DeFlora - Tumori_professionali

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DeFlora - Tumori_professionali
EPIDEMIOLOGIA E PREVENZIONE
DEI TUMORI PROFESSIONALI
Silvio De Flora
GE
NUEN
SE
ATHE
NAE
UM
Università di Genova
Dipartimento di Scienze della Salute
Sezione di Igiene e Medicina Preventiva
OBIETTIVI
Epidemiologia descrittiva
Epidemiologia analitica
Epidemiologia molecolare
Prevenzione primaria, secondaria e terziaria
Meccanismi della cancerogenesi
Esistono soglie in cancerogenesi ?
Conclusioni
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
ITALY, 1901–2000 (RAW MORTALITY DATA)
1407
Deaths per 100,000
500
INFECTIOUS
AND
DIGESTIVE
ACCIDENTAL
TRACT
RESPIRATORY
DIS.
PARASITIC
DISEASES
DISEASES
CAUSES
(INCLUDING
FLU)
400
EPIDEMIOLOGIA
DESCRITTIVA
300
200
100
RESP
ACC
DIG
INF
0
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
2000
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
ITALY, 1901–2000 (RAW MORTALITY DATA)
1407
Deaths per 100,000
500
CARDIOVASCULAR
CEREBROVASCULAR
CANCER
DISEASES
400
CARD
300
CAN
200
CER
100
RESP
ACC
DIG
INF
0
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
2000
ETA’ E TUMORI
EVOLUZIONE DELLA SPERANZA DI VITA ALLA NASCITA
ETA’ E MALATTIE CRONICO-DEGENERATIVE
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
ITALY, 1901–2000 (AGE-STANDARDIZED MORTALITY DATA)
Deaths per 100,000
1436
500
CEREBROVASCULAR
DISEASES
M –72.4%
F –74.4%
400
CARDIOVASCULAR
DISEASES
M –51.9%
F –67.9%
CANCER
300
M –18.3%
F –12.9%
CARD
200
1
2
3
CAN
CER
100
ACC
RESP
INF
0
DIG
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
2000
MORTALITA’ PER TUMORI IN ITALIA
DATI GREZZI
350
Decessi per 100.000
300
Maschi
250
200
150
Femmine
100
50
0
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
2000
MORTALITA’ PER TUMORI IN ITALIA
DATI STANDARDIZZATI PER ETA’
350
Decessi per 100.000
300
250
Maschi
200
150
Femmine
100
50
0
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
2000
DATI DI INCIDENZA DEI TUMORI IN ITALIA
Oltre 20 milioni di italiani
(36,1% della popolazione)
vivono in aree coperte
dall’attività dei Registri Tumori
(Dati 2011)
PRINCIPALI TUMORI IN ITALIA (AIRTUM Working Group, 2009)
Maschi
Polmone
27.043
23.969
Colon-retto
9.752
29.283
175.449
Prostata
7.460
˜ 42.000
NA
Stomaco
6.244
62.463
7.261
36.273
Femmine
Mammella
11.476
38.286
Colon-retto
8.315
19.650
Polmone
7.350
Stomaco
138.314
7.082
4.376
0
472.112
10
16.052
4.583
20
30
Morti nel 2006 (x103)
0
10
24.234
20
30
40
Casi incidenti
attesi nel 2010 (x103)
0
100 200 300 400 500
Casi prevalenti
stimati (x103)
SOPRAVVIVENZA A 5 ANNI PER TUMORE IN ITALIA (2002–2004)
DATI AIRTUM 2011
Pancreas
5%
Ossa
55%
Melanoma cutaneo
85%
Mesotelioma
7%
Testa e collo
56%
Linfoma di Hodgkin
84%
Esofago
11%
Tratto urinario
57%
Sarcoma di Kaposi
85%
Vie biliari
13%
Colon retto
58%
Mammella
87%
Polmone
13%
Ghiandole salivari
60%
Prostata
88%
Fegato
14%
Linfoma non Hodgkin
60%
Tiroide
94%
Sistema nervoso
17%
Cervice uterina
67%
Testicolo
95%
Leuc. mieloide acuta 17%
Rene
68%
Leuc. linfatica acuta
26%
Leuc. linfatica cronica
69%
Stomaco
29%
Pancreas
70%
Ovaie
41%
Vescica urinaria
76%
Mieloma
42%
Corpo uterino
78%
L. mieloide cronica
49%
Intestino tenue
49%
TUTTI eccetto t. cutanei
non melanoma
56%
Diade di Ippocrate
AMBIENTE
UOMO
EPIDEMIOLOGIA
MALATTIA
INFETTIVA
ANALITICA
Causa necessaria
ma non sufficiente
AGENTE
EZIOLOGICO
FATTORI DI
RISCHIO
MALATTIE
FR 1
M1
MORTI PER TUMORE - RISCHIO ATTRIBUIBILE
FR 2
Tabacco 30%
M2
Dieta 40%
Inattività fisica 2%
FR 3
Inquinamento 3%
Farmaci <1%
FR
FR 44
Infezioni 15%
Occupazione 3%
Radiazioni ionizzanti
e luce 6%
M3
M4
DIETA, ALIMENTAZIONE E CANCRO
FATTORI DI RISCHIO
FATTORI PROTETTIVI
Dieta ipercalorica
Esercizio fisico
Dieta iperproteica ?
Dieta iperglucidica (carboidrati semplici)?
Dieta iperlipidica (< 30% Cal; < 10% a. grassi saturi)
Contaminanti naturali (micotossine)
Componenti naturali (idrazine, pesticidi naturali)
Contaminanti artificiali (pesticidi)
Conservanti/additivi/coloranti
Precursori di cancerogeni endogeni
Inibitori nitrosazione (Vit. C)
Eccesso di NaCl
Salatura alimenti
Conservazione alimenti
Affumicatura alimenti
a bassa temperatura
Abbrustolimento e frittura alimenti
Forni a microonde
Eccessiva temperatura
Vitamine antiossidanti (A, ac. folico, C, E)
Elementi chimici (Se, Ca)
Clorofillina
Vari composti protettivi (crucifere)
Fibre indigeribili
Prodotti lattiero-caseari fermentati
Frutta e verdura, bevande (vino, thé)
Tumori del polmone e dello stomaco in Italia
MASCHI
FEMMINE
Decessi per 100.000
100
90
80
70
60
50
40
DATI GREZZI
30
20
10
0
100
90
80
70
60
50
40
DATI STANDARDIZZATI
30
20
10
0
Anno
MAINSTREAM
SMOKE
SIDESTREAM
SMOKE
ENVIRONMENTAL
CIGARETTE
SMOKE (ECS)
5000
200
Men
Women
4000
Smoking
Lung cancer
150
3000
100
Smoking
2000
50
1000
Lung cancer
0
0
1900
1920
1940
1960
Annual lung cancer deaths per 100,000 population
Annual per capita consumption of cigarettes
INCREASING CONSUMPTION OF CIGARETTES IS FOLLOWED BY
A STEEP RISE IN DEATHS FROM LUNG CANCER
1980
Lung cancer deaths in England and Wales show a close correlation with the
number of cigarettes smoked in earlier years. Source: J. Cairns.
