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CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 1
Brad Stockert, PT, PhD
Professor of Physical Therapy
California State University, Sacramento
Inflammation, Atherosclerosis,
Neurodegeneration and Cancer� OBJECTIVES
Upon completion of this course, you will be able to:
1. provide a current definition of chronic inflammation.
2. describe the evidence that chronic inflammation plays a role in the development & propagation of atherosclerosis, some neurodegenerative disorders and some forms of cancer.
3. explain the impact of anti-inflammatory medications on chronic inflammation.
4. discuss the impact of obesity and physical activity on chronic inflammation.
Inflammation, Atherosclerosis,
Neurodegeneration and Cancer� Acute and chronic inflammation
� overview of inflammatory markers
� Chronic inflammation and atherosclerosis
� C-reactive protein and atherosclerosis
� Chronic inflammation and neurodegenerative disorders
� Multiple sclerosis
� Parkinson disease
� Alzheimer disease
� Chronic inflammation and cancer risk
� overall, breast and colorectal cancer risk
The problem
� Chronic Noncommunicable Diseases (CNDs)
� 60% of deaths world-wide
� cardiovascular disease
� breast & colorectal cancer
� chronic lung diseases
� neurodegenerative disorders
� insulin disorders
The problem
� Chronic Noncommunicable Diseases (CNDs)
� chronic low-grade inflammation
� significant role in pathological processes
� obesity
� physical inactivity
� behavioral/lifestyle disorders
Acute Inflammation
� characteristic response
� multiple chemical mediators released
� “cytokines”
� low molecular weight glycoproteins
� interferons
� used to fight viral infections
� interleukins
� modulate inflammatory processes
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 2
Acute Inflammation
� characteristic response
� multiple chemical mediators released
� sources of interleukins (ILs) during acute inflammation
� mast cells
� macrophages
� lymphocytes
Acute Inflammation
� characteristic response
� sequential appearance of interleukins
� tumor necrosis factor-alpha
� interleukin-1 beta
� interleukin-6
� interleukin-1 receptor antagonist
� soluble tumor necrosis factor-alpha receptor
Acute Inflammation
� characteristic response
� sequential appearance of interleukins
� tumor necrosis factor-alpha (TNF-α)
� interleukin-1 beta (IL-1β)
� secreted early in inflammatory process
� pro-inflammatory cytokines
Acute Inflammation
� characteristic response
� sequential appearance of cytokines
� interleukin-1 receptor antagonist (IL-1ra)
� soluble tumor necrosis factor-alpha receptor (sTNF-R)
� secreted later in inflammatory process
� anti-inflammatory cytokines
� resolution/repair
Acute Inflammation
� characteristic response
� sequential appearance of cytokines
� interleukin-6 (IL-6)
� secreted after TNF-α & IL-1β
� secreted before IL-1ra & sTNF-R
Changes in Interleukins with Sepsis
TNF-α
IL-1
IL-6
sTNF-R
IL-1ra
pro-inflammatory anti-inflammatory
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 3
Acute Inflammation
� characteristic response
� sequential appearance of cytokines
� interleukin-6 (IL-6)
� stimulates liver production & secretion
� “acute-phase response” proteins in blood
Acute Inflammation
� characteristic response
� sequential appearance of cytokines
� “acute-phase response” proteins in blood
� sensitive markers of inflammation
� erythrocyte sedimentation rate (ESR)
� C-reactive protein (CRP)
� CRP strongly associated with CNDs
Chronic Inflammation
� characterization in absence of acute inflammation
� persistent 2-3 fold increase in pro-inflammatory cytokines
� TNF-α
� IL-6
� persistent 2-3 fold increase in inflammatory markers
� CRP
� ESR
Chronic Inflammation
� characterization in absence of acute inflammation
� 2-3 fold increase in pro-inflammatory cytokines & markers
� advanced age (>50 y.o.)
� obesity
� smoking
� atherosclerosis
� insulin-related disorders
Endocrinology of Adipose Tissue
� Adipose tissue secretes
� hormones
� leptin & adiponectin
� regulation of body weight, insulin sensitivity and
fuel oxidation
Endocrinology of Adipose Tissue
� Adipose tissue secretes
� hormones
� leptin & adiponectin
� “adipokines”
� cytokines (interleukins) from adipose tissue
� TNF-α
� IL-6
� CRP
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Brad Stockert, PT, PhD 4
Endocrinology of Adipose Tissue
� Adipose tissue secretes: TNF-α
� adipose tissue is main source without acute inflammation
� level proportional to obesity
� level decreases with weight loss
� level proportional to insulin resistance
� TNF-α impairs insulin receptors
Endocrinology of Adipose Tissue
� Adipose tissue secretes: IL-6
� 30% of IL-6 in nonobese individuals at rest
� level of IL-6 elevated with obesity
� adipose tissue is main source of IL-6 with obesity
� proportional to degree of obesity
� visceral fat > subcutaneous fat
Endocrinology of Adipose Tissue
� Adipose tissue secretes: IL-6
� 30% of IL-6 in nonobese individuals at rest
� level of IL-6 elevated with obesity
� main source of IL-6 with obesity
