Exam 2 Spring Flashcards
(308 cards)
1
Q
neoplasm
A
new growth: disorder of cell growth triggered by series of mutations affecting a single cell and its clonal progeny
“tumor”
“neoplasia”
2
Q
all tumors have what basic cmpts?
A
parenchyma
- primary basis of classification of tumors and their bio behavior
reactive stroma - CT, bv, cells of immune sys
- what growth and spread of tumors depend on
3
Q
demsoplasia
A
when parenchymal cells stim formation of abundant collagenous stroma
- some can be stony hard (scirrhous) - female breast ca
4
Q
benign tumors
A
gross and microscopic = localized, no spread, can be excised via local sx
5
Q
naming of benign tumor
A
name of cell origin + “-oma”
naming for epithelial tumors more complex
- cell of origin
- microscopic pattern
- macroscopic architecture
6
Q
adenoma
A
derived from glands
but MAY OR MAY NOT form glandular structures
- like renal tubule cells - hterogenous mass of adrenal cortical cells growing as solid sheet
7
Q
papillomas
A
beningn epith neoplasm
fingerlike, warty projections
8
Q
cystadenomas
A
form LARGE cystic masses
ex: ovary
9
Q
papillary cystadenoma
A
pap projections INTO cystic spaces
10
Q
polyp
A
neoplasm (benign or malignant) projfects above mucus surf into lumen
if polyp has glandular tissue = adenomatous polyp
11
Q
A
colon polyp
goes ABOVE mucus surf and into colon lumen
12
Q
malignant tumors
A
ca - can invade and desroy adjacent structures and spread to met
13
Q
naming malignant tumors
A
solid mesenchymal masses = sarcoma
blood-forming cells = leukemia
ectoderm dericed epidermis, mesoderm derived renal tubes, endoderm dervied lining of GIT = carcinomas
- can be furthur classified by their tissue of origin before the carcinoma name
14
Q
mixed tumor
A
occurs during divergent differentiation of a single clone
ex:
- salivary gland: epithe cmpts with stroma of cartilage or bone = pleomorphic adenoma
15
Q
great majority of neoplasms are composed of cells from…
A
a single germ layer
exception = teratoma
16
Q
teratoma
A
recog mature/immature cells/tissues to more than 1 germ layer
- origin from totipotent norm present in ovary and testis
- sometimes found in abnormal midline emb rests
ex: dermoid cyst (ovarian cystic teratoma)
* differn prim along ectoderm lines = cystic tumor lined by skin with hair, sebaceous glands, and tooth structures
17
Q
A
mixed tumor of the parotid gland
- epith + cartilage stroma
18
Q
A
19
Q
hamartomas
A
disorg benign masses of cells indigeous to involved site
20
Q
choristoma
A
heterotpic rest of cells
- ex: well-dev & normal panc tissue found in submucosa of stom/duod/sml intestine
21
Q
differentiation
A
exntent which neoplastic parenc cells resemble correstponding normal parenc cells: morph & fx
22
Q
anaplasia
A
LACK of differentiation
23
Q
in general, benign tumors are _________
A
well-diffen
only growth of these cells into a dis crete mass reveals its neoplastic nature
24
Q
compare and contrast these…
A
leiomyoma or uterus
- well-differn tumor of bundles of smooth M cells that are VIRTUALLY identical to normal smooth M cells
adenocar of colon
- ca gland cells are irregular in shape and size and DO NOT resemble normal colon glands (top = normal, bottom = ca)
- differentiation b/c gland formation is seen
- invaded M layer of color
25
malig neoplasms, display usually _______ but exceptions?
usually wide range of parenc cell different
BUT:
* can have lack of differentiation =anaplasia
26
Anaplastic tumor
27
these are showing WELL-DIFFERN tumors
* benign adenoma of thyroid
* malig sq-cell carc of skin
28
anaplasia is often assoc with... (5)
1. pleomorphism: variation in size and shape
* tumor giant cells: single **huge** polymorphic nuc more **several** large hyperchromatic nuc
2. abnorm nuclear morph: LARGE nuc and can be hyperchromatic, often irregular shaped
3. mitoses: many **atypical & bizzare** cells in mitosis state - tri/quad/multi-polar spindles
4. loss of polarity: loss of orientation
5. defic in vasc stroma --\> large central areas of ischemic necrosis
29
what is considered a hallmark of malgnancy?
anaplasia - "to form backward"
30
Pleomorphic tumor: rhabdomyosarc
* note: pelomorphism, hyperchrom nuc, tumor GIANT cells
31
benign neoplasm and well-differn carc usually...
retain fx capabilities of normal counterpart --\> secr horm char of origin --\> INCREASED lvls of horms --\> detection
32
higly anaplastic undifferen cells...
lose esemblance to origin cells --\> new and unanticipated fx
* rapidly growth ana tumors = less likely to have specialized fx
ex: expr of fetal proteins or expr of proteins found in OTHER types of adult tissues
* brochogenic carc may prod other horm --\> paraneoplastic syndromes
33
main difference in cells of benign and malig ca
well-diffen and represent cells of origin
more/less diffen with SOME **derangement** of differn present
34
metaplasia
replacement of one cell type with another
* **always** found in assoc with tissue dmg/repair/regen usually better suited to local environ
ex: GI reflux changes sq epith of esop --\> glandular gastric epith
35
dysplasia
disorder growth --\> loss in uniformity & arch orientation
* encountered princ in **epithelia**
usu display pleomorph & large hyperchromatic nuc with high nuc:cytop ratio
36
dysplastic sqamous epith
norm progession of mature tall cells in basal layer to FLAT cells of surf layer fails --\> basal-appearing cell with hyperchrom nuc and more abund mitotic figures
37
carcinoma in situ
dysplatic changes that involve full thickness of epith **but** lesions DOES NOT invade BM
* dysplastic changes often adjance to foci of invasive carc --\> may be precursor to malig txform but DOES NOT ALWAYS progress to ca
once it invades BM --\> **invasive**
38
growth of ca is accompaied by... (3)
1. progressive infilt
2. invasion
3. destruction of surr fissue
39
how is the grwoth of ca different from benign tumors?
benign tumors usually:
1. grow cohes
2. remain localized
3. do not filt/invade/met
**b/c of slow expansion --\> usu dev rim of compressed fib tissue called** **CAPSULE that sep from host tissue**
40
capsule of benign tumors
mostly ECM dep by stomal cells (fibroblasts) activated by hypoxic dmg from PRESSURE of expanding tumor
does NOT prevent growth but makes the tumor discrete, readily pal, movable, and easily excised by ex
41
hemangioam
neoplasm of tangled bv - **no capsule** but BENIGN and permate site from which they arise
* may be not excisable when extensive
42
notice the difference b/w benign and malig
* left: fibroadenoma of breast - SHARP demarcation
* right: ductal carc of breast: retraction of lesion & stony and hard on palp and poorly demarc
43
slowly expanding malig tumors
pseudo-encap: may develop enclosing fib cap
rows of cells penetrating and infilt adjacent structures
**crab-like** pattern of growth = poplar image of ca
44
next to dev of mets, _______ is more reliable feature that differentiaties ca from benign tumors
invasiveness
do not recog normal anat bound --\> hard to resect even us tumor appears well-circumscribed --\> necc to removed considerable margin of NORMAL tissue adj to neoplasm
45
carc in situ are usually found in...
skin, breast, **uterine cervix**
have not invaded BM yet but with time MOST penetrate BM
46
metastasis
spread of tumor to sites physically discon't with primary tumor
* approx 30% newly dx solid tumors met (excluding skin ca other than melanoma)
* **strongly reduces poss of cure**
oppor provided by penetrance into bv, lymph, body cav
ALL malig tumors can met but some do so very infreq
* gliomas, basal cell carc
* **properties of invasion and met are separable**
47
likelihood or pirmary tumor met correl with... (4)
1. lac of differentitation
2. aggressive local invasion
3. rapid grwoth
4. large size
**in general b/c MANY exceptions**
48
blood ca
leuk & lymphomas
"liquid tumors" - norm have cap to enter bloodstream --\> often disseminated at dx and are ALWAYS taken to be malig
49
dissenination of ca pathways: (3)
1. direct seeding of body cav/surf
2. lymph
3. hematogenous
50
why are biopsies of testicular masses never done?