MORTALITA’ PER TUMORI POLMONARI
(DATI STANDARDIZZATI PER 100.000)
90
80
UNGHERIA
Maschi
70
USA
60
UK
50
ITALIA
40
30
30
GIAPPONE
20
20
10
10
USA
Femmine
UK
UNGHERIA
GIAPPONE
ITALIA
0
1965-69 70-74 75-79 80-84 85-89
92
0
1965-69 70-74 75-79 80-84 85-89
92
PASSIVE SMOKING IN MUTANT MICE
R. Yao et al. K-Ras mutations in lung tumors from P53 mutant mice
exposed to cigarette smoke. Exp. Lung Res. 31, 271–281, 2005
S. De Flora et al. Molecular alterations and lung tumors in P53 mutant
mice exposed to cigarette smoke. Cancer Res. 63, 793–800, 2003
A. Izzotti et al. Gene expression in the lung of P53 mutant mice exposed
to cigarette smoke. Cancer Res. 64, 8566–72, 2004
F. D’Agostini et al. Early loss of Fhit in the respiratory tract of rodents
exposed to environmental smoke. Cancer Res. 66, 3936–41, 2006
S. De Flora et al. Molecular alterations induced by cigarette smoke in
mice heterozygous for Fhit. Cancer Res. 67, 1001–6, 2007
R. Balansky et al. Influence of Fhit on benzo(a)pyrene induced tumors
and alopecia in mice. PNAS 103, 7823–8, 2006
GENOMIC CHANGES IN MOUSE LUNG AT BIRTH
A. Izzotti et al., Mutat. Res. (Rev. Genetic Toxicol.), 544, 441-449, 2003
Lung of newborn mice / fetuses
UNTREATED
PREGNANT
MICE
NAC–TREATED
PREGNANT
MICE
8-oxo-dGuo
DNA adducts
1.9
5.0
P < 0.05
P < 0.001
0.9
NS
2.0
NS
Expression of 746 genes
MICE EXPOSED TO SMOKE AFTER BIRTH
LUNG TUMORS
UNTREATED
PREGNANT
MICE
LUNG
HYPERPLASIA
EMPHYSEMA OF BLADDER
EPITHELIUM
61.1 %
16.7 %
20.4 %
6.4 %
2.1 %
NAC–TREATED
PREGNANT
MICE
17.0 %
NAC - R. Balansky et al., Carcinogenesis 30, 1398-1401, 2009
AsA - R. Balansky et al., CCDT 12, 164-169, 2012
THE PREVENTION OF INFECTION–ASSOCIATED CANCERS
(S. De Flora and P. Bonanni, Carcinogenesis 32, 787-795, 2011)
Pathogen
IARC
Main asociated cancer
Group
Hepatitis viruses
HBV
HCV
HDV
1
1
3
4.9% of all cancers
Hepatocellular carcinoma
85.5%
of all
HCCs
Hepatocellular
carcinoma
None
Pathogen
IARC
Group
Main asociated cancer
1
3
1
Adult T-cell leukemia/lymphoma
Retroviruses
HTLV-I
HTLV-II
HIV-I
Papillomaviruses HPV
a HPV type 16
a HPV types 18, 31, 33, 35,
39, 45, 51, 52, 56, 58, 59
a HPV type 68
1
Cancers at several sites
1
Cervical cancer
5.2%
of all cancers
2A
Cervical cancer
a HPV types 26, 30, 34, 53,
66, 67, 69, 70, 73, 82, 85, 97
100% of cervix cancers
2B
Cervical cancer
b HPV type 5 and 8
2B
Skin cancer
a HPV type 6 and 11
3
None
Other b and g HPV types
3
None
Polyomaviruses
JCV
NA
MCV
NA
SV40
NA
CNS tumors and colorectal
cancer?
Skin cancer (Merkel cell
carcinoma)
Malignant mesothelioma ?