� visceral fat > subcutaneous fat
� level of IL-6 is proportional to insulin resistance
� impairs insulin receptors
� increases resting level of CRP
Endocrinology of Adipose Tissue� Adipose tissue secretes: CRP
� liver tissue is main source without acute inflammation
� nonobese individuals
� adipose tissue is main source without acute inflammation� obese individuals
� CRP level sensitive to changes in weight & training� CRP decreases with loss of weight
� CRP decreases with chronic training
Endocrinology of Adipose Tissue� Adipose tissue secretes: CRP
� indicator of pro-inflammatory state
� strong predictor of future problems
� insulin-related disorders
� vascular diseases: atherosclerosis & dementia
� amplifies impact of other pro-inflammatory cytokines
� suppresses fibrinolysis
� enhances thrombus formation
Endocrinology of Adipose Tissue
� Obese individuals
� obesity is strongly associated with chronic inflammation
� elevated level of pro-inflammatory mediators & markers
� TNF-α
� IL-6
� CRP
� increased incidence vascular & insulin-related disorders
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Endocrinology of Adipose Tissue
� Obese individuals
� increase risk of developing
� vascular disorders
� atherosclerosis (MI, CVA, some dementias)
� dyslipidemia
� hypertension
� erectile dysfunction
� insulin-related disorders
� insulin resistance
� type II diabetes
Endocrinology of Muscle� Muscle tissue
� largest body tissue in nonobese
� secretes hormones & interleukins when active
� “myokines”
� interleukins from active muscle tissue
� IL-6
� IL-1ra
� sTNF-R
Endocrinology of Muscle
� Acute exercise without injury
� myokines secreted: IL-6
� secreted from Type I & II fibers
� amount secreted proportional to:
� duration & intensity of exercise
� IL-6 may increase 100-fold with intense exercise
Endocrinology of Muscle
� Acute exercise without injury
� myokines secreted: IL-6
� secreted from Type I & II fibers
� amount secreted proportional to:
� duration & intensity of exercise
� suppresses TNF-α production
� stimulates glucose uptake
Endocrinology of Muscle
� Acute exercise without injury
� myokines secreted: IL-1ra and sTNF-R
� inhibit signal transduction
� IL-ra blocks the IL-1 receptor
� sTNF-R competes with TNF-α receptor
� block inflammatory impact of IL-1β & TNF-α
Endocrinology of Muscle
� Acute exercise without injury
� no pro-inflammatory cytokines released
� IL-1 and TNF-α are not secreted
� systemic levels of IL-1 & TNF-α are not changed
� IL-1ra and sTNF-R secreted from active muscle
� inhibit signal transduction
� action of IL-1 and TNF-α is blocked/impaired
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Changes in Interleukins with Sepsis
TNF-α
IL-1
IL-6
sTNF-R
IL-1ra
pro-inflammatory anti-inflammatory
Changes in Interleukins with Exercise
IL-6
sTNF-R
IL-1ra
anti-inflammatory
Endocrinology of Muscle� Acute exercise and endotoxin
� Petersen AMW; J Appl Physiol 2005; 98:1154-1162.
� endotoxin (Escherichia coli)
� physically inactive subjects injected with endotoxin
� 2-3 fold increase in TNF-α after endotoxin
Endocrinology of Muscle� Acute exercise and endotoxin
� endotoxin (Escherichia coli)
� physically inactive subjects injected with endotoxin
� 2-3 fold increase in TNF-α after endotoxin
� physically active subjects injected with endotoxin
� after riding stationary exercycle 2.5 hours
� no increase in TNF-α following endotoxin� exercise suppressed rise in TNF-α
Endocrinology of Muscle
� Acute exercise without injury
� additional myokines secreted:
� Interleukin-8 (IL-8)
� neutrophil chemotaxis during acute inflammation
� stimulates local angiogenesis following exercise
� substantial local increase in concentration of IL-8
� acts in paracrine manner to stimulate local angiogenesis
Endocrinology of Muscle
� Acute exercise without injury
� additional myokines secreted:
� Interleukin-15 (IL-15)
� local concentration increases with strength training
� local anabolic impact on muscle
� increase in synthesis of muscle proteins
� decrease in degradation of muscle proteins
� reduction in adipose tissue mass
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Interleukin - 6
� absence of acute inflammation
� nonobese individuals
� ~30% from adipose tissue
� obese individuals
� majority from adipose tissue
� level proportional to degree of obesity
Interleukin - 6
� absence of acute inflammation
� IL-6 known to cause:
� production of acute phase response proteins (CRP)
� liver
� adipose tissue
� increased level of CRP
� increased risk of behavioral/lifestyle disorders
Interleukin - 6
� absence of acute inflammation
� IL-6 high resting level
� equivalent to traditional risk factors for heart disease
� hypertension
� hypercholesterolemia
� physical inactivity
� smoking
Interleukin - 6
� absence of acute inflammation
� IL-6 high resting level
� equivalent to traditional risk factors for heart disease
� IL-6 is strongly associated with physical inactivity
� IL-6 decreases with chronic training
� IL-6 increases with physical inactivity
Interleukin - 6� Thompson, J Appl Physiol 2010;108:769-779.
