originally grew is called a 'primary cancer' Places where a cancer spreads and starts growing is called 'secondary cancer' or 'metastasis' Cancer spread and mortality 90% of cancer deaths occur because of secondary, not primary, cancers Most metastaticcancer induce pre-metastaticniches/landing pads, allowing cancerous cells to colonize a secondary organ When cancer cells travel to a vital organ, they often overwhelm the organ and cause it to shut down By the time a cancer is found, it may have been present for years, but the immune system has controlled their proliferation How Hematologiccancers cause death "non-solid" tumors Hematologic(blood) cancers kill because the componentsof the blood are no longer fulfilling their duties The immune system is no longer working effectively The platelet count drops, causing hemorrhaging Red cells are significantly reduced, causing reduced oxygen, and then heart attack Increased white blood cell count causes viscous blood, clogging the arteries How solid cancers kill Solid cancers kill in mechanical ways Ovarian cancer kills by obstructing the bowels, like colon and GI tract cancers Lung cancers kill by eroding into an artery or obstructing the airway Breast cancer kill by metastasis into the brain Brain cancers kill by intracranial pressure 40% of cancer patients die from malnutrition, not the cancer itself Tumors induce a hyper metabolic state and secrete cachectin (TNF-[alpha]) that results in weakness and weight loss Vasculogenesis = formation of brand-new blood vessels when there are no pre-existing ones Angiogenesis = formationof new blood vessels from pre-existing ones Juda Folkman Working for the Navy in the 1960son blood substitutes, he began experimentingwith tumors and found they all grew to the same size and stopped Hypothesized tumors must use angiogenesis or else they wouldn't have enough blood to grow larger larger Trade name for antiangiogenesis drug = Avastin, formed by creating antibody proteins that fight the human protein Statin = stop Tumor angiogenesis: When they # only 100-300,the cancer cells have created new, fully-functioning blood vessels Grows form small localized tumor to a tumor that can grow and spread There are 3 ways a cancer spreads Local spread Blood circulation Through lymphatic system Steps involved into metastaticprocess Ability to invade differs among cancers and tumnors Blood flow patterns often dictate where cancers will spread to Relativelyfew cacner cells survive voyage throuhg blood stream Cancer cells ableto incade because of Decreased adhesiveness Activated motility Proteaseproduction Modern medicine, modern problems Biomedicine/immunologic Avastin (bevaciumab)[-mab], monoclonalantibody 5 billion $ industry Chemo ~250k Chemo plus avastin ~500k Difference in time w/o progression, merely months Personalized medicine, genome-based Biomarker- gene mutation shown to be associated with a positive response to given treatment Positive= 5 months w/o increase in cancer cells Colon and lung cancer biomarkers still being evaluated No longer recommendedfor breast cancer cases More money medicine Macular degeneration Lucentis is a purified form of avastin $2000vs $20/dose Off-label use Infections with avastin due to sloppy procedure? *Lecture7 - IMMUNOLOGY Monday, February 11, 2013 11:38 AM Evidence for immune reactivity to tumors Certain tumors regress spontaneously There is an increased incidence of malignancies in immunodeficient patients Antibodies and immune T-lymphocyteshave been detected in patients with tumors Young and very old have increased incidence Body can be immunized against tumors InflammatoryResponse: 1. damaged tissues release histamines in response to bacteria 2. Increased blood flow to the area is conducive to histamines causing capillaries to leak, releasing phagocytes and clotting factors into the wound 3. Phagocytesengulf bacteria, dead cells, and cellular debris 4. Platelets moveout of the cells to clot the wound Antigen = foreign substance that induces production of antibodies because it is recognized by the immune system as a threat Antibody - protein produced in response to antigen invasion histocompatibility *Lecture8 - EPIDEMIOLOGY Friday, February 15, 2013 4:30 PM Cancer Causation history Clear by 1900s exposure caused cancer Chimney sweeps: coal tar/adenocarcinoma Radium watch dials Benzene liver cancer Animal models agree Tobacco smoke,asbestos, coal tar vinyl chloride, benzene What is Epidemiology? The study of how often diseases occur in different groups of people and why Looksfor causes and risk factors of disease to propose effective strategies for disease prevention and control Epidemiologicalstudies fall into 3 types 1. Experimental i. Human equivalent of animal testing, providing or withholding a substance to determine its toxic or beneficial effects