can be **iatrogenic** (spead of ca due to medical exam/tx)
RARE
51
seeding of body cav and surf
malig neoplasm penetrates into "open field" lacking physical barries
mostly in peritoneal cav
partic char of OVARIAN ca --\> spread to peritoneal surf --\> coated with heavy ca glaze --\> BUT remian confied to surf of ab viscera with penetration --\> can fill cav with psuedomyxoma peritonei (gelat neoplastic mass due to mucus secr of carc)
52
Colon carcinoma invadeing pericolonic adipose
53
Axillary lymph node with metastatic breast carcinoma
notice how the tumor in node and how it dilated the lymph channnel
54
what is the most common pathway for initial dissem of carc?
txp through lymph
* tumors do NOT contain fx lymphatics and lymph vessels loc near tumor margins are suffic for lymph spread & follow natural routes of lymph drainage
some sarcomas also use this route
55
carc of breast
usually arise in upper outer quads --\> 1st invade ax lymph nodes
inner quad drain to nodes of internal mamm arteries -- infracalv and super clav nodes invovled
56
skip mets
bypass of local lymph nodes b/c venous-lymp anast or inflammation/radiation has oblit lymph channels
57
sentinal lymph node
first node in regional lymph basin that receives lymph flow from primary tumor
biopsy of sentinel nodes usually done to assess met lesion to avoid considerable sx morbidity of full ax lymph node dissections
58
regional nodes serve as...
effective barriers aga furthur dissem
enlg nodes can be due to met OR immune response = red flag but not necc equated with dissem of tumor
59
hematogenous spread
typ of sarcomas but also seen in carcinomas
veins \> art (due to thicker wall)
* may occur when tumor cells pass **pulm** cap beds/AV shunts
venous invasion results in tumor cells coming to rest at first cap bed they encounter --\> why **liver and lungs** are most freq involved
ca close to v-column --\> paravert plexus
* thyroid, prostate
60
ca with propensity of venous invasion
renal cell carc --\> renal vein branches --\> renal vein --\> "snakelike" to IVC --\> right atrium
hepatocell carc --\> protal and hepatic radicles
61
colonic adenocarc --\> lung mets
62
liver mets
63
Comparisons Between Benign and Malignant Tumors
64
what are some mets unexplaeind by anat loc and venous drainage?
breast --\> bone
bronchogenic --\> adrenals & brain
neuroblastoma --\> liver and bones
**skeletal M and spleen are RARELY sties of secondary ca despite getting lots of blood flow**
65
uterus ca pic comparision
66
A 20-year-old woman has an ovarian tumor removed. The surgical specimen is 10 cm in diameter and cystic. The cystic cavity is found to contain black hair and sebaceous material. Histologic examination of the cyst wall reveals a variety of benign differentiated tissues, including skin, cartilage, brain, and mucinous glandular epithelium. What is another common name for this tumor?
A) Pleomorphic adenoma
B) Embryonal carcinoma
C) Cystadenoma
D) Teratocarcinoma
E) Dermoid cyst
67
A 59-year-old man has recently noticed blood in his urine. Cytoscopy shows a 4-cm exophytic mass involving the right bladder mucosa near the trigone. Biopsy specimens are obtained, and the patient undergoes a radical cystectomy. Examination of the excised specimen shows that a grade IV urothelial cell carcinoma has infiltrated the bladder wall. Which of the following statements regarding these findings is most appropriate?
A.The neoplasm is a metastasis
B.The patient has a poorly differentiated neoplasm
C.A paraneoplastic syndrome is likely
D.The stage of the neoplasm is low
E.The patient is probably cured of the cancer
68
most common tumors in men v women in US v dev world
US:
* men: prostate, lung, colon/rectum
* women: breast, lung, colon/rectum
dev world:
* men: lung, stomach, liver
* women: breast, cervix, lung
69
what is the dominant risk factor for most ca?
environment:
* infectious agents: 3x higher in developing v developed world
* smoking
* reprod hx
* environ carcinogens
70
single most environ fac --\> premature death in US?
smoking
71
what environ fac work synergistically to incr ris of ca in upper airways and digestive tract?
alcohol and smoking
72
exposure to _________ increases risk of breast and endometrial ca?
long cumulative estrogen stim **unopposed** by progesterone
73
age and ca
most \>55 y/o: due to accum of somatic mut & decline of immune competence
* women: 40-79
* men: 60-79
decline after 80 is due to lower number of indiv who reach this age
74
children and ca
cas in children sig different from those seen in adults
* carcinomas (MOST COMMON in adults) = RARE in children
ex:
* neuroblastoas: small, round, blue cell tumors
* wilm's tumor
* retinaoblastoma
* acute leuk
* rhabdomyosarc
75
acquired conditions that predispose to ca (3)
1. chronic inflam
* increased cell replication
* most carc: mesothelioma, lymphomas
2. precursor lesions
* high risk: endometiral hyperplasia, luekoplakia (thickening of sq-epith in oral cav/penis/vulva
* neoplasms @ risk for amlignant txform (villous adenoma)
3. immunodeficiency status
* partic deficients in T-cell immunity
76
genetic predisposition to ca
inherited trait usually due to germline mutations in tumor suppressor gene
* BRCA: 3x high in women born after 1940 prob due to chnages in reprod hx
diff to sort hered and nonhered contributions
can sig infl likelihood of dev environ-induced ca
* polymorphisms of enz that metab procarcinogens
* ex: cyt p450
77
incidence of ca varies with... (4)
1. geography: different environ exposures
2. age
3. race
4. genetic bg
78
huge flowchart of cell progression to ca
79
role of genetic and epigentic alterations in ca (4)
1. nonlethal genetic dmg
2. clonal expansion of a single precursor cell with genetic dmg
3. ca targets regulatory genes
4. accumulation of stepwise mutations over time
80
nonlethal genetic dmg
may be:
* environ exposure
* germline inherited
* spont & random
81
how does clonal expansion result in ca?
a single precursor cell may have genetic dmg
alt in DNA are heritable and can be passed to daughter cells
82
what regulatory genes are the principal targets of ca-causing mutations?
1. proto-oncogenes: gain of fx - dominant
2. TS genes: loss of fx - recessive
* sometimes loss of single TS gene allele (haploinsufficiency) reduces activity of encoded protein enough to release brakes of cell prolif and surv
3. apop reg : gain of fx
4. DNA repair: loss of fx --\> genomic instab
83
accumulation of mutations over time...
ca hallmarks: excessive growth, local invasion, distant mets
driver mutations = initating mutation that will acquire addn mutations --\> ca
usually loss of fx that maintain integrity is early step --\> malig partic in solid tumors
* incr likelihood of acquiring driver mutations and also passenger mtuations (mut of no phenotypic conseq that accompany driver mutations - most common that driver)
84
once est, tumors evolve genetically via...