HIV-II
2B
HERV-K
NA
Helicobacter pylori
Schistosomes
S. haematubium
S. japonicum
S. mansoni
None
Kaposi’s sarcoma, non-Hdgkin’s
lymphoma, Hodgkin’s lymphoma,
cervical cancer, anus cancer,
conjunctive cancer
Kaposi’s sarcoma, non-Hodgkin’s
lymphoma
Human breast cancer
5.5%Gastric
of all
cancers
cancer, MALT
63.4% of stomach cancers
1
1
2B
3
Urinary bladder cancer
Colorectal and liver cancers
None
Liver flukes
Opistorchis viverrini
Opistorchis felineus
Chlonorchis sinensis
1
3
1
Cholangiocarcinoma
None
Cholangiocarcinoma
Herpesviruses
EBV or HHV4
1
KSHV or HHV8
1
Burkitt’s lymphoma, sinonasal
angiocentric T-cell lymphoma,
immunosuppressor-related nonHodgkin’s lymphoma, Hodgkin’s
lymphoma, nasopharyngeal
carcinoma
Kaposi’s sarcoma, primary
effusion lymphoma
Infectious agents cause 17% of all cancers
worldwide, 26% in developing world,
8% in developed world
D.M. Parkin, Int.J.Cancer 15, 3030-44, 2005
UV-R-250 -280
-340
Sunlight
Fluorescent
lamp
FONTI DI
ILLUMINAZIONE
ARTIFICIALE
Halogen
lamp
ESPOSIZIONE DI TOPI HAIRLESS ALLE
LAMPADE ALOGENE
CANCEROGENICITA’ CUTANEA DELLE LAMPADE ALOGENE
WITHOUT COVER
WITH COVER
S. De Flora & F. D’Agostini, Nature (London) 356, 569, 1992
Agenti cancerogeni in Lista I del Ministero del Lavoro
(G.U. 19/03/2010, n. 65)
Polmone
Vescica
Asbesto, Berillio, (Bis)Clorometiletere,
Cadmio, Nickel, Cromo(VI), IPA, TCDD,
Radon, Silice, Fumo passivo
Ammine aromatiche, IPA
Pleura
Arsenico, IPA, Radiazioni solari
Cute
Asbesto, Erionite
Sistema emolinfopoietico
Nickel, Cromo(VI)
Benzene, 1,3-Butadiene, Ossido di etilene,
Radiazioni ionizzanti
Nasofaringe
Linfomi
Formaldeide
TCDD, HIV
Fegato
Sarcomi
Arsenico, Cloruro di vinile, HBV, HCV
TCDD, HIV
Cavità nasali e seni paranasali
MONITORAGGIO BIOTOSSICOLOGICO
DELL’ACQUA
Bioindicatori alterati in trote stabulate
nel punto C:
Mutagenicità della bile (1)
Induzione di enzimi microsomiali epatici (2)
MONITORAGGIO BIOTOSSICOLOGICO
DEI SEDIMENTI
A] Iniezione di estratti di sedimenti in
trote adulte
Eliminazione di metaboliti fluirescenti con
la bile (1)
Induzione di enzimi microsomiali epatici (2)
Induzione dell’attivazione metabolica di un
cancerogeno nel fegato(2)
B] Esposizione per contatto di larve di trota
Effetti citogenetici (micronuclei in
Induzione di enzimi microsomiali in estratti
eritrociti(3)
di larva (2)
A
FIUME
LAMBRO
CONTROLLI
Indicatori biotossicologici
IN ACQUARIO
(1) Marcatore di esposizione
B
C
(2) Marcatore di effetto biologico
precoce
(3) Marcatore di danno genetico
FIUME PO
MUTAGENICITY OF SEDIMENTS ALONG THE PO RIVER AND
GENOTOXICITY BIOMARKERS IN FISH
L. Viganò et al., Mutat. Res. 515, 125–134, 2002
ADDOTTI BPA–DNA IN VITRO
SPOTS AUTORADIOGRAFICI
DOSE–DIPENDENZA
Adducts/108 nucleotides
8
7
6
5
4
3
2
1
0
0
50
100
150
200
250
BPA dose (ng/l)
A. Izzotti, S. Kanitz , F. D’Agostini, A. Camoirano & S. De Flora, Mutat. Res. 679, 28-32, 2009
FRAMMENTAZIONE DI SPERMATOZOI DI RATTI INDOTTA DA BPA
A. Izzotti, S. Kanitz , F. D’Agostini, A. Camoirano & S. De Flora, Mutat. Res. 679, 28-32, 2009
Impianto da 60.000 ton/anno BPA
Studi epidemiologici suggeriscono che la qualità e quantità dello
sperma umano sono diminuite durante gli ultimi 6 decenni
FATTORI
PROTETTIVI
MALATTIE
FP 1
M1
FP 2
M2
FP 3
M3
FP 4
M4
DISEASES
DECODING THE BLACK BOX
EARLY
BIOLOGICAL
DAMAGE
EPIDEMIOLOGIA
MOLECOLARE
EXPOSURE
MARKERS
RISK
FACTORS
Analysis of
metabolites
BIOLOGICALLY
EFFECTIVE
DOSE
Metabolic alterations
DNA damage and repair
Protein adducts Cytogenetic effects
Activation of oncogenes
DNA adducts
8-oxo-dG
Deletion/mutation of oncosuppressor genes
Proliferation, differentiation, apoptosis, etc.
Mutagenicity
of escreta
GENOME
C
G
o
S lo
m e
H r
n
A e
m e
M d
u L
b
is
v y
( t
s :
4 :
8
C
4
S
)
,
MIRNOME
TRANSCRIPTOME
D
e
f
a
u
lt
I
n
t
e
r
p
r
e
t
a
t
io
n
PROTEOME
(
s
h
a
m
.
t
x
t
)
PROTECTIVE FACTORS
DISEASES
EARLY
BIOLOGICAL
DAMAGE
EXPOSURE
MARKERS
STOP
RISK
FACTORS
Analysis of
metabolites
BIOLOGICALLY
EFFECTIVE
DOSE
Metabolic alterations
DNA damage and repair
Protein adducts Cytogenetic effects
Activation of oncogenes
DNA adducts
8-oxo-dG
Deletion/mutation of oncosuppressor genes
Proliferation, differentiation, apoptosis, etc.
Mutagenicity
of escreta
GENOME
C
G
o
S lo
m e
H r
n
A e
m e
M d
u L
b
is
v y
( t
s :
4 :
8
C
4
S
)
,
MIRNOME
TRANSCRIPTOME
D
e
f
a
u
lt
I
n
t
e
r
p
r
e
t
a
t
io
n
PROTEOME
(
s
h
a
m
.