� IL-6 measured at baseline & after 12 & 24 weeks of training
� moderate intensity aerobic exercise program
� IL-6 decreased after 12 & 24 weeks of training
� decrease in IL-6 inversely related to starting point
� those with the highest IL-6 at start had largest decrease
� IL-6 returned to baseline after 2 weeks of detraining
Interleukin - 6
� absence of acute inflammation
� IL-6 resting level
� decreases with chronic endurance training
� increase in IL-6 receptor number
� decrease in IL-6 resting level
� increase in IL-6 sensitivity
� decrease in risk of behavioral/lifestyle disorders
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 8
Interleukin - 6
� absence of acute inflammation
� IL-6 resting level
� independent risk factor for future
� cardiovascular disorders
� MI
� CVA
� dementia
� erectile dysfunction
C-Reactive Protein (CRP)
� CRP levels at rest
� inversely related to level of aerobic fitness
� children and adults (obese & nonobese)
� powerful predictor of future cardiovascular disorders
� myocardial infarction
� cerebrovascular accident
� hypertension
� diabetes
C-Reactive Protein (CRP)
� CRP levels at rest
� marginally correlated with LDL cholesterol
� LDL and CRP both highly correlated with future problems
� identify different pathological processes or groups at risk
� ~1/2 of MIs occur in people with normal LDL cholesterol
C-Reactive Protein (CRP)
� CRP levels at rest
� statin therapy
� Lipitor, simvastatin
� lowers LDL cholesterol level
� reduces CRP level
� reduction in chronic inflammation
� reduces risk more than reduction in LDL cholesterol
� reduction in chronic inflammation
C-Reactive Protein (CRP)
� CRP levels at rest
� statin therapy
� aspirin therapy
� given to reduce platelet adhesion
� reduces risk of thromboembolism (MI, CVA)
� reduces CRP level
� reduces chronic inflammation & risk of behavioral/lifestyle disorders
� acts synergistically with statins to reduce level of chronic inflammation
C-Reactive Protein (CRP)� CRP levels at rest
� statin therapy
� aspirin therapy
� physical activity
� reduces CRP level
� independent of weight loss
� independent of statin &/or aspirin therapy
� aerobic and resistive exercises both work
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Chronic Inflammation
� Chronic inflammation is associated with
� physical inactivity
� obesity
� elevation in pro-inflammatory mediators/markers
� TNF-α
� IL-6
� CRP
Chronic Inflammation
� Chronic inflammation is decreased with
� physical activity
� decrease in obesity
� anti-inflammatory medications
� each reduces level of pro-inflammatory mediators
� TNF-α
� IL-6
� CRP
Chronic Inflammation� Chronic inflammation is associated with
� behavioral/lifestyle diseases
� vascular diseases
� atherosclerosis
� MI
� CVA
� dementia
� erectile dysfunction
Chronic Inflammation� Chronic inflammation is associated with
� behavioral/lifestyle diseases
� vascular diseases
� insulin-related disorders
� insulin resistance
� type II DM
� metabolic syndrome
Chronic Inflammation� Chronic inflammation is associated with
� behavioral/lifestyle diseases
� vascular diseases
� insulin-related disorders
� cancers:
� breast
� colorectal
Chronic Inflammation� Chronic inflammation is associated with
� behavioral/lifestyle diseases
� vascular disorders
� insulin-related disorders
� cancers
� neurodegenerative disorders:
� Alzheimer Disease
� Multiple Sclerosis
CPTA Annual Conference 2013 9/20/2013
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Chronic Inflammation
� Reduction in risk of behavioral/lifestyle disorders
� changes in behavior/lifestyle
� use of anti-inflammatory medications
� most anti-inflammatory medications have increased risk of
� GI distress
� ulcers
� adverse drug reaction
� interaction with other medications
Brad Stockert, PT, PhD
Professor of Physical Therapy
California State University, Sacramento
Inflammation & Atherosclerosis
� Previously held view of atherosclerosis
� cholesterol storage disease
� passive deposition of lipids into arterial walls
� continuing deposition of lipids encrusts arterial walls
� progressing stenosis provokes occlusive thrombic event
Inflammation & Atherosclerosis
� Current view of atherosclerosis
� active process
� arterial walls are dynamic structures
� altered cellular behavior
� changes mediated by molecular signals
� cytokines
Inflammation & Atherosclerosis
� Current view of atherosclerosis
� Why doesn’t it get better over time instead of worse???
� primordial role for inflammation
� inflammation links risk factors with lesion formation
� inflammation transduces risk factors to changes in
biology and cell function
Inflammation & Atherosclerosis
� Current view of atherosclerosis
� ~50% of CV deaths occur in people without hyperlipidemia
� plaque rupture is poorly correlated with degree of stenosis
� ~50% of infarctions occur in arteries with <50% occlusion
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Brad Stockert, PT, PhD 11
Inflammation & Atherosclerosis
� Current view of atherosclerosis
� C-Reactive Protein (CRP)
� produced during acute inflammation
� level increases 1000-fold with acute infection
� level remarkably stable over time without infection
� measure of systemic inflammation
� strong predictor of future MI & CVA
Inflammation & Atherosclerosis� CRP predicts risk beyond traditional risk factors
� CRP <1 mg/l = low risk
� CRP 1-3 mg/l = moderate risk
� CRP >3 mg/l = high risk
� highest vs. lowest tertile of CRP
� 2-fold increased risk CV event with elevated CRP
� risk elevated regardless of cholesterol level
� TC, LDL-C & HDL-C
Inflammation & Atherosclerosis� Physician Health Study (1997)
� Ridker PM, N Eng J Med 1997;336:973-979.
� apparently health males followed for 8 years
� CRP higher among those that suffered MI or CVA
� CRP highest quartile vs. lowest quartile
� 3-fold increased risk of MI
� 2-fold increased risk of CVA
� independent of lipid & nonlipid risk factors
Inflammation & Atherosclerosis� Women’s Health Initiative
� Pradhan AD; JAMA 2002;288:980-987.
� prospective, case controlled study
� 75,000 females in US initially enrolled
� 304 developed heart disease
� 304 case-matched controls (age, smoking, ethnicity)
� CRP significantly elevated in those with heart disease
� 2-fold increased risk of heart disease
Inflammation & Atherosclerosis� Women’s Health Study
� Ridker PM; Lancet 2001; 358:946-947.
� 28,263 postmenopausal women
� monitored prospectively
� CRP & LDL-C significant predictors of CV risk
� CRP higher prognostic value
� high CRP & high LDL-C 8-fold increase risk
� CRP & LDL-C minimally correlated
� appear to identify separate pathological groups at risk
Inflammation & Atherosclerosis� Coronary angioplasty outcomes
� Buffon A; J Am Coll Cardiology 1999; 34:1512-1521.
� CRP measured before PTCA procedure
� assessed early & late outcomes
� restenosis
� complications
CPTA Annual Conference 2013 9/20/2013
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Inflammation & Atherosclerosis� Coronary Angioplasty outcomes
� Buffon A; J Am Coll Cardiol 1999; 34:1512-1521.
� CRP measured before PTCA procedure
� acute problems occurred
� 22% of patients with high CRP
� none in patients with normal CRP
� one year follow-up
� 63% with high CRP had restenosis
� 27% with normal CRP had restenosis
Inflammation & Atherosclerosis� Statin therapy
� lowers LDL-C
� inhibits cholesterol synthesis in liver
� powerful vascular anti-inflammatory agent
� lowers CRP
� impact greatest in people with highest CRP
� reduces CRP rapidly and for extended period
� change in LDL-C and CRP are not correlated
Inflammation & Atherosclerosis� Statin therapy
� Ridker PM; N Eng J Med 2001; 344:1959-1965.