ii. Greatly limited by ethical/legal considerations as well as securing the cooperationof a large group of people 2. Descriptive i. Analyzes data on the distribution and extent of health problems in various populations ii. Attempts to find correlationsamong characteristics such as diet, air quality, and occupation iii. Comparisonsare frequently made b/w countries and smaller geographic regions iv. Attempts to uncover and portray the occurrence of the condition or problem 3. Observational Limits of epidemiology Can never prove causation; cannot prove a specific risk factor actually causes the disease being studies Epidemiologicalevidence can only show that a risk factor is associated with a higher incidence of disease in a population The strength of an epidemiologicalstudy depends on the sheer number of cases and controls in the study The Ames test for potential carcinogens Not everything that causes a change/mutationis a bad thing Sometimesthey change using the metabolism Screens for gain of function, forward mutation, rather than destructivemutations Pro-mutagen:additional substance that causes mutations Alcohol: a promutagen with complexeffects Epidemiologicalstudies Case-controland cohort studies Both are observationalstudies Lecture 9 - CAUSES Tuesday, February 19, 2013 11:04 AM 90% cancer is environmental The remaining 5-10% genetic cancers are usually childhood or early-onsetcancers Cancer Causes and risk factors (Environmental) 1. Growing older Scientifically tested and proven based on data and observationsin the previous generation. Usually bumps up around 60 years old, especially 2. Tobacco 3. Sunlight UV especially causes skin cancer 4. Radiation 5. Chemicals Stomach ulcers often lead to cancer, ulcers are from bacteria. 6. Viruses/bacteria 7. Certain hormones Family history of cancer 8. Alcohol 3 drinks a day increases the risk of estrogen- and progesterone-positivecancer by up to 51% Obesity/dietand nutrition Plays a role on 30-35%of all fatal cancers Sedentary lifestyle Synergy When the data shows that heavy drinker and heavy smokers interact vausign mouth and throat cancer Not additive - more than additive Lecture 10 - Cancer Genetics Friday, March 08, 2013 11:15 AM Heredity Two of the following would indicate an inherited gene mutation ○ Cancer in several closely related people, in several generations, on the same side of the family ○ Cancer at younger ages than usual (ex breast cancer @ 30) ○ More than one diagnosis of cancer in the same person ○ Specific types of breast cancer linked to specific genes (e.g breast cancer & ovarian cancer, or colon cancer &endometrialcancer) Germ line vs somaticcancer Somatic mutations:new changes to the genes in the cells of the body; occurs as a random mutation Mutations in somaticcells cannot be inherited Inheritance of a mutationin a germ (egg/sperm)cell Hereditary cancer Cancer resulting from inheritance generally presents as an autosomaldominant trait of a germline alteration in one gene, conferring a genetic susceptibility to the developmentof cancer Terminology Alleles - different versions of a gene Penetrance - frequency with which an allele yields an expected trait in a population Inherited Cancer Only 5-10% if all cancers are related to an inherited gene mutation Inheriting the gene mutation does not mean that the child is born with cancer The child inherits a higher risk of development Many genes are involved in cancer formation,so not everyonewho inherits a gene mutationwill develop cancer Cowden Disease (multiple hamartomasyndrome) Characteristics Multiple haratomatouslesions (noncancerous tumors of the skin and other organs) Inherited mutations in the PTEN gene have been found in ~80%of people with Cowden syndrome Usually present by late 20s Increased risk of breast, thyroid, endometrial, and uterine cancer Inherited Polyposissyndromes Majorityof colorectal cancers are sporadic ~10% of cases are inherited Adenomatouspolyposis syndromes are inherited colorectalcaner syndromes that are associated with multiple precancerous (adenomatous) polyps in the colon Familial Retinoblastoma Normal child has a 1-in-20,000chance of developing retinoblastoma In families of retinoblastomasurvivors, ~50%of th children develop the disease ~40% of retinoblastomacases are familial Children with the familial form typically develop multiple tumors; sporadic cases usually have a single tumor single tumor Two-hit model for cancer (if you have a sheet o cells in which all the cells have a mutation inherited, any mutation will cause the call to become cancerous. In a sheet of cells with no mutations, it takes two mutations to hit one cell to cause cancer) Li-Fraumeni Syndrome LFS is a cancer predisposition syndromeassociated with soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma,melanoma,and other cancers Extremelyrare, only