t
x
t
)
Cigarettes / day
40
30
r = 0.57
P < 0.05
20
10
0
0
50
100
150
200
BPDE-DNA adducts (FU)
A. Izzotti et al., Carcinogenesis 12, 1281-1285, 1991
THE 'OMICS TECHNOLOGIES
S. De Flora & A. Izzotti, Mutat. Res., 667, 15–26, 2009
DNA
mRNA
microRNA
Proteins
GENOME
Co lo r e d b SHAM
y:
v s CS,
G e n e L is m
t : m u ( 484)
De f a u lt
I n t e r p r e t a t io n (
sham . t xt )
MIRNOME
TRANSCRIPTOME
PROTECTIVE FACTORS
PROTEOME
Chronic
degenerative
diseases and
critical
periods of
life
ENVIRONMENTAL CIGARETTE SMOKE IN RAT LUNG
MicroRNA
CIGARETTE SMOKE
DNA
mRNA
Proteins
10000
100
10
1
1000
0,1
0,01
0,01
0,1
1
10
100
1000
10000
SHAM
SHAM
SHAM
126 / 484 miRNAs
(26.0%)
downregulated by ECS
107 / 4858 genes
(2.9%)
upregulated by ECS
50 / 518 proteins
(9.7%)
upregulated by ECS
A. Izzotti et al., FASEB J. 23, 806–812, 2009
THE ICEBERG OF CHRONIC DEGENERATIVE DISEASES
DIAGNOSIS
CARDIOVASCULAR
DISEASES
THERAPY
COPD
CANCER
EPIDEMIOLOGY
PREVENTION
RISK FACTORS AND PROTECTIVE FACTORS
COMMON PATHOGENETIC MECHANISMS
De Flora & D’Agostini, Nature 1992
Stem cell
susceptibility
Balansky et al, Cancer Res. 1996
Age–related
diseases
Perinatal
vulnerability
Cancer
Atherosclerosis
Degenerative
heart diseases
DNA damage
Epigenetic mechanisms
Oxidative stress
Chronic inflammation
Transplacental
damage
Genetic predisposition
Neurological
disorders
Skin ageing
and alopecia
Metabolic
syndrome
Balansky et al, PNAS 2006
Chronic obstructive
pulmonary diseases
Eye diseases
Diabetes
HUMAN ABDOMINAL AORTA
WITH ATHEROSCLEROTIC
LESIONS
Extraction of DNA from smooth muscle cells
MOLECULAR EPIDEMIOLOGY
OF ATHEROSCLEROSIS
S. De Flora et al., FASEB J. 11: 1021-1031, 1997
The levels of 32P postlabelled DNA adducts in the aorta from
85 atherosclerotic patients were significantly correlated with:
-Age of patients
-Number of cigarettes smoked currently
-High blood pressure
-Blood triglycerides
-Blood cholesterol (total/HDL)
-SFS-positive DNA adducts
-Oxidative DNA damage (8-OH-dG)
8–oxo–dG
DNA ADDUCTS
DANNO OSSIDATIVO AL DNA NEL TRABECOLATO OCULARE
8–oxo–dG/105 nucleotidI
(A. Izzotti et al., Am. J. Med. 114, 638-646, 2003)
25
20
15
10
5
0
GSTM1 - nulli
GSTM1 +
Controlli (n = 47)
GSTM1 - nulli
GSTM1 +
Malati di glaucoma (n = 39)
DNA DAMAGE, DNA REPAIR, AND TAU ALTERATIONS IN MOUSE BRAIN
S. La Maestra et al., Toxicol. Sci., 123, 471-479 2011
DNA DAMAGE, DNA REPAIR, AND TAU ALTERATIONS IN MOUSE BRAIN
S. La Maestra et al., Toxicol. Sci., 123, 471-479 2011
DNA DAMAGE, DNA REPAIR, AND TAU ALTERATIONS IN MOUSE BRAIN
S. La Maestra et al., Toxicol. Sci., 123, 471-479 2011
PROLIFERATION AND CHRONIC DEGENERATIVE DISEASES
DNA damage and repair
Oxidative stress
Chronic inflammation
Epigenetic mechanisms
Cancer
Atherosclerotic
plaque
Degenerative
diseases of
the myocardium
Neurodegenerative
diseases
1963
1973
2012
I LIVELLI DELLA PREVENZIONE
PREVENZIONE PRIMARIA
Prevenzione di una malattia in individui sani (prevention of
occurrence)
STRATEGIE DI
PREVENZIONE SECONDARIA
PREVENZIONE
Diagnosi precoce,
possibilmente in fase preclinica, seguita
da terapia tempestiva (prevention of progression)
PREVENZIONE TERZIARIA
Prevenzione delle complicazioni e delle ricadute di una
malattia, dopo terapia
CRESCITA DELLA
MASSA NEOPLASTICA
Divisioni
cellulari
No. Di
cellule
0
10 0
10-9
10 1
10-8
2
-7
5
10
10
20
25
30
10-6
4
-5
10
10 5
10-4
10 6
10-3
10 7
10-2
10
8
-1
10
9
10
10
0
10
1
11
10
2
10 12
10
3
1010
35
10
40
10
10 3
10
15
Peso
(g)
PROCESSO DI
CANCEROGENESI
Dose espositiva
TOSSICOCINETICA
E METABOLISMO
Dose cellulare
DANNO E RIPARO
DEL DNA
Dose farmacologica
Dose bersaglio
STRATEGIE DI
INTERVENTO
Ambiente e
stile di vita
Dose molecolare
INIZIAZIONE
(giorni - settimane)
PREVENZIONE
PRIMARIA
PROMOZIONE
(anni - decenni)
Organismo
ospite (chemio prevenzione)
TUMORE BENIGNO
PROGRESSIONE
(~ 1 anno)
PREVENZIONE
SECONDARIA
CANCRO
INVASIONE
MASSA NEOPLASTICA
METASTASI
TERAPIA e
PREVENZIONE
TERZIARIA
PREVENZIONE SECONDARIA / SCREENING ONCOLOGICI
Razionale e criteri
La malattia deve essere un problema di sanità pubblica e
coinvolgere un gran numero di persone
Esistono lesioni precancerose o stadi precoci della
malattia che è possibile diagnosticare
Esiste un metodo diagnostico sicuro e di facile
esecuzione, non eccessivamente costoso, non invasivo,
non dannoso e dotato di elevata performance
(sensibilità e specificità)
Il trattamento precoce è vantaggioso in termini di
riduzione dell’incidenza e/o della mortalità
Esistono strutture qualificate in grado di effettuare
diagnosi e terapie adeguate
Osservatorio Nazionale Screening (ONS)
Gruppo Italiano per lo Screening Mammografico (GISMa)
Gruppo Italiano per lo Screening Cervicale (GISCi)
Gruppo Italiano per lo Screening Colorettale (GISCoR)
Questi programmi di screening sono stati individuati come LEA
Obiettivi del Ministero della Salute (fine 2007):