darwinian selection
competition among tumor cells --\> allows cas to be more aggressive over time (tumor progression) --\> extremely heterogen tumors @ time of clinical dx even though tumors are clonal in origin (passenger mutations)
can explain changes in tumor behavior following therapy that **resist** original therapy given
85
epigenetic contributions to malig ca
DMA methylation & histone mods
can be passed to daughter cells
86
fundamental hallmarks of ca (8)
1. alt cell metabolism
2. self-sufficiency in growth sig
3. insens to growth inhib sig
4. evade apop
5. evade host immunity
6. able to invade and met
7. sustained angiogenesis
8. immortality
87
ca hallmarks may be accelerated by
genomic instab
ca-prom inflamm
88
self-sufficiency in growth signals
oncogenes prom autonomous cell growth in ca
* created by mutations in PROTO-ONCOGENES --\> promote cell growth in absence of normal growth-prom signals
mutations usually inactivate internal reg elems of protos --\> progress of ca
* GPCR, JAK/STAT, WNT, notch, hedgehog, TGBbeta/SMAD, NF-KB
89
RAS
GF --\> RTK --\> (+) RAS --\>
* RAF --\> MAPK --\> (+) Ts
* PI3K --\> AKT/PKB
90
GAP and PTEN
GAP inactivates RAS by cleaving GTP to GDP
PTEN inactivates PI3K
91
single most common abnorm of proto-oncogenes in human tumors?
point mut of RAS
92
EGFR
sarcomas, lung ca (ERBB1)
TGF-alpha overexpression
93
HER2
ERBB2 --\> gene amp --\> breast ca
94
JAK2
RTK point mutation --\> myeloprolif disorders
95
gene rearragements of RTK
deletion of chr 5 fuses part of ALK with EML4 --\> (+) RTK activity --\> lung adenocarc
96
NF1
encodes GAP
mutation --\> neurofibromatosis
97
BRAF
ser/thr protein kinase that tops MAPK fam
mutations --(+)--\> Ts fac
* mutations in MAPK fam downstream of BRAF uncommon --\> mut affector factors near TOP of RAS/MAPK cascade prod significant pro-growth singals in most cell types
98
CML
txloc chr 9 & 22 --\> philadelphia chr --\> ABL-BCR hybrid --\> (+) TK
99
burkitt lymphoma
MYC oncogene (chr 8) --\> txloc to Ig heavy chain gene (chr 14) --\> increased MYC
100
MYC
expressed in virtually all euk cells --\> rapid and transiently induce RAS/MAPK following GF stim of quiescent cells
fx:
* (+) D cyclins
* upreg expressison of rRNA genes and processing --\> incr protein synth
* (+) warburg effect: (+) GLUT 1 & 4
* (+) telomerase
**one of Ts that can regprogram somatic cells into pluripotent stem cells** --\> ca immortality
101
cyclins and CDKs
cyclins bind to CDKs --\> (+) --\> proceed through cell cycle
* G1/S checkpoint more important in ca --\> can lead to dysreg grwoth and mutator phenotype
* gain of fx mutations in D cyclin
* amp of CDK4
* TS proteins: RB & p53 inhib this checkpoint
102
"two-hit" hypothesis of oncogenesis
2 mutations of RB in chr 13 required to produce retinoblastoma
* 1st hit = defective copy
* 2nd hit = random/spont mut
* **most with adefective copy get mut on 2nd allele --\> auto-dom trait**
103
RB
"governor of prolif"
(P) RB --\> release E2F --\> S phase
* (P) in conditions of high CDK/cyclin D/E, also **HPV E7 protein**
inhib by p16/INK4a
104
p53
"guardian of the genome" - most freq mutated gene in human ca
TS gene on chr 17 that (-) G1/S checkpoint
* requires mutations in BOTH copies --\> Li-Frameni syndrome
* degraded by MDM2 (overexpr in malig) via ubiq & E6 protein (HPV)
p53 (+) due to:
* DNA dmg or hypoxia by ATM and ATR --\> (P) MDM2 --\> allows p53 to accumulate
* "oncogenic stress" --\> (+) RAS --\> increased expression p14/ARF --\> binds MDM2 --\> displaces p53 --\> accum p53
results in:
* transcient cell cycle arrest (allows time for DNA repair)
* scnescence (perm cell cycle arrest)
* apop: BAX, PUMA causing cyt c leak from mito (+) capsaces
105
APC
"gatekeeper of colonic neoplasia"
TS: adenomatous polyposis coli: chr5
* cmpt of WNT signally pathway: cell fate, adhesion, polarity during emb dev
* degrades beta-catenin (proto-oncogene)
mutation --\> FAP --\> colon ca
* stab beta-catenin --\> nuc --\> (+) Ts of MYC and cyclin D
106
CDH1
E-cadherin: cell surf protein that maintains intercellular adhesion
* beta-catenin binds cytop tail of E-cadherin
* loss of cell-cell contact (like injury) releases interaction --\> allows beta-catenin to nuc --\> repair
mutation --\> familial gastric carcinoma
107
NF1
GTPase that (~) RAS-GTP --\> inactivated RAS-GDP
mutation --\> neurofibromas
108
WT1
chr 11: pediatric kidney ca
encodes Ts for genitourinary tiss dev = TS gene
overexpressed in leuk & breast carc = may fx as oncogene in these ca
109
warburg effect
ca cells pref anaerobic metab (glycolysis) even in presence of HIGH O2 --\> **high** lvls glucose uptake
* provides rapidly div tumor cells with metabolic inter-med needed for synth of cellular cmpts not avail via mito ox-phos
* mito ox-phos prod ATP but no carbon intermed for cellular cmpts for growth
* ca uses mit ox-phos primarily to carry out rxns to gen metab intermed used as precursors in cell synth (ex: acetyl-coa)
can be seen via PET (18F-fluorodeoxyglucose)
110
how to trigger warburg effect?
signally cascades downstream of GF receptors persist due to oncogenes and loss of fx TS genes
* PI3K/AKT: upreg GLUT txptors and glycolytic enz
* (+) RTK: which (P) M2 isoform of PK --\> (-) PK activity --\> no PEP to pyruvate --\> shunts to production of DNA, RNA, protein
* in contrast to growing tissues and ca cells, post-mit tissues with high demand for ATP (brain) expr **M1** isoform of PK = insens to GF signally pathways
* MYC: upreg to (+) anabolic metab and cell growth
* most imp: glutaminase = essen for mito util of gln
111
many TS that induce growth arrest will also...
suppress the warburg effect
112
autophagy
severe nut deficiency --\> (-) cell growth **&** cannibalize self for E prod
tumor cells somehow able to growh under marginal environ conditions without triggering autophagy: poss deranged autophagy pathway
* may use autophagy to be "dormant" --\> can resist therapies
113
apoptosis and ca
2 pathways for (+) of apop: extrinsic (Fas/FasL) or intrinsic (mito)
* intrinsic freq disabled in ca
* stress --\> DNA dmg --\> p53 --\> sensed by BH3 proteins (BAD, BID, PUMA) --\> overwhelms apop-inhib by BCL-2, BCL-XL, MCL-1 --\> (+) BAX/BAK to form pores in mito --\> leakage of cyt c --\> binds APAF1 --\> (+) capsace 9 --\> (+) capsace 3 (executioner capcase) --\> apop
* extrinsic
* FasL binds FAS --\> trimerization --\> FADD (death domains) --\> recruits pro-capsace-8 --(cleavage)--\> capsace 8 --\> BID --\> instrinsic pathway
114
BCL-2 overexpression
b-cell lymphoma
* ca cell survival and drug resistance
115
immortality of ca
all ca have cells that are immortal with limitless replicative potential
1. evasion of senescence
* senes state usually assoc with upreg of p53
2. evasion of mitotic crisis
* erosion of telomeric DNA --\> can be apop **or** non-homologous "naked" end joining --\> dsDNA breaks --\> "bridge-fusion-breakage" cyles --\> mit catastrophe --\> cell death
* ca: reactivate telamerase
3. capacity for self-renewal
* asymm div of stem cells = retains "stemness"
116
how do solid tumors grow beyound \_\_\_\_\_\_?