a few hundred families worldwide Susceptibility to cancer in general Transmitted from parent to offspring These individuals have a mutation in one copy of the p53 gene Inheritance and Breast Cancer Risk between identical and non-identical twins as allowed a good estimate of how much of all breast cancer risk is inherited Data from twin and cancer registries in Sweden, Denmark, and Finland reported that 25-27%of total risk of breast cancer was due to inherited factor Women with family history of breast cancer make up only 5-7% of all women with breast cancer Of people who develop breast cancer 5% have hereditary syndrome 20% have a familial risk 75% have no strong family history BRCA mutations dramatically increase the risk of developing cancer Women born after 1940with BRCA 1 or 2 genes have higher breast cancer rates than women born before 1940 with the same mutations This difference indicated that non-genetic factors influence breast cancer risks even in individuals who inherit high risk mutations Inheritance and prostate cancer Hereditary prostate cancer accounts for 5-10% of all prostate cancers Men who inherit prostate cancer tend to get the disease at a younger age Tumor grade, symptoms,initial therapy, and survival were similar in the hereditary and control groups Possible benefits of gene testing Allow for more accurate cancer risk assessment If positive, doctor=s can screen earlier for cancers In negative, individuals may not have to screen as aggressively Early cancer screening can be offered to other at-risk family membersis a mutation Is identified No physical risks involved in genetic testing Possible risks of gene testing Genetic testing can be emotionallydifficult regardless of results Emotionalstress on relative who make untested assumption about their own genetic status Health insurance coveragefor cancer screening Possibility of employeror insurance provider discrimination based on genetic test results Lecture 11/12 - Smoking Friday, March 08, 2013 11:15 AM Cigarette smoke decreases levels of monoamineoxidase B (MAO B) Can lead to depression, schizophrenia, ADHS, substance abuse Smoke as a MAO inhibitor = more/longer+effect Second hand smokeand pets Secondhand smoke has been associatedwith oral cancer and lymphoma in cats, lung and nasal cancer in dogs, and lung cancer in birds There is a higher incidence of nasal tumors in long-nosed dogs living in a smoker's house as opposed to dogs in a smoke-freeenvironment Shorter or medium-noseddogs showed higher lung cancer rates Third-hand smoke is chemical residue that clings to clothes and surfaces What cigarettes are made of Cigarettes: optimized nicotine delivery vehicle Tar, tobacco, nicotine More than 600 additives can be legally added to tobacco products Cocoa, when burned, produces bromine gas that dilates the airways and increases the body's ability to absorb nicotine Menthol numbs the throat and enables the smoke to inhale more Ammonia compoundsspeed the delivery of nicotine to smokersby raising the alkalinity of tobacco smoke Acetaldehyde and pyridine act to strengthen nicotine's impact on the brain and central nervous systems Sweetenerscan be added to make cigarettes more appealing to young people Also: methane,acetic acid, arsenic, methanol, ammonia,hexamine, stearic acid, cadmium, butane... E-cigarettes Concentrationsrange from 0 nicotine, low, midrange, high, and extra-high doses "variable and potentially fatal amounts of nicotine in e-cigarette nicotine solutions" Recommendationsvary, but its safer though there is no unknown risk, no attractive and poisonous Hookah: yes, filters more and is better for you, but smokers smoke3-7 times as much in a single session as compared to cigarette-smokers Governmentmakes a lot of money off federal cigarette taxes Nicotine Addiction Nicotine is the tobacco plant's natural insecticide Within 8secs of first puff, nicotine arrives at brain's central reward pathways Once in the brain, nicotine gains control over more than 200 neurochemicals Men who don't quit smoking lose ~13.2 years, women14.5 years First it movesto lungs, where it is absorbed into the bloodstream,which takes it to the brain Drug-Addiction rates Alcohol - 15.4% Cocaine - 16.7% Heroin - 23.1% Tobacco - 31.9% 440,000deaths per year due to smoking There is no safe tobacco product. Cigarettes, cigars, pipes, dip; mentholated,low tar, naturally grown, additive free, all can cause cancer and adverse health effects Lung Cancer 163,510deaths per year Most deadly lung cancer (more people and more deaths) First year survival rate is 49% if just in lung, 16% if spread within chest, 2% is present in other organs Cigarette Tar Sticky brown substance that causes yellow-brownstains on fingers, teeth , clothes, and furniture Mixture of substances that form a sticky mass in the lungs Paralyzes cilia