Copertura di tutto il territorio nazionale per gli screening mammografici
(donne di 50–69 anni) e cervicali (donne di 25–64 anni)
Invito almeno al 50% della popolazione di 50–69 anni per lo screening
colorettale
CRESCITA DELLA
MASSA NEOPLASTICA
Divisioni
cellulari
0
5
10
15
20
25
30
No. Di
cellule
10
0
40
STOP Dose espositiva
Dose farmacologica
TOSSICOCINETICA
E METABOLISMO
Dose cellulare
-9
10
10 1
10-8
10 2
10-7
10 3
10-6
10
4
-5
10
5
10
Dose bersaglio
DANNO E RIPARO
DEL DNA
10 7
10-2
10
8
-1
10
9
10
10
0
10
1
PROMOZIONE
(anni - decenni)
STOP
Organismo
ospite (chemio prevenzione)
TUMORE BENIGNO
PROGRESSIONE
(~ 1 anno)
10
2
10 12
10
3
PREVENZIONE
SECONDARIA
CANCRO
INVASIONE
1011
Ambiente e
stile di vita
PREVENZIONE
PRIMARIA
10
10-3
STRATEGIE DI
INTERVENTO
Dose molecolare
INIZIAZIONE
(giorni - settimane)
-4
10 6
1010
35
Peso
(g)
PROCESSO DI
CANCEROGENESI
MASSA NEOPLASTICA
METASTASI
TERAPIA
RIABILITAZIONE
PREVENZIONE
TERZIARIA
A
VITAMIN A SOURCE
C
VITAMIN C SOURCE
F
FIBER SOURCE
*
CRUCIFEROUS VEGETABLE
NCI/NIH
PIANO DI SVILUPPO PER GLI AGENTI
CHEMIOPREVENTIVI DEL CANCRO
N-Acetil-L-cisteina (NAC)
18b- Acido glicirretinico
Aspirina
Calcio
b-Carotene e altri carotenoidi
DHEA Analogo 8354
2-Difluorometilornitina (DFMO)
N-(4-Idrossifenil)retinamide (4-HPR)
Ibuprofene
Oltipraz
Piroxicam
Proscar
Sulindac
Tamoxifene
Vitamina D3 e analoghi
Vitamina E
G J. Kelloff and C.W. Boone (Eds.), J. Cell. Biochem. Suppl. 20, 1-303, 1994
MECHANISMS OF CANCER CHEMOPREVENTIVE AGENTS
S. De Flora and C. Ramel, Mutat. Res., 202, 285–306, 1988
3. Inhibition of tumor promotion
PRIMARY PREVENTION
1. Inhibition of mutation and cancer initiation in the extracellular environment or in nontarget cells
1.1. Inhibition of uptake of mutagens/carcinogens
1.1.1. Inhibition of penetration
1.1.2. Removal from the organism
1.2. Inhibition of the endogenous formation of mutagens
and carcinogens
1.2.1. Inhibition of the nitrosation reaction
1.2.2. Modification of the intestinal microbial flora
1.3. Complexation, dilution and/or deactivation of
mutagens/carcinogens outside cells
1.3.1. By physical or mechanical means
1.3.2. By chemical reaction
1.3.3. By enzyme–catalyzed reaction
1.4. Favoring absorption of protective agents
1.5. Stimulation of trapping and detoxification in nontarget cells
3.1. Inhibition of genotoxic effects (see 1 and 2)
3.2. Antioxidant activity and scavenging of free radicals
3.3. Antiinflammatory activity
3.3.1. Cyclooxygenase inhibition
3.3.2. Lipooxygenase inhibition
3.3.3. Inhibition of inducible nitric oxide synthase
3.3.4. Leukotriene receptor antagonism
3.4. Inhibition of proteases
3.5. Inhibition of cell proliferation
3.5.1. Inhibition of ornithine decarboxylase
3.5.2. Promoting proteasomal degradation of cyclins
3.5.3. Interference with multiple signaling pathways
3.6. Induction of cell differentiation
3.7. Modulation of cell apoptosis
3.8. Signal transduction modulation
3.9. Protection of intercellular communications
SECONDARY PREVENTION
2. Inhibition of mutation and cancer initiation in target cells
2.1. Modification of transmembrane transport
2.1.1. Inhibition of cellular uptake
2.1.2. Stimulation of extrusion outside cells
2.2. Modulation of metabolism
2.2.1. Inhibition of activation of promutagens/ procarcinogens by
Phase I enzymes
2.2.2. Induction of Phase I detoxification and Phase II
conjugation pathways, or acceleration of decomposition
of reactive metabolites
2.2.3. Stimulation of activation, coordinated with
detoxification and blocking of reactive metabolites
2.3. Blocking or competition
2.3.1. Trapping of electrophiles by either chemical reaction or
enzyme–catalyzed conjugation
2.3.2. Antioxidant activity and scavenging of reactive species
2.3.3. Protection of DNA nucleophilic sites
2.4. Inhibition of cell replication
2.5. Maintenance of DNA structure and modulation of DNA metabolism and repair
2.5.1. Increase of fidelity of DNA replication and repair
of repair and/or reversion of DNA damage
2.5.3. Inhibition of error-prone repair pathways
2.5.4. Correction of hypomethylation
2.5.5. Inhibition of histone deacetylation
2.5.6. Blocking of telomerases or inhibition of their activity
2.6. Control of gene expression
2.6.1. Targeted inactivation of oncogenes
2.6.2. Inhibitionofoncogene expression
2.6.3. Inhibition of oncogene sequences or activity
2.6.3.1. Inhibition of translation targeted to oncogene mRNA
2.6.3.2. Inhibition of transcription of specific DNA sequences
2.6.3.3. Blocking of target genes
2.6.2.4. Farnesyltransferase inhibition
2.6.4. Neutralization or post–translational modification of oncogene products
2.6.5. Replacement of deleted tumor suppressor genes
2.6.6. Mimicking the DNA binding of tumor suppressor genes by antiidiotypic antibodies
2.6.7. Killing of cells lacking tumor suppressor genes
S. De Flora and L.R. Ferguson, Mutat. Res., 591, 8–15, 2005