need capcity to induce angiogenesis to enlarge beyond 1-2mm in diameter
* neovasculization
* perfusion supplies needed nut and o2
* new endothelial cells stim growth of adj tumor cells by secreing IGFs (insulin-like GF) and PDGF (platelet-dep GF)
new TUMOR vessels are **leaky and dilated** --\> which allows tumor cells access to met
117
factors that influence angiogenesis
hypoxia stab HIF1α --(+)--\> VEGF & bFGF
p53:
* (+) thrombospondin1 --\> (-) angiogensis
* (-) VEGF
118
angiogenesis inhib
used with adv ca to prolong life but **not curative**
119
ca invasion of ECM
metastatic cascade:
1. "loosen" up tumor cell - tumor cell interactions
* loss of E-cadherin fx
2. degrad ECM
* secr of proteolytic enq or inducing stromal cell ECM-seq GFs
* MMP9 (matrix metalloprotease/cathepsins) degrades college type IV in BM and stim release of VEGF from ECM-seq pools
3. attachment to novel ECM cmpts
* cleavage of BM allows novel sites to bind to tumor cells to stim migration
4. migration and invasion
* chemotaxis
120
anoikis
apop stim by loss of adhesion
121
tumor cells in circulation
tumor cells tend to aggregate in clumps
* homotypic adhesions
* heterotypic adhesions with platelets --\> may enhance surv & implateability
can also bind and activate coag fac --\> form emboli
solid tumors often express CD44
* usu expressed by T lymphocytes for migration to sites of infection
122
site @ which circulating tumor cells leave capillaries to form secondary deposits due to... (3)
anat loc
* most in 1st cap bed they encounter (why high number in lung and liver ca)
vasc drainage
tropism
* expr of adhesion mol pref for endothelial cells of a partic organ
* prostate --\> bone
* bronchogenic --\> adrenals, brain
* neuroblastomas --\> liver, bone
* chemokines
* breast ca cells expr CXCR4 & CCR7
* some host tissues like skel M and spleen have "unfav soil"
123
dormancy
prolonged survival of micromets without progression
often in breast and prostate ca
124
ca immunoediting
ab of immune sys to shape and mold immunogenic properties of tumor cells that ult leads to darwinian selection of subclones best able to avoid immune elim
125
tumor antigens
antigens found in tumors that elicit immune response
classes:
1. products of mutated genes
2. overexpressed/aberrantly expressed cellular proteins
3. antigens produced by oncogenic viruses
4. oncofetal antigens
5. altered cell surf glycolipids and glycoproteins
6. cell-type specific differentiation antigens: mol normal present on cells of origin
126
mechanisms used by ca to escape/evade immune system
1. selective outgrowth of antigen-negative variants
2. loss/reduced expression of MHC mol
3. immunosuppression
* prevent sensitization and induce long-lived unresponsiveness in tumor-specific T cells
* secretion of immunosuppress factors: TGF-β, galectins, IL-10, PGE2, PD-1 ligand
* induction of Tregs: regulatory T cells that immunosuppress
127
genetic instability usually results from
inherited mutations of genes in DNA repair sys --\> greatly incr risk of dev ca
* mutation are NOT oncogenic themselves
examples:
1. HNPCC - mismatch repair --\> FAP --\> colon ca
* **microsatellite instab:** tandem repeats that are unstable and create alleles not found in normal cells of same pt: MLH1/MSH2
2. xeroderma pigmentosum - NER --\> skin ca
* cannot repair pyridimine dimers
3. Bloom, AT, Fanconi anemia - HR DNA repair
* hypersens to DNA-dmging agents like ionizing radiation
4. lymphoid neoplasms - RAG1/RAG2/AID for V(D)J recombin of T and B cells
128
infilt ca provode...
chronic inflam rxn
* can cause systemic signs @ symptoms (anemia, fatigue, cachexia)
* may also mod local tumor microenviron --\> enable hallmarks of ca
129
ca-enabling effects of inflam cells and resident stromal cells: (6)
1. (+) prolif:
* infilt leukocytes and activated stromal cells secr:
* GF
* proteases that lib GF from ECM
2. degrade of ECM int-act --\> removes growth barrier
3. (+) invasion and mets
* macrophage proteases remodel ECM
* TNF/EGF may directly (+) tumor cell motility
* stromal cells secr TGF-β --\> allow migration of tumor
4. (+) VEGF
5. tumor-assoc macrophages secr integrins to int-act with tumor cells --\> prevent anoikis
6. evade immune destruction
* TGF-β (-) Treg cells & CD8+ cytotoxic T cells
* adv ca mainly (+) M2 --\> promote angiogenesis, fibroblast prolif, collagen deposition and **suppress host immune response**
130
what associated neoplasm resuts from these chronic inflamm states
## Footnote
hep B/C
h. pylori
HPV
EBV
HTLV-1
hep B/C --\> hepatocellular carc
H. pylori --\> gastric adenocarcinoma, MALT lymphoma
HPV --\> benign warts, cerv-ca, oropharyngeal ca
EBV --\> Burkitt's, B-cell lymphomas
HTLV-1 --\> **retrovirus** (can be latent)--\> adult T-cell leuk/lymphoma
131
Molecular model for the evolution of colorectal cancers
132
promoters and initators and ca
initiation cause perm DMA dmg (mut) --\> make cells more capable of giving rise to tumor
do not affect DNA directly -\> induce tumors to arise from init cells --\> enhancing prolif and acquire new mutations
**promotion alone not suffic for tumor formation**
133
direct-acting v indirect-acting carcingens
direct-acting require no chemicals coversions to become carcinogenic
indirect-aciting require chem conversion to ULTIMATE carcinogen to become active
134
direct actig carcinogens
most = weak carcinogens
ex: alkylating agents
* ca chemotherapy BUT later evoke second ca (usually AML)
135
indirect-acting carcinogens
benzo[a]pyrene
* polycyclic hydrocarbons = fossil fuels: some of most potent
* cig-smoking & charred meats --\> lung ca
β-naphthylamine
* aromatic amines & azo dyes
* aniline dye and rubber workers --\> bladdar ca
136
most known carcinogens are metab by...
cyt p450 dep monooxygenases: polymorphic genes
suscept to carcinogenesis partly due to partic allele inherit --\> cna assess ca risk by genetic analysis of enz polymorphisms
137
Aflatoxin B₁
natural prod of Aspergillus flavus (fungus) in nuts and grains --\> hepatocellular carc
138
mmol actions of chem carcinogens
direct & ult = highly reactice electrophile (electron deficient) groups that form chem adducts with nucleophilic (electron rich) sites in cells, like DNA
preferentially DNA seq/bases = mut "hotspots"
* Aflatoxin B₁: signature mutation in codon 249 of TP53 --\>hepatocell carc
* transversion from G:C --\> T:A
139
promotion of chem carcinogenesis
pormotors not mutagenic BUT stim cellular prolif
* unopposed estrogen --\> endomet and breast
* chronic inflam with tissue repair
* IBS
* chronic hep
* barrett's
140
UV carcinogenesis
UV --\> sq-cell carcinoma, basal cell carc, melanoma
* UVB (280-320) --\> pyrimidine dimers --\> cutaenous ca
* usually repaired by NER but process if overwhelmed by excessive sun exposure --\> mutations
* UVC (200-280) --\> filt out of ozone layer
141
Xeroderma pigmentosum
inherited defect in NER --\> incr predispos to skin ca
142
ionizing radiation in carcinogenesis
x-rays --\> skin CA
minors of radioactive elem --\> lung ca
a-bomb --\> leukemia --\> solid tumors
kids with repeat CT scans --\> leuk, brain tumors
143
hierachy of vulnerability of tissues to radiation-induced ca
1. myeloid leuk (granulocytes and precursers)
2. thyroid (only in young)
3. breast, lung, salivary gland
any cell can be transformed into ca by sufficient exposure to radiant E
144
human T-cell lymphotropic virus 1
HTLV-1 = tropism for CD4 T cells
* viral protein Tax (+) pro-growth/surv --\> polyclonal expansion of T cells --\> incr risk of mutations and genome instab
dev leuk after 40-50 year latency
* can arise due to new nutations/chr abnorm in host genome
145
HPV
6, 11: benign genital warts
16,18: sq-cell carc of cervix, anogenital region, head, neck
* E6:
* degrades p53
* (+) TERT
* E7:
* binds Rb --\> releases E2F --\> allow proeed from G1/S checkpoint
* (-) CDK p21 --\> (+) CDK4/cyclin D --\> (+) cell cycle
* **both lead to immortality!**
146
cerv ca
primary importance = HPV infection
others:
* mutated Ras
* cig smoking
* coexisting microbial infections
* diet deficiencies
* horm chnages
coinfection of high risk HPV (16,18) **&** HIV --\> HIGHER risk
147
EBV
herpesvirus fam:
* Burkitts
* B-cell lymphoma with T-cell immunosuppr (HIV, organ txplant)
* Hodgkin's lymphoma
* nasopharyngeal carc
148
EBV-1
encodes LMP1 & EBNA2 --(+)--\> normal B-cell prolif
* LMP1 (+) BCL2
virus "borrows" normal B-cell activation pathways to expand pool of latently infected cells
* usually polyclonal B-cell prolif readily controlled = asymptomatic or self-lim episode of infectious mono
149
burkitt lymphoma
chr 8 --\> 14 txloc: (+) MYC gene
but not all tumor cells carry EBV genome so how does it contrib to burkitt's?
