Exercise - cancer and MS - L5 Flashcards
What is evidence based medicine?
The integration of the best research evidence with clinical expertise and patient values. It is the physician’s duty to find the best and most current information and apply it judicously for the benefit of the patient.
Explain the following terms:
* therapeutic effect
* toxic effect
* ED50
* TD50
- therapeutic effect: the desired effect of drug administration
- toxic effect: an adverse effect of a drug administered
- ED50: the dose of a medication that produces a beneficial/desired effect in 50% of the population
- TD50: the dose of a medication that produces an adverse effect in 50% of the population
What is the problem with treatment of cancer regarding exercise?
Less than 20% of cancer patient meet WHO recommendations regarding exercise, while evidence is strong that for a variety of cancers, exercise reduces the relative risk for cancer for up to 36%.
What is cancer?
Mutations that are induced by physical, chemical or biological stimuli that may alter protein function preventing cells from apoptosis and increasing the risk for further mutations. It is characterized by: unregulated growth, lack of differentiation, and lack of function.
What is the tumor microenvironment?
The ecosystem that surrounds a tumor inside the body. A tumor and its microenvironment can interact with each other and influence each other either positively or negatively. Usually, tumors alter their microevironment in a way that it is beneficial for tumor growth such as inhibiting tumorcompetitive lymphocytes and promoting vascular changes to provide oxygen and nutrients for the tumor.
Name tumor characteristics that influence treatment options.
- Cancer type (side, mutations, immune sensitivity, etc.)
- Stage of disease (size, location, metastasis, etc.)
- Patient related conditions (age, comorbidities, etc.)
What is meant with hot and cold tumors?
- Hot tumor: tumors that show signs of inflammation, meaning that the tumor has been infiltrated by T cells rushing to fight the cancerous cells. Therefore, in hot tumors, the immune system is activated.
- Cold tumor: tumors that have not yet been infiltrated with T cells. Therefore, in cold tumors, the immune system is not (yet) activated.
Which immune cells are known to reside in the tumor microenvironment of cold tumors?
Myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs), known to dampen the immune response and inhibit T cells.
What effect was found for prostate cancer patients who underwent a 12 week HIIT program compared to the control group?
HITT increased cardiorespiratory fitness levels and decreased prostate specific antigens (PSA) levels, PSA velocity and prostate cancer cell growth in men with localized prostate cancer.
Note: not statistically significant, but major differences were found.
What effect was found for breast cancer patients undergoing radiotherapy who did resistance exercise compared to the healthy subjects?
That resistance training reduced kynurenine pathway metabolites
Also found for pancreatic cancer patients
What was found in pre-clinical animal studies on the effect of exercise on tumor growth?
That exercise reduces tumor growth and that the earlier animals started exercise, the better the outcome was.
Can changes in immune cell activity/count be observed post intensive running? If yes, which cells decrease/increase after running?
Yes. Post intensive running is associated with an increase in granulocytes and a decrease in T cells.
(Endurance) training is also known to increase CD8+/Treg ratio in tumor tissues. What is the effect of this CD8+/Treg ratio increase?
The increase in this ratio, means that more Treg cells are supressed and more CD8+ T cells are activated, resulting in increased tumor microenvironment infiltration and a more efficient immune response to the tumor.
Acute exercise is also known to be associated with the recruitment and activation of NK cells. Describe how acute exercise can lead to NK cell recruitment and activation.
Acute exercise causes the release of epinephrine and IL-6. Epinephrine can mobilize NK cells to the blood stream. IL-6 enhances this process. NK cells can therefore enter the tumor tissue and aid in reduced tumor growth.
NK cell activation as a result of exercise may be driven by altered receptor expression. Explain this statement.
Exercise causes epigenetic modifications (specifically acetylation) in the DNA of NK cells. This results in the translation of additional NK cell receptors that ar needed to activate the NK cell. NK cells of a patient who exercises, is thus associated with enhanced NK cell activation.
Name other processes that are known to change with exercise (except changes in immune cell activity).
- Exercise may alter drug delivery
- Exercise may alter the vascular architecture in tumors
- Exercise alters systemic and local inflammation
Name characteristics of MS.
- Auto-immune disase
- Most common chronic inflammatory disease of the CNS
- Demyelination of axons which can occur everywhere in the CNS
- Different disease courses
- Risk factors: jevenile adipositas, smoking, viral infections.
What is the outside in hypothesis in MS?
- Chronic systemic inflammation
- Lack of BBB integrity
- Infilitration of immune cells
- Auto reactivity with CNS structures
How does EBV infection result in MS?
EBV shares protein structures with components of the central nervous system. Upon infection and immune activation, the immune system is mislead to also attack its own nervous system (such as myelin). Besides this, EBV can modulate the immune system, affecting its regulation and potentially contributing to the development of MS.
What evidence is there that exercise is beneficial for MS patients?
- RCTs in humans: evidence low
- Animal models: substanial evidence
Name the indirect and direct effects of exercise on systemic inflammation and describe for the direct effects the acute and chronic effects of exercise.
- Indirect effects of exercise: sedentary lifestyle or obesity is associated with a Th1 response, leading to the production of IFN-y and TNF-a (Th1 cytokines) that promote the mobilization of M1 macrophages, ultimately resulting in a pro-inflammatory environment. Excess glucose in obese people enhances the mobilization of M1 macrophages.
- Direct acute effects of exercise: IL-6, TNF-R, IL-1Ra, IL-10 increase after exercise, which are cytokines known to have an anti-inflammatory effect (most also normalize over time).
- Direct chronic effects of exercise: intensity-dependent effect of chronic exercise on Treg-cell number.
What is associated with disease progression and prognosis in MS patients and does exercise modify this?
The neutrophil-lymphocyte ratio (NLR) is associated with disease progression and prognosis in MS patients. Exercise, specifically HIIT, was found to reduce NLR in MS patients.
What DNA modifying process occurs in an age-dependent manner that can be slowed down with exercise?
When aging, a process of demethylation of pro-inflammatory genes occurs, meaning that genes that were inactive, are activated. Exercise counteracts this age-dependent demethylation of pro-inflammatory genes.
Does the intensity of exercise matter in neuroinflammation?
Yes, a study investigated the difference between moderate exercise (swimming) and high intensity exercise (swimming). Their results strongly suggest that high intensity exercise has beneficial effects in MS patients.