4. Inhibition of tumor progression
2.5.2. Stimulation
4.1. Inhibition of genotoxic effects (see 1 and 2)
4.2. Antioxidant activity and scavenging of free radicals
4.3. Inhibition of proteases
4.4. Signal transduction modulation
4.5. Effects on the hormonal status
4.5.1. Selective estrogen receptor modulation
4.5.2. Aromatase inhibition
4.5.3. Selective blocking of prostaglandin E2 receptors
4.5.4. Decrease in ovarian hormones by dietary isoflavones
4.5.5. Inhibiting the pituitary secretion of luteinizing hormone
4.5.6. Preventing conversion of testosterone into
dehydrotestosterone by 5a–reductase
4.5.7. Selective androgen receptor antagonism
4.6. Effects on the immune system
4.7. Inhibition of angiogenesis
4.8. Antineoplastic activity by either mechanical, physical, chemical, or biological means
TERTIARY PREVENTION
5. Inhibition of invasion and metastasis
5.1. Antioxidant activity and scavenging of free radicals
5.2. Signal transduction modulation
5.3. Inhibition of cell proliferation (see 3.4)
5.4. Modulation of cell apoptosis
5.5. Induction of cell differentiation
5.6. Inhibition of angiogenesis
5.7. Effect on cell-adhesion molecules
5.8. Inhibition of proteases involved in basement membrane degradation and
modulation of the interaction with the extracellular matrix
5.9. Activation of antimetastasis genes
PREVENTION OF LUNG TUMORS
IN MICE
NUMBER OF TUMORS/MOUSE
0.35
11.06
1.95
CONTROLS
(STANDARD DIET)
URETHANE
(STANDARD DIET)
URETHANE
(DIET WITH NAC 0.2%)
S. De Flora et al., Cancer Lett. 32, 235-241,1986
EXPRESSION OF 4858 GENES IN RAT LUNG
A. Izzotti et al., Mutat. Res. 591, 212–223, 2005
SMOKE-FREE RATS
SMOKE-EXPOSED RATS
SAFETY
SHAM
NAC
OPZ
OPZ 5,6-BF
+ NAC
PEITC
I3C
EFFICACY
PEITC
+ I3C
ECS
OPZ
NAC
5,6-BF
OPZ
+ NAC
I3C
PEITC
+ I3C
PEITC
EFFECT OF ENVIRONMENTAL CIGARETTE SMOKE AND
CHEMOPREVENTIVES ON miRNA EXPRESSION IN RAT LUNG
0 .6
PCA component 2
0 .5
ECS + PEITC + I3C
0 .4
ECS + OPZ + NAC
0 .3
ECS + PEITC
0 .2
ECS + NAC
ECS + I3C
ECS + OPZ
0 .1
ECS
ECS + BF
0
NAC
-0 .1
BF
SHAM
NAC + OPZ
PEITC
-0 .2
OPZ
-0 .4
-0 .3
PEITC + I3C
- 0 .2
- 0 .1
0
0 .1
0.2
0 .3
0 .4
0 .5
0.6
0 .7
0 .8
PCA component 1
A. Izzotti et al, Cancer Prev. Res. 3, 62–72, 2010
ANGIOGENESI E
ANTIANGIOGENESI
VASCOLARIZZAZIONE DI SPUGNE DI MATRIGEL
NAC –
NAC +
T. Cai et al., Lab. Invest. 79, 1151-1159, 1999
CRESCITA DI SARCOMA DI KAPOSI UMANO IN TOPI NUDI
CONTROLLI
NAC
1.5
0.5
0
4.0
3.5
F
E
M
M
I
N
E
M
A
S
C
H
I
M
A
S
C
H
I
3.0
2.5
2.0
1.5
)3
Volume del tumore (cm 3 )
1.0
F
E
M
M
I
N
E
+
+
1.0
0.5
0
5 10 15 20 25 30 5 10 15 20 25 30
Tempo (giorni)
A. Albini et al., Cancer Res. 61, 8171-8178, 2001
THRESHOLDS IN CARCINOGENESIS?
CARCINOGENESIS
PROCESS
TOXICOKINETIKS
AND METABOLISM
DNA DAMAGE
AND REPAIR
Exposure dose
Pharmacologic dose
Cellular dose
Target dose
Molecular dose
INITIATION
(days - weeks)
MECCANISMI SOGLIE ?
Apoptosis
DNA repair
PROMOTION
(years - decades)
BENIGN TUMOR
PROGRESSION
(~ 1 year)
CANCER
INVASION
NEOPLASTIC MASS
METASTASIS
CARCINOGENICITY OF CHROMIUM IN HUMANS
(IARC, Vol. 49, 1990)
There is inadequate evidence for the carcinogenicity
of metallic chromium and of Cr(III) compounds
(Group 3)
There is sufficient evidence for the
carcinogenicity of Cr(VI) compounds (Group 1)
as encountered in the chromate production,
chromate pigment production and
chromium plating industries
o/e deaths ± 95% C.I.
LUNG CANCER DEATHS IN CHROMATE
PRODUCTION WORKERS
3.0
H.J. Gibb et al.
Am. J. Ind. Med. 38: 115–126 (2000)
2.5
2.0
1.5
1.0
0.5
234
2,184
15,600
233,480
Exposure quartiles [ng Cr(VI)/m3–years]
“For cancers other than those of
the lungs and sinonasal cavity,
no consistent pattern of cancer
risk has been demonstrated in
those workers exposed to
chromium”
International Agency for Research on Cancer (1990) Vol. 49
M.D. Cohen et al. (1993) Crit. Rev. Toxicol. 23: 255–281
R.B. Hayes (1997) Cancer Causes Control 8: 371–385
ATSDR, U.S. Dept. of Health and Human Services (2000)
S. De Flora (2000) Carcinogenesis 21: 533-541
CARCINOGENICITY ASSAYS OF CHROMIUM
COMPOUNDS IN RODENTS (IARC, 1990)
Cr(VI)
Cr(III)
Other Cr
compounds
or mixtures
Metallic Cr
3.6%
41.5%
58.5%
65 studies
Positive
Negative
Uncertain
9.5%
90.5%
21 studies
100%
6 studies
10.7%
85.7%
28 studies
CARCINOGENICITY OF Cr(VI) COMPOUNDS IN RODENTS
Sodium chromate
Chromic acid
–+
Calcium chromate
–
+––
Zinc yellow
Zinc chromates
Barium chromate
Lead chromates
–––
–
++
––
–
–––
–––
–
intramuscolar
intrafemural
––
+
++–
++
Strontium chromate
subcutaneous
–––
–
–––
intravenous
+
intraperitoneal
intrabronchial
+
intrapleural
intratracheal
Sodium dichromate
inhalation
Compound
oral
Administration route
+++
+
+
–
–
––
+
+++
+++
+––
+
+
+++
––
+––
The results are those reviewed in Table 22 of IARC (1990), plus Snyder et al. (1997).
+, significant increase of tumors in treated animals; –, no significant increase.
