Master Catania (2 Modulo

7/27/2019 Master Catania (2 Modulo

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MECCANISMI DELLACANCEROGENESI


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Pancreatic Skin Breast

BrainLung Prostate

Leukemia Hodgkins Non-Hodgkins

SOLID

CANCERS

LIQUIDCANCERS


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5

0

10

15

20

25

30

35

10

10

10

10

10

10

10

10

10

10

10

10

0

1

2

3

4

5

6

7

8

9

10

11

10

10

10

10

10

10

10

10

10

10

10

10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

Divisioni

cellulari

No. Di

cellule

Peso

(g) Ambiente estile di vita

PREVENZIONEPRIMARIA

Organismo

ospite (chemio -prevenzione)

PREVENZIONESECONDARIA

TERAPIA,RIABILITAZIONE e

PREVENZIONETERZIARIA

TUMORE BENIGNO

INIZIAZIONE(giorni - settimane)

PROMOZIONE(anni - decenni)

CANCRO

PROGRESSIONE(~ 1 anno)

INVASIONE

Dose espositiva

Dose farmacologica

Dose cellulare

Dose bersaglio

Dose molecolare

TOSSICOCINETICAE METABOLISMO

DANNO E RIPARODEL DNA

METASTASI

CRESCITA DELLAMASSA NEOPLASTICA

PROCESSO DICANCEROGENESI

STRATEGIE DIINTERVENTO

12

40 10

310 MASSA NEOPLASTICA

CHEM

IOPREV

ENZIO

NE

S. De Flora et al., Mutat. Res. 480481, 922, 2001

Multistadi / field cancerization


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Controlli

NACDMBADMBA + NAC

8-oxo-dG/105 nucleotidi

.0 .1 .2 .3 .4 .5 .0 .1 .2 .3 .4 .5 .0 .1 .2 .3 .4 .5

ControlliNACDMBADMBA + NAC

Addotti al DNA/108 nucleotidi

0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5

Controlli / DMBAEspressione diCx43

Cellule M13SV1 Cellule M13SV1R2 Cellule M13SV1R2N1

CELLULE EPITELIALI MAMMARIE UMANEDI ORIGINE STAMINALE


Celluleapoptotiche (%)

0 2 4 6 8 10 0 2 4 6 8 10 0 2 4 6 8 10

Differenze significative

DMBA vs. controlliS. De Flora et al., Int. J. Oncol., 29, 521529, 2006


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Controlli

NACDMBADMBA + NAC

8-oxo-dG/105 nucleotidi

.0 .1 .2 .3 .4 .5 .0 .1 .2 .3 .4 .5 .0 .1 .2 .3 .4 .5


Addotti al DNA/108 nucleotidi

0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5

Controlli / DMBAEspressione diCx43

Cellule M13SV1 Cellule M13SV1R2 Cellule M13SV1R2N1


Celluleapoptotiche (%)

0 2 4 6 8 10 0 2 4 6 8 10 0 2 4 6 8 10

Differenze significative

DMBA vs. controlliS. De Flora et al., Int. J. Oncol., 29, 521529, 2006

CELLULE EPITELIALI MAMMARIE UMANEDI ORIGINE STAMINALE


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INIZIAZIONE DEL CANCRO

Tossicocinetica e metabolismo

Danno genotossico

Riparazione del DNA


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METABOLISMO DEGLI XENOBIOTICI


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ATTIVITA METABOLICHE DI FASE I E DI FASE IIE LORO POLIMORFISMI GENETICI

Drug-metabolizing enzymes known to exhibit common polymorphisms at thegenomic level that have been associated with changes in drug effects; however,almost every gene involved in the drug metabolism is subject to commongenetic polymorphisms that may contribute to interindividual variability in drugresponse and drug toxicity.