* endemic regions have concimitant infecitons (malaria) that impair immune competence --\> ALLOWS B-cell prolif
* eventually T-cell immunity elim most of EBV-infect B cells and small # cells downreg epxr of immunogenic antigens BUT these cells persist indef
\*EBV is not directly oncogenic, but by acting as a polyclonal B-cell mitogen, it sets the stage for the acquisition of the (8;14) translocation and other mutations that ultimately produce a full-blown cancer
150
EBV (+) lymphomas in immunosuppressed pt
usulaly lack MYC txloc
immunosuppression --\> dev EBV (+) extranodal lymphomoas @ multiple sites (GIT, CNS)
* polyclonal onset --\> monoclonal neoplasms
**can be subdued by improvement in immune status or withdrawl from imm-suppr drugs**
151
nasopharyngeal carcinona
assoc with EBV infeciton: endemic in southern china
* **100% nasophargyngeal carc contain EBV! = cenral to genesis of carc**
* restricted distribution = poss genetic or environ co-factors
152
Hep B and C
dominant oncogenic effect - imm-med chronic inflam + hepatocellular injury --\> stim of hepatocyte regen --\> --\> genomic dmg
* activated immune cells prod ROS --\> mutagenic
may contain genes that directly promote dev of ca
* HBx (Hep B) (+) Ts
* HCV core protein (Hep C) = growth-prom
* **(+) sig-txduction pathways --\> cacinogenesis**
153
H. pylori
--\> gastic adenocarcinoma
* chronic inflamm --\> increase epith cell prolif & prod of ROS
CagA:
* "pathogenicity island"
* H. pylori is NONINVASIVE but this gene that H. pylori has penetrates gastric epith --\> (+) singally cascade mimicing unreg GF stim
--\> gastic MALT lymphomas
* B-cell origin
* mimic some features of normal peyer's patches = MALTomas
* cured by eradication of H. pylori in early stages
154
tumor effects on pt (5)
1. impinge adjacent structures
2. horm synth --\> paraneoplastic syndromes
3. ulceration --\> bledding and infections
4. obstrution
5. cachexia
155
Neoplasms of Pancreatic Beta Cells Produce Hyperinsulinemia
156
high cortisol in cushings
157
Gastric Carcinoma - tumor ulcerating through surf
158
colon adenocarcinoma --\> intest obstruction
* notice APPLE CORE sign
other types of obstruction: small carc of bile duct --\> bile accum --\> jaundice
159
Cancer Cachexia
progressive loss of fat and mass --\> profound weakness, anorexia, anemia
* **elevated BMR**
* evidence of SYSTEMPIC inflamm caused by release of cytokines by TUMOR or HOST **not by nutritional demands of tumor**
med by macrophages releasing TNFα
160
Paraneoplastic Syndromes
ca not readily explained by anat distrib or the horm indig to tissue from which tumor arose
* may be earliest manifestation of occult neoplasm
* may rep sig clinical illnes --\> can be fatal
* may mimc mets
161
common paraneoplastic syndromes
hypercalcemia
cushings
nonbac thrombotic endocarditis
162
neoplasms most commonlhy associate with paraneoplastic syndromes
lung, breast, hemato
163
Paraneoplastic Syndrome
Hypercalcemia
most important = parathyroid hormone-related protein (PTHrP) by tumor cells
* tothers:
* TGF-α which activates osteoclasts
* active vitamin D
osteolytic metastatic disease of bone
* unrelated to hypercalcemia from skel mets
164
Paraneoplastic Syndrome:
Cushing Syndrome
ectopic ACTH or ACTH-like polypep by ca cells (like small cell carc of lung)
165
Paraneoplastic Syndrome:
Hypercoagulability
* Migratory thrombophlebitis
* Disseminated intravascular coagulation
* Nonbacterial thrombotic endocarditis
* pic is of mitral valve
166
grading of ca
degree of differentitation, number of mitoses, or architectural features
* low grade & high grade **or**
* I, II, III, IV
since histo appearance =/= biological behavior --\> common to char a neoplasm in descriptive terms
–“Well differentiated adenocarcinoma with no evidence of vascular or lymphoid invasion”
–“Highly anaplastic sarcoma with extensive vascular invasion”
167
staging of cancers
"American Joint Committee on Cancer Staging" criteria:
* size of primary lesions: T
* extend of spread to regional lymph nodes: N
* presence/absense of bloodborne mets: M
**TMN system**
–T1, T2, T3, T4 – increasing size primary tumor
–N0, N1, N2, N3 – progressively advancing regional lymph node involvement
–M0, M1 – absence or presence of distant metastases
based on radio exam (CT/MRI) sometimes sx
168
Laboratory Diagnosis of Cancer
* Morphologic methods
* Tumor markers
* Molecular diagnosis
* Molecular profiling of tumors
169
Laboratory Diagnosis of Cancer:
Morphologic Methods
* Biopsy
* Frozen section biopsy
* Fine needle aspiration
* Cytologic (Papaniculaou) smears
* Immunocytochemistry
* Flow cytometry
* Circulating tumor cells
170
Several Types of Skin Biopsies
171
Intra-operative Examination of Breast Lumpectomy by Frozen Section
172
Fine Needle Aspiration of Thyroid Nodule
173
Cytologic (Pap) Smear of Cervix
normal --\> mild dysplasia --\> carc in situ
174
Flow Cytometry:
Rapidly Examining Physical and Chemical Characteristics of Thousands of Cells Suspended in Fluid
175
Tumor Markers usefulness
**Cannot** use for definitive diagnosis
Useful for:
* screening tests
* quantitating response to therapy
* detecting disease recurrence
176
Prostate Specific Antigen (PSA)
tumor marker for prostate adenocarcinoma
* **low sensitivity and low specificity!!**
* PSA can be high in BPH
* no lvl ENSURES that pt does not have ca
177
Molecular Diagnosis:
Molecular Techniques Used to Assess Tumors
•Diagnosis of neoplasms
* PCR: BCR-ABL in CML
•Prognosis of neoplasms
* PCR: amplified HER2/NEU in breast cancer
•Detection of minimal residual disease
* PCR: BCR-ABL in CML
•Diagnosis of hereditary predisposition to cancer
* (BRCA1, BRCA2) or oncogenes (RET)
•Guiding therapy with oncoprotein-directed drugs
* BRAF in melanoma
178
BRAF mutation can result is what types of tumors?