� high CRP & low LDL-C higher risk of CV event than
low CRP & high LDL-C
� people with low or normal LDL-C and high CRP may
benefit significantly from statin therapy
Inflammation & Atherosclerosis� Statin therapy
� decreases recurrent events after stent placement in
in patient with high CRP independent of LDL-C
� survivors of MI over 5 year follow-up
� CRP increased with standard treatment & placebo
� statin therapy decreased CRP regardless of LDL-C
� statin therapy associated with better clinical outcomes
in patient with initially higher CRP
� Walter DH; J Am Coll Cardiol; 2001; 37:839-846
Inflammation & Atherosclerosis� Statin therapy
� ~25% of current U.S and European adults have:
� high CRP
� low LDL-C
� not currently given statins for primary prevention
Inflammation & Atherosclerosis� Aspirin therapy
� reduces risk of first CV event by 44%� N Eng J Med 1989;321:129-135.
� several contradictory studies relating aspirin with CRP
� few controlled for initial CRP level
� low dosage of aspirin used� low dosage has anti-platelet activity
� low dosage is not anti-inflammatory
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 13
Inflammation & Atherosclerosis� Aspirin therapy
� reduces risk of first CV event by 44%
� several contradictory studies relating aspirin with CRP
� few controlled for initial CRP level
� low dosage of aspirin used
� impact greatest in person with high CRP
� largest impact on quartile with highest CRP level
� impact declines in direct proportion to CRP level
Inflammation & Atherosclerosis� Summary of findings
� Increased risk of cardiovascular event associated with:
� elevated LDL-cholesterol
� elevated CRP
� Decreased risk of cardiovascular event associated with:
� reduction in LDL-cholesterol
� statins
� reduction in CRP
� statins
� aspirin
Brad Stockert, PT, PhD
Professor of Physical Therapy
California State University, Sacramento
Neurodegenerative Disorders� Glial cells have inflammatory properties
� glial cells can secrete:
� TNF-α
� IL-1β
� TNF-α and IL-1β elevated with
� Parkinson Disease
� Multiple Sclerosis
� Alzheimer Disease
� Huntington Disease
� ALS
Neurodegenerative Disorders� Glial-mediated inflammation
� beneficial acutely
� acute insults trigger compensatory neurogenesis
� chronic inflammation inhibits neurogenesis
� NSAIDs attenuate inflammation� restore neurogenesis
� Marchetti B; Trends in Pharmacol Sci 2005; 26:517-525.
� Monje ML; Science 2003; 302:1760-1765.
Neurodegenerative Disorders� Parkinson Disease
� majority of cases are idiopathic
� degenerative disorder of basal ganglia
� abnormal movement pattern
� loss of dopamine neurons in substantia nigra
� evidence of chronic inflammation
� microglia activity high in areas of degeneration
� elevated TNF-α
� elevated IL-1β
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 14
Neurodegenerative Disorders� Parkinson Disease
� majority of cases are idiopathic
� degenerative disorder of basal ganglia
� abnormal movement pattern
� loss of dopamine neurons in substantia nigra
� evidence of chronic inflammation
� chronic NSAID use decreases risk ~45%
� Cox-2 inhibitors reduce neuronal damage� demonstrated in animal models only
� Lucas S; Brit J Pharm 2006; 147:S232-S240.
Neurodegenerative Disorders� Multiple Sclerosis
� demyelinating CNS disorder
� T-cell mediated autoimmune disorder
� chronic glial cell activation
� elevated level of proinflammatory cytokines
� TNF-α and IL-1β
� spontaneous remyelination occurs
� process is not robust
� process is inhibited by inflammation
Neurodegenerative Disorders� Multiple Sclerosis
� detailed autopsy study
� 67 with MS and 28 without MS� Frischer JM; Brain 2009; 132:1175-1189.
Neurodegenerative Disorders� Multiple Sclerosis
� detailed autopsy study
� 67 with MS and 28 without MS
� pronounced inflammation found in
� acute and relapsing forms
� progressive forms
� all lesions
� all stages of disorder
� correlation between axonal injury & disability
Neurodegenerative Disorders� Multiple Sclerosis
� demyelinating CNS disorder
� proinflammatory cytokines
� TNF-α and IL-1β elevated locally
� levels correlate with stage of disorder� Marchetti B; Trends in Pharmacol Sci 2005; 26:517-525.
Neurodegenerative Disorders� Multiple Sclerosis
� demyelinating CNS disorder
� proinflammatory cytokines
� TNF-α and IL-1β elevated locally
� levels correlate with stage of disorder
� injection of TNF-α &/or IL-1β (rat model)
� extensive demyelination
� blocking TNF-α &/or IL-1β (rat model)
� decreases expression of disorder� Lucas S; Brit J Pharm; 2006;147:S232-S240.
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 15
Neurodegenerative Disorders� Multiple Sclerosis
� demyelinating CNS disorder
� proinflammatory cytokines
� TNF-α and IL-1β
� NSAIDs impact
� ameliorate & delay progression
� effectiveness related to “COX-2” inhibition
� Statins impact
� no evidence of effectiveness� Marchetti B; Trends in Pharmacol Sci 2005; 26:517-525.
Neurodegenerative Disorders� Multiple Sclerosis
� demyelinating CNS disorder
� proinflammatory cytokines
� TNF-α and IL-1β
� Cannabinoids impact
� anti-inflammatory properties� cannabidiol > THC
� Pletcher MJ. JAMA 2012; 307:173-181
� ameliorate progression & symptoms (rat model)� Walter L; Brit J Pharmacol 2004; 141:775-785.