Phase I Phase II

DPD

NQO1

Epoxidehydroxylase

others

CYP1A1/2CYP1B1

CYP2A6

CYP2B6CYP2C8

CYP2C9

CYP2C19

CYP2O6

CYP2E1

ADHALDH

CYP3A4/5/7

others

NAT1

NAT2

GST-M

GST-TGST-P

GST-A

UGTSSTS

HMT

COWTTPWT

oxidases


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OO

O

HO

OH

HO

OH OH

OH

OH

HO

O

HO

OH

O

9,10Diol7,8oxide 7,8Diol9,10oxide

9,10Dihydrodiol 7,8Dihydrodiol

Mono-oxygenase

Epoxide hydratase

4,5Dihydrodiol

9,10Oxide 7,8Oxide 4,5Oxide

Mono- oxygenase

Benzo[a]pyrene K region

Bay region1

2

3

4

567

8

9

10

11

12

Phenols and quinones

Simple epoxides

Dihydrodiols

Diol- epoxides

Attivazione metabolica del benzo[a]pirene


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GLUCOSE

G6P G6PD 6PG 6PGD

NADPH

NADP + H+

GSSG

REDUCTASE

GSSG

2 GSH

GSH

PEROXIDASE

2H2O

H2

O2

GLUCOSO

G6P G6PD 6PG 6PGD

NADPH

GSSG

REDUTTASI

GSSG

2 GSH

GSH

PEROSSIDASI

2H2O

H2O2NADP + H+

CICLO DEL GLUTATIONE


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GSH = Glutatione ridotto

GST = Glutatione S-trasferasi

GSTM1

GSTT1


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GSTM1 GENOTYPE STATUS AND DNA ADDUCT LEVELSIN SMC OF HUMAN ATHEROSCLEROTIC LESIONS

*P< 0.05, **P< 0.01 A. Izzotti et al., FASEB J. 15, 752-757, 2001

32P postlabelledDNA adducts

GSTM1+(n = 36)

GSTM1(n = 39)

Ratio(/+)

Spot 1Spot 2Spot 3

Spot 4Spot 5Spot 6Spot 7Spot 8Spot 9DRZ

Total

0.460.110.23

0.100.130.260.360.250.64

10.8013.80

0.630.250.49

0.180.350.270.480.351.076.169.77

0.580.200.51

0.280.280.460.860.772.74

16.4122.67

0.740.280.74*

0.430.57**0.521.23*1.40**5.97**10.63**18.63**

1.31.82.2

2.82.21.82.43.14.31.51.6


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METABOLIC DEACTIVATION OF MUTAGENSS. De Flora, Nature 271, 455-456, 1978


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METABOLIC DEACTIVATION OF MUTAGENSS. De Flora, Nature 271, 455-456, 1978


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CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELLPOPULATIONS AND FLUIDS IN THE HUMAN DIGESTIVE SYSTEM

De Flora et al., Carcinogenesis 18, 531537, 1997

PORTAL SYSTEM BLOOD[187 - 234 mg Cr(VI)]

INTESTINAL BACTERIA[11 24 mg Cr(VI) eliminateddaily with bacteria in feces]

GASTRIC JUICE[> 84 88 mg Cr(VI)/day]

SALIVA [0.7 2.1 mg Cr(VI)/day]

LIVER CELLS[3,300 mg Cr(VI)]

BRONCHIALTREE CELLS

PERIPHERALLUNG PARENCHYMACELLS [260 mg Cr(VI)]

ELF [0.9 1.8 mg Cr(VI)]

PAM [136 mg Cr(VI)]

BLOOD[187 234 mg Cr(VI)]


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BENIGN TUMOR

INITIATION(days - weeks)

PROMOTION(years - decades)

CANCER

PROGRESSION(~ 1 year)

INVASION

Exposure dose

Pharmacologic dose

Cellular dose

Target dose

Molecular dose

TOXICOKINETIKSAND METABOLISM

DNA DAMAGE

AND REPAIR

CARCINOGENESISPROCESS

NEOPLASTIC MASS

METASTASIS

THRESHOLDS IN CARCINOGENESIS?

DNA repairDNA repair ApoptosisApoptosis


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Danno genotossico

Riparazione del DNA


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CARIOTIPO UMANO


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C

NC

GNGAmes reversion test

Accuracy = 74.7% (68/91)

23.2%(16/69)

Sensitivity

76.8%(53/69)

31.8%(7/22)78.2%(15/22)

Specificity

C

NC

GNGDNA-repair test

Accuracy = 73.7% (59/80)

20.7%(12/58)

Sensitivity79.3%(46/58)

40.9%(9/22)59.1%

(13/22)Specificity

CORRELAZIONE FRA

MUTAGENICITA ECANCEROGENICITA


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EFFETTI PATOLOGICI DELLE MUTAZIONI NELLUOMOEFFETTI PATOLOGICI DELLE MUTAZIONI NELLUOMO