179
Molecular Profiling of Tumors:
Whole genome sequencing may allow identification of all potentially targetable mutations
Potentially allows refocusing treatment of tumors from tissue of origin to the molecular lesions
180
”The Global Burden of Disease” (GBD)
WHO (1990): est burder imposed by environ disease
uses DALY (disability to adjusted life years)
* metric comparison of different diseases --\> 30.5 years lost to disability and earlier mortality
181
Environmental Effects on Global Disease Burden
1. Dramatic increases in mortality due to HIV/AIDS and associated infections
2. in developed countries leading causes of death = Ischemic heart disease and cerebrovascular disease
3. In developing countries, 5/10 leading causes of death = infectious diseases.
4. single leading global cause of health loss = Under nutrition (defined as morbidity and premature death).
5. 50% of all deaths in children \< 5 y/o = 3 all preventable: pneumonia, diarrheal diseases, and malaria.
182
what stands to becom the preeminent global cause of environ disease in 21st century?
climate change:
* global warming accel in past 50 years --\> rapid loss of glacial and sea ice
* partly man made: greenhouse gases (CO2) from fossil fuels, ozone, methane
183
Health effects of climate change
* Cardiovascular, cerebrovascular, and respiratory diseases.
* Gastroenteritis, cholera, and other foodborne and waterborne infectious diseases.
* Vector-borne infectious diseases, such as malaria and dengue fever.
* Malnutrition.
* Melting=raise of sea levels.
184
what is a poison?
can be anything but is **STRICTLY** dependent on dosage
185
xenobiotics
exogenous chem in environ that can be absorbed through inhal, ingest, skin contact
186
what happens to chemicals in the body (general)?
excreted in urine/feces
breathing
accumulate in bone, fat brain, tissues
187
most solvent and drugs are \_\_\_\_\_\_
lipophilic: helps with txp in blood and going through PM of cells
188
how are most drugs/solvents/xenobiotics metabolized?
detox into inactive water-soluble products
activated to form toxic metabolites
**occurs in 2 phases**
* phase I: hydrolysis/oxidation/reduction
* phase II: glucuronidation/sulfation/methylation/conjugation with glutathione --\> water soluble --\> excretion
189
most important cayalyst of phase I rxns
cyt p450 in ER of liver (primarily)
* heme-containing enz
catalize rxn to either detox xenobiotics, or, less commonly, convert into active cmpds that cause injury
* both cause ROS
190
what consitutes smog? (6)
–Sulfur dioxide (!)
– Carbon monoxide
– Ozone (Ground-level Ozone) (!)
– Nitrogen dioxide (!)
– Lead
– Particulate matter (dust/soot) (!)
191
ozone
"good ozone"
* produced by interaction of ultraviolet (UV) radiation and oxygen (O2) = O3
"bad ozone" = ground-
* Nitrogen oxides and volatile organic compounds in the presence of sunlight
192
ozone toxicity
production of free radicals
* •Injury of epithelial cells along the respiratory tract
* Damage to type I alveolar cells
* Release of inflammatory mediators
* Worst for those with pre-existing condition
193
sulfur dioxide Produced by
power plants burning coal and oil, from copper smelting, and as a byproduct of paper mills.
194
toxicity of sulfur dioxide
(~) sulfuric acid and sulfuric trioxide
* burning in nose and throat --\> diff breathing ---\> asthma is suscep indiv
195
soot
paritculate matter emtted by coal and oil fired powerplants
industrial processes burning these fuels
diesel exhaust
196
soot toxicity
phago via macrophage and neutrophils --\> release inlam mediators --\> pulm inflam and 2ndary CV effects
197
what kinds of particles are the most harmful?
fine/ultrafine particles less than 10 μm in diameter b/c they are readily inhaled into alveoli
larger particles are of lessser consequence b/c they were generally removed in nose or trappe by muco-ciliary epith of airways
198
Cities with highest smog levels:
* Beijing, China
* Cairo, Egypt
* Los Angeles, USA
* Mexico City, Mexico
* Houston, USA
* São Paulo, Brazil
•
•
199
CO
systemic asphyxiant: important cause of accidental and suicidal death
* Hb with 230x greater affinity for CO than O2
symptoms:
* **cherry-red** skin and mucous membranes (used in meat industry to keep meat appearing fresh!) --\> systemic hypoxia
* early = flu-like
* late = mental confusion --\> death
200
most common indoor air pollutant
tobacco smoke
201
indoor air pollutants
1. wood smoke - nitrogens and carbon particulates (polycyclic hydrocarbons) --\> lung infections
2. bioaerosols: like allergens --\> legionnaires, viral pna, common cold
3. radon: radioactive gas from uranium from soil and homes
4. formaldehyde - CARCINOGEN
5. sick building syndome: poor ventilation
202
radon
radioactive **gas from uranium** from soil and homes
causes **lung ca** in uranium miners
203
legionellosis
bacteria --\> pna
* txmit via aspiration from WATER SOURCES
204
what bacteria and thrve in stagnant water and can travel in aerosols?
psudomonas, klebsiella
205
asbestos
naturally occuring fibrous minerals --\> separated into thin, durable threads
* used for insulation and roofing
fibers can be breathed into --\> trapped in lungs --\> accumulate --\> scarring and inflammation
**carcinogen**
* dose related
* debilitating and fatal
* latent 10-20 years
206
CO
livor mortis: color of death
* pooling of blood = lividity in 2hrs
* blanching of pressure points
207
petechail hemorrhage in CNS
extravasation of blood cells out of caps
208
CO tx
remove from exposure --\> 100% o2 --\> hyperbaric tx
survivors have some signs of brain injury
209
CO detector
CO tends to rise with warm air --\> ideal to place @ considerable height
210
Mushroom poisoning
- Amanita muscaria: one of most iconic and distinctive of british fungi (see pic)
* muscimol and ibotenic acid
- Amanita phalloides
211
Amanita muscaria
Muscimol:
* Structurally similar to GABA.
* Main psychoactive component --\> sedative and dissociative manifestations.
Ibotenic acid:
* Structurally similar to the excitatory neurotransmitter glutamic acid.
Muscarine:
* Cholinergic toxin
212
presentation of amanita muscaria
and tx?
30-90 min after ingestion
* PNS (Ach) effects - **pupil constriction**
* ****perception anomalies
* usually falls into deep sleep
* hallucinogenic: agonist of GABA (presynaptic inhib)
tx: RARELY lethal
213
Amanita phalloides
amanitin (cyclopeptidide) --\> STRONGLY inhib RNA Pol II
* most dmg in liver then kidney
214
presentation and tx of amanita phalloides
6-24 hrs after ingestion
* GI
* liver: pulminant hepatitis
* kidney: acute tubular necrosis
* cardiac
--\> DEATH
tx: EXTREME life support (with dialysis) and liver transplant: **lethal due to tx very often not offered in time**
215
Aspergillus flavus
216
blight potato
moldy potato --\> spina bifida = MOST common disably birth defect
217
pregnancy and cheese
avoid soft cheese that are not pasteurized: feta, brie, camembert, blue--veined, mexican
ESP during 1st trimester
218
botulism
•**Clostridium botulinum [botulism]**
* canning
* spores can be killed by heating
* **why infants should not have honey**
* Clostridium welchii (or perfringens)[gas gangrene]
* Clostridium difficile[pediatric enterocolitis]
219
lead (Pb)
most common chronic metal poisoning in us: mostly children
* leaded gasoline still used by AIRLINES (teta-ethyl lead)
220
pathogenesis and symptoms of lead
ROS --\> cell dmg --\> heme problems --\> neuro dmg (esp CNS)
early symptoms:
* fatigue/headache, upset stomach
later symptoms:
* memory problems, kidney, weak wrist/ankles
221
most of absorbed lead is incorporated into...
what other effects of lead are there?
bone and dev teeth --\> **competes with calcium**
higher intestinal absorption and more permeability of BBB in children create a high susceptibility to brain dmg --\> (-) neuroT caused by disruption in calcium hoemostasis
other effects:
* "lead" lines (bone density) by interfering with normal cartilage remodel in epiphyses in children & in gingiva
* inhib healing of fxs but incr condrogenesis and delaying mineralization
* inhib 2 enz of heme synth --\> heme deficiency due to rise in protoprophyrin lvls --\> microcytic hypochronic anemia
222
lead lines
223
Basophylic stippling of RBC's: microcytic hypochronic anemia
224
tx fo lead poisoning
stop exposure
chelating agents
225
arsenic salts lead to tox most prominent in...