Neurodegenerative Disorders� Alzheimer Disease
� severe cognitive dysfunction
� neurofibrillary tangles
� amyloid plaques contain
� activated microglia
� inflammatory mediators
� TNF-α and IL-1β are elevated
Neurodegenerative Disorders� Alzheimer Disease
� original association with inflammation
� patients with Rheumatoid Arthritis
� patients with heart disease
� take high dose NSAIDs chronically
� reduced incidence of Alzheimer Disease
Neurodegenerative Disorders� Alzheimer Disease
� original association with inflammation
� clinical trials using NSAIDs
� no benefit in some studies
� design flaws?
� late initiation
� dosage used
� no change in inflammatory markers
Neurodegenerative Disorders� Alzheimer Disease
� original association with inflammation
� clinical trials using statins
� may be protective
� cross-sectional study of 3 hospital data-bases
� incidence of AD 60% lower in patients taking statins� Liao JK; Ann Rev Pharm Toxicol: 2005; 45:89-118.
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 16
Neurodegenerative Disorders� Alzheimer Disease
� original association with inflammation
� clinical trials using statins
� Rotterdam study with 6992 participants
� prospective clinical trial
� 9 year follow-up� Haag M; J Neurol Neurosurg Psychiatry 2009; 80:13-17.
Neurodegenerative Disorders� Alzheimer Disease
� original association with inflammation
� clinical trials using statins
� Rotterdam study with 6992 participants
� prospective clinical trial
� 9 year follow-up
� statin use associated with 60% decreased incidence
� non-statin cholesterol lowering medication
� no effect on incidence of AD
Neurodegenerative Disorders� Alzheimer Disease
� original association with inflammation
� physical activity as an intervention
1) longitudinal study of 5925 older females
� walking more associated with ~35% decreased risk
Yaffe K; JAMA 2001; 161:1703-1708.
2) longitudinal study of 349 adults >55 years of age
� higher levels of cardiorespiratory fitness associated with
less cognitive decline over 6 years
Barnes DE. Exc & Sport Sci Rev 2007;35:24-29.
Neurodegenerative Disorders� Alzheimer Disease
� original association with inflammation
� physical activity as an intervention
3) longitudinal study of 4615 adults
Laurin D. Arch Neurol; 2001:58:498-504.
� physical activity associated with:
42% decrease in level of cognitive decline
50% decrease in incidence of AD
37% decrease in incidence of any form of dementia
Brad Stockert, PT, PhD
Professor of Physical Therapy
California State University, Sacramento
Cancer
� uncontrolled growth of cells
� multiple forms
� multiple causes
� multiple locations
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 17
Top 3 New Cancer Sites by Gender
� males:
� prostate (25%)
� lung/bronchus (15%)
� colorectal (10%)
� females:
� breast (27%)
� lung/bronchus (14%)
� colorectal (10%)
Cancer and Inflammation� Theodor Boveri (1862-1915)
� first postulated link between cancer & inflammation
� tumorigenesis promoted by chronic inflammation
� Several subsequent investigators & studies have shown� elevated CRP associated with increased cancer risk
� association shown with many forms of cancer
� lung, breast, rectum & prostate cancers
� association not found with infectious cancers
Cancer and Inflammation� Rotterdam study
� Siemes C. J Clinical Oncology 2006;24:5216-5222.
� 7,017 participants >55 years of age
� mean follow-up time = 10.2 years
� high levels of CRP [>3mg/L]
� compared risk vs. subject with low CRP [<1mg/L]
� associated with increased risk of incident cancer
� lung cancer association strongest
Cancer and Inflammation� Greek study
� Trichopoulos D. Cancer Epidemiol Biomarkers Prev 2006;15:381-384.
� prospective study with 28,572 volunteers at start
� 496 cancer cases
� 996 case-matched control cases
� matched for age, smoking, BMI and other attributes
Cancer and Inflammation� Greek study
� Trichopoulos D. Cancer Epidemiol Biomarkers Prev 2006;15:381-384.
� prospective study with 28,572 volunteers at start
� 496 cancer cases
� 996 case-matched control cases
� matched for age, smoking, BMI and other attributes
� CRP levels were higher in cases with cancer
� 4.1 mg/L for cancer cases
� 2.6 mg/L for control cases
� association strongest for lung cancer
Cancer and Inflammation� Impact of physical activity on overall cancer risk
� Thune I. Med Sci Sports Exc 2001;33:S530-S550.
� review of cohort & case-control studies
� occupational & recreational physical activities
� both provide protection against overall cancer risk
� graded dose-response manner
� regardless of gender
� confounding variables had little impact
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 18
Breast Cancer and Inflammation� Breast cancer
� excess body weight causes 20% cancer death in
women >50 years of age in the U.S.
� obesity is a risk factor for breast cancer
� obese females have increased incidence of:
-metastatic cancer at time of diagnosis
-poorer outcome
Breast Cancer and Inflammation� Breast cancer
� excess body weight causes 20% cancer death in
women >50 years of age in the U.S.
� obesity is a risk factor for breast cancer
� weight loss is associated with decreased risk in
post menopausal females
� weight gain is associated with increased risk in
pre-menopausal females � Pichard D; Maturitas; 2008; 60: 19-30.
Breast Cancer and Inflammation� Breast cancer
� females post menopause
� high estrogen levels promote breast cancer
� adipose tissue is primary source of estrogen
� adipose tissue is primary source of TNF-α
� TNF-α stimulates estrogen synthesis
� TNF-α stimulates angiogenesis
� TNF-α is proinflammatory
� obese females have elevated estrogen
� obese females have higher risk of breast cancer
Breast Cancer and Inflammation
� Breast cancer and anti-inflammatory medications
� aspirin inhibits cyclooxygenase activity
� aspirin lowers prostaglandin levels
� lowering prostaglandins reduces aromatase activity
� lower level of estrogen observed
� Bardia A. Breast Cancer Res Treat 2001;26:149-155.