Morte cellulare (apoptosi)

Tumori e altre malattie cronico-degenerative

Invecchiamento e patologia associata

MUTAZIONI IN CELLULE SOMATICHE(in et adulta o in epoca embrionale)

MUTAZIONI IN CELLULE SOMATICHE(in et adulta o in epoca embrionale)


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EFFETTI PATOLOGICI DELLE MUTAZIONI NELLUOMOEFFETTI PATOLOGICI DELLE MUTAZIONI NELLUOMO

Sterilit, aborto, morte perinatale(mutazioni dominanti letali)

MUTAZIONI IN CELLULE GERMINALIMUTAZIONI IN CELLULE GERMINALI

Malattie genetiche nei neonati(mutazioni dominanti non letali)

Malattie genetiche in generazioni successive(mutazioni recessive)


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mtDNA

AGEING


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R. Balansky et al., Cancer Res. 56, 1642-1647, 1996

NAC

NAC +

mtDNA

nDNA

ADDOTTI AL DNA POLMONARE IN RATTI ESPOSTI AFUMO DI SIGARETTA


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Danno genotossico

Riparazione del DNA


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XP

AT

AF

Suscettibilit individuale

RIPARAZIONEDEL DNA


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Mechanisms

XPC

hHR

23B

33

55

TF

IIH

G1G1

SS

G2G2

MM

Cell

Cy

cle

Cell

Cy

cle

p21

Chk2

PNK

DNA-PKcs

RNAPol

Rad1

XAB2

X

P

B

TFIIH

XPG

ERC

C1

XPF

NERNER

Cross-

LinkingC

ross-

Linkin

g

Ku70/80Ku70

/80

XRCC4Li

gIV

Rad50

PARP

UV LightUV Light

BRCA1

SSBreakbyX-Rays

S

SBreakbyX-Rays

DNA-DamageCheckpoint

DNA-DamageCheckpoint

p53Degrada

tion

p53Degrada

tion

UbU

b Ub

Ub

Rad51

Rad51

BARD1

IG

F1

BRC

A1

DSB

DSB

P PP

P

JNK/SAPK

DSB

DSB

Ligase

PCNA

PCNA

PCNA

NBS1 MR

E11

Pol-

/

FEN1 Po

l-

NHEJNHEJ

ApoptosisApoptosis

Cell ProliferationCell Proliferation

GADD

45

MGMT

DNAPol

Oxygen RadicalsAlkylating Agents

Spontaneous Reactions

Oxygen RadicalsAlkylating Agents

Spontaneous Reactions

MMRMMR

BERBER

Deacetylatio

n &Demethy

lationof

GuanineDeace

tylation &De

methylation

of

Guanine

NucleusNucleus

BE

R

BE

R

MMRMMR

BERBER

BERBER

SS-Break

s

byX-Ray

sSS-Break

s

byX-Ray

s

Repair

Repair

Depurination& Deamination

Depurination& Deamination

DNA-

Dam

age

Chec

kpoin

t

DNA-

D

am

ag

e

Chec

kpoin

t

Endogenous Agents(Water & ROS)

Endogenous Agents

(Water & ROS) ReplicationErrors(DNAPol&IDLs)

ReplicationErrors(DNAPol&IDLs)