Last puff can contain more that 2x as much tar as the first puff Linking cigarettes to cancer 1. Burning tars in cigarettes create benzo pyrene (BP) which is absorbed by lung tissue 2. BP modified to BPDE in cell nucleus and binds to tumor-suppressing gene p53 3. BPDE causes mutations at 3 hotspots on p53 gene, resulting in unrestricted cell division (cancer) Lecture 13 - Colon Cancer Friday, March 08, 2013 11:15 AM Hallmarks of cancer 1. Self-sufficiency growth signals 2. Insensitivity to antigrowth signals 3. Evasion of apoptosis 4. Limitless replicative potential 5. Sustained angiogenesis 6. Tissue invasion and metastatis Anatomy Duodendum - first part of small intestine Colon - large intestine or large bowel Most bowel cancers develop in the lower descending colon, sigmois colon, or rectum Over age 50 Colorectalcancer more likely to occur as people get older More than 90% diagnosed after age 50 Average age of diagnosis is 72 Colorectalcancer problem Colorectalcancer is the second leading cause of cancer-related deaths in the US 21% of all US cancers Potentiallyone of the most curable of gastrointestinal cancers New cases: 142,570(colorectal) Deaths: 51,370(colorectal) Causes 655,000deaths worldwide per year Geographic distribution Great variability in worldwide incidence and mortality rates of colon cancer Industrialized nations appear to have the greatest risk while most developing nations have lower rates North America, West Europe, Australia, and New Zealand have high rates for colorectal neoplasms Tumor Typing/ B catenin mutations Only half of colorectalcancers related to obesity and inactivity (54%) CTNNB1 positive colorectalcancer (46% of cases) appeared independent of lifestyle choices Progressionof Colorectal Cancer 1. Begins with the developmentof polyps in the epithelium of the colon (polyps are benign) 2. As time passes, polyps grow 3. At some point, malignant cells nest within polyps 4. If polyp is not removed,some malignant cells will escape from the primary tumor and metastasize 5. At least 2 gene mutationsinvolved ○ Deletion of the APC (adenomatouspolyposis coli) tumor suppressor gene on chromosome5 of p53 (chromosome17) ○ A mutant proto-oncogene(often RAS) Colon cancer stages Stage 0: cancer has not grown beyond inner layer of colon wall Stage 1: grown to outer layer of wall Stage 1: grown to outer layer of wall Stage 2: tumor spread through wall, not spread to lymph nodes Stage 3: spread to lymph nodes Stage 4: cancer metastasized Normal tissue forms a polyp projecting from colon wall, which , over time, becomes a tumor. Risk Factors Most people have no identifiable risk factors 50-60%sporadic 30-40%familial 3-5% non-polyposis syndromes 1% genetic Polyps Family history Age Long-tem inflammation of the coon (ulcerativecolitis or Crohn's disease) A diet high in fat and low in fiber Physical inactivity Screening recommendations Beginning at age 50: 1. Fecal occult blood testing annually 2. Flexible sigmoidoscopyevery 5 yrs 3. Double-contrastbarium enema every 5-10 years 4. Colonoscopyevery 10 years Colonoscopy Most widely used diagnostic method to study the colon and has the highest diagnostic sensitivity and specificity of all available tests 90-95%if colon can be examined Take 60 mins or less Offers flexibility of performing biopsy and ability to perform endoscopic polyectomy Detectionof polyps at 1cm or greater and tumors is at 95%+ Colonoscopyis the preferred procedure for diagnosis of symptomaticpatients Lecture 14/15 - Breast Cancer Friday, March 08, 2013 11:16 AM Statistics 12-13% of women in US will develop invasive breast cancer ~207090 new cases of invasive breast cancer diagnosed in 20120, and 54010 new cases of non-invasivebreast cancer About1970 new cases of invasive breast cancerdiagnosed in men in 2010 Breast Cancer types Noninvasive breast cancer (LCIS) For patients with Lobular carcinoma in situ (LCIS) the risk for developing invasive cancer in the same breast is 18% (14% in other breast) after 20 years InvasiveDuctal Carcinoma (IDC) Invasivebreast cancer that penetrates the wall of a duct Compromises 70-80% if all breast cancer cases Invasive Lobular Carcinoma (ILC) Accounts for 10-15% of breast cancers Hormones A hormone is a chemical messenger from one cell to another Function as a signal to the target cells Actions can include stimulation or inhibition of growth, induction of suppression of apoptosis, activation or inhibition of the immune system, regulating metabolism and preparation for a new activity or phase of life Estrogen Effects Maintain body temp Preserve bone strength Stimulate development of breasts and mammary glands, maturation of ovaries, and start of menstrual cycle, maintain a lubricated and thick vaginal lining and uterus etc Estrogen and cancer Can be h
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