� theoretically lower estrogen should translate to
a lower rate of breast cancer
Breast Cancer and Inflammation
� Breast cancer and anti-inflammatory medication
� large, prospective cohort design
� Bardia A. Breast Cancer Res Treat 2001;26:149-155.
� 26,580 post menopausal females
� linked to cancer registry
� self-reported use of aspirin and NSAIDs
� 13 year follow-up
Breast Cancer and Inflammation� Breast cancer and anti-inflammatory medications
� 1,581 incident breast cancers reported
� aspirin users:
-lower incidence of breast cancers vs. non users
-relative risk 0.8
-dose response relationship observed
-aspirin use >6 times/week had relative risk 0.7
-results did not vary by tumor receptor status
-independent of hormone-receptor signaling pathway
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 19
Breast Cancer and Inflammation� Breast cancer and anti-inflammatory medications
� 1,581 incident breast cancers reported� Bardia A. Breast Cancer Res Treat 2001;26:149-155.
� non-aspirin NSAID users:
-no association with reduction in cancer incidence
-no association regardless of tumor receptor status
Breast Cancer and Inflammation� Breast cancer and anti-inflammatory medications
� statins have anti-inflammatory properties
� theoretically could reduce the risk of breast cancer
� statins have other anti-cancer properties
� inhibit tumor growth
� induce apoptosis
� inhibit angiogenesis
� induce regression of tumor metastasis� Hindler K. The Oncologist 2006;11:306-315.
Breast Cancer and Inflammation� Breast cancer and anti-inflammatory medications
� statins have anti-inflammatory properties
� statins have other anti-cancer properties
� response to statins varies
� response varies by tumor type
� breast, colorectal and prostate cancers reduced
� response varies by type of statin used
� lipophillic responses > hydrophillic responses� Hindler K. The Oncologist 2006;11:306-315.
Breast Cancer and Inflammation� Breast cancer and anti-inflammatory medications
� statins have anti-inflammatory properties
� statins have other anti-cancer properties
� response to statins varies
� statins reduce the incidence of breast cancer
� 72% reduction in incidence
� found with all statins� Cauley JA. J Womens Health 2003;12:749-756.
Breast Cancer and Inflammation� Breast cancer and anti-inflammatory medications
� statins have anti-inflammatory properties
� statins have other anti-cancer properties
� response to statins varies
� statins reduce the incidence of breast cancer
� statins reduce the incidence of prostate cancer
� 56% reduction in incidence
� found with all statins� Shannon J. Am J Epidemiol 2005;162:318-325.
Breast Cancer and Inflammation� Breast cancer and physical activity
� Thune I. Med Sci Sports Exc 2001;33:S530-S550.
� review of 41 studies with 108,031 breast cancer cases
� occupational & recreational physical activities
� both provide protection against breast cancer risk
� graded dose-response manner
� impact higher if activity was >4.5 MET
� impact higher with more MET-hours/week
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 20
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� noninfectious chronic inflammation associated with:
increased incidence colorectal and lung cancer
� idiopathic inflammatory bowel disease
� colorectal cancer incidence increases over time
� ~25% colorectal cancer cases are familial
� most cases develop from adenomatous polyps
� 90% of colorectal cases in patients >50 years of age
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� prospective case control study
� Gunter MJ. Cancer Res 2006;66:2483-2487.
� 29,133 Finnish male smokers
� 130 cases of colorectal cancer
� 260 case matched controls
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� prospective case control study
� Gunter MJ. Cancer Res 2006;66:2483-2487.
� CRP 25% higher in subjects with colorectal cancer
� odds ratio was 2.9 in highest vs lowest CRP quartile
� “dose-response” relationship observed
� risk of colorectal cancer increased with higher CRP
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� prospective cohort study
Il’yasova D. Cancer Epidemiol Biomarkers Prev 2005;14:2413-2418.
� 2438 male and female subjects 70-79 years of age
� 296 incident cancers
� 5.5 year follow-up
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� inflammatory markers strongly associated with cancer death
� hazard ratio for cancer death with inflammatory markers
1.64 for elevated CRP
1.82 for elevated TNF-α
� elevated CRP & TNF-α strongly associated with
increased incidence of lung cancer deaths
� elevated CRP strongly associated with increased
incidence of colorectal and breast cancer deaths
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� aspirin for prevention of colorectal cancer
� review of RCTs, case control studies and cohort studies� Dube C. Annals of Internal Medicine 2007;146:365-375.
� relative risk (RR) of colorectal cancer in aspirin users
� RCT – RR = 0.82
� case control studies – RR = 0.87
� cohort studies – RR = 0.72
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 21
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� aspirin for prevention of colorectal cancer
� prospective study of 47,363 males � Chan AT. Gastroenterology 2008;134:21-28.
� 18 year follow-up
� 975 cases of colorectal cancer
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� aspirin for prevention of colorectal cancer
� prospective study of 47,363 males � Chan AT. Gastroenterology 2008;134:21-28.
� determined dose-response relationship
� 0.5 – 1.5 tablets/week – RR = 0.94
� 2.0 – 5.0 tablets/week – RR = 0.80
� 6.0 – 14.0 tablets/week – RR = 0.72
� >14.0 tables/week – RR = 0.30
� required 6-10 years of use to show effectiveness
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� aspirin for prevention of colorectal cancer
� review of 5 RCTs (14,033 subjects)� Rothwell PM. Lancet 2010. (published online, October, 2010)
� primary and secondary prevention trials
� 30-1200 mg/day
� 20 year follow-up
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� aspirin for prevention of colorectal cancer
� review of 5 RCTs (14,033 subjects)
� >75 mg/day resulted in decreased:
- cancer incidence
- cancer mortality
� benefit increased with duration of use
- required 5+ years of use
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� aspirin for prevention of colorectal cancer
� 2 large cohort studies analyzed� Chan AT. New Eng J Med 2007;356:2131-2142.