UU

33

55

GGOx

oOx

oRF

-PLo

ads

RF-P

Load

s

PCNA

onto

DNA

PCNA

onto

DNA

Homo

logou

sReco

mbina

tion

Homo

logou

sReco

mbina

tion

ProofReading

ProofReadingIRDa

mageIRDamage

hN

TH

TRE

X1

UNG2

TRE

X2

MutS MutSMSH2

MSH3

MS

H2 MutS MutS

Smoki

ngSmoki

ng

OHOHPP

X-Rays &Anti-Tumor Agents

X-Rays &Anti-Tumor Agents

AbasicSite

AbasicSite

NERNER

p53

MDM2

Recom

binatio

nal

Repair

Recom

binatio

nal

Repair

FANCs

Po

l-SNM1

Estrogen

Estrogen

R

PA

XPD Rad

24Rad17

Mec1

CSA

Trans

cripti

on

Coupl

ed-

NER

Trans

cripti

on

Coupl

ed-

NER

ATMAT

R

Chk1

p53

UV Light Ionizing Radiation, BulkyAdducts& ROS

UV Light Ionizing Radiation, BulkyAdducts& ROS

Proteasome

XRCC1

BRCA1

UV & BulkyAdducts

UV & BulkyAdducts

X

P

A

C

S

B

Rad9

BRCA2

Hu

s1

Rad9

LigIII

hOGG1

GGMeMe

M S H 6

MBD4

SMUG1

AP

E1

Rad52

2009ProteinLounge.com


C


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PROMOZIONE DEI TUMORI


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PROMOZIONE DEL CANCRO

Promotori fisici / meccanici

Promotori biologici

Promotori chimici


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Promotori biologici

Promotori chimici


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SPECIE REATTIVE DELLOSSIGENO

O2

H2O

e

e

e

e

OSSIGENO MOLECOLARE

O2 ANIONE SUPEROSSIDO

H2O2 IDROGENO PEROSSIDO

OHRADICALE IDROSSILE


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SPECIE REATTIVE DELLOSSIGENO

O2Lucecoloranti

OSSIGENO MOLECOLARE

O2 OSSIGENO SINGOLETTO


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Promotori biologici

Promotori chimici

ORGANOSPECIFICITA DEI PROMOTORI


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ORGANOSPECIFICITA DEI PROMOTORI

NaCl Stomaco

Saccarina Vescica

Componenti della bile Colon

Estrogeni Mammella

Fenobarbital Fegato

Componenti del fumo Polmone

TPA Cute


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5

0

10

15

20

25

30

35

10

10

10

10

10

10

10

10

10

10

10

10

0

1

2

3

4

5

6

7

8

9

10

11

10

10

10

10

10

10

10

10

10

10

10

10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

Divisionicellulari

No. Dicellule

Peso(g) Ambiente e

stile di vita

PREVENZIONEPRIMARIA

Organismo

ospite (chemio -prevenzione)

PREVENZIONESECONDARIA

TERAPIA ePREVENZIONE

TERZIARIA

TUMORE BENIGNO

INIZIAZIONE(giorni - settimane)

PROMOZIONE(anni - decenni)

CANCRO

PROGRESSIONE(~ 1 anno)

INVASIONE

Dose espositiva

Dose farmacologica

Dose cellulare

Dose bersaglio

Dose molecolare

TOSSICOCINETICAE METABOLISMO

DANNO E RIPARO

DEL DNA

METASTASI

CRESCITA DELLAMASSA NEOPLASTICA

PROCESSO DICANCEROGENESI

STRATEGIE DIINTERVENTO

12

40 103

10MASSA NEOPLASTICA


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ANGIOGENESI E

ANTIANGIOGENESI


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ANGIOGENESI E LINFANGIOGENESI

GENI IMPLICATI IN LINFANGIOGENESI (K. Alitalo et al., Nature, 2006)


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Pathway

VEGFA,VEGFC,VEGFD


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VEGF

R2

PLC

PIP3

PIP2PI3K P

P PIP2

P

p38

MKK3/6

FAK

Paxillin

SHC

GRB2SOS

Pathway

P

P

P

BAD

P

Caspase9

HSP90

eNOS

MAPKAPK2/3MAPKAPK2/3

ActinReorganization

ActinReorganization

DAG

MEK1/2

Ras

IP3

VEGFD

Sck

VRAP

HSP27

ERK1/2

PKC

Raf1

Ca2+

cPLA

Endo

thelial

Cell

Endo

thelialC

ell

Focal Adhesion

Turnover

ProstaglandinProduction

Vascular CellPermeability

Gene Expression & CellProliferation

ANGIOGENESIS

Cell Survival

Nitric Oxide

Production

Src

Akt/PKB

CellMigration



C


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REGOLAZIONE GENETICA DELLA

PROLIFERAZIONE CELLULARE


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IL CICLOCELLULARE

ReplicativeReplicative

Cyclins and Cell Cycle

Regulation

Cyclins and Cell Cycle

Regulation

2009ProteinLounge com

2009ProteinLounge com

C


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P

P

PP

CDK1

CDK1

CDK1

CDK1

Cyclin-A

Ub

Rb

PP

P

PP

P

P

P

P

PPP

PRb

PP P

P

P

ATR

P P

E2FDP1

DP1

E2F

P

Rb

Rb

CDC25A

P

UbUb

UbiquitinationUbiquitination

UbiquitinationUbiquitination

Cyclin-H

CDC25A

E2F

Rb

Cyclin-

B

Cyclin-A

CDC25A

P

Wee1

MYT1

p21

E2F

Rb

Wee1

PP2A

Raf1

CDC2

5A

p21

P

Cyclin-A

Wee1p21

Wee1

TGF

p19(INK4D)