Cr(VI) CARCINOGENICITY IN ANIMAL MODELS
IS GOVERNED BY THRESHOLDS MECHANISMS
Most results were negative (58.5%), due to complete
Cr(VI) detoxification
–
Positive results (41.5%) were generated at one dose
only, without any dose–response curve
Cr(VI) induced tumors exclusively at implant sites,
through administration routes that do not reproduce
any human exposure and by–pass detoxification
mechanisms
MTD
DOSE
– +
Cr(VI) mostly induced tumors in tissues having poor
detoxification capacities
The same Cr(VI) dose that was weakly carcinogenic,
when massively given once per week, failed to
induce tumors when subdivided into 5 weekly doses
+
–
RESULTS OBTAINED WITH CHROMIUM COMPOUNDS
IN CELLULAR SYSTEMS
S. De Flora et al., Mutat. Res. 238, 99–172, 1990
700 data relative to 32 chromium compounds
tested in 130 experimental test systems
RESULTS OBTAINED WITH CHROMIUM COMPOUNDS IN
CELLULAR SYSTEMS (S. De Flora et al., 1990)
High solubility
Medium solubility
Low solubility
12.3%
Cr(VI)
94.0%
6.0%
86.7%
13.3%
56.1%
31.6%
319 results
60 results
57 results
4.7%
11.8%
Cr(III)
24.3%
71.0%
23.5%
64.7%
29.4%
52.9%
17.7%
169 results
17 results
Positive
Positive only following artificial solubilization
Positive but contaminated with Cr(VI)
Negative
17 results
NUCLEUS
CYTOPLASM
(TARGET DOSE)
EXTRACELLULAR
(CELLULAR DOSE)
mito
c hon drio n
Cr(V)
ic
as m
l
p
o
end
m
culu
i
t
e
r
DNA
(PHARMACOKINETIC DOSE)
Cr(III)
cytosol
Cr
2–
METABOLIC REDUCTION
glutathione, cysteine, H 2O 2,
ascorbate, riboflavin,
cytochrome P-450,
DT diaphorase, aldehyde oxidase
L-Cr(III)
anion
channel
protein
CrO 4
REDUCTION IN
BODY FLUIDS OR
NONTARGET CELLS
blood, digestive tract,
lumen of terminal airw ays
REACTIVE PRODUCTS
ACTIVATION
TRA
NSC
R
Cr(VI) esters, Cr(V),
Cr(IV), Cr(III), HO , RS , R
DETOXIFICATION
L
3+
Cr
L
IPT
IO N
mRNA
TRA
N
SL AT
ION
enzyme
substrate
L
L
L
product
S. De Flora and K.E. Wetterhahn, Life Chem. Rep. 7, 169-244, 1989
L
METABOLIC DEACTIVATION OF MUTAGENS
S. De Flora, Nature 271, 455-456, 1978
METABOLIC DEACTIVATION OF MUTAGENS
S. De Flora, Nature 271, 455-456, 1978
REDUCTION OF Cr(VI) BY HUMAN GASTRIC JUICE
(S. De Flora et al., Mutat. Res. 192, 169–174, 1987)
D
I
N
N
E
BR
R
E
LA
U
K
N
F
C
A
pH
im
0
5
0
4
0
3
0
2
0
1
0
0
0
T
6
4
2
H
D
o1 u28
e
a
y
2r0
I
22
24
4
6
8
1
I
10 12
I
14 16
T
8
Cr(VI) reduced (mg/ml/h)
6
H
S
REDUCTION OF Cr(VI) BY HUMAN ERYTHROCYTES
(FL. Petrilli and S. De Flora 54,139–147, 1978)
CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELL
POPULATIONS AND FLUIDS IN THE HUMAN DIGESTIVE SYSTEM
SALIVA [0.7 – 2.1 mg Cr(VI)/day]
LIVER CELLS
[3,300 mg Cr(VI)]
PORTAL SYSTEM BLOOD
[187 - 234 mg Cr(VI)]
GASTRIC JUICE
[> 84 – 88 mg Cr(VI)/day]
INTESTINAL BACTERIA
[11 – 24 mg Cr(VI) eliminated
daily with bacteria in feces]
De Flora et al., Carcinogenesis 18, 531–537, 1997
LETHAL DOSE OF ORAL Cr(VI) IN HUMANS
Amount of ingested compound (g)
100
10
1
0.1
K2Cr2O7
Na2Cr2O7
CrO3
0.01
Survived
Died
S. De Flora et al., Marcel Dekker, New York, 1995, pp. 716–725
ORAL CHROMIUM(VI) DOES NOT AFFECT THE FREQUENCY OF MICRONUCLEI
S. De Flora, M. Iltcheva & R.M. Balansky, Mutat. Res. 610, 38–47, 2006
Adult BDF1 mice
A single intraperitoneal injection of Cr(VI) (50 mg/kg b.w. = 1.2 g in a 70 kg man)
increased the frequency of micronucleated PCE in bone marrow
A single intragastric injection of Cr(VI) (50 mg/kg b.w. = 1.2 g in a 70 kg man) did
not affect the frequency of micronucleated PCE in bone marrow
Cr(VI), given daily with the drinking water for 210 consecutive days, up to 500 mg/l
(10000 times the drinking water standard), did not affect the frequency of micronuclei
either in bone marrow PCE or in peripheral blood NCE
Pregnant Swiss albino mice and their fetuses
Cr(VI), given daily with the drinking water during pregnancy, up to 10 mg/l (200
times the drinking water standard), did not affect the frequency of micronuclei in
hematopoietic cells either of dams (bone marrow PCE) or of transplacentally
exposed fetuses (liver and peripheral blood PCE)
OCCUPATIONAL EXPOSURE TO Cr(VI) AND GASTROINTESTINAL CANCERS: A META-ANALYSIS
N.M. Gatto et al., Cancer Epidemiol. 34, 388–399, 2010
ORAL
ESOPHAGEAL
STOMACH
COLON
RECTAL
17 studies
Meta-SMR = 1.02
15 studies
Meta-SMR = 1.17
29 studies
Meta-SMR = 1.09
13 studies
Meta-SMR = 0.89
20 studies
Meta-SMR = 1.17
Cr(VI) REDUCTION BY HUMAN ALVEOLAR MACROPHAGES (PAM)
(F.L. Petrilli et al., J. Clin. Invest. 77, 1917–24, 1986)
Nonsmokers
Exsmokers
*
Smokers
*
Recent smokers
0
1
2
3
4
5
6
Amount of Cr(VI) reduced
(mg/106 PAM)
*
P < 0.01, as compared to nonsmok ers and exsmok ers
7
8
Cr(VI) REDUCTION BY HUMAN LUNG PARENCHYMA PREPARATIONS