� 82,911 females and 47,363 males
� 22 years of follow-up
� 636 cases of colorectal cancer
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� aspirin for prevention of colorectal cancer
� 2 large cohort studies analyzed� Chan AT. New Eng J Med 2007;356:2131-2142.
� 636 cases of colorectal cancer
� 423 (67%) had moderate to strong expression of COX-2
� 213 (33%) did not express COX-2
� COX-2 promotes inflammation & proliferation
over-expressed in many forms of cancers
CPTA Annual Conference 2013 9/20/2013
Brad Stockert, PT, PhD 22
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� aspirin for prevention of colorectal cancer
� 2 large cohort studies analyzed� Chan AT. New Eng J Med 2007;356:2131-2142.
� 636 cases of colorectal cancer
� 423 (67%) had moderate to strong expression of COX-2
� 213 (33%) did not express COX-2
� 2 regular aspirin tablets/day vs COX-2 expression
� RR = 0.64 for tumors expressing COX-2
� RR = 0.96 for tumors not expressing COX-2
Colon Cancer and Inflammation� Colorectal cancer and inflammation
� statins for prevention of colorectal cancer
� 47% decrease in incidence of colorectal cancer� used statins >5 years
� all statins effective� Poynter JN. N Eng J Med 2005;352:2184-2192.
� Hindler K. The Oncologist 2006;11:306-315.
Colon Cancer and Inflammation� Impact of physical activity on colon cancer risk
� review of 48 studies 40,764 colon cancer cases� Thune I. Med Sci Sports Exc 2001;33:S530-S550.
� occupational & recreational physical activities
� both provide protection against colon cancer risk
� graded dose-response manner
� impact higher if activity was >4.5 MET
� impact higher with more MET-hours/week
Bibliography
slides 1-55
� American Heart Association. Reducing the gastrointestinal risks of anti-platelet therapy and NSAID Use. Circulation. 2008;118:1894-1909.
� Bardia A, Olson JE, Vacon CM, et al. Effect of aspirin and other NSAIDs on postmenopausal breast cancer incidence by hormone receptor status. Breast Cancer Res Treat. 2011;126:149-155.
� Fantuzzi G. Adipose tissue, adipokines and inflammation. J Allergy Clin
Immunol. 2005;115:911-919.
� Fisher M, Cushman M, Knappertz V, et al. An assessment of the joint associations of aspirin and statin use with C-reactive protein concentration. Am Heart J. 2008;156:106-111.
� Flossman E and Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. The Lancet. 2007;369:1603-1613.
Bibliography
slides 1-55
� Lau DC, Dhillon B, Yan H, et al. Adipokines: molecular links between obesity and atherosclerosis. Am J Physiol Heart Circ Physiol. 2005;288:H2031-H2041.
� Majka DS, Chang RW, Vu T, et al. Physical activity and high-sensitivity C-reactive protein. Am J Prev Med. 2009;36:56-62.
� Marchetti B and Abbracchio MP. To be or not to be (inflamed) - is that the question in anti-inflammatory drug therapy of neurodegenerative disorders. Trends in Pharmacol Sci. 2005;26:517-525.
� Mathur N, Pedersen BK. Exercise as a mean to control low-grade systemic inflammation. Mediators of Inflammation. 2008;2008:1-6.
� Pedersen BK, and Saltin B. Evidence for prescribing exercise as therapy in chronic disease. Scand J Med Sci Sports. 2006;16:3-63.
Bibliography
slides 1-55
� Pedersen BK, Åkerström TCA, Nielsen AR, et al. Role of myokines in exercise and metabolism. J Appl Physiol. 2007;103:1093-1098.
� Pedersen BK. Edward F. Adolph distinguished lecture: Muscle as an endocrine organ: IL-6 and other myokines. J Appl Physiol. 2009;107:1006-1014.
� Petersen AMW and Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol. 2005;98:1154-1162.
� Thompson D, Markovitch D, Betts JA, et al. Time course of changes in inflammatory markers during a 6-mo exercise intervention in sedentary middle-aged men: a randomized-controlled trial. J Appl Physiol 108:769-779, 2010.
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Bibliography
slides 56-74
� Albert CM, Ma J, Rifai N, et al. Prospective Study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation. 2002;105:2595-2599.
� Buffon A, Liuzzo G, Biasucci LM, et al. Preprocedural serum levels of C-reactive protein predict early complications and late restenosis after coronary angioplasty. J Am Coll Cardiol. 1999; 34:1512-1521.
� Burke AP, Tracy RP, Kolodgie F, et al. Elevated C-reactive protein values and atherosclerosis in sudden coronary death. Circulation. 2002;105;2019-2023.
� Libby P and Ridker PM. Inflammation and atherothombosis. J Am Coll
Cardiol. 2006;48:A33-46.
� Pradhan AD, Manson JE, Rossouw JE. Inflammatory biomarkers, hormone replacement therapy and incident coronary heart disease. JAMA. 2002;288:980-987.
Bibliography
slides 56-74
� Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men N Eng J Med.
1997;336:973-979
� Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999;100:230-235.
� Ridker PM, Hennekens CH, Buring JE, et al. C-Reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Eng J Med. 2000;342:836-843.
� Ridker PM, Role of inflammatory biomarkers in prediction of coronary heart disease. The Lancet. 2001;358:946-947.
� Ridker PM, Cannon CP, Morrow D, et al. C-Reactive protein levels and outcomes after statin therapy. N Eng J Med. 2005;352:20-28.
Bibliography
slides 56-74
� Steering Cmt of Physicians’ Health Study Research Group Final report on the aspirin component of the ongoing Physicians’ Health Study. N Eng J
Med. 1989;321:129-135
� Walter DH, Fichtlscherer S, Sellwig M, et al. Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation. J Am Coll Cardiol. 2001;37:839-846.
� Walter DH, Fichtlscherer S, Britten MB, et al. Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation. J Am Coll Cardiol; 2001;38:2006-2012.