MYT1

Cyclin-D/D1

Cyclin-E

p18(INK4C)

p16(INK4A)p15(INK4B)

GSK3 p27(KIP1)

Cell CycleProgression


NucleusNucleus

S-Phase Genes[Cyclin-A, E,E2F, CDC2]

S-Phase Genes[Cyclin-A, E,E2F, CDC2]

ReplicativeScenescece

ReplicativeScenescece

ContactInhibition

ContactInhibition

MM

G2G2

ReplicativeSenescence

pSenescence

GrowthF

actor

Withd

rawal

Growth

Facto

r

Withd

rawal

C

IP/KIPFamily

CIP/KIPFamily

OffOff

OnOn

G1G1

RegulationRegulation

DNADamage

DNADamage

CDK4/6

ATM

p27(KIP1)

CDK7

Cyclin-H

CDK2CDK2

Cyclin-A

CDK2

CDK2

p27(KIP1)

p27(KIP1)Degradation

p27(KIP1)Degradation

SCFSCF

HDACs

p53

ProteinLounge.comProteinLounge.com


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PROTOONCOGENI

ONCOGENI


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TRASLOCAZIONE CROMOSOMICA


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MUTAZIONI PUNTIFORMI


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AMPLIFICAZIONE GENICA

GENI ONCOSOPPRESSORI


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GENI ONCOSOPPRESSORI


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Sindrome di Li-Fraumeni

Sindrome di von Hippel-Lindau

ChemotherapyChemotherapyIonizing

Radiation

IonizingRadiationHypoxiaHypoxia p53 SignalingUVUV

D

F

a


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p38

HIF1

Ub

Ub

14-3-3

MDM2

P P

P

P

E2F

c-FosP

Rb

P

P

BRCA1

AngiogenesisInhibition

AngiogenesisInhibitionCell Cycle

Progression


Gene ExpressionGene Expression

Cell SurvivalCell Survival

DNA DamageDNA Damage

Hypoxia InducedHIF1 Expression

Hypoxia InducedHIF1 Expression

ApoptosisApoptosis

p53Degradation

p53Degradation

DNA RepairDNA Repair

Ac

AcCAK

MDM2

PIAS1

JNK

Caspase

BCL2

BAI1

TSP1

GADD45

RbCDK2

CyclinD1

CDK4

CyclinE E2F

PCAF

DNA-PK

PTEN

ATM

p53

Akt

p53

p53

Ub

ATR

Sirt

HDAC

c-Abl

p53PML

p21CIP

PTEN

ProteasomeProteasome

HIPK2 CSNK1

p53

GSK3

Bax

D

R

5

a

s

Ac

p53

p300

Chk2

Chk1



C


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LOSS OF FHIT EXPRESSION IN SPRAGUE-DAWLEYFHIT


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Bronchialepithelium

Kidneytubular

epithelium

SHAM

1.4 0.74%

1.1 0.64%

RATS EXPOSED TO CIGARETTE SMOKE FOR 28 DAYS

ECS

4.9 1.96%P < 0.001 compared to SHAM

1.4 0.52%

ECS + NAC

3.1 1.7%P < 0.05 compared to ECS

1.3 0.71%

F. DAgostini et al., Cancer Res. 66, 393641, 2006

TUMORI DELLA MAMMELLA O DELLOVAIO


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U O O O O


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Colorectal carcinogenesis: adenomacarcinoma sequence. (Adapted from Kelloff GJ, Hawk ET,Crowell J, et al: Oncology 10(10):147184, 1996 and Ilyas M, Straub J, Tomlinson IP, et al: Eur J Cancer35:33551, 1999 and reprinted with permission (131, 132).


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Master Catania (2 Modulo

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