(S. De Flora et al., Cancer Res. 47, 4740–45, 1987)
CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELL
POPULATIONS AND FLUIDS IN THE HUMAN DIGESTIVE SYSTEM
BRONCHIAL
TREE CELLS
PERIPHERAL
LUNG PARENCHYMA
CELLS [260 mg Cr(VI)]
ELF [0.9 – 1.8 mg Cr(VI)]
PAM [136 mg Cr(VI)]
BLOOD
[187 – 234 mg Cr(VI)]
De Flora et al., Carcinogenesis 18, 531–537, 1997
NUCLEUS
CYTOPLASM
(TARGET DOSE)
EXTRACELLULAR
(CELLULAR DOSE)
mito
c hon drio n
Cr(V)
ic
as m
l
p
o
end
m
culu
i
t
e
r
DNA
(PHARMACOKINETIC DOSE)
Cr(III)
cytosol
Cr
2–
METABOLIC REDUCTION
glutathione, cysteine, H 2O 2,
ascorbate, riboflavin,
cytochrome P-450,
DT diaphorase, aldehyde oxidase
L-Cr(III)
anion
channel
protein
CrO 4
REDUCTION IN
BODY FLUIDS OR
NONTARGET CELLS
blood, digestive tract,
lumen of terminal airw ays
REACTIVE PRODUCTS
ACTIVATION
TRA
NSC
R
Cr(VI) esters, Cr(V),
Cr(IV), Cr(III), HO , RS , R
DETOXIFICATION
L
3+
Cr
L
IPT
IO N
mRNA
TRA
N
SL AT
ION
enzyme
substrate
L
L
L
product
S. De Flora and K.E. Wetterhahn, Life Chem. Rep. 7, 169-244, 1989
L
MAIN POSTGENOMIC ALTERATIONS INDUCED
BY INTRATRACHEAL Cr(VI) IN RAT LUNG
EXTRACELLULAR
TRANSPORT
MDR
Cr(VI)
REDUCTION
DT diaphorase
P450 reductases
GSH peroxidase
GSH S-transferase
Aldehyde dehydrogenase
EXTRACELLULAR
TRANSPORT
MDR
Cr(VI)
REDUCTION
Percent Cr(VI) recovery
100
80
60
Cr(VI) + Microsomes
Cr(VI) + NADPH
40
Cr(VI) + Microsomes +
NADPH
20
0
DT diaphorase
P450 reductases
GSH peroxidase
GSH S-transferase
Aldehyde dehydrogenase
0
1
2
3
4
5
6
24
Incubation period (hours)
From J.E. Gruber and K.W. Jennette, B.B.R.C. 82, 700, 1978
EXTRACELLULAR
TRANSPORT
MDR
DECREASE OF Cr6+ MUTAGENICITY BY LUNG S12 FRACTIONS
FROM RATS RECEIVING Cr6+ i.t.a
1200
without
Cr(VI)
REDUCTION
DT diaphorase
P450 reductases
GSH peroxidase
GSH S-transferase
Aldehyde dehydrogenase
Revertants per plate
1000
S12
1x1.25 mg/Kg/week
( weakly carcinogenic
800
b)
5x0.25 mg/Kg/week
( not carcinogenic b )
600
400
200
TOXIC
0
0
10
20
30
40
50
Sodium dichromate (mg/plate)
a
Petrilli et al., Cancer Res. (1985) b Steinhoff et al., Exp. Pathol. (1986)
MITOCHONDRIAL
DAMAGE
INDUCTION OF APOPTOSIS BY I.T. Cr(VI)
EXTRACELLULAR
TRANSPORT
(F. D’Agostini et al., Carcinogenesis 23, 587–593, 2002)
Ca++
5 – fold
increase
MDR
APOPTOSIS
Bcl2DP
Bcl2x short
BclKP
OXIDATIVE
DAMAGE
22 – fold
increase
Superoxide dismutase
Cr(VI)
REDUCTION
DT diaphorase
P450 reductases
GSH peroxidase
GSH S-transferase
Aldehyde dehydrogenase
1.2 – fold
variation
DNA DAMAGE
DNaseI
MITOCHONDRIAL
DAMAGE
DNA REPAIR
Topoisomerase
DNA polymerases
AP endonuclease
EXTRACELLULAR
TRANSPORT
CELL CYCLE
Ca++
MAPKs
JNKs
CDKs
Cyclins
MDR
APOPTOSIS
Bcl2DP
Bcl2x short
BclKP
PROTEIN
DAMAGE
OXIDATIVE
DAMAGE
Superoxide dismutase
Cr(VI)
REDUCTION
DT diaphorase
P450 reductases
GSH peroxidase
GSH S-transferase
Aldehyde dehydrogenase
Crystallins
T complexes
Heat shock p.
Calnexin
PROTEIN
REPAIR/REMOVAL
METABOLIC MECHANISMS AND Cr(VI) DETOXIFICATION
The IARC Working Group (1990) “interpreted
these findings as indicating mechanisms that
limit the activity of Cr(VI) compounds in vivo ”
The U.S. Environmental Protection Agency
(1991) concluded that “the body’s normal
physiology provides detoxification for Cr(VI)”
The U.S. Department of Health and Human
Services (2000) indicated that these
“mechanisms limit the bioavailability and
attenuate the potential effects of Cr(VI)
compounds in vivo ”
LE TECNOLOGIE 'OMICS
S. De Flora & A. Izzotti, Mutat. Res., 667, 15–26, 2009
DNA
RNA
MicroRNA
Proteine
CONCLUSIONI
GENOME
Co lo r e d b SHAM
y:
v s CS,
G e n e L is m
t : m u ( 484)
De f a u lt
I n t e r p r e t a t io n (
sham . t xt )
MIRNOME
TRANSCRIPTOME
FATTORI PROTETTIVI
PROTEOME
Malattie
cronicodegenerative
e periodi
critici della
vita
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
ITALY, GENERAL MORTALITY DATA, 1901–2000
35
ITALY, 2000
Population: 58 million
Deaths: 1,276,000
Mortality rate: 22‰
Rates per 100.000
30
25
ITALY, 2000
Population: 58 million
Deaths: 560,000
Mortality rate: 9.7‰
20
15
10
5
ITALY, 1901
Population: 33 million
Deaths: 726,000
Mortality rate: 22‰
0
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
2000
UNIVERSITA’ DI GENOVA
DIPARTIMENTO DI SCIENZE DELLA SALUTE
Laboratorio di Mutagenesi Ambientale e Prevenzione del Cancro
Sebastiano
La Maestra
Giorgia
Travaini
Rosanna
Micale
Mariagrazia
Longobardi
Silvio
De Flora
Roumen
Balansky
Alberto
Izzotti
Tanya M.
Pennisi
Cristina
Cartiglia
Vinesh Kumar
Thidil
Pulyappadamba
Carlo
Bennicelli
Ilaria
Righi
Maria
Bagnasco
Alessandra
Pulliero
Anna
Camoirano
Patrizia
Larghero
Francesco
D’Agostini
Alessandra
Battistella

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