� Willerson JT and Ridker PM. Inflammation as a cardiovascular risk factor. Circulation. 2004;109:II-2-II-10.
Bibliography
slides 75-94
� Barnes DE, Whitmer RA and Yaffe K. Physical Activity and Dementia: The Need for Prevention Trials. Exerc Sport Sci Rev. 2007;35:24-29.
� Chen H, Zhang SM, Hernan MA, et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol. 2003;60:1059-1064.
� Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain.
2009;132:1175-1189.
� Haag M, Hofman A, Koudstaal PJ, et al. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam study. J Neurol Neurosurg Psychiatry. 2009;80:13-17.
� Krabbe KS, PedersenM and Bruunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol. 2004:39:687-699.
Bibliography
slides 75-94
� Laurin D, Verreault R, Lindsay J, et al. Physical activity and risk of cognitive impairment and dementia in elderly persons Arch Neurol. 2001;58:498-504.
� Liao JK and Lauf U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118.
� Lucas S, Rothwell NJ and Gibson RM. The role of inflammation in CNS injury and disease. Brit J Pharmacol. 2006;147:S232-S240.
� Marchetti B and Abbracchio MP. To be or not to be (inflamed) – is that the question in anti-inflammatory drug therapy of neurodegenerative disorders. Trends in Pharmacol Sci. 2005;26:517-525.
� Milda T, Hirayama S and Nakamura Y. Cholesterol-independent effects of statins and new therapeutic targets: Ischemic stroke and dementia. J Atheroscler Thromb. 2004;11:253-264.
� Monje ML, Toda H and Palmer TD. Inflammatory blockade restores adult hippocampal neurgenesis. Science. 2003;302:1760-1765.
Bibliography
slides 75-94
� Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain, Behav
Immun. 2004:18:407-413.
� Schiess M. Nonsteroidal anti-inflammatory drugs protect against Parkinson neurodegeneration. Arch Neurol. 2003;60:1043-1044.
� Walter L and Stella N. Cannabinoids and neuroinflammation. Brit J
Pharmacol. 2004;141:775-785.
� Wolozin B, Kellman W, Ruosseasu P, et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl Coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439-1443.
� Yaffe K, Branes D, Nevitt M, et al. A prospective study of physical activity and cognitive decline in elderly women. Arch Intern Med. 2001;161:1703-1708.
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Bibliography
slides 95-129
� Bardia A, Olson JE, Vachon CM, et al. Effect of aspirin and other NSAIDs on postmenopausal breast cancer incidence by hormone receptor status: results from a prospective cohort study. Breast Cancer Research.
2011;126:149-155.
� Boudreau DM, Gardner JS, Malone KE, et al. The association between 3-hydroxy-3-methylglutaryl coenzyme A inhibitor use and breast carcinoma risk among postmenopausal women. Cancer 2004;100:2308-2316.
� Cauley JA, Zmuda JM, Lui L, et al. Lipid-lowering drug use and breast cancer in older women: a prospective study. J Women’s Health. 2003; 12:749-755.
� Chan AT, Ogino S and Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. New Eng J Med. 2007;356:2131-2142.
Bibliography
slides 95-129
� Chan AT, Giovannucci EL, Meyerhardt JA, et al. Aspirin dose and duration of use and risk of colorectal cancer in men. J Gastro. 2008;134:21-28.
� Cooper K, Squires H, Carroll C, et al. Chemoprevention of colorectal cancer: systemic review and economic evaluation. Health Technol Assess
2010;14:1-206.
� Dube C, Rostom A, Lewin G, et al. The use of aspirin for primary prevention of colorectal cancer: a systematic review. Ann Int Med. 2007;146:365-375.
� Flossman E, and Rothwell PM. Effects of aspirin on long-term risk of colorectal cancer: consistent evidence from randomized and observational studies. The Lancet. 2007;369:1603-1613.
� Gunter MJ, Stolzenberg-Solomon R, Cross AJ, et al. A prospective study of serum C-reactive protein and colorectal cancer risk in men. Cancer
Research. 2006;66:2483-2487.
Bibliography
slides 95-129
� Hindler K, Cleeland C, Rivera E, et al. The role of statins in cancer therapy. The Oncologist. 2006;11:306-315.
� Il’yasova D; Colbert LH, Harris TB, et al. Circulating levels of inflammatory markers and cancer risk in the heath aging and body composition. Cancer Epidemiol Biomarkers Prev 2005;14:2413-2418.
� Lagiou P and Trichopoulos D. Inflammatory biomarkers and risk of lung cancer. JNCI 2011;103:1073-1075.
� Pichard C, Plu-Bureasu G, Castro MN, et al. Insulin resistance, obesity and breast cancer risk. Maturitas: The European Menopause Journal. 2008;60:19-30.
� Poynter JN, Gruber SB, Higgins PDR, et al. Statins and the risk of colorectal cancer. N Eng J Med. 2005;352:2184-2192.
� Rose DP, Komninou D and Stephenson GD. Obesity, adipocytokines, and insulin resistance in breast cancer. Obesity Reviews. 2004;5:153-165.
Bibliography
slides 95-129
� Shannon J, Tewoderos S, Garzotto M, et al. Statins and prostate cancer risk. Am J Epidemiol 2005;162:318-325.
� Siemes C, Visser LE, Coebergh J, et al. C-Reactive protein levels, variation in the C-reactive protein gene, and cancer risk: The Rotterdam Study. J Clin Oncology 2006;24:5216-5222.
� Thune I, and Furberg A-S. Physical activity and cancer risk: dose-response and cancer, all sites and site-specific. Med Sci Sports & Ex.2001;33:S530-S550.
� Trichopoulos D, Psaltopoulou T, Orfanos P, et al. Plasma C-reactive protein and risk of cancer: A prospective study from Greece. Cancer Epidemiol Biomarkers Prev; 2006;15:381-384.
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