GI
NS
skin
heart
226
characteristics of As
metalloid
"poison of kings" - perfect poison: tasteless and colorless
227
sources of As
in nature - **ground water**
in many minerals, usually in conjuction with sulfur and metals
* can also be pure
was common in cosmetics and medicine
228
pathogenesis of As
skin/ingestion --\>
* interfere with mito ox-phos
* binds to disulfide bonds --\> disturb protein fx
CUMULATIVE: but also dose dependent
229
As presentation
acute:
* "garlic breath" --\> hemorr gastroenteristis --\> CNS tox
chronic:
* malaise/ stomach pain --\>
* **hyperpig** and dermatitis, **mee's lines**
* peripheral neuropathy
* heme dysfx
* **carcinogenesis**
230
mee's lines: chronic arsenic poisoning
231
Hyperkeratosis - chronic As pois
232
skin ca - chronic As poisoning
233
neuro changes in chronic As poisoning occur....
2-8 weeks after exposure: sensorimotor neuropathy
234
As type of dmg on DNA is usualy removed via...
NER
235
tx of As
Treatment and outcome
* Chelating agents (Dimercaprol and dimercaptosuccinic acid)
* Bind the arsenic ions and prevent them from inihibiting enzymes.
* Chelation therapy has side effects as well.
* Amputation of the limbs with non healing ulcers
236
mercury sources
power plants
fish: swordfish, shark, bluefish
used to be in old cleaning solvents: particularily in men's hats "**mad hatter"**
237
pathogenesis of mercury
binds sulfhydryl grps --\> dmg CNS and kidney due to lipid solubility
* tremors, demential delirium
* acute tubular necrosis
* major CNS defects in utero - dev brain EXTREMEMLY SENS to methyl merc
* Minamata disease: cerebral palsy, deaf, blind, mental retard
238
tx Hg
stop exposure
chelating agents
239
cadmium: soruces and pathogenesis
sources:
* batteries
patho:
* uncertain (maybe ROS) --\>
* obstructive lung disease: necrosis of alveolar cells
* runal tubular dmg --\> ESRD
240
copper sources
coins
insecticides/fungicides
wire
vit/mineral: essen but too much can be deadly
241
pathogenesis of Cu
accum in mito and lyso --\> hepatocyte dmg --\> cell degen/necrosis
* hemolytic anemia
* oxidation of Hb --\> MetHb (unable to carry O2)
* kidney dmg
242
copper toxicity
used to be due to copper cooking vessels: high heat releases more Cu ions
idian childhood cirrhosis: mostly south India (nearly disappeared)
243
cyanide
sources: **almonds**, peaches, apricot seeds
patho: binds ferric iron of cyt oxidase --\> (-) cell respiration --\> death in 2 min
autopsy findings:
* generalized petechial hemmorhages --\> esp into stomach
* **bitter almond scent**
* bright cherry lividity
244
what kind of ca's usually result from soot?
scrotal
lung
bladdar
245
vinyl chloride
colorless gas with mild sweet odor
from plastic industry
patho: **angiosarcoma of liver** and CNS depression
246
Carbon tetrachloride
organic solvent: degrease, dry cleaning, paint removers
patho:
* centrilobular necrosis and fatty changes in liver
* kidney
* CNS
247
Organophosphates
pesticides: parathion, malathion
patho: **irreversible cholinesterase inhib** --\> SLUDGE (PNS symptoms)
* salivation
* lacrimation
* urination
* defecation
* GI upset
* emesis
248
β-naphthylamine and aniline dyes.
dye and rubber --\> bladder ca
249
Abrasions - superficial dmg to skin usually caused by tangential force
heals rapidly without scar
250
contusion: when bv close to surf of skin breaks
251
contusion healing progress
252
deliberate oepning of skin by cutting - SHARP edges with clean separation of tissues
253
laceration
split/tear of skin common over bone prominences - **irregular and usually contaminated** (unlike incised which is CLEAN)
* crushed margins = abraded
* stetched = sim to incision
**usually NOT from** sharp objects (like incised wound)
254
puncture wounds
objects penetrate into tissues with small surface opening
injury is high variable
255
bulnt force injuries
non-penetrating with variable result depedning on injury site
256
blunt force trauma: head
brain
* dmg: possible skull fx or due to cerebral trauma/intracranial hemorr
* laceration: penetrating skull frag 2ndary to fx
* contusion (coup/countercoup)
257
blunt force injuries; thorax
1. rib fx
2. hemothorax
3. penumothorax
258
blunt force trauma: abdomen
1. contusion
2. spleen/liver --\> severe hemorrhage
3. intestines -- \> peritonitis
259
entrance: (inverted)
* smaller (sometimes smaller than bullet due to sin elasticity)
* round: may see metal ring
* CLEANER
* may be cherry red due to CO
exit: (everted)
* larger to due bullet tumbling
* irreg/stellate
260
clinical significance of burn depends on: (4)
1. depth
2. % of body involved
3. internal injuries due to heat/toxic fumes
4. promptness/efficacy of therapy - esp flud and electrolyte management and control of infections
261
thermal injury according to depth
superficial:
* epidermis
* painful/red --\> heals spont in days --\> no scarring
partial thickness:
* dermis
* blister/shiny & pink or red --\> heal via reepithliation by stem cells from skin appendages --\> possible scarring due to lvl of dermal involvement
full thickness:
* subQ
* hard/dry, PAINLESS --\> heal via skin graft --\> significant scarring
* may also involve muscle (prev known as 4th degree burns)
262
rule of 9's and palm method
body can be split into multiples of 9%'s
a person'a hand is about 1% --\> how to est % burned
263
what are the greates threats to life in burn pts?
shock
sepsis
respiratory insufficiency
264
common complications of thermal injuries (5)
1. smoke/toxic fume inhalation --\> pulm/systemic dmg
* usually w/in 24-48 hours after burn --\> airway obstruction
2. hypovolemia via fluid/electrolyte loss
3. curling ulcer: acute gastric ulcer assoc with severe burns
4. infeciton: Pseudomonas aeruginosa = most common cause of late fatalities
* burn sepsis --\> organ sys failure
* NEED to removal burn wound to decrease infection and also reduces need for reconstructive sx
5. ulcerating sq-cell cacrcinoma: with long-standing burn wounds (Marjolin ulcer)
265
hyperthermia
prolonged exposured to high ambient temps
* cramps: lsos of electrolytes due to sweating
* exhaustion: most common
* stroke: HIGH temp, HIGH humidity, AND exertion
manifests:
* hot & dry skin
* AMS
* hypotension BUT tachycardia and hypervent
**usually in young OR elderly after exertion in high temps**
266
hypothermia
Prolonged exposure to low ambient temperature
direct:
* physical disruptions within cells by high salt concentrations caused by the crystallization of intra- and extracellular water
indirect:
* circulatory changes: slow chill leading to vasoconstriction and increased vasc perm --\> edema and hypoxia
267
chemical burns rules
brush off dry powders BEFORE flushing with LOTTTSSS of water
do no contaminate uninjured areas while flushing
con't to flush on way to hospital
268
electrical injury
completion of electrical circuit through a person --\>
* burns: erythematous lesions with blister OR charred white lesion
* v-fib (@75-100 milliamps)--\> cardiac and respiratory failure
injury depends on:
* str (amps)
* duration
* path in body
269
Lichtenberg sign: high intensity current (lightning) --\> arborescent skin pattern
270
radiation injury
waves/high-speed particles
1. nonionizing: UV/IR/microwave/sound: can move atoms resulting in VIBRATION but cannot displace
2. ioniziing: has enough E to remove electrons
271
ionizing radiation
dmg:
* hyperthermia & burns
* DNA dmg by x-linking --\> ROS --\> dsDNA breaks
effect depends on:
* dose and field: SINGLE to WHOLE BODY \> fraction to regional
* cell division: rapidly dividing cells MORE sensitive
*
272
complications of ionizing radiation (4)
1. fibrosis
2. pulm changes
3. GI inflam/ulcer
4. carcinogenesis --\>
* **skin ca**
* heme alterations: bone marrow depression, myeloid leukemias (neoplasia)
273
largest cause of preventable death in US
tabacco --\> leading cause of lung disease
274
main known carcinogens in tobacco
Polycyclic aromatic hydrocarbons
Nitrosamines
Aromatic amines
275
time tobacco takes off of your life
1 cig = 12 min
1 pack (20 cigs) = 4 hours
276
Lung cancer incidence curve occurs at about
25 pack years --\> **reversible with cessation of smoking**
277
pathogenesis of tobacco
inhib respiratory mucus cilia and absorbed into blood to exert its effects
* 90% of all lung cas
* chronic brochitis, emphysema, COPD, asthma
* MI
* systemic atherosclerosis
* PVD
* CVD
for infants: low birth wt and SIDS (maternal smoking is ONLY known assoc)
278
Thromboangiitis obliterans
buerger's disease
Recurring progressive inflammation and thrombosis (clotting) of small and medium arteries and veins of the hands and feet.
279
smoking and pregnancy
smoking (+) vasospasms in placenta and fetal circulation
incr risk of: abortion, premature birth, intrauterine growth retardation
SIDS
280
passive smoking
exposure to environ smoking: SAME as if smoking itself
can measure exposure in blood lvls of cotinine (metabolite of nicotine)
281
Smokeless tobacco
snuff, chewing --\> **oral ca**
282
tobacco and alcohol
tobacco and occupational exposures
alcohol --\> MULTIPLIES risk of cas
* oral
* layngeal
* esop
environ: asbetos, uranium...
* lung ca
283
vaping
almost all contain nicotine
can contain formaldehyde
potetially safe due to FEMA GRAS?!
284
ethanol
most widely abused legal drug in the world
* 80 mg/dL (0.08 grams%) = drunk driving
* 200mg/dL = drowsiness (higher --\> stupor and coma)
metabolism:
* ETOH --(alcohol DH)--\> acetaldehype via cyt p450 and catalase --(alde DH)--\> acetic acid
* oxidation by alcohol DH depletes NAD --\> accumulation of fat in liver nad metab acidosis
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alcohol flush
missing aldehyde DH gene
asan and native americans
286
ETOH cirrhosis & fatty change --(may)--\> hepatocellular carcinoma
287
ETOH & GI sys
* Increased parotid gland (Sialosis/Sialadenosis)
* Gastritis (ulcers and bleeding)
* Esophageal varices (bleeding)
* Pancreatitis.
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ETOH and brain
wernicke-kozakoff's
* thiamine (vit b1) deficiency
* TRIAD: confusion, ophtalmoplegia (eye M paralysis/weakness), ataxia
* also: confabulation, personality change, mem loss
presents as hemorrhage into the mammillary bodies and cerebellar degeneration
289
Delirium tremens
shaking frenzy due to severe alcohol withdrawal
290
ETOH on heart
dilated cardiomyopathy
htn
decreased HDL lvls
291
ETOH and testicles
atrophy due to changes in testosterone
292
what can give someone a highest risk of dev ca of esophagus?
drinkers with only one copy of ALDH2 gene
293
FAS
acetaldehype crosses placenta --\> dmg fetus
MOST common type of preventable mental retardation
294
methanol
methanol --(alcohol DH)--\> formaldehype --(oxidation)--\>formic acid --\> **blindness** and renal failure
tx with ethanol --\> compete with methanol for alcohol DH
295
adverse drug rxns
types:
* A: direct actions of drug
* B: hypersens rxns
most freq:
* oral anticoag: warfarin, dabigatran
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warfarin (coumadin)
vit K antagonist: blocks formation of active forms of coag facs via **inhibition** of vit K 2,3-epoxide reductase
monitored with INR measurements from prothrombin time
foods/drugs rich in vit k and INTERFERE!
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dabigatran
direct thrombin inhib (DTI) --\> prevent venous thromboemb (VTE) & CVD in a-fib
Idarucizumab can be given for reversal of the anticoagulant effect in emergency settings
no lab monitoring
effects can be measured with ecarin clotting time, PTT, TT
298
MHT
menopausal hormone therapy: manages symptoms
* estrogen alone or combined with progestin
**not indicated for tx of:**
* CVD (may be cardio protective \< 60 y/o)
* osteoporosis (but can reduce fxs)
* dementia
increased risk of:
* breast ca: estrogen-progestin combo around 5-6 years of use
* stroke, VTE during first 2 years of tx
299
oral contraaceptive
symthetic estradiol and variable amount of progestin --\> INHIB ovul or PREVENT implantation
* –No increase in breast cancer risk
–Decreased risk of endometrial and ovarian cancers
–Increased risk of cervical cancer, venous thrombosis and pulmonary embolism (3-6x), coronary artery disease in women \>35 yrs who smoke, hepatic adenoma
300
Anabolic Steroids
synth testosterone to tx male hypogonad & senescence
popular for performance enhancement BUT increases estrogens
* in males --\> can lead to more female features, stunted growth, acne
* in female --\> can lead to more male features
can result in: psych distrubances and incr risk of MI
301
Acetaminophen
| (paracetamol)
most commonly used analgesic in US
RDS: no more than 4g/day
\*unintential OD = most common cause of tox
* GI upset --\> jaundice (days): **centrolobular necrosis**
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ASA
analgesic, antipyetic, antiinflamm, antithrom
OD usu due to suicide
acute OD --\> metaboli acidosis
* tx: alkalinize urine
chronic OD
* neuro: headache, tiniitus/hearing, confusion, drowsy
* GI: erosive gastritis
* heme: excessive bleeding (blcoks TXA2)
* renal: analgesic nephropathy
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cocaine
PNS:
* blcoks epi/NE reuptake (sympathomimetic) --\> MI, lethal arrhythmias
CNS:
* blcoks dopamine reuptake --\> hyperpyrexia & seizures
Preg:
* fetal hypoxia, neuro impairment, intrauterine death
\*nasal septum perforation
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opiates
heroin
* euphoria/hallucinations/somnolence
* adverse:
* pulm edema, emboli, **foriegn body granuloma**
* **R side endocarditis due to s. aureus**
* viral hepatitis
* cutaneous infection, scarring ,thrombed veins
* renal amyloidosis
oxycodone/oxycontin
* therapeutic analgesic --\> potent respir suppress
305
types of Amphetamines
meth
MDMA
marijauna
306
Methamphetamine
crystal meth, speed
* hydrogenation of ephedrine or pseudoephedrine
* smoke, snort
acute effects: sim to coke
complications:
* seizure, arrhyth, hyperthermia
* chronic --\> mood and cog changes
307
MDMA
E, molly --\> euphoria, wakeful, disinhibition, halluc
increases serotonin release in CNS
may increase perip dopa and adrenergic effects
308
Marijuana
∆9-tetrahydrocannabinol (THC) from Cannabis sativa
acute: sensory and motor impairment
chronic: CVD
Used therapeutically:
* relieve nausea: chemotherapy
* chronic pain refractory to other conventional analgesics
